RENAL REVIEW

BODY COMPARTMENTS

Plasma osmolality is the concentration of

all the solutes (electrolytes and

nonelectrolytes) in plasma.

Plasma osmolality is normally between

285 and 295 mmol/L.

Water Distribution

• The distribution of water among the three body water

compartments (intracellular, interstitial and plasma

compartments) is determined by two forces:

• Osmotic pressure

• Hydrostatic pressure

• The balance of these forces determines the amount of

water in each compartment.

• Osmotic pressure is the force exerted by solutes

• Hydrostatic pressure is the force exerted by water

60-40-20 Rule

The amount of water contained in the

body, total body water, is 60% of a

person's weight. Since 1 liter of water

weighs 1 kilogram, calculating totalbody

water (TBW) is simple.

Effects of Gender and Age on TBW

• Men are about 60% water by weight and women are 50-55% water by

weight.

• Women have a lower TBW because they have a higher proportion of

body fat, which contains little water.

• Age also affects total body water. Infants have a high percentage of

water by weight. The elderly have a lower percentage of water by

weight.

• Full-term in-fants are about 70% water which decreases to 60% after

6 months to a year.

Electrolyte Distribution

• The electrolyte compositions of the intracellular and extracellular

compartments are different. The intracellular compartment has a high

concentration of K+ (140 mEq/L) and the extracellular compartment

has a high concentration of Na+(135-145 mEq/L).

• Because the cell membrane is impermeable to sodium and

potassium, Na-K-ATPase pumps located in the cell membrane are

required to move these ions in and out of the cell.

• Although the intracellular and extracellular compartments have

different solute compositions, the two compartments have the same

osmolality because the cell membrane is permeable to water.

Electrolyte Distribution

Gibbs Donnan Effect

• Plasma and interstitial fluid composition differ by about 5% in concentration of diffusible ions.

• The interstitial fluid contains little protein and no blood cells because the capillary walls exclude the passage of larger protein molecules.

• Unequal distribution of proteins Increased plasma concentration of cations and slightly lower concentration of anions like Cl-

• Gibbs-Donnan Equilibrium:

• The movement of ions is governed by:

• 1. Concentration difference

• 2. Permeability of the membrane

• 3. Voltage gradient across the membrane

Intracellular vs. Extracellular

• Major extracellular cations: Na+

• Major extracellular anions: Cl-, HCO3-

• Major intracellular cations: K+, Mg2+

• Major intracellular anions: Organic phosphates, proteins

• The ionic composition of intracellular fluids differs from the

extracellular compartment due to the presence of a large lipid bilayer,

which prevents the diffusion of almost all solutes except for those that

are very small or non-polar.

• Most solutes move across the compartments via specific transporters,

such as Na+/K+ ATPase.

Water Loss and Expansion

• Water distributes to all compartments in the body so the gain in water

with intake or decrease in water with loss are all based on what

percentage of total body water is in that compartment.

• 2/3 will distribute to ICF

• 1/3 will distribute to ECF

• 1/4 of the ECF will distribute to Plasma

Normal Ranges

• Water intake:

• Water: 1200 ml

• Food: 1000 ml

• Metabolic: 300 ml

• Total: 2500 ml

• Water loss

• Insensible (mainly respiratory): 700 ml

• Sweat: 100 ml

• Feces: 200 ml

• Urine: 1500 ml

• Total: 2500 ml

Dextrose is used in in situations of solute

free fluid loss such as hypernatremia

D5W initially only distributes to the

extracellular compartment but over time it

distributes amongst all three fluid

compartments

Over time it is metabolized to CO2 and

Water and distributes across body

compartments

Saline Infusions

Effects of Saline Infusions

• Isotonic saline (0.9%) delivers NaCl and water to the plasma and interstitial compartments.• Used for dehydration and hypovolemia

• Hypotonic saline (0.45%) delivers water to all three body water compartments and NaCl to the extracellular compartment.• Used as maintenance IV

• Hypertonic saline (3%) removes water from the intracellular compartment.• Used in hyponatremia

• Lactated Ringer's is a more physiologic isotonic solution than 0.9% NaCl and remains in the plasma and interstitial compartments

GLOMERULAR

FILTRATION

Clearance

• Clearance equation: C=UV/P

• Units of C are ml/min

• UV= rate of excretion (moles/min)

• [U]x = urine concentration of a substance X (mg/ml)

• V= urine flow rate per min (ml/min)

• P= plasma concentration (moles/ml)

• Renal clearance is the volume of plasma completely cleared of a

substance by the kidney per unit time

• “Virtual quantity” b/c the kidney does not completely clear the plasma

of any substance, though PAH comes close

GFR

• Glomerular filtration rate (GFR) is the flow rate of filtered fluid through

the kidney, i.e. the volume of fluid filtered from the glomerular

capillaries into Bowman's capsule per unit time.

• Typical value: ~125 mL/min

• 180L/day

• Filtration fraction represents the amount of plasma entering the

kidneys/nephrons that actually passes into the renal tubules

• It is equal to GFR/RPF

• Typical value: 0.15 - 0.2

Estimating GFR

• GFR can be measured by the clearance of inulin

• GFR = Cinulin = UinulinV/Pinulin

• Clearance of any substance can be compared with the

clearance of inulin and expressed as the clearance ratio:

• Cx/C=1: clearance of X equals the clearance of inulin - the

substance x must be filtered but neither reabsorbed nor secreted

• Cx/C<1: clearance of X is lower than clearance of inulin. Either the

substance is not filtered, or it is filtered and subsequently

reabsorbed

• Cx/C>1: clearance of X is higher than the clearance of inulin. The

substance is filtered and secreted

Inulin vs. Creatinine for GFR

• Inulin (the perfect glomerular marker)

• Not bound to plasma proteins, uncharged

• Freely filtered across the glomerular capillary wall

• Completely inert in the renal tubule

• Creatinine (not perfect, but it’s good)

• Freely filtered across the glomerular capillaries

• Secreted to a small extent

• Clearance of creatinine slightly overestimates the GFR.

• Creatinine is more convenient b/c it’s endogenous and you don’t have to infuse it like you do for inulin

• Plasma level of creatinine is related to age, gender, and muscle mass of the patient

Glomerular Filtration Rate Forces

• GFR = Kf [(PGC – PBS) – πGC]

• Kf is defined by water permeability per unit of surface area and the

total surface area. It is much higher in the glomerular capillaries

• PGC: Hydrostatic pressure in glomerular capillaries (45)

• PBS: Hydrostatic pressure in Bowman’s space (10)

• πGC : Oncotic pressure in glomerular capillaries

• Increases along capillaries

Changes in Oncotic Pressure

• As GFR increases, the oncotic pressure (colloid osmotic pressure) of

the peritubular capillary of that nephron will increase, while the

hydrostatic pressure will decrease.

• Both of these changes encourage water and solutes to move into the

peritubular capillaries.

• As GFR increases, there is more resorption in the proximal tubules

because peritubular capillary hydrostatic pressure decreases and

oncotic pressure increases.

• The major driving force is the high oncotic pressure.

Estimating RPF and RBF

• RPF can be estimated from the clearance of an organic acid para-

aminophippuric acid (PAH)

• RPF = UPAHV/PPAH

• RBF can be calculated from the RPF and the hematocrit

• RBF = RPF/(1-Hct)

On average RBF is 1800L per day

Cockcroft-Gault

• Cockcroft-Gault formula predicts the CrCl (creatinine clearance) from

the weight, age, and serum Creatinine

• CrCl=[(140-age) x Kg/(72*Cr)] * 0.85 for women

• Less accurate in weight extremes

• Derived from 24hr urine collection on hospitalized male veterans,

therefore multiplying by 0.85 is supposed to correct for lower muscle

mass in women.

• No empiric data was collected from women

MDRD

• MDRD: requires 3 demographic variables (age, race, and gender)

and one biochemical variable (creatinine). Uses regression analysis

to estimate the GFR (as opposed to CrCl used in the CG equation)

CKD-EPI

• Estimates GFR from serum creatinine, age, sex, and race for adults

>18years old.

• GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × (0.993*Age) ×

1.018 [if female] × 1.159 [if black]

• Scr is serum creatinine in mg/dL,

• κ is 0.7 for females and 0.9 for males,

• α is -0.329 for females and -0.411 for males,

• min indicates the minimum of Scr /κ or 1, and

• max indicates the maximum of Scr /κ or 1

Renal Handling of Glucose

• Glucose is filtered across glomerular capillaries and reabsorbed by the epithelial cells of the proximal and convoluted tubule.

• Because there is a limited number of glucose transporters the mechanism has a transport maximum, or Tmax.

• Splay: phenomenon where the Tmax for glucose is approached gradually, rather than sharply. Splay is the portion of the titration curve where reabsorption is approaching saturation, but is not fully saturated and glucose is excreted in the urine before resorption levels off at the Tmax value

• Explanations for Splay:• Low affinity of Na+/glucose cotransporter.

• Nephron heterogeneity - Tm for whole kidney reflects average Tm of all nephrons, yet all nephrons do NOT have the same Tm.

Glomerular Filtration Barrier• Endothelium

• Pores 70-100nm in diameter- these are relatively large so fluid, dissolved solutes, and plasma proteins are all filtered across this layer

• Pores are not large enough for RBCs to be filtered

• Basement membrane

• Composed of 3 layers • lamina rara interna- fused to the endothelium

• lamina densa

• lamina rara externa- fused to the epithelial cell layer

• The multilayered basement membrane does not permit filtration of plasma proteins

• Epithelium • Specialized cells called podocytes

• Filtration slits of 25-60nm in diameter

• small size of the filtration slits important barrier to filtration

• Negatively charged glycoproteins on filtration barrier enhance filtration of cations

• Also create an electrostatic barrier to filtration of plasma proteins

• In certain glomerular diseases removal of these charges leads to proteinuria

Damage to endothelium would cause

hematuria while damage to basement

membrane would cause proteinuria

Renal Blood Flow

• Renal Vasculature • Blood enters kidney via renal artery, which branches into interlobar

arteries, arcuate arteries, and then cortical radial arteries

• First set of arterioles = afferent arterioles

• Deliver blood to the glomerular capillaries, across which ultrafiltration occurs

• Second set of arterioles = efferent arterioles

• Remove blood from the glomerular capillaries

• Deliver blood to the peritubular capillaries

• Solutes and water are reabsorbed into the peritubular capillaries.

• Typical values

• GFR: 125 mL/min (70 kg person)

• RBF: 1200 mL/min

Afferent and Efferent Arterioles

• Constriction of the afferent arteriole

• Decrease RPF

• Decrease PGC (less blood volume, less hydrostatic pressure)

• Decrease GFR

• Constriction of the efferent arteriole

• Decrease RPF

• Increase PGC (blood is blocked from leaving capillaries)

• Increase GFR

Myogenic Autoregulation

• Increased renal arterial pressure causes increased pressure in the

afferent arteriole.

• In the absence of autoregulation, the RBF and GFR would increase,

but in response to the increased pressure, the afferent arteriole

constricts, which prevents an increase in the RBF and GFR.

• The opposite response (dilation of afferent arteriole) occurs when the

arterial pressure decreases.

• Involves opening of stretch-activated calcium channels in the smooth

muscle cell membranes (inc. Ca2+ and contraction of SMC)

Tubuloglomerular Feedback

• The juxtaglomerular apparatus (located in the distal tubule) allows

each tubule to regulate its own glomerulus

• Increased delivery of NaCl to the macula densa leads to decreased

GFR ATP and adenosine are released from cells in the JG

apparatus, which constrict afferent arterioles, reducing RBF and GFR

• Decreased delivery of NaCl to the macula densa leads to increased

GFR PGI2 and NO are released, leading to vasodilation and

increased RPF and GFR

• Increased pressure on JG cells causes release of renin

Sympathetic NS Activity

• The sympathetic nerve activity is stimulated by decreased BP or

decreased ECF volume.

• Since RBF is determined by total resistance, the vasoconstriction of

both afferent and efferent arterioles will decrease the RBF.

• The GFR is influenced by the glomerular capillary pressure, so

constriction of the afferent arteriole will decrease GFR, while

constriction of the efferent arteriole will increase GFR.

• RBF decreases a lot while GFR decreases less in response to

sympathetic nerve activity.

Angiotensin II

• Angiotensin II is a potent vasoconstrictor of both afferent and efferent

arterioles.

• The efferent arteriole is more sensitive to angiotensin II than the

afferent arteriole, and this difference in sensitivity has consequences

for its effect on GFR

• Low levels of angiotensin II produce an increase in GFR by

constricting efferent arterioles, while high levels of angiotensin II

produce a decrease in GFR by constricting both afferent and efferent

arterioles.

Prostaglandin Formation

• Prostaglandins (E2 and I2 ) are produced locally in the kidneys and cause vasodilation of both afferent and efferent arterioles.

• The same stimuli that activate the sympathetic nervous system and increase angiotensin II levels in hemorrhage also activate local renal prostaglandin production.

• The vasodilatory effects of prostaglandins are clearly protective for RBF.

• Thus, prostaglandins modulate the vasoconstriction produced by the sympathetic nervous system and angiotensin II.

• Unopposed, this vasoconstriction can cause a profound reduction in RBF, resulting in renal failure. Nonsteroidal antiinflammatory drugs

• (NSAIDs ) inhibit synthesis of prostaglandins and, therefore, interfere with the protective effects of prostaglandins on renal function following a hemorrhage.

Renal Artery Stenosis

• Renal artery stenosis will lead to a decrease in renal blood flow. GFR

is dependent on renal plasma flow.

• In the normal range the dependence isn’t very significant.

• When the RPF is low, in the dashed box, the GFR is heavily

influenced by the RPF.

• The RPF can decrease significantly in renal artery stenosis leading to

a significantly decreased GFR as well.

• This can lead to renal failure.

OSMOLALITY

Sodium and Osmolality

• Normal range of dietary Na+ intake: <2.5g/d

• Low Na+ diet: .05g/d

• Major routes of Na+ loss from the body: Kidneys

• Sodium is the major determinant of plasma osmolality (Posm)

• Increased sodium leads to increased plasma osmolality osmotic movement of water into the extracellular space

• Retention of water w/o sodium lowers PNa and Posm, so water will move into the intracellular compartment until osmotic equilibrium is reached.

• Administration of isotonic saline leads to no change in Posm. That means no net movement of water into the intracellular compartment and ECF is increased more effectively than with just water

Renin Release

• Factors that can promote renin release:

• Decreased afferent arteriolar pressure sensed by baroreceptors in

the wall of the afferent arteriole

• Increased SNA regulated by cardiac and arterial baroreceptors

• Increased circulating catecholamines regulated by cardiac and

arterial baroreceptors

• Decreased macula densa NaCl delivery

Angiotensin stimulates sodium

reabsorption in the proximal tubules

Aldosterone stimulates sodium

reabsorption in the TAL, DCT and

collecting ducts.

ANP blocks ENAC and decreases sodium

reabsorption in DCT and collecting ducts.

Renin Angiotensin System

• Renin converts angiotensinogen (from liver) to angiotensin I

• Angiotensin converting enzyme (from lungs) converts ATI ATII

• ATII stimulates AT1 and AT2 receptors

• AT1 receptor stimulation:

• Increased aldosterone (in the adrenal gland)

• Vasoconstriction

• Increased proximal tubule Na+ reabsorption

• Increased thirst

• Increased ADH release

• Decreased RBF, but maintains GFR

• AT2 receptor stimulation:

• Vasodilation

Aldosterone

• 1. Increases number of Na-K-ATPase pumps in basolateral

membrane

• 2. Increases sodium channels and sodium resorption

• 3. Increased sodium resorption increases electrical gradient for

potassium secretion

• 4. Increases number of potassium channels

• Increased sodium reabsorption and potassium excretion!

ADH

• The osmoreceptors of the hypothalamus are very sensitive to changes in osmolality. A change in plasma osmolality of only 1% is detectable by the hypothalamus.

• An increase in plasma osmolality stimulates ADH and thirst. A decrease in plasma osmolality suppresses ADH and thirst

• In the absence of ADH, the collecting tubules are impermeable to water.

• In the presence of ADH, the collecting tubules are unlocked and water inthe collecting tubules is resorbed. ADH causes aquaporin channels to be inserted into the tubular membrane, allowing the resorption of water.

• Water flows through the channels into the concentrated medullary interstitium

Osmolality is the most sensitive stimulus

for ADH release.

3 Actions of ADH

• (1) It increases the water permeability of the principal cells of the late

distal tubule and collecting ducts.

• (2) It increases the activity of the Na-K-2Cl cotransporter of the thick

ascending limb, enhancing countercurrent multiplication and the size

of the corticopapillary osmotic gradient.

• (3) It increases urea permeability in the inner medullary collecting

ducts, enhancing urea recycling and the size of the corticopapillary

osmotic gradient.

Effective circulating volume is the fraction

of the blood volume that is effectively

perfusing tissues at a particular time.

Secondary Hypertension

• The RAAS is activated in volume depleted states but can

also be activated in particular pathologies:

• Renal artery stenosis

• Hyperaldosteronism

• Glucocorticoid excess

• Coarctation of aorta

• Sleep apnea

• Pheochromocytoma

• Genetic diseases

Glomerulotubular Balance

• Glomerulotubular balance = a mechanism for coupling reabsorption to

the GFR; ensures that a constant fraction of the filtered load is

reabsorbed by the proximal tubule (67%)

• Mechanism: Increased filtration means more water was lost in the

glomerulus. This leads to increased oncotic pressure in the

peritubular capillary. This leads to a starling force that favors

reabsorption into the capillaries.

Volume is regulated by changing Na+

reabsorption; osmolality is regulated by

changing water reabsorption.

Volume: Angiotensin II, Aldosterone,

Catecholamines

Osmolarity: ADH

Hypovolemia

Hypervolemia

Symptoms of Hypovolemia

• Orthostatic hypotension/lightheadedness on standing

• Tachycardia

• Decreased skin turgor

• Cool, pale skin

Pressure Natriuresis

• Compensatory mechanism in which increased blood pressure causes

decreased reabsorption of Sodium and Water to normalize blood

pressure

• Liddle’s Syndrome and Renal artery stenosis disrupt this mechanism

ACUTELY

Hyponatremia Cerebral Edema

Hypernatremia Cerebral Shrinkage

Be careful in treating compensated

hypo/hypernatremia

Hyponatremia

• Hyponatremia is a plasma sodium concentration less than 135 mEq/L. Since sodium is the major contributor to plasma osmolality, a low sodium concentration is usually associated with hypoosmolality

• In all cases hyponatremia is due to a relative EXCESS of water.

• IMPAIRED WATER EXCRETION, INCREASED ADH

• Causes• Psychogenic polydipsia is a disorder of compulsive water drinking.

• Renal failure decreases urine output so that even modest water intake cannot be excreted by the kidney.

• Increased ADH activity causes hyponatremia in two settings: appropriate and inappropriate ADH release. • Appropriate: diarrhea, vomiting, burns, CHF, cirrhosis

• Inappropriate: SIADH, hypothyroidism, adrenal insufficiency

Loop diuretics are less likely than thiazide

diuretics to cause hyponatremia because

loop diuretics disrupt the interstitial

gradient and oppose water reabsorption in

the distal tubule.

Pseudohyponatremia

• Hyponatremia in the face of a normal or elevated plasma osmolality

• Can be due to hyperproteinemia, hyperlipidemia or increased levels

of osmotically active solutes such as glucose or mannitol in the

plasma.

Urine Sodium for Diagnosis

• The urine sodium can give important details on the volume status of the patient. Hyponatremia could be either associated with volume depletion or SIADH.

• In either case, the urine osmolality would be elevated indicating the presence of ADH.

• However, in one case (volume depletion) the stimulus for ADH secretion is physiological and in the other case (SIADH) it is inappropriate.

• In SIADH, the patient is volume expanded and the urine sodium levels approximate intake (usually about 40-60 mEq/L).

• In a volume depleted state, the urine sodium is usually very low and reflects avid sodium reabsorption by the renal tubules in an effort to maintain vascular volume.

ADH Release

• Osmolality is sensed by hypothalamic osmoreceptors

• Supraoptic & paraventricular nuclei cause stimulation of release of

ADH from the pituitary (activated in cases of HIGH osmolality/volume

depletion) → increase water reabsorption → low volume/high

osmolality urine → restore plasma osmolality

• Lateral pre-optic area regulates thirst (suppression in response to

volume expansion, increased thirst in response to volume depletion)

SIADH

• In SIADH, circulating levels of the hormone ADH are abnormally high owing to either excessive secretion from the posterior pituitary following head injury or secretion of ADH from abnormal sites such as lung tumors.

• In these conditions, ADH is secreted autonomously, without an osmotic stimulus; in other words, ADH is secreted when it is not needed. In SIADH, the high levels of ADH increase water reabsorption by the late distal tubule and collecting ducts, making the urine hyperosmotic and diluting the plasma osmolarity

• Normally, a low plasma osmolarity would inhibit secretion of ADH; however, in SIADH, this feedback inhibition does not occur because ADH is secreted

• Treatment: IV hypertonic saline, fluid restriction, demeclocycline

Diagnosis of SIADH

• SIADH is recognized by four characteristics:

• 1. Hypotonic hyponatremia

• Low plasma osmolality and low plasma sodium concentration

• 2. Euvolemia

• 3. High urine sodium (>20 mEq/L)

• 4. High urine osmolality (>200 mmol/L)

Oversecretion vs. Undersecretion of ADH

• Oversecretion: SIADH, Adrenal Insufficiency

• Undersecretion: Diabetes Insipidus

Hypernatremia

• Hypernatremia is a plasma sodium concentration greater

than 145 mEq/L. Since sodium is the major contributor to

plasma osmolality, hypernatremia always causes

hyperosmolality

• Due to an excess of sodium or a loss of water

Only osmostic diarrhea predisposes to

hypernatremia, most GI secretions are

iso-osmotic!

Maintenance of hypernatremia is due to

inability to ingest water

A plasma sodium concentration of greater

than 150 mEq/L is virtually never seen in

an alert patient who has access to water.

Thus, the patient must have a

hypothalamic lesion affecting the thirst

center, resulting in diminished sensation

of thirst (hypodipsia).

Nephrogenic/Central Diabetes Insipidus

• Central diabetes insipidus is characterized by the inability of the brain

to release ADH.

• Nephrogenic diabetes insipidus is characterized by the inability of the

kidney to respond to ADH.

• The urine of patients with diabetes insipidus is dilute with a low

concentration of sodium. Because of the large amount of dilute fluid

lost in the urine, patients are predisposed to hypernatremia.

Distinguishing DI and Polydipsia

• The plasma sodium concentration tends to be in the high-normal

range in diabetes insipidus (142-146 mEq/L) due to tendency toward

water loss and the need to keep up with the water loss by thirst.

• In primary polydipsia, the sodium is in the low-normal range (136-139

mEq/L) due to the continuing excess water intake.

• Thus, a finding at either extreme is helpful diagnostically, whereas a

plasma sodium concentration of 140 mEq/L is of little help.

Water Deprivation Test with administration

of ddAVP to distinguish Central DI from

Nephrogenic DI

Aldosterone acts at principle and

intercalated cells.

The action of aldosterone at the principle

cell is important in volume regulation and

potassium balance (causes K+ secretion);

Its action at the intercalated cell is

important in acid-base balance (can

cause metabolic acidosis)

The two primary stimuli for release of

aldosterone are volume depletion and

hyperkalemia

Effects of Aldosterone

• Increased serum sodium

• Decreased serum potassium

• Blood pressure and volume increased

TUBULAR FUNCTION

Early Proximal Tubule Overview

• (1) The entire proximal tubule reabsorbs 67% of the filtered Na

• (2) The entire proximal tubule also reabsorbs 67% of the filtered

water. The tight coupling between Na and water reabsorption is called

isosmotic reabsorption.

• (3) This bulk reabsorption of Na and water is critically important for

maintaining ECF volume.

• (4) The proximal tubule is the site of glomerulotubular balance, a

mechanism for coupling reabsorption to the GFR.

Early Proximal Tubule Transport

• Cotransport mechanisms: Na-glucose(SGLT), Na–amino acid, Na -

phosphate, Na –lactate, and Na-citrate

• Countertransport mechanism: Na-H+ exchange

• SITE OF ANGIOTENSIN II ACTION

• Contraction alkalosis!!!

• Na-K+-ATP Transporter

• 100% of glucose is absorbed

• 85% of filtered HCO3- is absorbed

Late Proximal Tubule

• Filtrate has high Cl- concentration

• This drives Na-H+ exchange and Cl-Formate exchange on the

luminal side.

• The high Cl- gradient allows for paracellular diffusion into the blood

• The Na-K+-ATP exchanger moves sodium into the blood

Loop of Henle

• The thin descending limb is passively permeable to small solutes and

water while the thin ascending limb is passively permeable to small

solutes but not to water and creates a hyposmotic tubular fluid

• The thick ascending limb absorbs 25% of sodium by means of the

Na-K+-2Cl- transporter.

• Diffusion of K+ backwards creates a lumen positive potential

difference that drives absorption of Mg2+ and Ca2+

• Impermeable to water Dilution

• Site of Loop Diuretics and Bartter’s Syndrome

Early Distal Tubule

• Absorbs 5% of filtered Na via the Na-Cl- transporter

• Na-K+-ATP transporter moves Na into blood

• Cl- diffuses into the blood

• Site of Thiazide diuretics and Gittelman’s Syndrome

• Impermeable to water Dilution

Late Distal Tubule and Collecting Ducts

• The principal cells are involved in Na+ reabsorption, K+ secretion,

and water reabsorption

• The intercalated cells are involved in K+ reabsorption and H+

secretion.

• Absorb 3% of Na

• ENAC Na channels

• Site of K+ sparing Diuretics, Aldosterone

• Water permeability is controlled by ADH

Transport ATPases

• Na+/K+ ATPase• Generates Na+ gradient by pumping Na out of the cell which allows

many other solutes to be reabsorbed along with it

• Basolateral side of the glomerulus and nephron

• H+/K+ ATPase• Secretes H+ and reabsorbs K+

• Mostly in the collecting duct (also distal tubule) on the lumenal side of the intercalated cells

• H+ ATPase• Secretes H+ into the lumen, stimulated by aldosterone

• Collecting duct and distal tubule

Ion and Water Channels

• (ROMK)• Potassium recycling in thick ascending limb and potassium secretion in cortical

collecting duct, located on lumenal side

• Mutations lead to Bartter Syndrome

• ENaC• Principal cells of collecting tubule and late distal tubule on lumenal surface

• Makes lumen electronegative by reabsorbing Na+, allowing for K+ secretion

• Target of potassium sparing diuretics (amiloride)

• Liddle’s Syndrome: mutation leads excess channels and Na+ reabsorption causing increased ECF volume and hypertension

• Aquaporins• Selectively conduct water into cell

• Placed in late distal tubule and collecting duct in response to ADH

Coupled Transporters

• Na+ glucose- Early proximal tubule

• Na+/H+ antiporter- Late proximal tubule

• Na+ K+ 2Cl symporter (NKCC)- TAL

• Na+ phosphate symporter- Early proximal tubule

• Na+ Cl symporter- Early distal tubule

• Na+ HCO3 symporter- Intercalated cells of collecting duct and late

distal tubule

• Cl/HCO3 antiporter- Intercalated cells of collecting duct and late distal

tubule, some in proximal tubule

CONCENTRATION AND

DILUTION

Urine osmolality can vary from 50 to 1200

mosmole/kg water and urine volume can

range from 0.5 to 20 liter/day

ADH

• ADH is released in response to increased osmolality or decreased volume

• Osmolality is a much more sensitive stimulus• Significant release of ADH in response to tiny (1%) increases in plasma osmolality

(280 –290 mosmole/kg water is normal)

• ADH release in response to decreased volume or pressure is not as sensitive (5-10% change)

• In presence of high ADH, urine is low in volume, high in osmolality

• Rapid onset and termination of ADH responses

• ADH elevates cAMP which causes insertion into luminal membrane of vesicles containing aquaporin-2, a water channel protein

• ADH also increases urea permeability of inner medullary collecting tubule and may increase NaCl reabsorption in TAL

There is a gradient of osmolality in the

medulla: 300 mosmolal at cortico-

medullary border and 1200 mosmolal at

the tips of the papillae in the presence of

high ADH

Countercurrent Multiplier

• Ion transport in the TAL is the engine of the countercurrent

multiplier

• Na-K+-2Cl- transporter

• Na-K+-ATP transporter keeps intracellular Na+ low

• K+ recycles across membrane (ROMK)

• + Charge in tubular lumen pushes Ca2+ and Mg+ across junctions

• SITE OF LOOP DIURETICS

• Wasting of magnesium, calcium and potassium

• But LESS likely to cause hyponatremia

CONCENTRATION occurs in the thin

descending limb

DILUTION occurs in the thick ascending

limb and early distal tubule

Osmolar Clearance

• Total solute excretion (in osmoles/min) is UosmV (osmole/ml x ml/min =

osmole/min)

• Osmolar clearance (Cosm) is then defined as (UosmV)/Posm; the units

are ml/min

• This is equal to the ml of plasma that would have to be cleared each

minute of all solute to account for the rate of solute excretion

When urine is iso-osmolar to plasma,

osmolar clearance equals urine flow rate

Water Clearance

• Cwater = V – Cosm

• If Cwater is positive, osmolality of body fluids increases due to urine

formation

• If Cwater is negative, osmolarity of body fluids decreases due to urine

formation

POTASSIUM

Normal Values

• 3.5-5.0 mEq/L

• 98% of Potassium is intracellular

• Small changes have dramatic clinical consequences

What determines Renal Potassium

Excretion?

• Aldosterone

• K+ in diet

• Sodium Delivery to distal tubule

• Diuretics increase K+ secretion

• Tubular Flow Rate

• Non-reabsorbable negative charge

• Acid base changes

• Acidosis decreases K+ secretion

• Alkalosis increases K+ secretion

• H+-K+ ATPASE at basolateral membrane

Potassium Handling

• Compensation

• A potassium load is buffered by the movement of potassium into cells by Na-K-ATPase.

• This immediate defense against hyperkalemia is stimulated by:• Catecholamines

• Insulin

• Increased plasma potassium

• Plasma pH

• Cellular destruction/synthesis

• Correction

• Hyperkalemia is corrected by renal excretion of excess potassium

• This long-term defense against hyperkalemia is stimulated by:• Elevated plasma potassium

• Aldosterone

• Increased flow through the distal tubules

Potassium Buffering

• Acutely, Potassium is taken into cells

• Electroneutrality is maintained by pushing H+ out of cells

• This produces an intracellular alkalosis less of a gradient to

secrete H+ ions in intercalated cells

• The major stimulus for ammonium secretion is an intracellular

acidosis

• Alkalosis reduces excretion of ammonium which prevents excretion

of acid load

Potassium Secretion in Distal Tubule

• Step one• Na-K-ATPase pump maintains a low concentration of sodium and a

high concentration of potassium in the cells.

• Step two• Low intracellular sodium concentration allows sodium to flow down

its concentration gradient into the tubular cells. The flow of sodium into the tubular cell is the rate-limiting step in potassium secretion.

• Step three• Movement of positively charged sodium into tubular cell without an

associated anion creates an electrical gradient between the tubule and the tubular cells. The tubular lumen is negatively charged.

• Step four• Potassium passively flows down both electrical and chemical

(concentration) gradients into the tubular fluid

1. Elevation in plasma potassium

concentration tends to increase excretion

by direct effects

AND

2. Hyperkalemia causes aldosterone

secretion

Increased Plasma Potassium Effects

• 1. Increased number of Na-K-ATPase pumps

• 2. Increased sodium channels and sodium resorption

• 3. Increased electrical gradient for potassium secretion

• 4. Weaker than aldosterone’s effect!

Increased Flow to Distal Tubule

• Increased distal flow enhances the chemical gradient by quickly

washing away any secreted potassium. This prevents the

accumulation of potassium in the tubule which would decrease the

chemical gradient.

• Increased delivery of sodium to the distal nephron increases sodium

re-sorption and enhances the electrical gradient, favoring potassium

excretion

Nonresorbable Anions

• Normally, the tubule fluid is negatively charged and attracts the

positively charged potassium. The negative charge is created by the

resorption of sodium without chloride by the tubular cell.

• As the movement of sodium causes the tubule fluid to become more

electronegative, some of this negative charge is lost as chloride slips

between the tubule cells and is resorbed.

• If the predominant anion in the tubules is not chloride, but rather a

nonresorbable anion, none of the negative charge is lost. If none of

the negative charge is lost, the tubule will attract more potassium!

Aldosterone Effects on Potassium

• 1. Increases number of Na-K-ATPase pumps in basolateral

membrane

• 2. Increases sodium channels and sodium resorption

• 3. Increased sodium resorption increases electrical gradient for

potassium secretion

• 4. Increases number of potassium channels

How is potassium maintained in a high

salt diet?

• Volume expansion induced by high-salt diet will decrease activity of

renin-angiotensin-aldosterone system

• Reduction of aldosterone secretion, diminishes potassium secretion,

counteracting the effect of the increased distal flow.

Acid Base Balance and Potassium

• In alkalosis, there is a deficit of H+ in the ECF. H+ leaves the cells to

aid in buffering, and K+ enters the cells to maintain electroneutrality.

The increased intracellular K+ concentration increases the driving

force for K+ secretion, causing HYPOKALEMIA.

• In acidosis, there is an excess of H+ in the ECF. H+ enters the cells

for buffering, and K+ leaves the cells to maintain electroneutrality. The

intracellular K+ concentration decreases, which decreases the driving

force for K+ secretion, causing HYPERKALEMIA.

Potassium Regulation

• Potassium can be reabsorbed by intercalated cells and the H+-K+

ATPase

• OR

• Potassium can be secreted by principal cells

Hypokalemia

Disorders of excess mineralocorticoid

activity are all characterized by

hypokalemia, metabolic alkalosis,

hypertension and mild hypernatremia

If urine potassium is high in patients with

hypokalemia, think of a renal cause

• Hypertension with Hypokalemia

• In renal stenosis, renin is high

• In hyperaldosteronism, renin is low

• Also vomiting

Nonresorbable Anions

• Etiology of hypokalemia Anion

• Diabetic ketoacidosis...............................ßhydroxybutyrate

• Vomiting...................................................Bicarbonate

• Renal tubular acidosis (proximal)..............Bicarbonate

• Penicillin derivatives.................................Penicillin deriv.

• Toluene (glue sniffing)..............................Hippurate

Vomiting causes a metabolic alkalosis due

to loss of HCl and hypokalemia due to

increased quantities of nonresorbable

anions.

Urine potassium should be high.

Diarrhea causes a normal anion gap

hyperchloremic metabolic acidosis

and hypokalemia from loss of potassium

in stool.

Type I Renal Tubular Acidosis causes a

normal anion gap hyperchloremic

metabolic acidosis with hypokalemia due

to renal loss of potassium

The most common symptom of

hypokalemia is muscle weakness and

cardiac arrythmias

Hypokalemia Treatment

• Potassium Chloride

• Potassium Bicarbonate (if metabolic acidosis)

• If patient is on a diuretic: Potassium-sparing diuretic

Hyperkalemia Etiology

• Increased K+ intake from diet or medications• IV fluid, penicillin, blood transfusions

• Movement of K+ out of cells• Cell death

• Metabolic acidosis

• Lack of insulin

• Hypertonic plasma and solute drag

• Beta-blockers and digoxin

• Severe exercise

• Impaired renal excretion• Renal failure

• Effective volume depletion Sympathetic/RAAS decrease GFR

• Hypoaldosteronism• NSAIDS, ACE inhibitors, ARBs, Cyclosporine

• Addisons: (TB and HIV associated)

• Spironolactone

If a patient has persistent hyperkalemia,

then there is a defect in the renal

excretion of potassium

Symptoms of Hyperkalemia

• Muscle weakness

• Cardiac

• Peaked T waves

• Increased P-R interval

• Widened QRS complex

• Lost P wave

• Sinusoidal EKG

Hyperkalemia treatment

• CHECK EKG if there is an EKG change then give IV calcium

immediately

• Glucose and Insulin

• Bicarbonate

• Beta agonist (inhaled), causes tachycardia

• Binding resin to increase GI excretion

• Dialysis

CALCIUM, MAGNESIUM

AND PHOSPHATE

Filtered load of Ca and P

• Filtered Ca2+ load = (GFR) x (plasma concentration of Ca2+) x 0.6

• Filtered Phosphate load = (GFR) x (plasma concentration of

phosphate) x 0.9

Reabsorption of Ca2+ and P

• Calcium• 70% is reabsorbed in the proximal tubule and 20% is reabsorbed in the thick

ascending limb

• Loop diuretics cause increased Calcium excretion by inhibiting Na reabsorption in the TAL

• 8% is reabsorbed in the distal tubule and collecting duct by an active process

• <1% is normally excreted

• PTH increases Ca reabsorption in the distal tubule

• Thiazide diuretics increase Ca2+ reabsorption in the distal tubule and can be used to treat Kidney Stones.

• Phosphate• 85% of fitered phospate is reabsorbed in proximal tubule by Na+-phosphate

cotransport. Distal segments of the nephron do not reabsorb phospate so 15% is excreted in the urine.

• PTH inhibits phosphate reabsorption in proximal tubule via cAMP inhibition of transporter phosphaturia

PTH

• PTH is secreted in response to low calcium levels, as sensed by the calcium sensing receptors in the thick ascending loop of henle and the chief cells in the parathyroid gland

• Bones:• PTH receptors are located on osteoblasts. Initially, administering PTH will cause an

increase in bone formation. However, the long-lasting effect of PTH causes an increase in bone resorption. The long-lasting effect is mediated by cytokines released from osteoblasts.

• Kidneys:• 1) Inhibit phosphate reabsorption by inhibiting Na+-phosphate cotransport in the

proximal convoluted tubule. Leads to phosphaturia and increase in urinary cAMP.

• 2). PTH acts on the distal convoluted tubule to stimulate Ca2+ reabsorption.

• Intestine:• PTH stimulates renal 1alpha-hydroxylase. 1,25-dihydroxycholecalciferol (active

vitamin D) will stimulate intestinal Ca2+ and P absorption.

Rapid PTH Secretion

• Parathyroid cell membrane has Ca2+ sensing receptors that are linked, via a G protein to phospholipase C.

• Increased Ca2+

• When extracellular Ca2+ is increased, Ca2+ binds to the receptor and activates phospholipase C

• Activated phospholipase C leads to increased levels of IP3/Ca2+, which inhibits PTH secretion.

• Decreased Ca2+

• When extracellular Ca2+ is decreased, there is decreased Ca2+ binding to the receptor

• Phospholipase C is not activated, so there are not increased levels of IP3/Ca2+. This lack of inhibition then allows for PTH secretion.

Calcium and Acid Base Balance

• During acidemia more H+ will bind to albumin which leaves less sites

for Ca2+ to bind ⇒ Increase in free ionized Ca2+ concentration.

• During alkalemia: less H+ will bind which allows Ca2+ to bind to

albumin ⇒ Decrease in the free ionized Ca2+ concentration.

Vitamin D

• Human skin-derived VD3 is produced from 7-dehydroxycholesterol upon exposure to ultraviolet B radiation (UVB, wavelength 290–315 nm)

• As a fat-soluble vitamin, dietary vitamin D is incorporated into chylomicrons and transported via lymphatics into the venous circulation

• Exogenous and endogenous Vitamin D is transported to the liver. Here, it is metabolized by the cytochrome P450 enzymes vitamin D 25-hydroxylases to 25-hydroxy vitamin D (25(OH)D)

• In classical calcium-related responses, another cytochrome P450 enzyme, 1α-hydroxylase (CYP27B1), converts 25(OH)D to the biologically active form of vitamin D, 1,25-hydroxy vitamin D (1,25(OH)2D) in the proximal tubule of the kidneys

Vitamin D

• PTH stimulates renal 1alpha-hydroxylase (enzyme used to convert 25-hydroxycholecalciferol—> 1,25-dihydroxycholecalicferol)

• Vitamin D is going to promote mineralization of new bone, and its actions are coordinated to increase both [Ca2+] and [phosphate] in plasma so that these can be deposited into new bone material.

• Vitamin D has opposite effects on phosphate, than PTH, on the kidney. PTH stimulates Ca2+ reabsorption and inhibits phosphate reabsorption, and 1, 25-dihydroxycholecalciferol (Vit D) stimulates the reabsorption of both ions.

• Vitamin D also increases absorption of Ca2+ and phosphate in the intestine via induced synthesis of calbindin D28K

• In children, vitamin D deficiency→ Rickets

• In adults, vitamin D deficiency→ Osteomalacia

Sources of Vitamin D

• Sun - D3 is synthesized in skin by UV exposure

• Food (Vitamin D3): Cod liver oil, swordfish, salmon, tuna fish, milk

• Supplements (Vitamin D2): vitamin D fortified milk, vitamin tablets

Calcitonin

• Hormone secreted by parafollicular cells of thyroid

• Acts directly on osteoclasts

• Inhibits bone resorption (in the setting of high plasma Ca++), thus

LOWERS plasma Ca++

• Inhibits bone resorption thus LOWERS plasma phosphate

Symptoms of Hypocalcemia

• Hyperreflexia

• Spontaneous twitching

• Muscle Cramps

• Tingling and numbness

• Chvostek sign

• Trousseau sign

Symptoms of Hypercalcemia

• Stones, bones, groans and psychiatric overtones

• Constipation

• Polyuria (excessive urine)

• Polydipsia (excessive thirst)

• Hyporeflexia

• Lethargy

• Coma

• Death

• TREAT WITH IV FLUIDS

Familial hypocalciuric hypercalcemia

• Autosomal dominant inactivating mutation of calcium sensing

receptors in PT glands and ascending limb of kidney

• High PTH

• High Vitamin D

• Hypercalcemia

• Hypocalciuria

• Hypophosphatemia

• Hyperphosphaturia

• Usually asymptomatic

Humoral hypercalcemia of malignancy

• Some malignant tumors secrete PTH-related peptide

• Low PTH

• High Vitamin D

• Hypercalcemia

• Hypophosphatemia

• Hyperphosphaturia

Pseudohypoparathyroidism

• Autosomal dominant mutation of Gs protein in kidney and bone

• High PTH

• Low Vitamin D

• Hypocalcemia

• Hyperphosphatemia

• Hypophosphaturia

• Short stature, short neck, obesity, subcutaneous calcification, and

shortened 4th metatarsals and metacarpals

Hypoparathyroidism

• Common consequence of parathyroid/thyroid surgery

• less common is autoimmune and congenital

• Low PTH

• Low Vitamin D

• Hypocalcemia

• Hyperphosphatemia

• Hypophosphaturia

• Paresthesia, muscle cramps and tetany (severe spasms)

• Chvostek’s sign and Trousseau’s sign

• Fatigue, headaches, bone pains

Secondary hyperparathyroidism

• Chronic hypocalcemia from Vitamin D deficiency or chronic renal

failure

• High PTH

• Low Vitamin D

• Hypocalcemia/normal [but never high]

• *Hypophosphatemia

• *Hyperphosphaturia

Primary Hyperparathyroidism

• Parathyroid adenoma

• High PTH

• High Vitamin D

• Hypercalcemia

• Hypercalciuria (due to overload)

• Hypophosphatemia

• Hyperphosphaturia

• “Stones, bones, and groans”

• Stones from hypercalciuria

• Bones from increased bone resorption

• Groans from constipation

Distinguish Primary hyperparathyroidism

from Familial Hypercalciuric

Hypercalcemia based upon urine calcium

TUBULAR DYSFUNCTION

Bartter’s syndrome

• Bartter’s syndrome is an autosome recessive disorder characterized

by a mutation of the Na-K-2Cl cotransporter (loss of function of the

NKCC2 gene) or ROMK channel which are in the thick ascending

LOOP OF HENLE.

• In children, it presents as failure to thrive.

• Bartter’s syndrome is associated with renal stones and has an

electrolyte picture identical to chronic loop diuretic use: hyponatremia,

hypokalemia, metabolic alkalosis and hypercalcuria (which causes

the stones).

• Magnesium deficiency tends to be mild.

Bartter’s Syndrome Signs

• SIGNS:• NOT HYPERTENSIVE

• Metabolic alkalosis

• Hypokalemia

• Hypomagnesemia

• Hypocalcemia (hypercalciuria)

• Hyperaldosteronism (because body detects low sodium)

• Elevated Plasma Renin Activity (PRA)

• Resistance to angiotensin II infusion

• Renal salt wasting

• JGA hyperplasia

• SYMPTOMS:• Mental and growth retardation

• Seizures, paresthesias

• Muscle weakness

• Polyuria and polydipsia

• Kidney stones

Bartter’s syndrome has a clinical

presentation very similar to

Diuretic/laxative abuse and vomiting

Gitelman’s syndrome

• Gitelman’s syndrome is a autosomal recessive disorder characterized

by a defect in the Na+-Cl- transporter in the distal tubule. It often

presents in adulthood, but it is a life-long congenital disorder. The

electrolyte picture is consistent with chronic thiazide diuretic use.

These patients have hypocalcuria and do not develop renal stones.

• Patients with Gitelman’s syndrome have profound hypomagnesemia.

Gittelman’s Syndrome Signs and Sx

• Signs

• NOT HYPERTENSIVE

• Hypokalemia

• Metabolic Alkalosis

• Hypercalcemia

• Hypocalciuria

• Hypomagnesemia

• Symptoms

• Muscle cramps

• Fatigue

• Chondrocalcinosis

Patients with Bartter syndrome tend to

have a blunted response to a loop

diuretic, while patients with Gittelman’s

syndrome tend to have a blunted

response to a thiazide diuretic.

Measurement of urinary calcium can help

distinguish between the two disorders

Bartter’s: Hypercalciuria

Gittelman’s: Hypocalciuria

Think of Bartter’s and Gittelman’s as

equivalen to being constituitively on a

diuretic… so patients are NOT

hypertensive.

Whereas Liddle’s mimic primary

hyperaldosteronism hypertension

Liddle Syndrome

• Liddle's syndrome is a rare autosomal dominant condition in which

there is a primary increase in collecting tubule sodium reabsorption

and, in most cases, potassium secretion.

• A truncated or missense mutation in the ENaC channel leads to a

CONSTITUTIVELY ACTIVE Na channel.

• The mutation increases the number of channels, and increases

probability that a given channel is open.

• Affected patients typically present with hypertension, hypokalemia,

and metabolic alkalosis, findings that are similar to those seen in

other disorders caused by mineralocorticoid excess. Most patients

present at a young age.

Liddle Syndrome Signs and Sx

• Signs

• Hypertension

• Hypokalemia

• Metabolic Acidosis

• Young Age

• Hypoaldosteronism

Therapy in Liddle's syndrome consists of

prescribing amiloride or triamterene,

potassium-sparing diuretics that directly

block the collecting tubule sodium

channels and can correct both the

hypertension and, if present, the

hypokalemia

ACID BASE BALANCE

Acid-Base

Normal Arterial Plasma Values

• pH: 7.35-7.45; Mean: 7.40

• Limits compatible with life: 6.8 - 8.0

• PCO2: 35-45 mmHg: Mean: 40 mmHg

• [HCO3-]: 22-26 mEq/L: Mean: 24 mEq/L

Normal Acid Base Dynamics

• The typical American diet generates net H+ from protein catabolism -

for each H+ buffered, one HCO3- is consumed! The kidney can’t

afford to lose all this HCO3-, so the kidneys:

• Reabsorb almost all filtered HCO3-

• Metabolically generate new HCO3-

• Actively excrete H+ in an amount equal to the H+ generated

metabolically and ingested

Acid Production

• 2 types of acid are produced in the body

• Volatile acid: CO2

• CO2 + H2O H2CO3 which dissociates into H+ and HCO3-

• This reaction is catalyzed by carbonic anhydrase

• Fixed acids: Sulfuric and Phosphoric (40-60mmol/day)

• Volatile acid = 13,000 mEq of carbonic acid /day (H2CO3)

• Excreted by lungs as CO2

• Non-volatile acid = 40-80 mEq of fixed acid/day (H+ and HCO3-)

• Excreted by kidneys

Henderson Hasselbalch

• A- is the base form of the buffer (H+ acceptor)

• HA is the acid form of the buffer

• When A- = HA the pH = pKa of the buffer

Bicarbonate is the major buffer of the

extracellular fluid.

2CO

3

P03.0

]HCO[log1.6pH

Carbonic Anhydrase

• Luminal membrane Na+/H+ exchanger secretes H+ into the lumen

• H+ in lumen combines with filtered HCO3- to form H2CO3 and decomposes into CO2 and H2O, catalyzed by a brush border carbonic anhydrase.

• The CO2 & H2O cross the luminal membrane and enter cell.

• Inside cell, CO2 and H2O recombine to form H2CO3, catalyzed by intracellular carbonic anhydrase.

• H2CO3 decomposes back to H+ and HCO3-.

• HCO3- is transported across the basolateral membrane into the blood by Na+/HCO3- cotransport and Cl-/HCO3- exchange.

Reabsorption of HCO3-

• Reabsorption occurs primarily in the proximal tubule• There is net reabsorption of HCO3- but NOT net secretion of H+

• Increases in the filtered load result in increases of reabsorption until the capacity is exceeded [40mEq/L] and HCO3- will be excreted in the urine

• Increases in PCO2 result in increased HCO3 reabsorption • RENAL COMPENSATION FOR RESPIRATORY ACIDOSIS

• Decreases in PCO2 result in decreased HCO3 reabsorption• RENAL COMPENSATION FOR RESPIRATORY ALKALOSIS

• ECF Volume expansion decreased reabsorption

• ECF Volume contraction Increased reabsorption

• Contraction alkalosis

• Angiotensin II increased reabsorption

There is no net excretion of H+ in the

proximal tubule.

Mechanisms of H+ Excretion

• In the intercalated cells H+ is secreted into the lumen by an H+-ATPase and HCO3- is absorbed into the blood.

• The H+-ATPase is increased by aldosterone resulting in net secretion of H+ and net resorption of HCO3-

• METABOLIC ALKALOSIS IN EXTREME CASES

• The amount of H+ secreted as NH4+ depends on the amount of NH3 synthesized by renal cells and the urine pH.

• In the intercalated cell, H+ is secreted into the lumen and combines with NH3 to form NH4+ which is excreted (diffusion trapping)

• The lower the pH of the urine, the greater the NH4+ excretion (gradient for NH3 diffusion is increased as well)

• In acidosis an adaptive increase in NH3 synthesis occurs

• Hyperkalemia inhibits NH3 synthesis (SEEN IN HYPOALDOSTERONISM and Type 4 Tubular Acidosis)

Greater delivery of K+, lumenal neg.

potential, and higher flow rate all promote

increased secretion of H+ by intercalated

cell.

Serum Anion Gap

• [Na+] – ([Cl-] + [HCO3-])

• Represents unmeasured anions in serum

• (phospate, citrate, sulfate, protein)

• Normal value 12mEq/L (range 8-16)

• In metabolic acidosis an anion must increase to maintain

electroneutrality and replace los HCO3-

• If the anion is chloride Normal Anion Gap

• If the anion is unmeasured Increased Anion gap

Anion gap acidoses must be recognized

quickly as they can be life-threatening.

Metabolic Acidosis

• Normal Anion Gap• Diarrhea

• Type 1 Renal Tubular Acidosis

• Type 2 Renal Tubular Acidosis

• Type 4 Renal tubular acidosis

• High Anion Gap• Ketoacidosis

• Lactic acidosis

• Chronic renal failure

• Salicylate intoxication

• Methanol, formaldehyde intoxication

• Ethylene glycol intoxication

In response to sustained acidosis, the

kidney increases excretion of titratable

acid and dramatically increases

metabolism of glutamine and excretion of

NH4+. The latter response begins in

days, but may take a few weeks to reach

its maximum

Metabolic Alkalosis

• Vomiting

• Loss of gastric H+; leaves HCO3- behind in blood, worsened by

volume contraction, hypokalemia, high urine potassium

• Hyperaldosteronism

• Increased H+ secretion by distal tubule; increased HCO3-

absorption METABOLIC ALKALOSIS

• Loop or Thiazide diuretics

• Volume contraction alkalosis

• Bartter, Gitelman and Liddle

All diuretics except those that act on

principal cells cause enhanced secretion

of H+ and K+

ALKALOSIS

HYPOKALEMIA

Respiratory Acidosis

• Opiates

• Sedatives

• Anesthetics

• Guillain-Barre syndrome

• Polio

• ALS

• Multiple Sclerosis

• Airway obstruction

• COPD

Respiratory Alkalosis

• Pneumonia

• Pulmonary Embolus

• High Altitude

• Psychogenic

• Salicylate Intoxication

Mixed Disorders

• Calculate the starting bicarbonate

• Delta gap + bicarbonate = Starting bicarbonate

• In cases of a pure anion gap metabolic acidosis, the rise in the anion

gap from 12 should equal the fall in bicarbonate from 24 (a

bicarbonate was lost for each additional acid).

• If there is a significant discrepancy, then another metabolic disorder is

present:

• If the starting bicarbonate is too high: metabolic alkalosis

• If the starting bicarbonate is too low: non-gap metabolic acidosis

Winter’s Formula for Metabolic Acidosis

• Expected pCO2 = (1.5 x serum bicarbonate) + 8 (+/-2)

Tubular Acidosis

Chloride and Metabolic Alkalosis

• Chloride-responsive metabolic alkalosis involves urine chloride levels

of less than 10 mEq/L and is characterized by decreased ECF volume

and low serum chloride levels, such as occurs with vomiting. This

type responds to administration of chloride salt.

• Chloride-resistant metabolic alkalosis involves urine chloride levels of

more than 20 mEq/L and is characterized by increased ECF volume.

As the name implies, this type resists administration of chloride salt.

Primary aldosteronism is an example of chloride-resistant metabolic

alkalosis.

The 2 major divisions of Metabolic Alkalosis

Chloride responsive’ group (urine chloride < 10 mmol/l)

Key Feature: Chloride Deficiency

Typical causes in the low urine chloride group are:

•Loss of gastric juice (eg vomiting esp if pyloric obstruction,

or nasogastric suction)

•Diuretic therapy

‘Chloride resistant’ group (urine chloride > 20 mmol/l)

Key Feature: Excess Steroids or Current Diuretic Use

Typical causes:

•Excess adrenocortical activity (eg primary aldosteronism,

Bartter’s syndrome, Cushing’s syndrome, other causes of

excess adrenocortical activity)

•Current diuretic therapy

•‘Idiopathic’ group

Alkalosis may cause symptoms of

hypocalcemia because H+ and Ca2+

compete for binding on plasma proteins

and decreased H+ increased Ca2+

binding

GLOMERULAR

HISTOLOGY AND INJURY

Glomerulus

The Glomerular Filtration Barrier• A thin layer of fenestrated endothelial cells, each fenestra being 70 to 100 nm in

diameter.

• A glomerular basement membrane (GBM) with a thick, electron-dense central layer, the lamina densa, and thinner, electron-lucent peripheral layers, the lamina rara interna and lamina rara externa. The GBM consists of collagen (mostly type IV), laminin, polyanionic proteoglycans, fibronectin, and several other glycoproteins.

• Podocytes, which are structurally complex cells that possess interdigitatingprocesses embedded in and adherent to the lamina rara externa of the basement membrane. Adjacent foot processes are separated by 20- to 30-nm-wide filtration slits, which are bridged by a thin slit diaphragm composed in large part of nephrin.

• The glomerular tuft is supported by mesangial cells lying between the capillaries. Basement membrane–like mesangial matrix forms a meshwork through which the mesangial cells are scattered. These cells, of mesenchymal origin, are contractile and are capable of proliferation, of laying down collagen and other matrix components, and of secreting a number of biologically active mediators.

H&E (hematoxylin and eosin)

PAS (periodic acid Schiff) stain

Jones methenamine silver stain

Trichrome stain (fibrosis/sclerosis)

Immunofluorescence

Granular = immune complexes

Linear = autoantibodies to GBM

Diffuse, Focal, Segmental, Global Injury

• Focal: < 50% of glomeruli damaged

• Diffuse: > 50% of glomeruli damaged

• Segmental: Glomerulus is partially damaged

• Global: Entire glomerulus is damaged

Electron Dense Deposits

• Injury of the glomerulus from immune complex deposition or

destruction of tissue

• Supepithelial: Membranous glomerulonephropathy

• Subendothelial and Intramembranous: MPGN

Localization of immune

complexes in the glomerulus:

(1) Subepithelial humps, as in

acute glomerulonephritis

(2) Epimembranous deposits, as

in membranous nephropathy

and Heymann nephritis

(3) Subendothelial deposits, as

in lupus nephritis and

membranoproliferative

glomerulonephritis

(4) Mesangial deposits, as in IgA

nephropathy.

Podocyte Effacement

Mesangial Expansion Pattern

Nodular/lobular

Diabetic glomerulosclerosis

Amyloidosis

LCDD

Branching

IgA nephropathy

Lupus nephritis

Mesangial Hypercellularity

• More than 2 cells per tuft

Endocapillary Hypercellularity

• Obliteration of the capillary, loops by swollen endothelial cells and

inflammatory cells

• Often described as proliferative glomerulonephritis

• MPGN and Lupus

Extracapillary Hypercellularity

• A cellular crescent is defined as a

proliferation of parietal epithelial

cells and inflammatory cells, more

than 2 cell layers thick

• Always associated with fibrin

which indicates active necrosis

• Always implies a Rapidly

Progressive Glomerulonephritis

FSGS

• Segmental and Focal

• Histology: Increased mesangial

matrix, obliterated capillary

lumina, hyalinosis, and lipid

droplets.

• On EM, podocytes exhibit

effacement of foot processes.

IHC Staining

• Deposition of circulating immune

complexes gives a granular

pattern.

• Anti-GBM antibody

glomerulonephritis displays a

linear pattern.

Primary vs. Secondary GN

Mechanisms of Glomerular Injury

• 1. Injury by antibodies reacting in situ within the glomerulus, either

binding to insoluble fixed (intrinsic) glomerular antigens or extrinsic

molecules planted within the glomerulus Electron dense deposits

• Membranous nephropathy (PLA2)

• Granular IF staining

• Anti-GBM Goodpasture syndrome

• Linear IF staining

• 2. Injury resulting from deposition of circulating antigen-antibody

complexes in the glomerulus.

• Infectious Glomerulonephritis

• Lupus nephritis

• IgA Nephropathy

Complement and Glomerular Injury

• Antibody-mediated immune injury is an important mechanism of

glomerular damage, mainly via complement- and leukocyte-mediated

pathways. Antibodies may also be directly cytotoxic to cells in the

glomerulus.

• Alternative complement pathway activation occurs in the

clinicopathologic entity called dense-deposit disease, until recently

referred to as membranoproliferative glomerulonephritis (MPGN type

II), and in an emerging diagnostic category of diseases broadly

termed C3 glomerulopathies.

• Low Complement GN: MPGN, Post-streptococcal

glomerulonephritis, SLE

Podocyte Injury

• The podocyte is crucial to the maintenance of glomerular barrier function. Podocyte slit diaphragms are important diffusion barriers for plasma proteins, and podocytes are also largely responsible for synthesis of GBM components.

• Podocyte injury can be induced by:• Antibodies to podocyte antigens

• Toxins (i.e. ribosome poison puromycin)

• Cytokines

• Circulating factors (i.e. focal segmental glomerulosclerosis)

• Morphologic changes of podocyte injury:

• Effacement of foot processes

• Vacuolization

• Retraction and detachment of cells from GBM

• PROTEINURIA

ELECTROLYTE

DISORDERS

CHF and Cirrhosis in Hyponatremia

• Conditions such as liver cirrhosis congestive heart failure are

associated with third spacing and low effective circulating volume

• This leads to an increase in ADH secretion because the body thinks it

is hypovolemic. The increased ADH leads to water retention which in

turn dilutes the sodium concentration and therefore causes

hyponatremia.

• Clinical clues: presence of peripheral edema, pleural effusion,

pulmonary edema or ascites, low blood pressure, rapid hear rate,

drop of BP when standing from supine position

Assessing volume state

Reduced effective circulating volume is

associated with low urinary sodium

concentration (<20 mmol/L)

Diagnostic Work up

• 1. Check urine osmolality

• if < 100 → no ADH (primary polydipsia)

• 2. Check serum osmolality

• If low → true hyponatremia

• If elevated --> hyperglycemia etc. (dilutional hyponatremia)

• If normal → pseudohyponatremia (high protein or lipid levels)

• 3. Check urine Na+

• If < 20 → RAA activated → heart failure or cirrhosis

• If > 40 euvolemic hyponatremia (SIADH, adrenal insufficiency,

hypothyroidism)

Sosm

• Calculated Sosm = 2 x Na+ + glucose/18 + BUN/2.8

• Example; [Na+] = 140, Glucose = 90, BUN = 14

• Sosm = 2 x 140 + 90/18 + 14/2.8 = 290

• You should check the difference between calculated and measure

Sosm (osmolal gap) to see if there unusual osmoles in the blood

(occurs in alcohol intoxication, mannitol infusion)

• Normal osmolal gap <9

Serum osmolality is high in dilutional

hyponatremia and normal in

pseudohyponatremia

Dilutional Hyponatremia

• Dilutional hyponatremia occurs in the case of diabetes

(hyperglycemia causes water to come out of the cells) OR in

transurethral resection of the prostate or bladder OR in hysterectomy

(sorbitol or glycine may be used during the surgery to irrigate which

are absorbed and cause a shift in water outside of the cells).

• In the case of dilutional hyponatremia caused by diabetes, serum

osmolality is usually high. However, the osmolal gap is normal

because glucose is accounted for in that formula. For every 100

mg/dL increase in glucose, expect a 1.6 mmol/L drop in [Na+].

Psuedohyponatremia

• Pseudohyponatremia is rare and occurs in the presence of

hyperlipidemia and hyperprotinemia. Normally, water makes up 93%

of the plasma, and proteins and lipids make up 7% of the plasma. The

increase in proteins and lipids upsets this balance and therefore the

apparent concentration of Na+.

• To test for this, look at lipid and protein levels in the plasma. Also look

at serum osmolality, which should be normal.

Thiazide diuretics are more likely to cause

hyponatremia than loop diuretics

Pain and nausea may cause increased

secretion of ADH

SIADH

• Diagnostic Criteria for SIADH:

• Low serum osmolality

• High unregulated ADH secretion leads to a constant high rate of water reabsorption in the CD causing dilution of the serum despite euvolemia

• High urine osmolality (greater than 100 mosm/kg) and high urine sodium concentration

• The high rate of water reabsorption means that the kidney is constantly concentrating urine

• Low urine uric acid

• Uric acid tends to follow the water in the kidney (it maintains a constant concentration between compartments). So by reabsorbing a lot of water, the tubular water compartment is small and very little uric acid can be excreted

• Euvolemia

• SIADH is a Diagnosis of exclusion!- hormones, heart, liver function, GFR must all be normal

Medical Conditions SIADH

• Pulmonary infections: TB, lung abscesses, bacterial/viral pneumonia

• CNS problems (cause disruption of the normal inhibitory mechanisms

of ADH release from the posterior pituitary)

• Infection: meningitis, encephalitis, abscess

• Injury: stroke, trauma, subarachnoid hemorrhage

• Malignancies (certain tumors/ cancers have ectopic ADH production)

• Small cell carcinoma of lung (most common)

• Rarely other lung cancers

• Less common: other head/neck cancers, extrapulmonary small cell carcinomas

*Medications causing SIADH*

IMPORTANT

• Thiazide diuretics (lots of NaCl excretion)

• Carbamazepine (increases ADH secretion)

• Vincristine- chemotherapy (increases ADH secretion)

• Ifosfamide- chemotherapy (increases ADH secretion)

• Antipsychotics/antidepressants (increase ADH secretion)

• Oxytocin and dDAVP (ADH analogs)

• Cyclophosphamide (potentiate renal action of ADH)

• NSAIDs (potentiate renal action of ADH)

• SSRIs (unknown mechanism)

Endocrine Disorders • SIADH

• LOW serum osmolality

• HIGH urine osmolality

• HIGH urine sodium concentration

• LOW serum uric acid

• Euvolemia

• Adrenal Insufficiency• LOW serum osmolality

• Very HIGH urine osmolality

• HIGH urine sodium concentration

• LOW serum uric acid

• Euvolemia

• Hypothyroidism• LOW serum osmolality

• HIGH urine osmolality

• HIGH urine sodium concentration

• LOW serum uric acid

• Euvolemia

Management of Hyponatremia

• Fluid restriction: for everyone with hyponatremia

• Hypertonic 3% NaCl solution

• For symptomatic patients (seizures, altered mental status)

• Hypertonic saline increases ECV osmolality acutely

• Furosemide: Loop diuretic (you could use another loop diuretic too)

• Reduces medullary gradient

• DO NOT CORRECT TOO QUICKLY

• Avoid correction faster than 0.5-1mmmol/hr or >10-12 mmol/day

Risks of Sodium Correction

• Edema due to acute hyponatremia safely corrects when Na+ is added

to the ECF.

• Chronic hyponatremia is usually asymptomatic because the body has

adapted by moving solute into the cells, thereby decreasing ECF

volume. Adding Na+ too quickly results in overcorrection, pulling too

much water out of the cells.

• Appropriate correction: 0.5-1.0 mmol/hr, or 10-12 mmol/day

• Risk of rapid correction: Central Pontine Myelinolysis

• Delayed neurological symptoms: dysarthria, altered mental status show up

about a week later with MRI signs (hyperintensity in the pons).

Osmotic Demyelination Syndrome

• Osmotic demyelination syndrome (ODS) was first described in alcoholism, but myelin loss may also be present in other conditions such as liver transplantation, malnutrition, and AIDS.

• It may occur, in the context of rapid restoration or overcorrection of the serum Na+ concentration. Thus patients inadvertently subjected to rapid correction must be monitored carefully.

• Majority of cases are asymptomatic and the onset of symptoms may be delayed (usually taking 24-48 hours to manifest) which is why you should check Na+ often to ensure you’re not replenishing too quickly

• Classical clinical features: quadriparesis (weakness in all four limbs) and pseudobulbar palsies (inability to control facial movements)

• Classic findings on T2- weighted image MRI are hyperdense (white areas) in the central pons. This lesion reflects increased water content in the area.

Hypernatremia

• GI: Severe diarrhea, vomiting, or adenomas

• Renal: Diabetes insipidus or osmotic diuresis

• Insensible and sweat losses: Burns, fever, respiratory infections

• Impaired thirst or inability to consume water

Diagnosing Hypernatremia

• Urine osmolality• Isolated thirst disturbance

• Urine will be appropriately concentrated (>800 (600) mOsm/kg H2O)

• Diabetes Insipidus• A urine osmolality of <150 (300) mOsm/kg H2O)

• Osmotic Diuresis• If urine osmolality is persistently at or near 300mOsm/kg H2O an osmotic diuresis is likely

• Grey zone• Urine osmolality 150-800 mOsm/kg H2O, Consider:

• Partial variants of diabetes insipidus

• Impaired countercurrent multiplication (CCM) (usually caused by tubulointerstitial kidney injury)

• Response to ADH:• Response to ADH can help one to differentiate between central diabetes insipidus

(CDI) or nephrogenic diabetes insipidus (NDI)

• Only CDI will respond to exogenous ADH

Free Water Deficit

• The free water deficit is used to estimate the amount of water needed

to correct hypernatremia.

• Water Deficit = TBW x ([Plasma Na+/ 140]-1)

• TBW= total body water (weight in kg x 0.6 for men/ weight in kg x 0.5

for women)

Free Water Clearance

• Cwater = V – Cosm

• Cosm = (UosmV)/Posm

Management of Hypernatremia

• Treatment Complications

• Rapidly lowering Na+ concentration in plasma may precipitate cerebral edema as water redistributes into intracellular compartment. Thus one has to reduce the serum Na+ concentration gradually (over 48-72 hours)

• Guidelines for patients with hypernatremia:• First restore volume contraction with normal saline before initiating

therapy with dilute solutions

• Can give ½ of water deficit back in 24 hours.

• Water deficit = TBW ([Na/140]- 1)

• Replace ongoing water and sodium losses (e.g urine, sweat) with an intravenous solution of comparable tonicity

In metabolic alkalosis associated with

vomiting - use urine chloride to check

volume instead of sodium

Chloride will be low in volume depleted

states.

Considerations in Assessment

• Volume State

• Urine osmolality

• Urine sodium

• Medical Conditions

• Drugs

Na+ and K+ in Collecting Tubules

• Sodium reabsorbed by ENaC or the NaCl symporter

• Pumped out of the cell with Na/K ATPase

• K is pumped out by ROMK to help rectify the inward Na

• More Na uptake drives out more K

• Aldosterone binds to a mineralocorticoid receptor to increase the

uptake of Na and the excretion of K

• If Na isn’t delivered to that portion of the tubule, K won’t be

exchanged for it

• If Na is highly delivered (increased absolute presence, increased flow,

loop/thiazide diuretics), K will be highly exchanged

• If Na is highly taken up (lots of aldosterone, mutations in Liddle’s), K

will be highly exchanged

Factors Affecting Potassium Uptake

• Drugs:

• Insulin

• Beta-2 adrenergic agonists

• Alpha adrenergic antagonists

• Alkalosis (Base and Beta agonists)

• Hyposmolarity

Factors Increasing Potassium Excretion

• High K+ diet

• Hyperaldosteronism

• Alkalosis

• Thiazide diuretics

• Loop diuretics

• Luminal anions

• High urinary flow

Causes of Hyperkalemia

• Movement out of cells• Insulin Deficiency

• Beta-2 adrenergic antagonists

• Alpha adrenergic agonists

• Acidosis (Acid and Alpha agonists)

• Hyperosmolarity

• Cell lysis (tumor cells, rhabdomyolysis, hemolysis)

• Exercise

• Impaired renal excretion• Renal failure

• Effective volume depletion Sympathetic/RAAS decrease GFR

• Hypoaldosteronism

• NSAIDS, ACE inhibitors, ARBs, Cyclosporine

• Addisons: (TB and HIV associated)

• Spironolactone

Acid Base Balance and Potassium

• The plasma membrane of some cells contain a K+/H+ ATPase

(exchanger; e.g. intercalated cells of late distal tubule, parietal cells of

the stomach). This exchanger is utilized to internally balance K+ in

response to acid-base disturbances

• Acidemia- too much H+ in the blood causes the H+ to be shifted in (in

order to utilize our intracellular buffering mechanisms) in exchange for

K+ shifting out, which leads to hyperkalemia

• Alkalemia- too little H+ in the blood causes intracellular H+ to be

shifted out of the cell in exchange for K+. Less K+ extracellularly

leads to hypokalemia

Insulin, Hyperglycemia, and Potassium

• Insulin stimulates the Na+/K+ pump, resulting in K+ being taken up by

the cell. With insulin deficiency, lower Na+/K+ pump activity leads to

hyperkalemia.

• Hyperglycemia → High ECF osmolarity compared to ICF. Water flows

out of the cell due to the osmotic gradient to equalize osmolarity

across the two compartments. As water leaves the cell, the

intracellular K+ concentration increases, which then drives its

diffusion out of the cell (think of it as water dragging K+ with it)

Hyporeninemic Hypoaldosteronism

• Also known as type IV renal tubular acidosis- caused by a deficiency

in the adrenal glands leading to a decrease in aldosterone.

• Characterized by a mild-normal anion gap metabolic acidosis

• Serum bicarbonate: 15-20 mmol/L

• Hypoaldosteronism less K+ secretion

• Hyperkalemia limits NH3 synthesis decrease in H+ excretion

• It is usually associated with reduced GFR

• Most commonly associated with diabetes mellitus

GFR and Hyperkalemia

• Severely reduced GFR (GFR < 20 mL/ min) leads to hyperkalemia

because at this point, tubular flow is so low that the kidney is unable

to excrete adequate amounts of potassium.

• Remember that the rate of K+ is secretion is affected by:

• Delivery of Na+ to the distal tubule

• Low tubular flow delivers less Na+ to the distal tubule, and less K+ is

transported into the lumen for excretion

• The driving force on K+ that makes it want to leave cells

• Low tubular flow can cause K+ already secreted into the lumen of the

cortical collecting duct (CCD) to accumulate, reducing the gradient that

favors K+ excretion in that part of the nephron

• Low tubular flow → lower K+ excretion

Reduced Renal Excretion

• Obstructive uropathy can cause reduced excretion and hyperkalemia

which is higher than the degree expected for the degree of GFR

reduction

• Drugs such as trimethoprim, pentamidine , cyclosporin and tacrolimus

• Potassium sparing diuretics, ACE inhibitors and ARB, NSAIDs

• Reduced delivery of sodium to distal nephron (severe dehydration)

Symptoms of Hyperkalemia

• Ascending muscle weakness that starts in the legs and progresses to the trunk and arms• Can progress to a flaccid paralysis that mimics Guillain-Barre

• Cardiac conduction abnormalities• Bundle branch blocks

• AV block

• Arrhythmias (specifically bradycardia and V-fib)

• Hyperkalemia raises the resting membrane potential leading to ECG changes:• Tall, peaked T waves

• Wide QRS complexes

• Severe hyperkalemia can lead to life threatening tachyarrhythmias

Workup of Hyperkalemia

• Check GFR

• (if GFR >20 look for additional causes)

• If GFR<15 and K+ >6 Dialysis may be needed)

• Drugs:

• Beta blockers

• Potassium sparing diuretics

• NSAIDs

• Ace Inhibitors or ARBs

• Check blood glucose

• Status of RAAS

• Hypoaldosteronism causes hyperkalemia

Management of Hyperkalemia

• In mild to moderate hyperkalemia in a severely volume depleted patient, volume expansion with normal saline may be the only treatment needed

• Assess severity by checking for ECG changes (K > 6 mmol/L)• If ECG changes are present, stabilize the heart with IV calcium gluconate

• Lower Potassium levels

• Shift K+ into the cells by administering:• Insulin w/ glucose (fast action: effects within 30 mins)

• Beta-2 agonist (albuterol)

• Remove excess K+• Loop diuretics

• Potassium-binding resin (sodium polystyrene sulfonate)

• Dialysis• Reserved for those with intractable kidney disease

In cases with severe volume depletion

and reduced Na deliver to distal nephron,

volume expansion with intravenous

normal saline may be the only treatment

required for mild to moderate

hyperkalemia

Causes of Hypokalemia• K+ shift into the cell

• Drugs• insulin

• beta-2 agonists

• Alkalosis• [H+] is low, so intracellular H+ moves out of cells in exchange for K+

• Renal Loss• Diuretics

• Genetic Defects that affect transport• Bartter’s Syndrome (TAL)

• Gitelman’ Syndrome (DCT)

• Liddle’s Syndrome (CCD)

• Polyuria

• Hyperaldosteronism• Mineralocorticoid excess (aldosterone, progesterone → sodium retention)

• Hypomagnesemia• Mg+ blocks ROMK, so low Mg+ → high K+ excretion

• GI Loss• diarrhea (K+ concentration is high in the colon)

• laxatives

Renal Loss

• Diuretics (osmotic, loop and thiazide)

• Bartter, Gitelman and Liddle syndromes

• Polyuria

• High aldosterone state

• Primary

• Secondary

• Apparent mineralocorticod excess

• Hypomagnesemia

Assessing the History

• A history of:

• Diarrhea → K+ loss from the gut

• Vomiting → alkalosis, high urine potassium

• High urine output → polyuria

• Medications: insulin, albuterol, laxatives, diuretics

• High blood pressure → hyperactive RAAS → hyperaldosteronism

High urine potassium (> 25 mmol/ L) →

Renal loss, Vomiting

Low urine potassium (< 25 mmol/ L) →

Most likely GI loss

Symptoms of Hypokalemia

• Severe muscle weakness or rhabdomyolysis (similar to ascending

pattern in hyperkalemia

• Muscle cramping

• ECG abnormalities—presence of a U wave

• Cardiac conduction abnormalities

• Metabolic alkalosis

• Renal dysfunction—structural and functional changes in the kidney

• Glucose intolerance—via reduced insulin secretion

Potassium Depletion- Metabolic Alkalosis

• Chronic potassium depletion increases urinary acid excretion.

• Ammonium production and absorption are enhanced and bicarbonate reabsorption is stimulated.

• Chronic depletion also upregulates H, K-ATPase to increase potassium absorption at the expense of enhanced hydrogen ion loss.

• Hypovolemia• Vomiting

• Diuretic Use

• Bartter and Gittelman Syndromes

• Hypervolemia• Hyperaldosteronism

• Mineralocorticoid Excess

• Liddle Syndrome

AME

• Cortisol can have activate aldosterone receptors (mineralocorticoid

receptor)

• A local enzyme, 11-HSD, breaks down cortisol to cortisone, which

cannot activate MR

• Congenital deficiency of this enzyme AME

• Acquired deficiency occurs with high amount of licorice ingestion

The presence of distal or proximal RTA

should be considered in any patient with

an otherwise unexplained normal anion

gap (hyperchloremic) metabolic acidosis

Type I Renal Tubular Acidosis

• The primary defect in distal (Type 1) RTA is impaired distal

acidification. Diminished H-ATPase activity is probably the most

common cause of distal RTA. This defect impairs the ability to

maximally acidify the urine, and in most patients, the urine pH cannot

be reduced below 5.5. Patients present with a normal anion gap

metabolic acidosis and hypokalemia.

• ELEVATED URINE PH

• Commonly associated with hypokalemia

Sodium that is reabsorbed in the

collecting tubules must, to maintain

electroneutrality, be reabsorbed with an

anion, such as chloride or bicarbonate, or

in exchange for a cation, such as

potassium or hydrogen.

If hydrogen ion secretion is impaired,

potassium secretion generally increases.

Type II Renal Tubular Acidosis

• Proximal (Type 2) RTA is characterized by a reduction in proximal

bicarbonate reabsorptive capacity that leads to bicarbonate wasting in

the urine until the serum bicarbonate concentration has fallen to a

level low enough to allow all of the filtered bicarbonate to be

reabsorbed.

• It is often associated with diffuse proximal tubular dysfunction, known

as Fanconi syndrome.

• Sign of proximal tubule dysfunction in the urine (glucosuria, phosphaturia,

uricosuria, aminoaciduria)

• Mild hypokalemia may be seen

In the kidney, the resulting intracellular

acidosis stimulates both hydrogen

secretion and ammonia production. As

ammonia (NH3) diffuses into the tubular

lumen, it mostly combines with hydrogen

ions to form ammonium (NH4+). The

reduction in the free hydrogen ion

concentration elevates the urine pH.

Workup of Hypokalemia

• Rule out cellular shift: insulin, beta 2 agonist

• Check urine [K+]

• Low: diarrhea

• High: Renal Loss

• Check serum Mg (hypomagnesemia)

• If normal gap metabolic acidosis Type 1 or 2 RTA

• Check BP

• Low: vomiting, Gitelman, Bartter

• High: PRA

• High Renal artery stenosis, renin secreting tumor

• Low Primary hyperaldosteronism, Liddle syndrome, AME

Hyperchloremic Metabolic Acidosis

• Two common causes of hyperchloremic (ie, normal anion gap)

metabolic acidosis and hypokalemia are diarrhea and renal tubular

acidosis (RTA). Diarrhea generates potassium loss in the stool, while

RTA produces potassium loss in the urine.

• Measurement of urinary potassium excretion may help to distinguish

between gastrointestinal and renal losses of potassium

Management of Hypokalemia

• Treat the underlying cause

• No treatment if mild and asymptomatic

• Give potassium chloride supplement

• Cannot be infused any faster than 10 mmol an hour or in concentrations >40

mmol/L in a peripheral vein

• Need a central vein catheter placed if higher rates or concentrations needed

URINALYSIS

Urinalysis

• Urine Dipstick Test

• Only measures albumin

• 24 hour urine collection

• Spot morning urine protein to creatinine ratio

• Depends on the constancy of serum creatinine

Urine Color

Red Urine

• If clear (a substance is dissolved in the urine)

• Rifampin (antibiotic): orange to red

• Phenytoin (antiepileptic): red

• Chloroquine (antimalarial), Nitrofurantoin (antibiotic): brown

• Food dye, beets, rhubarb

• Hemoglobin or myoglobin: pink to red

• Bilirubin (jaundice): dark yellow to brown

• If turbid:

• Red blood cells: red to brown

Turbid Urine

• Cloudy

• Causes:

• Pathologic

• Phosphaturia

• Pyuria

• Chyluria

• Lipiduria

• Hyperoxaluria

• Food and Drug

• Diet high in purine rich foods

Normal Values

Component Normal

Specific Gravity

(SG)1.003 – 1.030

pH5.0 – 5.5 (range: 4.5 –

8)

Leukocyte (LE) negative

Blood negative

Nitrite negative

Ketones negative

Bilirubin negative

Urobilinogen negative

Protein negative

Glucose negative

Specific Gravity

• The osmolality of the urine can be inferred by measuring the urine specific gravity, which is defined as the weight of the solution compared with the weight of an equal volume of distilled water.

• Normal value of SG: 1.003 - 1.030

• The urine specific gravity generally varies with the osmolality, rising by approximately 0.001 for every 35 to 40 mosmol/kg increase in urine osmolality.

• Thus, a urine osmolality of 280 mosmol/kg (which is isosmotic to normal plasma) is usually associated with a urine specific gravity of 1.008 or 1.009.

• In presence of volume depletion maximum ADH secretion increased water reabsorption max SG = 1.030

• If above 1.030 then another substance is in the urine.

The specific gravity gives an indication of

the weight of the solute in the urine

When specific gravity is high, proteinuria

does not necessarily indicate nephrotic

syndrome

Urine pH

Normal range of urinary pH: 5.0 – 5.5 (range: 4.5 – 8)

Causes of high urine pH:

• UTI with urea splitting bacteria (e.g. proteus) (drives NH3 + H+ to

NH4+, causing decline in free H+)

• Ingestion of alkali

• Defect in urinary acidification in the collecting tubules (distal renal

tubular acidosis)

Normal Urinary Protein and Albumin

• Normal urinary protein excretion

• 40-80 mg/day

• upper limit of normal = 150 mg/day

• Normal urinary albumin excretion

• about 20 mg/day

• upper limit of normal = 30 mg/day

If urine dipstick protein is lower than

protein creatinine ratio, then there are two

possibilities:

1. Urine is dilute

2. Protein is not albumin and not

recognized by dipstick

Heme on Urine Dipstick

• Causes of positive blood on dipstick:

• Presence of intact red blood cells (hematuria)

• Presence of hemoglobin in urine from lysis of RBC in the

vasculature

• Presence of myoglobin in the urine from breakdown of skeletal

muscle cells (rhabdomyolysis)

• Differentiating between these causes:

• Urine microscopy

• Only in true hematuria red blood cells are seen in the urine

• With hemoglobinuria and myoglobinuria, microscopy does not show any

RBCs

• Look for clues in the pt history

False Positives and Negatives

• Dipstick blood is based on the reaction of heme moiety of hemoglobin

with peroxide and a chromogen to produce a change in color.

• False Positive:

• High number of bacteria such as enterobacter, staphylococci and streptococci can

cause false positive (pseudoperoxidase activity)

• False negative:

• Ascorbic acid (strong reducing agent) can cause a false negative

Protein Excretion via Urine Dipstick

• The reagent on most dipstick tests is sensitive to albumin

• Best at detecting glomerular proteinuria

• Results are affected by the urine concentration/specific gravity

• Concentrated sample (SG > 1.025) would OVERESTIMATE the albumin excretion

• Dilute sample (SG < 1.005) would UNDERESTIMATE albumin excretion

• In normal conditions small amount of albumin is filtered

into the urine, but it gets reabsorbed almost entirely in the

proximal tubules (PT)

Nephrotic Proteinuria

• Excretion of 3.5 or more grams of protein (PCR greater than 3) in

urine a day, caused by an increase in permeability of the capillary

walls of the glomerulus

• 3+ - 4+ protein with SG: 1.015 or lower usually suggests nephrotic

range

Positive Urinary Glucose

• Check a plasma glucose if you see glycosuria

• Elevated plasma glucose

• Inadequately controlled diabetes mellitus

• The filtered glucose load is increased to a level that exceeds proximal glucose

reabsorptive capacity

• Normal plasma glucose

• Indicative of proximal tubular defect and may be seen in combination with other

proximal tubular defects (bicarbonaturia)

• Think Fanconi, Type I Tubular Acidosis

Urinary Ketones and Nitrites

• Ketones

• Testing for ketones on the urinary dipstick is based on nitroprusside reaction with

acetoacetate and acetone

• Products of body fat metabolism, normally not found in the urine

• Most commonly associated with uncontrolled diabetes

• Can also occur during pregnancy, carbohydrate-free diets, and starvation

• Glucose is unavailable, so fatty acids break down into ketones.

• Nitrites

• Result when bacteria reduce nitrates to nitrites

• Seen in UTIs (proteus)

• Staph Aureus, Psuedomonas and Enterococcus do not cause positive nitrites

If case is associated with high serum

glucose, high anion gap metabolic

acidosis and positive blood and or urine

ketone, think about diabetic ketoacidosis

Leukocyte Esterase

• Leukocyte esterase (LE) on dipstick is based on indoxyl esterase activity released from lysed neutrophils and macrophages

• May signal pyuria associated with UTI• Organisms such as chlamydia and ureaplasma urealyticum should be considered in

patients with with pyuria and negative cultures

• Other causes of sterile pyuria include balanitis, nephrolithiasis, foreign bodies, exercise, glomerulonephritis, and corticosteroid and cyclophosphamide (cytoxan) use

• Needs confirmation with urine microscopy to see the actual leukocytes

• False positive: • Alkaline pH and low SG

• False negative: • High SG prevents leukocyte lysis

• High glucose and protein in urine

Proteinurias• Glomerular proteinuria

• Most common type

• Albumin is the primary urinary protein

• Increase in the permeability of the glomerular capillary wall that leads to abnormal filtration and excretion of larger, normally unfiltered proteins

• Can be seen with any form of glomerular disease

• Large amount of albumin is seen (filtration barrier damage)

• Tubular proteinuria• Results when malfunctioning tubule cells no longer metabolize or reabsorb filtered protein

• Low-molecular weight proteins predominate over albumin and rarely exceed 2g per day

• Not clinically important disorder unless accompanied by other defects in proximal function

• Mild albuminuria seen with proximal tube damage.

• Overflow proteinuria• Increased production of smaller proteins leads to a rate of filtration that exceeds normal proximal

reabsorptive capacity

• Low-molecular weight proteins overwhelm the ability of the tubule to reabsorb filtered proteins

Microalbuminuria

• The excretion of abnormal quantities of albumin below the level

detectable by the urine dipstick

• Measured as 30-300 mg of albumin in a 24-hour period

• (normal albumin secretion < 30 mg/day)

• Earliest clinically detectable stage of diabetic nephropathy

RBCs

• May originate from infrarenal vessels, glomeruli, tubules, or anywhere

in the GU tract

• Dysmorphic RBCs have been transformed by transit through

abnormal glomerulus

• Suggests glomerular disease (e.g. glomerulonephritis)

WBCs

• UTIs (most common)

• Acute interstitial nephritis

• Legionella

• Leptospira

• Chronic infections (e.g., TB)

• Allergic interstitial nephritis

• Atheroembolic disease

• Granulomatous disease (e.g., sarcoidosis)

• Tubulointerstitial nephritis uveitis syndrome

• Men typically have < 2 WBCs per HPF

• Women < 5

Tubular Cells

• Tubulointerstitial disease

• Ischemic and nephrotoxic injury

Eosinophils

• Allergic interstitial nephritis

• Atheroembolic disease

• Prostatitis

• Vasculitis

Squamous Epithelial Cells

• Contamination

Urinary Casts

• Tamm-Horsfall mucoproteins are produced in distal parts of the

nephron

• When urine flow is reduced, they get compacted and take the shape

of the tubule

• The tubular content (cellular debries, intact RBC, WBC, tubular cells,

fat droplets), if any, can get trapped in the mucoproteins and excreted

as casts

Hyaline

• Increased numbers after exercise

• Suggests dehydration (low urine flow)

• Seen in prerenal AKI

RBC Cast

• RBC cast = Glomerulonephritis

• Examples: acute post streptococcal GN, acute lupus nephritis, anti-

glomerular basement membrane disease

WBC Cast

• Tubulointerstitial nephritis (LOOK FOR EOSINOPHILS TOO)

• Pyelonephritis

Granular Cast

• Acute tubular necrosis

Epthelial Tubular

• Acute Tubular Necrosis

Waxy Cast

• Advanced renal disease (chronic tubular damage)

• Sharp borders; rectangular, refractile

Fatty Cast

• Lipid-laden renal tubule cells

• “Maltese crosses”

• Nephrotic syndrome (pathognomonic)

• Should see hypoalbuminemia and hyperlipidemia on blood test

Cystine Crystal

• Hexagonal, colorless

• Always abnormal cystinuria

• Present in acidic urine

Calcium Oxalate Crystal

• Can be seen in any pH

• Not pathognomonic for any diseases

• Can be seen in ethylene glycol poisoning (oxalic acid is a metabolite)

• Calcium oxalate stones are the most common stones

Triple Phosphate Crystals

• Triple phosphate crystals (coffin lid)

• Seen in association with urinary tract infections with GNR

• Associated with staghorn stones

Calcium Phosphate Amorphous

• Calcium phosphate crystals form in

alkaline pH

• Most likely diagnosis in this case is

distal (type 1) renal tubular acidosis

• Kidneys cannot excrete H+ and acidify the

urine

• Metabolic acidosis

• Alkaline urine

• These patients present with recurrent

calcium phosphate nephrolithiasis and

nephrocalcinosis

Uric Acid Crystals

• Rhomboid shape uric acid crystals

• Can be seen in normal individuals

• High numbers may be seen in patient with tumor lysis syndrome

(breakdown of large number of tumor cells releases large amount of

nucleic acids uric acid)

• Also with gout

APPROACH TO RENAL

DISEASE

Diabetes and Hypertension are the

leading causes of kidney disease in the

United States

Diagnosis of Kidney Disease

• Dysfunction:

• Reduced GFR (125mL/min or 180L/day)

• Proteinuria

• Abnormal Urine Sediment (RBCs, WBCs, casts and crystals)

• Imaging (hydronephrosis, small kidneys)

• Disturbances in urine volume (oliguria, anuria, polyuria)

• Electrolyte abnormalities

• Dyslipidemia

• Hypoalbuminemia

• C3,C4

• Infection (HIV, Hepatitis B/C)

• Abnormal histology on biopsy

Acute Kidney Injury• Abrupt increase in serum creatinine of 0.3mg/dL or a >50% increase

in serum creatinine or the development of oliguria (urine output

<0.5mL/kg/h for >6 hrs)

The strongest risk factor for AKI is

preexisting CKD. In addition, exposure to

nephrotoxins, CABG within a day or two

after coronary angiography (exposure to

contrast), NYHA class IV, valve surgery,

obesity, need for intra-aortic balloon

pump, hypotension and poor renal

perfusion are other risk factor for AKI after

cardiac surgery.

AKI Symptoms and Signs

• Low urine output

• Electrolyte and Acid Base disturbances

• Cardiac arrhythmias, muscle weakness, altered mental status

• Accumulation of endogenous waste products

• Confusion, lethargy, coma, seizures

• Nausea, vomiting, diarrhea, bleeding

• Pericardial disease

• Fluid retention

• Pulmonary and peripheral edema

• Signs/Sx of precipitating disease

• Rash and joint discomfort

• Aminoglycosides, Iodinated contrast

• Hep C

Chronic Kidney Disease

• Kidney damage for >3 months as defined by structural pathology or

functional abnormalities (hematuria, proteinuria, or abnormal imaging)

with or without decreased GFR

• OR

• GFR <60mL/min for >3 months

Symptoms and Signs of CKD

• Generalized fatigue, weakness, lethargy

• Pruritis, pallor due to anemia, petechia (bleeding), uremic frost

• Anorexia, nausea, vomiting, distorted taste

• Insomnia, irritability, paresthesias, confusion, asterixis, seizures

• Pulmonary and peripheral edema, and pericardititis

• ITCHY BITCHY TWITCHY

Complications of CKD

• Renal Bone Disease

• Hypocalcemia, vitamin D deficiency and phosphate retention

• Hypertension

• Anemia

• Decreased erythropoietin

• Bleeding

• Cardiovascular Disease

Differentiating AKI from CKD

• PRIOR CREATININE VALUES ARE MOST IMPORTANT

• CKD

• Kidney length <10 cm on US

• Plain film subperiosteal erosions

• Band keratopathy (soft tissue calcification of cornea)

• Severe anemia (hemoglobin <10g/dL)

• Relatively normal electrolyte and acid base status

Nephrotic vs. Nephritic Syndrome

• Urinalysis:

• Nephrotic syndrome• Proteinuria: Protein >3.5 g per 1.73 m2

• Hypoalbuminemia

• Hyperlipidemia (Oval fat bodies with “Maltese cross” appearance are characteristically seen in diseases associated with nephrotic syndrome)

• Lack of hematuria

• Nephritic syndrome• Limited proteinuria

• Oliguria, azotemia

• Salt retention (Low FEna)

• Hematuria

• Renal Biopsy is the most often required to make a diagnosis. • Nephrotic syndrome most often shows effacement of the the foot processes of the

podocytes

• Nephritic syndrome shows hypercellular inflamed glomeruli.

Creatinine Clearance

• Used clinically to determine GFR

• Tends to overestimate slightly the GFR

• Limitations

• Inadequate urine collection

• Severe renal insufficiency

Estimation of GFR: Pitfalls

• Body mass

• Very muscular patients may have high creatinine levels

• Malnourished patients may have low creatinine levels

• Substances

• Patients supplementing with creatine may have elevated creatinine

levels

• Catabolic state (corticosteroids, malnutrition) may elevate BUN

• TPN may elevate BUN

• Interference with creatinine assay in the lab

• Jaffe reaction – reads acetone as creatinine

Cockcroft-Gault Formula

• Employs patient’s age, body mass, and plasma creatinine

• Limitations:

• 1)”Normal” is hard to define and is dependent on age/sex/wt/race.

• 2) Serum creatinine concentration is dependent on both production and excretion

and it is produced in muscle --more muscle , higher serum creatinine

• 3) Affected by diet, drugs, and lab methods

MDRD and CKD-EPI

• Based upon serum creatinine, age, race, and gender

THESE FORMULAS CAN ONLY BE

USED IN STEADY STATE.

Pros and Cons of Formulas

• Serum creatinine is used to estimate creatinine clearance rather than

measuring the excreted creatinine in urine to measure clearance

directly.

• The use of serum creatinine to measure GFR does NOT inherently

overestimate GFR like the measurement of creatinine excretion would, at least

under normal circumstances.

• But in the case of progressed Chronic KD, GFR is overestimated.

• GFR is underestimated in early stages of CKD

• BUT

• 1)”Normal” is hard to define and is dependent on age/sex/wt/race.

• 2) Serum creatinine concentration is dependent on both production and

excretion and it is produced in muscle --more muscle , higher serum creatinine

• 3) Affected by diet, drugs, and lab methods

Spot Urine vs. 24 hour Collection

• 24hr Urine-collection

• Practical issues: impractical and prone to contamination and error

(someone might forget to pee in the jug and mess up the whole thing).

• Accuracy: When done properly, most accurate

• Interpretation of results: Make sure collection was done properly by

calculating expected creatinine and comparing (should be 15-

20mg/Kg*day female, or 20-25mg/Kg*day male).

• Spot Morning Urine Sample

• Practical issues: More practical than 24hr collection.

• Accuracy: Based on assumption that creatinine excretion is 1g, and

that creatinine excretion is stable over a period of time.

• Interpretation of Results: Keep in mind that the result is based on

assumptions.

Use 24 hour collection to assess protein in

Acute Kidney Injury. Creatinine cannot be

relied upon when not in steady state.

Normal UPCR is <0.15

Normals

• Protein: <150mg/day (usually 40-80mg) | UPCR of <0.15

• Albumin: <20mg/day | UACR <0.020

• upper limit = 30mg/day or 0.030

• Microalbuminuria: 30-300mg/day| UACR of 0.030 - 0.30

• DIABETIC NEPHROPATHY

• Macroalbuminuria: 300-3500mg/day | UACR 0.3-3.5

• Nephrotic range: >3500mg/day UPCR > 3.5

Gross vs. Microscopic Hematuria

• Gross hematuria: the presence of red or brown urine. Hematuria is

seen on sediment (the precipitate) with supernatant clear

(supernatant is the liquid above the sediment). As little as 1 mL of

blood per liter of urine can induce a visible color change.

• If supernatant isn’t clear, you have to look for other causes (e.g.

hemoglobinuria, myoglobinuria, etc).

• Microscopic hematuria: not grossly visible. Presence of 3 or more

RBC per high power field in spun urine sediment.

Causes of Microscopic Hematuria

• Hereditary nephritis, Alport Syndrome

• Membranoproliferative glomerulonephritis (GN)

• Small vessel vasculitis

• Postinfectious GN

• IgA Nephropathy

• Lupus nephritis

• Thin basement membrane nephropathy

Causes of Gross Hematuria

• Younger patients:

• UTI

• Transient and unexplained

• Acute glomerulonephritis

• Patients over 40 years old:

• Urologic malignancy

• Drug related

• Glomerulonephropathy (Eg IgA nephropathy)

GLOMERULAR DISEASE

Rapidly Progressive Glomerulonephritis

• Rapidly progressive glomerulonephritis (RPGN) is a syndrome

associated with severe glomerular injury, but does not denote a

specific etiologic form of glomerulonephritis.

• It is characterized by rapid and progressive loss of renal function

associated with severe oliguria and signs of nephritic syndrome; if

untreated, death from renal failure occurs within weeks to months.

• The most common histologic picture is the presence of crescents in

most of the glomeruli (crescentic glomerulonephritis) .

• These are produced predominantly by the proliferation of the parietal

epithelial cells lining Bowman capsule and by the infiltration of

monocytes and macrophages.

Etiologies of RPGN

• Anti-GBM antibody-mediated disease, characterized by linear deposits of IgG and, in many cases, C3 in the GBM. In some of these patients, the anti-GBM antibodies cross-react with pulmonary alveolar basement membranes to produce the clinical picture of pulmonary hemorrhage associated with renal failure (Goodpasture syndrome)

• RPGN can be a complication of any of the immune complex nephritides, including postinfectious glomerulonephritis, lupus nephritis, IgA nephropathy, and Henoch-Schönlein purpura

• Pauci-immune RPGN, defined by the lack of detectable anti-GBM antibodies or immune complexes by immunofluorescence and electron microscopy. Most patients with this type of RPGN have circulating ANCAs that are known to play a role in some vasculitides(granulomatosis with polyangiitis or microscopic polyangiitis)

Anti-GBM Disease

• IgG circulating autoantibodies against the noncollagenous domain of

alpha 3 chain of type IV collagen are seen in anti-GBM disease.

These IgG antibodies bind to the antigen on the GBM in the capillary

wall and are seen under IF microscopy as linear capillary loop

staining.

Crescents and Fibrin

Nephrotic Syndrome

• Nephrotic syndrome: glomerular disorders characterized by

proteinuria (>3.5g/day) and resulting in:

• Hypoalbuminemia → pitting edema

• Hypogammaglobulinemia → increased infection risk

• Hypercoagulable state → due to loss of antithrombin III

• Hyperlipidemia and hypercholesterolemia → fatty casts in urine

Minimal Change Disease

• General: MCC of nephrotic syndrome in kids.

• Usually idiopathic, may be associated with Hodgkin Lymphoma

• Histology: normal glomeruli, lipid may be seen in proximal tubule,

effacement of foot processes on EM

• IF: No immune complex deposition

• Clinical Course: Selective proteinuria and excellent response to

steroids. More than 90% of children respond to a short course of

steroids

Minimal Change Disease

FSGS

• General: MCC GN in Hispanics and African Americans

• Usually idiopathic may be associated with HIV, Heroin use, and Sickle cell disease

• Histology: Focal and segmental sclerosis, effacement of foot

processes on EM. Increased mesangial matrix, obliterated capillary

lumina, and deposition of hyaline masses (hyalinosis) and lipid

droplets.

• IF: No immune complex deposition

• Clinical Course: Nonselective proteinuria and high incidence of

hematuria and hypertension. Poor response to steroids, progresses to

chronic renal failure.

FSGS

Membranous Nephropathy

• General: MCC of nephrotic syndrome in Caucasian adults. • Usually idiopathic (autoantibodies) but can be associated with Hepatitis B, solid

tumors, SLE, or drugs (NSAIDS and penicillamines)

• TARGETS SLIT DIAPHRAGM

• Histology: Thick glomerular basement membrane and CAPILLARY LOOPS, subepithelial immunoglobulin-containing deposits with spike and dome appearance.

• IF: IgG staining showing granular deposits along GBM (SLIT DIAPHRAGM)

• Clinical Course: Proteinuria is nonselective and nonresponsive to steroids. Although 60% suffer persistent proteinuria, only 40% suffer progressive disease terminating in renal failure

Membranous Nephropathy

THINK CANCER

Screen for malignancy!!

Maltese bodies

MGPN• Mixed nephrotic/nephritic

• Associated with Hep C

• MGN Type I: most often caused by circulating ICs or planted antigen and manifestations are subendothelial

• MGN Type II (Dense deposit disease): caused by overactivation of complement and manifestations are intramembranous

• Histology: Glomeruli have an accentuated “lobular” appearance due to the proliferating mesangial cells and increased mesangial matrix. The GBM is thickened, and often shows a “double-contour” or “tram-track” appearance , especially evident in silver or PAS stains.

• IF: IgG and C3 are deposited in a granular pattern, and early complement components (C1q and C4) are often also present.

• Clinical Course: Clinical Course: Poor response to steroids and progression to renal failure. Can progress to RPGN. Dense deposit disease has worse prognosis than Type I.

MPGN

MPGN Tram Track

Diabetes Nephropathy

• General: High serum glucose leads to nonenzymatic glycosylation of vascular basement membrane → hyaline arteriosclerosis.

• Afferent and efferent arterioles (pathognomonic) are affected

• Microalbuminuria• Progresses to nephrotic syndrome with Kimmelstiel-Wilson nodules

• Histology: Enlarged glomeruli with increased mesangial matrix, Nodular lesions (Kimmelstiel-Wilson), Arteriolar sclerosis, GBM thickening on EM.

• Clinical Course: IF: Nonspecific deposition of IgG

• Clinical Course: Hyperfiltration and microalbuminuria progressing to macroalbuminuria over the course of years. Associated retinopathy, vascular disease and hypertension. ACE Inhibitors slow progression Controlling hypertx can be as important as controlling sugars.

• WATCH OUT FOR STEROIDS increase hyperglycemia

Diabetic Nephropathy

As opposed to Amyloidosis, Diabetic

Glomerulosclerosis will stain STRONGLY

PAS positive due to collagen being laid

down

Diabetics with long standing disease, #1

cause of ESRD globally

Native Americans, African Americans,

Latinos at higher risk

Type I and Type 2 equal risk

Presence of other microvascular diabetic

changes increases risk

Amyloidosis

• Etiology: Multiple Myeloma, TB, Rheum Arthritis

• Histology:• Diffuse “nodular” deposition of amorphous hyaline material, initially in the mesangium and

then in the capillary loops.

• Stains weakly with periodic acid-Schiff (PAS) and methenamine silver stain because they are composed mostly of amyloid fibrils and not extracellular matrix as in diabetes mellitus.

• IF: Lambda LC deposition in mesangium, vessels, glomerulus (infiltrative pattern)

• Congo red + (apple-green bifringence under polarized light)

• B pleated fibrils

• Clinical: Nephrotic (edema, hypoalbuminemia/ hyperalbuminuria, proteinuria >3.5, frothy urine, hypogammaglobulinemia- repeat infections, thromboembolism-loss of antithrombin III)

• Sx of Multiple myeloma: old, weak, anemia, hypercalcemia, large/normal kidney with decreased function, monoclonal LC, normal complement

• Treatment: • If Multiple Myeloma- chemotherapy

Amyloidosis

Nephritic Syndrome

• Nephritic Syndrome: Glomerular disorder characterized by glomerular

inflammation and bleeding.

• Limited proteinuria (<3.5g/day)

• Oliguria and azotemia

• Salt retention with periorbital edema and hypertension

• RBC casts and dysmorphic RBCs in urine

• Biopsy reveals hypercellular, inflamed glomeruli

• Immune complex deposition → complement → PMNs

Post-Streptococcal Glomerulonephritis

• General: Arises after Group A Strep infection of skin or pharynx

• Presents 2-3 weeks after infection as hematuria, oliguria, hypertension, and periorbital edema

• Low complement levels, Serum ASO+

• Histology: Enlarged hypercellular inflamed glomeruli. Large discrete subepithelial deposits are diagnostic for poststreptococcalglomerulonephritis. Antibodies cross the filtration barrier and bind the planted strep antigen in the subepithelial space.

• IF: By immunofluorescence microscopy, there are granular deposits of IgG, and C3, and sometimes IgM in the mesangium and along the GBM

• Clinical Course: Treatment is supportive, children rarely progress to renal failure while 25% of adults develop rapidly progressive glomerulonephritis

Post-Streptococcal Glomerulonephritis

IgA Nephropathy

• General: Most common nephropathy worldwide, IgA Immunocomplex

deposition in mesangium

• Presents during childhood as episodic gross or microscopic

hematuria with RBC casts following/during mucosal infections

• May have nephrotic and nephritic components

• Histology: Diffuse mesangial proliferation, tree branching pattern,

hypercellularity and matrix expansion.

• IF: IgA immune complex deposition throughout mesangium

• Clinical Course: Presents in 10-20s as single or recurrent hematuria

with a URI. May slowly progress to renal failure

IgA Nephropathy

IgA IF Staining

Alport Syndrome

• General: Inherited defect in Type IV collagen

• Most commonly X-linked

• Results in thinning and splitting of basement membrane

• Histology: Foam cells may be seen. With progression, increasing

glomerulosclerosis, vascular sclerosis, tubular atrophy, and interstitial

fibrosis are typical changes. GBM develops irregular foci of thickening

or attenuation with pronounced splitting and lamination of the lamina

densa, yielding a “basketweave” appearance.

• Clinical Course: Presents as isolated hematuria, sensory hearing

loss, ocular disturbances.

• Males are affected more frequently and severely

Alport Syndrome

Basketweave Appearance of GBM

Lupus Nephritis

• General: Caused by immune deposits (mostly anti-dsDNA) deposit in the subendothelial, mesangial, and/or subepithelial spaces.

• Complement activation plays a role – complement levels should be low

• Anti ANA, Anti DS-DNA, Anti Smith

• Histology: Endocapillary proliferative lesions, often with crescents. May be necrotic, with branching mesangial matrix.

• IF staining: “Full-house” staining with granular depositions of everything: IgA, IgG, IgM, C3, C1q

• Clinical Course: Usually presents with hematuria and at least moderate proteinuria. Malar rash, photosensitivity, joint pain, mouth ulcers.

• Treatment: Hydroxychloroquine +/-steroids/mycophenolate/cyclophosphamide

Lupus Nephritis- Classes

• I- Minimal mesangial change

• II- Mesangial proliferation (mesangial)

• III- Focal endocapillary proliferation and crescents (subendothelial)

• IV- Diffuse “” (>50% glomeruli) (subendothelial)

• V Membranous- looks like MN but full house IF (subepithelial)

• VI- Advanced sclerosing (global sclerosis)

What is the drug that can potentially

reverse the course of renal disease in

lupus?

Cyclophosphamide (cytoxan)

Lupus Nephritis

Cast Nephropathy

• Due to Multiple Myeloma

• Histology:

• Waxy rectangular casts blocking tubules

• Sharp corners, PAS -

• Multinucleated histiocytes lining the tubules

• Normal glomerulus

• Kappa LC overload in tubules Distal tubule obstruction and damage

• Clinical: (multiple myeloma in general)

• Older patient with weakness and anemia

• Hypercalcemia* (due to plasma cell release of cytokines in bone marrow causing

osteoclast activation…xray findings)

• Large/normal kidney size*

• Reduced kidney function*

• Monoclonal LC band in gamma region (in urine and blood)

• Normal complement

Light Chain Deposition Disease

• Due to multiple myeloma

• Histology:

• Deposits of kappa LC in GBM

• IF: granular, kappa LC

• Congo red negative!

• Clinical:

• Nephritic-nephrotic

• General multiple myeloma

• Older patient with weakness; Hypercalcemia*; Large/normal kidney

size*; Reduced kidney function; Monoclonal LC band in gamma region

(in urine and blood); Normal complement; anemia

ANCA Vasculitis• Histology

• Cellular Crescent (RPGN), Granulomatous injury around small vessels

• IF: pauci-immune

• EM: breaks in GBM

• Clinical- fever, arthralgias, malaise, weight loss

• Wegener’s cANCA (proteinase3)

• Cough, wheeze, hemoptysis, pulmonary hemorrhage

• Nephritic (low protein)

• Nasal symptoms, nasal crusting

• Microscopic Polyangitis pANCA, MPO-ANCA

• Palpable urpura

• CNS/PNS sx

• Fewer upper resp sx

• Churg-Strauss pANCA

• Granulomatous inflammation

• Asthma

• Eosinophilia

• Palpable urpura, CNS/PNS sx

Differential Diagnostic Tools

• Labs:

• Hepatitis B, C antibodies : Membranous Nephropathy, MPGN

• HIV : FSGS

• ANCA: Granulomatosis with polyangiitis [Wegener's] and microscopic

polyangiitis) RPGN

• anti-GBM: Goodpasture Syndrome RPGN

• ASO titer: Poststreptococcal glomerulonephritis

• C3, C4 low: Lupus nephritis, Postinfectious glomerulonephritis,

Membranoproliferative glomerulonephritis

• ANA +: Lupus Nephritis

• Anti-Smith, anti-dsDNA: Lupus nephritis

• SPEP and UPEP: Multiple myeloma

Treatment

• Minimal Change Disease: Steroids

• FSGS and Membranous nephropathy: Steroids, calcineurin inhibitors,

Immunosuppressants, rule out underlying causes of disease

• MGPN: Treat infections, Immunosuppresants + steroids

• Diabetes: BP control is PARAMOUNT, ACEIs and ARBS, Glucose

control, DON’T GIVE STEROIDS!!

• Lupus Nephritis: Hydroxychloroquine, Steroids, Mycophenolate

(Cyclophosphamide-severe)

• Amyloid and Myeloma: Chemotherapy

• IgA Nephropathy: ACEI and ARBs, steroids, Immunosuppresants

• Goodpasture Syndrome: Plasmapheresis

Nephritic vs. Nephrotic

• Highly nephrotic – Amyloidosis, Minimal Change Disease

• Nephrotic with some nephritic character – Diabetic, MGN, FSGS

• Highly nephritic – ANCA and Anti-GBM

• Nephritic with some nephrotic – Post-infectious GN, PSGN

• Usually nephritic but may have nephrotic range of proteinuria – IgA

• Do whatever they want (nephrotic or nephritic) – MPGN, Lupus

ACUTE KIDNEY INJURY

Epidemiology of AKI

• Morbidity:

• 5-7% of acute care hospitals admissions complicated by AKI

• Up to 30% in the critical care settings (ICU)

• Incidence of AKI in the US has been increasing at a fast pace

• (four fold the incidence 25 yrs ago)

• Mortality:

• Even a small rise in serum creatinine has been shown to be

associated with poor outcomes

• Mortality associated with AKI in the ICU reaches 50%

• GFR may not return to normal chronic kidney disease or even end

stage kidney disease

AKI

Do not use any formulae, including the

MDRD formula, to estimate GFR if serum

Cr is changing (pt not at steady state)

Causes of Acute Kidney Injury

Prerenal or Volume Responsive

Intrarenal Postrenal

Hypovolemia (severe

diarrhea, vomiting)

Reduced cardiac output

Reduced effective

circulating volume (HF

and cirrhosis)

Impaired autoregulation

(NSAIDs)

Tubular Necrosis

Acute GN

Interstitial nephritis

Retroperitoneal

fibrosis

Prostatic hypertrophy

Etiology

4%

38%58%

Hospital Acquired AKI

Volume Responsive

Intrinsic

Renal

Post

Renal

17%

72%

11%

Outpatient AKI

Intrinsic

Renal

Volume Responsive

Post

Renal

History

• Volume loss (diarrhea, vomiting)

• Medications:

• Prerenal: NSAIDs, tacrolimus, cyclosporine

• Intrarenal:

• ATN: Aminoglycosides, Cisplatin iodinated contrast,

• AIN: Amphotericin B, NSAIDs, penicillamines, cephalosporins, sulfonamides, diuretics

• Post-renal: Acyclovir, sulfonamides, methotrexate

• Procedures (vascular interventions, angiogram)

• Preexisting conditions (kidney disease, CHF, liver disease)

• Urine output

• Non-oliguric AKI has a better prognosis for renal recovery.

• Baseline GFR

• Best way to differentiate AKI and CKD would be to look for a previous GFR

level. CKD patients are at higher risks of AKI

Physical Examination

• Vital signs

• Mucus membranes

• Evidence of systemic disease• Rash

• Levido reticularis: atheroembolic disease

• Pruritic transient rash: AIN

• Purpuric rash: Vasculitis

• Malar rash: Lupus

• Arthritis

• Evidence of third spacing (edema, ascites, pulmonary edema)

• Evidence of anemia (pallor) or bleeding

• Evidence of other organ diseases (S3, jaundice, hepatomegaly)

Physical Examination

• Evidence of atheroembolic event

• Levido reticularis (red, non-blanchable, network pattern like lesions

of the skin)

• Abdominal bruit may be associated with renal artery

stenosis

• Spider angiomas and palmar erythema seen in cirrhosis

Sodium Excretion

• All of Na is filtered through the glomerulus

• Normal Resorption

• 60% in PT

• 30% in TAL

• 5-10% in DT

• 3% in Cortical CT - Aldosterone increases this, reducing excretion

• 1-2% excreted

• Regulators

• Aldosterone - increases Na and water absorption in the late distal

tubule and cortical collecting duct

• ANP - decreases reabsorption of the Na in the late DT and CCT

FENa

• The fraction of all filtered sodium into the Bowman’s space that is excreted in the urine (not reabsorbed)

• Usually less than 1%

• FENa = (UNa x SCr)/(PNa x UCr)

• FENa should NOT be used with diuretics Use FEUrea

• FEUrea would be below 30% in cases where effective circulating volume is low and >35% in intrinsic renal or postrenal AKI

• Pitfalls: situations in which urea production is high (No AKI)• GI bleeding

• Catabolic states

• Use of corticosteroids

• High protein diet (e.g. total parenteral nutrition)

1 2

433

Urine Microscopy is usually the most

useful test in a differential diagnosis of AKI

Prerenal AKI• Reduced Effective Circulatory Volume drop in GFR

1. Hypovolemia• Blood loss

• GI, skin or renal loss of fluids

• Third spacing

2. Low cardiac output• Myocardial infarction

• Cardiac tamponade

• Valvular heart disease (e.g., severe AS)

• Pulmonary hypertension

3. Systemic vasodilatation• Sepsis

• Cirrhosis

• Anaphylaxis

Prerenal AKI

4. Impaired renal autoregulation

• Vasoconstriction of afferent arterioles

• Prostaglandin blockers, NSAIDs

• Catecholamines

• Cyclosporin and tacrolimus

• Hepatorenal syndrome

• Vasodilatation of efferent arterioles

• RAAS blockade (ACE inhibitors or ARB)

• No structural renal abnormalities

• Correction of ECV (if possible) normalizes GFR

Renal Autoregulation

• Myogenic stretch reflex

• Afferent arterioles dilate in the presence of reduced pressure due to

hypoperfusion

• Tubuloglomerular feedback

• BLOCKED by NSAIDS

• Decreased RBF leads to decreased NaCl to the macula densa

cells, which secrete paracrine signals (prostaglandins) resulting in

arteriolar dilatation

• Increased local concentration of angiotensin II

• BLOCKED by ACEI / ARB

• Renin is released, from specialized smooth muscle cells in the

afferent arteriole, via signaling from the macula densa cells, which

leads to activation of the renin-angiotensin system

PreRenal AKI

• Pathophysiology: renal perfusion glomerular capillary

hydrostatic pressure GFR

• Effective circulating volume Activated RAAS increased Na+ reabsorption

Urine [Na+] <20 and/or FENa <1%

• Etiology: Volume loss, Diuretics, NSAIDs, ACE Inhibitors, Third

Spacing

• Dx: No Proteinuria, no hematuria, High BUN/Creatinine ratio, Low

FENa, High SG, Hyaline casts

Prerenal vs. Hepatorenal

• The only way to differentiate the two is to expand the intravascular

volume with albumin or normal saline.

• If renal function improves prerenal

• VOLUME RESPONSIVE

• If no improvement HRS

Intrinsic AKI

Glomeruli

Acute GN

- Lupus

nephritis

- Anti-GBM Dz

- Small-vessel

Vasculitis

Tubules

Ischemic Toxin induced Infection or sepsis induced

Vascular bed

- Malignant

Htn

- TTP/HUS

- Vasculitis

Interstitium

- Drugs

- Infections

- Drugs

- Myoglobin

- Hemoglobin

- Severe

volume

depletion

Intrarenal AKI

• MCC: ATN• Ischemic ATN

• Necrosis of tubular cells in medullary sections of PT (S3) and in the TAL of the loop due to high metabolic demand and low O2 pressure.

• Toxic ATN• Myoglobin

• Hemoglobin

• Aminoglycosides

• Cisplatin

• Iodinated Contrast

• Risk Factors• Preexisting kidney disease and reduced GFR

• Reduced effective circulating volume (HF and cirrhosis)

• Hypotension

• Elderly patients

• Diabetes

Diagnosis of ATN

• Could be oliguric or non-oliguric

• Urinalysis:

• Usually lower specific gravity

• No blood or protein or WBC

• Microscopy: granular or muddy brown casts

• Renal Indices

• Urine [Na] >40 mmol/L

• FENa >2%

• FEUrea >35%

• Low SG (Can’t concentrate urine)

Aminoglycoside-induced ATN

• About 5% - 10% of cases develop AKI after about a week of exposure

to AG antibiotics

• Risk may be as high as 50% in those with reduced GFR, hypotension,

elderly and pts on ACE inhibitors or NSAIDs

• Usually non-oliguric

• Urinary concentration ability is reduced (low SG)

• Hypomagnesemia is common

• Resolves after discontinuation of the drug

Contrast-Induced AKI

• Iodinated contrast media used in radiographs

• Pathophysiology

• Vasoconstriction

• Direct tubular damage by releasing reactive oxygen species

• Clinical Course

• Usually serum Cr starts to rise within 24 hours of exposure, Cr reaches its peak

in 3 -4 days and drops within a week.

• Dx:

• UA may show high SG

• Urine Na and FENA may be low because of vasoconstriction

• Prevention

• Volume expansion before, during and after exposure to contrast

• Stop medications such as ACE inhibitors or NSAIDs

Sepsis-associated AKI

• More than half of cases with severe sepsis are complicated with AKI

• In most cases AKI occurs with hemodynamic instability and when

vasopressors are required

• Pathophysiology

• Inflammation and interstitial edema

• Endothelial cell damage

• Microvascular thrombosis

• Efferent arteriolar dilatation early in the course (cytokines, NO)

• Activation of sympathetic NS, RAAS, vasopressin, endothelin

Rhabdomyolysis

• Release of Myoglobin from skeletal muscle

• Mostly seen in crush injury, after prolonged immobility, strenuous

exercise, drugs (statins)

• Higher K+ and phos (release from intracellular space)

• Hypocalcemia is common

• In cases with AKI, creatine kinase (CK) is rarely below 10,000 –

20,000

Mgb-induced AKI

• Early in the course vasoconstriction and tubular occlusion low

FENa

• Mgb can cause oxidant injury to tubular epithelial and endothelial

cells

• Ischemia and inflammation ATN high FENa

• Urinalysis: positive blood on dipstick and no RBC

• Microscopy: may see granular casts if ATN

• Therapy: AGGRESSIVE volume expansion

Amphotericin B binds to tubular

membrane cholesterol and introduced

pores

Induces vasoconstriction as well as direct

cellular toxicity

Dose and duration dependent

Acute Interstitial Nephritis (AIN)

• Causes

• Drugs

• Penicillins and cephalosporins

• Sulfonamides

• NSAIDs

• Diuretics

• Bacterial and viral infections

• Systemic autoimmune disorders

• Sjögren syndrome

• Sarcoidosis

• SLE

• Primary biliary cirrhosis

Diagnosis of AIN

• History is very helpful

• Skin rash and fever may oocur

• Peripheral blood eosinophilia and high urine eosinophil count

• Urinalysis: blood may be positive (not strongly), leukocyte esterase

may be positive

• Urine microscopy: WBC and possibly WBC casts, eosinophils with

Hansel staining

• FENa >2

Postrenal AKI

• Bilateral ureteral obstruction

• Retroperitoneal fibrosis

• Enlarged lymph nodes and mass effect in advanced cancer

• Bilateral obstructing stones

• Bladder outlet obstruction

• Prostatic hypertrophy

• Pelvic malignancies with mass effect

• Functional obstruction (neurogenic bladder)

Postrenal AKI

• Intratubular crystallization

• Uric acid (tumor lysis syndrome)

• Acyclovir

• Sulfonamides

• Calcium oxalate (oxalosis)

• Methotrexate

• Myeloma light chains (can also cause damage to proximal tubular

cells = intrinsic AKI)

Diagnosis of Post Renal AKI

• History

• Frequent urination, hesitancy, weak stream prostate hypertrophy

• Malignancy

• Imaging

• US for detection of hydronephrosis

• CT scan is the imaging modality of choice for stones, also helpful

for retroperitoneal fibrosis, LN, masses, etc.

• FENa >2%

Treatment of postrenal AKI

• Relieving the pressure, if done early, resolves AKI

• Bladder catheterization for outlet obstruction cases

• Nephrostomy tubes or stents for ureteral obstruction

Syndromes

• Hepatorenal syndrome

• AKI associated with liver disease

• Cirrhosis, portal hypertension and ascites in most cases

• Severe splanchnic vasodilatation and renal vasoconstriction

• Normal structure of the kidney

• Usually oliguric

• Very low FENa (<0.5%)

• Poor prognosis

Complications of AKI

• Uremia

• Build up of nitrogenous waste products

• Mental status changes and bleeding reported with BUN >100 mg/dL

• Volume overload

• Impaired salt and water secretion

• May lead to pulmonary edema

• Hyperkalemia

• Cardiac arrhythmias

• Most concerning complication

• Metabolic acidosis

• Usually high anion gap

Complications

• Hyperphosphatemia and hypocalcemia

• Reduced GFR high phos

• Deposition of calcium phosphate into tissues causes hypocalcemia

• Pericarditis

• Malnutrition

• Catabolic state

Treatment

• Supportive

• Treating the underlying factor/disease

• Volume expansion with colloid (human albumin, starch based

solutions), blood transfusion or crystalloid (lactated ringer’s, 0.9%

sodium chloride) solutions in volume responsive azotemia

• Loop diuretics for volume overload

• Infusion of sodium bicarbonate in cases with severe acidosis

• Insulin plus glucose, 2 adrenergic receptor agonist, loop diuretics,

exchange resins to treat hyperkalemia

Hemodialysis in AKI

• Indications

• Uremia as evidenced by asterixis or flapping tremor, evidence of

pericarditis (friction rub or effusion), altered mental status

• Intractable volume overload

• Intractable hyperkalemia

• Intractable acidosis

• Toxic ingestions

Nephropathy Associated with NSAIDs

• 1. AKI due to the decreased synthesis of vasodilatory prostaglandins

and resultant ischemia.

• Particularly likely to occur in the setting of renal diseases or volume depletion.

• 2. Acute hypersensitivity interstitial nephritis renal failure.

• 3. Acute interstitial nephritis and minimal-change disease

• 4. Membranous nephropathy

VASCULAR,

TUBULOINTERSTITIALAND

CYSTIC DISEASE

High levels of proteinuria are not

associated with tubulointerstitial disease.

Hypertension is the second most common

cause of ESKD

1. Chronic ischemic damage to small

arterioles gradual decline in kidney

function

2. Severe hypertension may cause end

organ damage (malignant hypertension),

including renal damage

Two Syndromes

• Nephrosclerosis:

• Commonly associated with hypertension

• Defined by the presence of varying degrees of glomerulosclerosis, interstitial fibrosis and tubular atrophy, arteriosclerosis, and arteriolosclerosis.

• Luminal reduction of the renal vasculature (arteries and arterioles) contributes to glomerulosclerosis (both global and segmental), which can subsequently cause interstitial fibrosis and tubular atrophy.

• Malignant nephrosclerosis

• Associated with malignant hypertension.

• Renal lesions manifest as fibrinoid necrosis of arterioles and hyperplastic arteriolosclerosis.

• Affects interlobular arteries and arterioles and is characterized by proliferation of smooth muscle cells of the arterial wall that are arranged concentrically Onion skinning

Hypertensive (arteriolar) Nephrosclerosis

• Prolonged hypertension Slowly progressive kidney disease

• Three groups at increased risk of developing renal failure: • People of African descent

• People with severe blood pressure elevations

• Persons with a second underlying disease, especially diabetes.

• Histopathologic changes are in arterioles

• Damage to the glomeruli and tubules occur due to chronic ischemia

• Since it is not a glomerular disease, heavy proteinuria is not expected (almost always <1 g/day proteinuria), no hematuria or dysmorphicRBCs

• JUST IN AFFERENT arterioles as opposed to diabetic nephropathy

• Treatment: Low salt diet and BP control

Pathophysiology

• Medial and intimal thickening, as a response to hemodynamic

changes, aging, genetic defects, or some combination of these

• Hyalinization of arteriolar walls, caused by extravasation of plasma

proteins through injured endothelium and by increased deposition of

basement membrane matrix

• Patchy ischemic atrophy, which consists of (1) foci of tubular atrophy

and interstitial fibrosis and (2) a variety of glomerular alterations

(collapse, periglomerular fibrosis, total sclerosis)

Hyalinization

Malignant Hypertension

• Rapidly progressive blood pressure elevations (usually >200/120 mm

Hg) with target organ injury including retinal hemorrhages,

papilledema encephalopathy, hematuria and declining kidney function

• Left untreated, mortality is >50%

• Histology:

• Fibrinoid necrosis of arterioles is one of typical pathologic findings

• Arterioles show concentric layering of collagen and proteoglycans (onion skinning)

which may lead to ischemia and infarction distal to abnormal vessels

• Clinical Presentation:

• Nausea, vomiting, altered mental status, visual disturbances, headaches

• Proteinuria and hematuria followed by rapid decline in GFR

• True medical emergency requiring aggressive and prompt antihypertensive therapy.

Onion skinning of arteriolar wall in

malignant hypertension

Fibrinoid necrosis due to epithelial

injury and increased permeability

Treatment

• Malignant HTN requires aggressive and prompt

antihypertensive therapy.

• Initial treatment is I.V. sodium nitroprusside

• Goal is to rapidly lower diastolic pressure to 100-105 mmHg within

2-6 hours. Maximum fall in BP should not exceed 25% of

presenting value

• More aggressive therapy is unnecessary and may lead to ischemic

events (stroke or coronary disease)

• Once BP is controlled, switch patient to oral therapy and bring

diastolic gradually to 85 to 90 mmHg over two to three months

• Often causes an initial decrease in renal function

• HTN therapy should not be withheld unless there has been an

excessive reduction in BP

Thrombotic Microangiopathies

• Thrombotic microangiopathy: platelet activation and deposition of thrombi in the microvasculature, accompanied by red cell hemolysis, tissue ischemia, organ dysfunction, and a consumptive thrombocytopenia.

• Typical HUS:• Shiga-like toxin produced by bacteria, most commonly E. coli strain O157:H7, is

responsible for producing platelet activation and thrombosis.

• Atypical HUS:• Aberrant activation of complement due to inherited mutations or acquired auto-

antibodies is the key pathogenic abnormality.

• TTP:• Deficiencies of ADAMTS13, a negative regulator of vWF, permits the formation of

abnormally large multimers of vWF that are capable of activating platelets.

HUS vs. TTP

• HUS

• Usually seen in children

• Hemolytic anemia, thrombocytopenia, and decreased kidney function

• In typical (epidemic, classic, diarrhea-positive) HUS, the trigger for endothelial injury

and activation is usually a Shiga-like toxin

• In inherited forms of atypical HUS the cause of the endothelial injury appears to be

excessive, inappropriate activation of complement.

• TTP

• Fever, altered mental status, reduced GFR, thrombocytopenia and microangiopathic

hemolytic anemia

• Initiating event appears to be platelet aggregation induced by very large multimers

of vWF, which accumulate due to a deficiency of ADAMTS13

• In many cases distinction between the two is not possible clinically

Fibrin stain showing platelet-fibrin thrombi

( red) in the glomerular capillaries,

characteristic of thrombotic

microangiopathic disorders.

extensive fibrin thrombi and platelet plugs filling up the capillary loops

Multiple Myeloma

• Hematologic malignancy (plasma cells)

• Monoclonal overproduction of light chains

• Patients present with bone pain, boney lytic lesions, anemia, kidney

disease, hyperuricemia, hypercalcemia

• Monoclonal Igs are usually first detected as abnormal monoclonal

protein “spikes” in serum or urine electrophoresis

• Overproduction of LC LC appear in the urine

• (Bence Jones proteins)

• In multiple myeloma, kidneys may filter 80 g of LC per day kidney

damage

3 Sites of Light Chain Deposition

• Glomerulus: Heavy albuminuria• Amyloidosis: lambda

• Light Chain Deposition Disease: kappa

• Negative Congo Red Stain

• Proximal Tubule: Minimal albuminuria• Acute Interstitial Tubular Nephritis

• Fanconi Syndrome

• Type II Proximal Acidosis

• Distal Tubule: Minimal albuminuria• Cast Nephropathy: MCC of Kidney disease

• Kappa light chain

Light Chain Cast Nephropathy

• The main cause of renal dysfunction is related to Bence-Jones (light-

chain) proteinuria, and correlates with the degree of proteinuria.

• Two mechanisms

• Ig light chains can be directly toxic to epithelial cells

• Bence-Jones proteins combine with the urinary glycoprotein (Tamm-Horsfall

protein) under acidic conditions to form large, histologically distinct tubular

casts that obstruct the tubular lumens and induce a characteristic inflammatory

reaction (light-chain cast nephropathy).

Bence Jones Proteins

Cast Nephropathy

Treatment

• Treat the underlying disease!

• This leads to recovery of renal function in up to 50% of pts

• Initial management: Aggressive hydration, alkalinization of the urine,

correction of hypercalcemia

• Chemotherapy

Nodular glomerulosclerosis: Diabetic

Nephropathy, Amyloidosis, LCDD

Use PAS stain to distinguish!

Atheroembolic Nephropathy

• Embolization of fragments of atheromatous plaques from the aorta or

renal artery into intrarenal vessels occurs in older adults with severe

atherosclerosis, especially after surgery on the abdominal aorta,

aortography, or intra-aortic cannulization.

• Emboli can be recognized in the lumens of arcuate and interlobular

arteries by their content of cholesterol crystals, which appear as

rhomboid clefts

• The clinical consequences of atheroemboli vary according to the

number of emboli and the preexisting state of renal function.

Frequently they are of no significance. However, acute renal injury or

failure may develop in older adults in whom renal function is already

compromised.

Atheroemboli

Tubulointerstitial Disease

• Cystic Renal Disease:

• Urine RBC’s, Abdominal pain, positive Family Hx

• Acute (Allergic) Interstitial Nephritis:

• Urine RBC’s and WBC’s, eosinophils in urine and blood, Rash, Hx of drug exposure

• Acute Pyelonephritis:

• Urine RBC’s and WBC’s, bacteria in urine, flank pain, fever

• Reflux nephropathy (Vesicoureteral Reflux):

• Urine WBCs, bacteria in urine, age <6

• Acute Tubular Necrosis:

• Exposure to low BP or tubular toxins, granular casts, muddy brown casts

• Chronic Interstitial Nephritis:

• Proteinuria (sometimes >3.5), Hx of exposure to offending agent

Cystic Diseases of the Kidney

• Renal Cyst: fluid filled sac lined by a single layer of epithelium

• Hereditary and acquired disorders

• Polycystic kidney disease (PKD)

• Autosomal Dominant (ADPKD)

• Autosomal Recessive (ARPKD)

• Acquired cystic Kidney Disease

• Medullary cystic disease

• Rare systemic disorders

• Tuberous sclerosis

• von Hippel-Lindau (VHL)

Acquired Cystic Kidney Disease

• Acquired cystic renal disease is commonly observed in pts with

chronic kidney disease.

• Cysts are usually <.5 cm but may be >2-3 cm. Kidneys are usually

small with <4 cysts per kidney

• Setting in Which Acquired:

• Long term Dialysis. Incidence increases with the length of dialysis, and is very

common after 7-10 years (50-80% of pts after 10 years on dialysis)

• Asymptomatic in 85% of cases

• Risk of Malignancy: Acquired cystic disease has a 5-10% risk of

malignancy, specifically renal cell carcinoma

• Inherited cystic diseases usually have no risk or only a slight increase in risk of

malignancy.

• Von Hippel-Lindau is the exception with a 60% risk of malignancy

Polycystic Kidney Disease

• ADPKD is autosomal dominant polycystic kidney disease, the most common inherited cystic disease of the kidneys with 1:4000-1:1000 live births. It is a hereditary renal cyst formation that occurs most commonly in the 3rd-4th decades, with hematuria as the most common presenting Sx.

• ADPKD1: More common with 85% of patients having this • Genetic Defect: Abnormal gene on the short arm of Chromosome 16

• Encoded Protein: Polycystin-1 (PC1). It is a large plasma membrane integral protein that plays a role in epithelial cell-cell interactions, planar cell polarity, and cell growth

• Prognosis: Worse than ADPKD2, with worse symptoms and complications. Median onset of end stage renal disease is at 55 years

• ADPKD2: Less common, in 15% of pts.• Genetic Defect: Abnormal gene on Chromosome 4

• Encoded Protein: Polycystin-2 (PC2). Member of the transient receptor potential channel (TRPC) family of proteins and is involved in Ca++ channel signalling. Is stimulated by PC1 which transduces mechanical stimuli (cilia bending)

• Prognosis: More favorable. Milder Sx which may remain undetectable, and mean age of onset of ESRD at 74.

ADPKD Signs and Symptoms

• Hematuria is the most common presenting clinical manifestation

• HTN, mild proteinuria, progressive renal loss of function eventually occurs

• Flank pain from cyst rupture, cyst infection, or kidney stones

• Extrarenal manifestations: • Cysts in liver (30-40%), pancreas and spleen but rarely cause organ failure.

More likely to hemorrhage or get infected).

• Ruptured intracerebral berry aneurysm is most ominous complication.

• Most cysts are asymptomatic.

• Other complications: renal calculi (20%), colonic diverticuli (70%), and cardiac valvular abnormalities (25%)

• Dx: Established by imaging, mostly ultrasound, to reveal cysts.

• > 3 cysts in one or both kidneys in an at risk patient < 40 years old is diagnostic• In older pts, there is less criteria since cysts are natural with age: generally > 2

cysts in each kidney for 40-59 years, and >/= 4 cysts in each kidney in patients older than 60

ADPKD Management

• RAAS blockers

• Vasopressin receptor antagonists

• Increased fluid intake

• Rigorous BP control

• First two points based on the concept that reducing fluid accumulation

will slow down expansion of the cysts. Fluid intake indirectly

suppresses ADH secretion, which will also prevent fluid accumulation.

Acute Pyelonephritis

• Pyelonephritis is one of the most common diseases of the kidney and is defined as inflammation affecting the tubules, interstitium, and renal pelvis. • Acute pyelonephritis is generally caused by bacterial infection and is

associated with urinary tract infection.

• Hematogenous seeding is much less common

• Chronic pyelonephritis is a more complex disorder; bacterial infection plays a dominant role, but other factors (vesicoureteral reflux, obstruction) predispose to repeat episodes of acute pyelonephritis.

• Risk factors• Vesicoureteral reflex

• Pregnancy

• Urinary catheter

• Urinary tract obstruction

• Urinary stasis

Acute Pyelonephritis

• Etiology• Most common pathogens are enteric gram-negative organisms

• E. coli (90% of all cases)

• Enterococcus faecalis

• Klebsiella

• Proteus

• Staphylococcus saprophyticus

• Clinical features• Costovertebral angle (flank) tenderness

• Fever

• Dysuria

• Urinary frequency & increased urgency

• Microscopic examination of urine• Numerous WBCs & RBCs

• White cell casts

• Low-grade proteinuria (<500 mg/d)

• Sometimes observed secondary to direct tubular injury

• Microorganisms (bacteria & fungi) +/- present

Acute Pyelonephritis Histology

• The hallmarks of acute pyelonephritis are patchy interstitial

suppurative inflammation, intratubular aggregates of neutrophils,

neutrophilic tubulitis and tubular necrosis.

• The suppuration may occur as discrete focal abscesses or large

wedge-like areas and can involve one or both kidneys

Complications

• Papillary necrosis is seen mainly in diabetics, sickle cell disease, and in those with urinary tract obstruction. Papillary necrosis is usually bilateral but may be unilateral. One or all of the pyramids of the affected kidney may be involved. On cut section, the tips or distal two thirds of the pyramids have areas of gray-white to yellow necrosis.• May lead to renal failure

• Pyonephrosis is seen when there is total or almost complete obstruction, particularly when it is high in the urinary tract. The suppurative exudate is unable to drain and thus fills the renal pelvis, calyces, and ureter with pus.

• Perinephric abscess is an extension of suppurative inflammation through the renal capsule into the perinephric tissue.

Treatment of Pyelonephritis

• Uncomplicated acute pyelonephritis

• Antimicrobial therapy for 7-10 days

• Fluoroquinolones or Cephalosporins (inpatient)

• Persistence of symptoms for longer than 48-72 hours → suspect possible

complications → may require more aggressive therapy

• Complicated pyelonephritis

• Use CT for diagnosis

• Antibiotic Treatment: fluoroquinolones or cephalosporins

• Treatment of pyonephrosis

• Nephrostomy drainage tube in the renal pelvis essential

• Treatment of perinephric abscess

• Surgical drainage +/- nephrectomy

Analgesic Nephropathy

• Analgesic nephropathy is a type of of chronic interstitial nephritis

• Etiology: Prolonged ingestion of non-narcotic analgesics (aspirin and

NSAIDs) for 3 or more years

• Evidence suggests that combination of phenacetin + NSAID is particularly

harmful

• Most patients are women >45 years of age with a history of chronic pain that

leads to the analgesic use

• Characterized by papillary necrosis and chronic interstitial nephritis

• In analgesic nephropathy, papillae can show various stages of

necrosis, calcification, fragmentation, and sloughing.

• Sloughing of renal papillae → gross hematuria, mild proteinuria, flank pain

• Elevated serum creatinine and hematuria are seen

Although several diseases produce

chronic tubulointerstitial alterations, only

chronic pyelonephritis and analgesic

nephropathy affect the calyces, making

pelvocalyceal damage an important

diagnostic clue.

PEDIATRIC NEPHROLOGY

Pediatric Proteinuria

• Transient Proteinuria: • Disappearance of urinary protein following one or more positive tests

• Found after heavy exercise, fever, heat or cold stress

• Ranges from mild to moderate; benign--no evaluation or therapy needed

• Orthostatic (Postural) Proteinuria: • Mild selective proteinuria that is only seen when the patient is upright;

• Hematuria, hypertension, hypoalbuminemia, edema, and renal dysfunction are absent (benign condition), can resolve or be permanent

• Protein levels will be normal during first morning void after being recumbent all night, but will be high when collected during the day after walking around (but still <1g/day)

• Persistent (Fixed) Proteinuria: • Non-orthostatic proteinuria of any degree; can be tubular or glomerular; is an

indication of underlying renal disease;

• Mild to moderate (500-1000 mg/day): Congenital dysplasia, reflux nephropathy, obstructive uropathy, tubular disorders

• Nephrotic syndrome or aggressive GN : >40 mg/m2/h or 3 grams/day

• All persistent proteinuria patients should be referred to a pediatric nephrologist

Normal 24 hr urinary protein excretion by age

Patient Group mg/24 h mg/24 h/m2

Premature babies 29 (14–60) 182 (88-377)

Full-term babies 32 (15–68) 145 (68-309)

Infants 38 (17–85) 109 (48-244)

Children:

2–4 years

4–10 years

10–16 years

49 (20–121)

71 (26–194)

83 (29–238)

91 (37-223)

85 (31-234)

63 (22-181)

Variation by age

• Proteinuria

• Hypoalbuminemia

• Edema

• Seen most commonly in the younger child • 2-6 years

• Often is initially mistaken for allergies• Child is well

• Mom claims periorbital edema

• Primary disease:• Minimal change disease (MCD)-77%

• Focal Segmental Glomerulosclerosis (FSGS)-10%

• Membranoproliferative Glomerulonephritis (MPGN)-5%

• Membranous Nephropathy (MN)-2%

• Other-6%

Nephrotic Syndrome

Complications of Nephrotic Syndrome

• Acute kidney injury

• Severe volume depletion can occur in the face of vomiting, diarrhea, diuretic

therapy, sepsis, or rapid removal of ascites

• Infection

• Serious infections with encapsulated (S. pneumonia, H. influenzae) organisms

• Thromboembolic events

• State of hypercoagulability: vascular stasis, increase in hepatic production of

fibrinogen and other clotting factors, decreased serum levels of anticoagulants,

increased plasma platelet production, and increased platelet activation

Minimal Change Disease

• Children: 90% of Nephrotic Syndrome (Age 1-6)

• Adults: 10-15% of Nephrotic Syndrome

• Dx:

• Absence of HTN, absence of gross hematuria (microscopic is possible), normal

complement levels, normal renal function, may see increased BUN

• Avoid biopsy in children

• Rx:

• Children: Does not progress to renal failure; respond quickly to steroids (8 wks until

complete remission)

• Adults: Respond much more slowly to steroids

• If left untreated, at high risk for infection and thromboembolism

• Immunizations are IMPORTANT

• Do not restrict fluids

• Treat hypertension

• Recent pharyngitis, skin infection• Post streptococcal GN

• Shortness of breath, edema, weight gain• Post infectious or other GN

• Concurrent respiratory illness• Ig A nephropathy

• Fevers, weight loss, alopecia, mouth ulcers, chest pain, fatigue, arthritis• SLE

• Hemoptysis, cough, palpable purpura• Wegener’s granulomatosis, Goodpasture’s syndrome

• Severe abdominal pain, joint pains and rash• Henoch–Schönlein

Gross hematuria-Glomerular

Post infectious glomerulonephritis

• Tea colored urine• Macroscopic hematuria more often

• Ranging from asymptomatic to complaints of malaise, HA, nausea, vomiting, abd pain, oliguria

• PE: edema, elevated BP that can be severe

• Occurs 7-21 days after infection

• Almost all have low C3 early that normalizes 6-8 weeks later

• Can have elevated BUN and Cr

• Supportive Treatment

Gross hematuria

Non Glomerular Symptoms

• Episodic flank pain, abdominal pain, dysuria

• Fever, pain

• Abdominal pain and mass

• Infant with birth asphyxia, umbilical catheters

• Urolithiasis

• Crystalluria

• UTI

• Renal Tumor-Wilms

• Renal Vein Thrombosis

Gross hematuria

Non Glomerular Symptoms

• Black child

• Heavy menses

• Football player who took a hard hit

• Concurrent respiratory illness

• Sickle cell trait

• Bleeding disorder

• ADPKD-bleed into cyst

• Adenovirus and TB

Persistent microscopic hematuria

• Most common diagnoses in children with persistent microscopic

hematuria WITHOUT proteinuria

• Benign persistent hematuria

• Benign familial hematuria

• Idiopathic hypercalciuria

• IgA nephropathy

• Alport’s syndrome

Indications for acute dialysis

Mnemonic: A-E-I-O-UAcidosis

Electrolyte disturbance

Ingestion

Overload (fluid)

Uremia

Pediatric Hypertension

• Confirm the diagnosis of hypertension

• BP readings on three or more separate visits about 1 week apart

• Pediatric BP norms are based off of population studies (5-95%tile)

• Organize a diagnostic approach

• Determine the severity of the hypertension

• Magnitude of the BP elevation

• End organ damage

• LVH

• Ophthalmic changes

• Treat the hypertension effectively

Peds vs. Adult BP

• Pediatric BP norms are based off population studies

• Statistical, not functional

• NOT based on outcome studies

• Based on age, height, and gender

• Based on manual and not digital readings

Grades of Hypertension

Diagnostic Approach

• Medications: Amphetamines, Corticosteroids, Contraceptives, Cyclosporine, Albuterol, Caffeine, OTC-cold meds

• Obesity

• Neonatal history: Asphyxia, Umbilical artery catheter, Renal vein thrombosis, Maternal substance abuse, Bronchopulmonary dysplasia

• Symptoms or signs: • Sx: headaches, nausea, vomiting, visual or auditory changes, nosebleeds,

respiratory complaints

• Signs: Cerebral infarction or hemorrhage, motor, visual, cognitive defects, hypertensive encephalopathy , seizures, mental status change, congestive heart failure, pulmonary edema, rapidly progressive renal dysfunction

• Trends in Family

• Endocrine: Hypo and hyperthyroidism, Hyperaldosteronism, Apparent mineralocorticoid excess, Pheochromocytoma

• Renal: Renovascular disease, Pyelonephritis, Glomerulonephritis, Hydronephrosis, Reflux nephropathy

• Cardiomegaly/CHF

• Tachypnea

• Lethargy

• Seizures

• FTT

• Mottling

HTN: Symptoms/Signs in Infants

Children and adolescents with primary

HTN are usually asymptomatic

• Coarctation of the aorta

• Palpation of distal pulses is more telling than an ECHO is certain situations

• End organ dysfunction

• LVH is an indication for hypertensive therapy, even in borderline patients.

HTN: Cardiovascular

Secondary Renal HTN

• Renovascular disease

• Pyelonephritis

• Glomerulonephritis

• Hydronephrosis

• Reflux nephropathy

Treatment

HUS

• Clinical diagnosis, with the triad of Thrombocytopenia, AKI, and

Microangiopathic hemolytic anemia

• Etiology

• Typical: Verotoxin producing E. coli (O157:H7) and Shigatoxin producing

Shigella

• Atypical: Streptococcus pneumoniae, Genetic: Complement defects, ADAMTS

13, HIV, Medications (cyclosporine, tacrolimus, clopidogrel, cisplatin), Defects

in vitamin B12 metabolism

• Pathophysiology: Endothelial injury, formation of platelet/fibrin

thrombi, ischemia, and cell death

• Dx: Schistocytes, LDH, AST, anemia with reticulocyte count

Treatment of HUS

Supportive care!Dialysis when/if indicatedEarly correction of volume depletionAvoidance of late fluid overloadBlood transfusions as needed

Treatments that may be harmfulAntibiotics for diarrheaPlatelet transfusions (except for active bleeding)

Treatments with no proven benefitEverything else (plasma exchange, toxin adsorption, antiplatelet therapy, anticoagulation, etc.)

CHRONIC KIDNEY

DISEASE AND RRT

Chronic Kidney Disease

• Chronic kidney disease (CKD) encompasses a spectrum of different

pathophysiologic processes associated with abnormal kidney function

and a progressive decline in glomerular filtration rate (GFR)

• Damage is rarely reversible

• Defined as: GFR persistently below 60 mL/minute/1.73 m2 for greater

than or equal to 3 months

• OR

• Evidence of kidney damage based on presence of hematuria,

proteinuria, or abnormal imaging (i.e. Stages 1 and 2 of CKD, which

have eGFRs of >90 and 60-89, respectively)

Complications begin at Stage 3.

Spectrum of CKD

• Lab abnormalities only Uremia

• Uremia describes the group of symptoms resulting from

accumulation of waste products as a result of severe

reduction in GFR

• Altered mental status

• Bleeding

• Pruritis

• Pericarditis

• General Fatigue, nausea

• Irritability, insomnia

• Complete failure of kidney function end stage renal

disease (ESRD or ESKD)

MDRD and CKD-EPI underestimate GFR

in the general population .

Epidemiology

• Incidence – 13% in general population

• Prevalence – Doubled in last 10-20 years, correlated with rise in

obesity and diabetes.

• MCC: Diabetes (1) and Hypertension (2)

Risk Factors

• 1) Diabetes/Diabetic Nephropathy

• Diabetic nephropathy is the #1 cause of kidney disease in patients on dialysis

• 2) Hypertension

• Increased intraglomerular pressure is a major cause of progression of CKD

• 3) Obesity

• Hyperlipidemia can enhance rate of progression

• 4) Smoking can enhance progression

• 5) High protein diet can enhance progression

• 6) Chronic metabolic acidosis can enhance progression (give

supplemental bicarb)

• Other less common risk factors for development: decreased renal

perfusion, nephrotoxic drugs, urinary tract obstruction (these can be

reversible causes)

Pathophysiology

• A. Systemic Response to loss of nephron mass: Increase BP to

increase blood delivery to kidneys HYPERTENSION

• B. Kidney response: increase pressure and filtration surface area to

maximize the filtration that can be done by the remaining, healthy

glomerul HYPERFILTRATION AND HYPERTROPHY

• Leads to Glogal glomerulosclerosis

CKD vs. AKI

• 1. Comparison to previous Cr or eGFR

• 2. Imaging• Thin and atrophied cortex on ultrasound suggests CKD

• Small kidneys suggest CKD

• Bright, Echogenic cortex CKD

• A few simple cysts (acquired cystic disease) CKD

• 3. Presence of CKD complications• High PTH (not definite)

• Anemia may or may not help, it is a complication of CKD, but it is also commonly seen with acute illnesses like sepsis that are associated with AKI

• Hyperkalemia, Hyperphosphatemia, Hypocalcemia, Uremia

• 4. Certain urinary findings• Waxy casts

• Broad casts (wider, because of tubular dilatation)

Lab Values

• Most CKD complications are seen with GFR <60 mL/min/1.73 m2

(stage 3 CKD)

• PTH is high, “trade-off” to keep phos and Ca normal

• Phos starts to increase when GFR drops below 20 (in most cases

around 15 mL/min/1.73 m2)

• High PTH phos excretion in the urine

• Hyperkalemia of CKD occurs at eGFR around 15 mL/min/1.73 m2

• Few sodium problems occur

• Urea goes up

• Accumulation of anions causes decrease of bicarbonate

• High anion gap acidosis

CKD with Diabetic nephropathy, Multiple

Myeloma and HIV associated

nephropathy may have large or normal

size kidneys instead of shrunken ones

size kidneys

Renal Bone Disease

GFR

Phosphorus

Phosphorus Excretion

Calcitriol

Chronic Kidney Disease

Calcium PTH

Primary Hyperparathyroidism:

hypercalcemia and hypophosphatemia

Overdose of Calcitriol: hypercalcemia

and hyperphosphatemia

Renal Bone Disease

• Stages 3 to 4 CKD

• High PTH

• Normal Phos

• Mild hypocalcemia

• Low calcitriol

• Advanced stage 4 and stage 5 CKD

• Higher PTH

• High phos

• Low Ca and calcitriol

Consequences of high PTH

• Osteitis fibrosa cystica

• Bone resorption

• Fractures

• Soft tissue and vascular calcification

• Increased mortality

Hypertension

GFR

Na Excretion

Chronic Kidney Disease

Activation of RAASVolume Expansion

Hypertension

Low salt diet

and Diuretics

ACE inhibitors

and angiotensin

receptor blockers

Hyperkalemia Tissue Ischemia

Anemia of CKD

• Causes

• Reduced production of erythropoietin by the kidney

• Reduced life span of RBC

• Malnutrition of vitamins and iron

• Hemodialysis patients lose blood

• Work up

• Normal size RBC (normocytic normochromic)

• Reticulocyte count (expect to be low)

• Check for iron stores

• Treatment: Subcutaneous erythropoietin or analogs of it

Metabolic Acidosis

• Cause: retention of hydrogen ions as GFR drops

• Usually seen when GFR <20 ml/min/1.73 m2

• Serum bicarbonate drops, but is rarely less than 10 mmol/L

• Chronic acidosis leads to • Bone buffering and release of calcium and phosphate

• This leads to worsening bone disease

• Breakdown of muscle and reduced albumin synthesis

• Treatment with alkali (sodium bicarbonate) to increase serum bicarbonate above 20 – 22 mmol/L

Malnutrition

• Uremia leads to reduced appetite

• Chronic acidosis can lead to reduced albumin synthesis and breakdown of muscle

• It is believed that patients with advanced CKD have low grade inflammation which can result in low albumin and malnutrition

• Diagnosis and screening• Need to monitor serum albumin and total cholesterol

• In dialysis patients, monitor serum creatinine (marker of muscle mass) as well as body weight

• Treatment• In those with stages 3 and 4 CKD, restrict protein intake to 0.8 – 1 g/kg body

weight to protect kidneys, but make sure 30 – 35 kcal/kg per day is provided in the daily diet

• For patients on HD, increase protein intake to 1.2 g/kg (loss during dialysis)

Cardiovascular Disease

• Patients with ESRD have high number of comorbid conditions

• Highest mortality rate is seen within the first 6 months after initiation

of dialysis

• CV disease is responsible for >50% of deaths

Management of CKD• Treat the underlying disease, if possible

• Good blood pressure control (<130/80 mm Hg)

• Treatment with a blocker of the RAAS• Check GFR after starting treatment to make sure AKI doesn’t occur

• Low protein diet (<0.8 mg/kg of body wt)• Vasodilates but can cause malnutrition

• Treatment of acidosis may slow progression of CKD• Treatment with alkali (Na bicarbonate) to increase serum HCO3 above 20 – 22 mmol/L

• Anemia: Erythropoietin analogs

• Renal Bone Disease• Lower phosphate with low phosphate diet and binding resins

• Calcium carbonate

• Calcium acetate

• Sevelamer

• Replace Vitamin D to reduce PTH secretion

Diuretic resistance is seen in advanced

stages of CKD

Indications for Renal Replacement

Therapy (RRT) in CKD

• Usually when accumulation of uremic toxins or fluid result in development of symptoms or when hyperkalemia or hypervolemia is difficult to treat medically

• Signs and symptoms of advanced CKD or uremia rarely occur before eGFR reaches a level <15 ml/min/1.73 m2 (stage 5 CKD)

• Uremic symptoms are nonspecific and include,• Fatigue and weakness, poor appetite, insomnia, nausea and vomiting,

confusion and memory problems, metallic taste, sexual dysfunction and possibly evidence of volume overload

RRT

• Best options for RRT,

1. Living-donor transplantation

2. Deceased-donor transplantation

3. Home dialysis (peritoneal or home hemodialysis)

4. In-center hemodialysis

The fastest option is placement of a

tunneled hemodialysis catheter in the

jugular vein and initiation of in-center HD

as soon as the catheter is in place.

Vascular access for HD

1. Native arteriovenous fistulas (AVF)

2. Synthetic arteriovenous grafts (AVG)

3. Tunneled central venous catheters (CVC)

• AVF have the lowest complication rates

• AVG have higher infection and thrombosis rates

• CVC have the highest infection and thrombosis rates

Indications for RRT

• AKI

• Intractable hyperkalemia

• Intractable metabolic acidosis

• Intractable volume overload

• Uremia (bleeding, altered mental status)

• CKD (GFR <15)

• Uremic symptoms

• Metallic taste, poor sleep, poor appetite, uremic neuropathy

• Severe volume overload

• Severe hyperkalemia

Hemodialysis or peritoneal dialysis will

treat hyperkalemia and volume overload

and improve uremic symptoms

No effect on CV outcomes!!

Causes of hyperkalemia out of proportion

to the decline in GFR

• Urinary tract obstruction

• Sickle cell disease (trait)

• Hyporeninemic hypoaldosteronism

• Diabetic nephropathy

• Chronic interstitial nephritis

• Adrenal insufficiency

• Drugs

URINARY TRACT

DEVELOPMENT

Development Period

• Kidney development begins in the 5th week of development

• Completed between the 32nd-36th week

• At the end of 36th week, all nephron formation ceases.

• Nephrons can be repaired, but no more new nephrons can be made

after this point.

Initiation

• Paired nephric ducts run on either side of the midline in the embryo

• A budding outgrowth, called the ureteric bud (UB below), from the

caudal end of the nephric duct, pushes into the metanephric

mesenchyme (MM below), initiating kidney development

Reiteritative Processes

• Process #1: Ureteric Bud Branching Morphogenesis• Establishes the entire collecting tube/duct system

• Occurs at the tips by bifurcation

• Tip cells are progenitor stem cells

• Divide into either more ureteric bud tips or into ureteric bud trunks

• The trunks will differentiate into the adult collecting tubes/ducts

• The tips disappear at the end of development

• Process #2: Nephrogenesis• All nephrons form from the metanephric mesenchyme

• This mesenchyme contains stem cells that self-renew in the cap

• Some of the cells, however, are induced to differentiate in each round of nephron induction

• This begins by forming the renal vesicle

Spatial Temporal Gradient

Ureteric Bud Defects

• Renal Agenesis: Bud fails to form entire kidney fails to form.

• Can be unilateral or bilateral (INcompatible with life)

• Associated with oligohydraminos or anhydraminos

• Additional Buds can lead to:

• Double ureters

• Ectopic Ureters: vesicoureteral reflux, hydroureter and hydronephrosis

• Duplex kidneys: either two kidneys on a side or an elongated kidney with a

duplicated nephric system

• Multicystic Dysplastic Kidney

4 Stages of Nephron Development

• Stage 1: Renal Vesicle – MM (metanephric mesenchyme) is induced and forms an assymmetric ball of cells.

• Stage 2: S-shaped body – divides into proximal, middle and distal segments. The proximal is the progenitor of renal corpuscle, has developing podocytes (columnar cells), parietal epithelium (squamous) and is where vasculature will begin to invade.

• Stage 3: Capillary Loop – glomerulus begins to look mature, microvilli appear in the proximal tubule.

• Stage 4: Maturing Nephron – looks like a usual nephron, all segments are present and brush border appears in proximal tubule. Podocytesare no longer columnar, and are organized around capillary loops. Slit diaphragms are formed.

Slit Diaphragm

• The “slit diaphragm” refers to the space, or filtration slit, between the

foot processes of podocytes.

• The major component of the slit diaphragm is Nephrin, a

transmembrane protein mediating outside-in signaling by maintaining

the connection to the actin cytoskeleton. Interestingly, this actin

cytoskeleton network is important for maintaining podocyte structure,

demonstrated by the fact that foot process effacement will occur if the

slit diaphragm is compromised.

• Thus, either foot process effacement or slit diaphragm disruption will

ultimately disrupt the function of this filtration barrier, ultimately

leading to proteinuria.

PCK

• Polycystic kidney disease results from absence or dysfunction of the primary cilium.

• Features of the primary cilium:

• Immotile

• Present in most mammalian cells

• Each cell has only one primary cilium

• Primary cilia are localized to the cell surface:

• Epithelial cells: the primary cilium of an epithelial cell tends to be on the apical surface protruding into the lumen of an epithelial tube

• Functions of the primary cilium:

• Primary cilium serve as a mechanosensory organ sensing fluid flow and inducing calcium influx

• Primary cilium also mediate signaling activities.

PKD1: Receptor sensing fluid shear force

imposed to the primary cilium

PKD2: Calcium ion channel regulating

intracellular calcium levels

Form a complex mediating the sensing

and response to fluid shear force at the

primary cilium in order to regulate

uriniferous tubule diameter.

CONGENITAL ANOMALIES

ARPKD vs. ADPKD

Polycystic Kidney Disease

ARPKD vs. ADPKD

• Autosomal Recessive

• Gene: PKHD1

• Protein: fibrocystin

• Incidence 1:10,000 to 1:40,000

• Dx:• Usually diagnosed in the first year mostly in

the first month

• Bilateral flank masses

• Oligohydramnios

• Pulmonary hypoplasia

• Pneumothorax

• Significant HTN

• Older children can present with hepatic phenotype

• Portal hypertension*

• Most severe: Potter syndrome (caused by oligohydramnios)

• Often asymptomatic.

• Enlarged kidneys bilaterally

• Autosomal Dominant

• Gene: PKD1 or PKD2

• Protein: polycystin

• Incidence: 1:500 to 1:1,000• Most common inherited kidney disease

• Dx:• Diagnosed by family history or incidental

findings

• Can present with hematuria

• HTN

• Urinary frequency

• Abdominal/flank pain

• UTI

• Proteinuria

• Cysts:Hepatic (benign), pancreatic, ovarian, testicular, splenic, pineal, arachnoid

• Intracranial /berry aneurysms

• Enlarged kidneys bilaterally with multiple cysts in ANY segment of the nephron

• Enlarged bilaterally

• Saturated with cysts with

spongy appearance

• Cystic ectasia of the

collecting ducts

• Microscopy with dilated

collecting ducts

• Perpendicular to the

surface

• Interstitial fibrosis and

tubular atrophy lead to

renal failure

Pathology/Histology ARPKD

• Potter syndrome refers to a group of findings associated with a lack of amniotic fluid in an unborn infant. • Renal agenesis vs. obstructive

uropathy vs. ARPDK

• Pulmonary hypoplasia

• Potter facies

• Eyes are widely separated with epicanthic folds

• Ears are low

• Nose is broad

• Chin receding

• Limb abnormalities

Potter syndrome

Workup of Solitary Kidney

• Confirm with ultrasound - assessing postnatal size of the kidney

• Voiding cystourethrogram (VCUG) to see if urine is backing up the

ureter towards the kidney - patients are at increased risk for

vesicoureteral reflux

• Serum Creatinine, sodium, BP, and other tests to confirm kidney

function

• NOTE: Serum creatinine on the first day of life is a reflection of their mother’s renal

function - thus checking it on the first day of life is not an accurate measurement of

the child’s renal function

Prognosis of a Solitary Kidney

• Increased workload on single kidney can predispose the patient to

hypertension, chronic kidney disease or end stage kidney disease.

• Debate about whether these children should avoid contact sports

• Reasons for avoiding contact sports: contralateral kidney is hypertrophied so

less protected by ribs; serious consequences to injury

• Reasons for not avoiding contact sports: we have a lot of other single organs

(like the brain); few reports of kidney loss due to injury

Management of Solitary Kidney

• Protect the functional kidney

• Routine US and urine testing

• Avoid HTN, UTI/pyelonephritis

• Avoid NSAIDs

• ACE inhibitors if they have proteinuria

• Avoid high salt diet and obesity

• Controversy on whether kids should avoid contact sports or not

• The functional kidney should hypertrophy over time making it at higher risk for

traumatic damage

• If MCDK, consider nephrectomy of the nonfunctional kidney

MCKD

• Dysplasia is a sporadic disorder that can be unilateral or bilateral and

is almost always cystic.

• The kidney is usually enlarged, extremely irregular, and multicystic.

• The cysts vary in size from several millimeters to centimeters in diameter.

• Characteristic histologic feature is the presence of islands of undifferentiated

mesenchyme, often with cartilage, and immature collecting ducts.

• Most cases are associated with ureteropelvic obstruction, ureteral agenesis or

atresia, and other anomalies of the lower urinary tract.

Indications for Nephrectomy - MCDK

• To treat or prevent abdominal or flank pain due to the pressure effects

of a MCDK

• To treat UTI that has involved the MCDK

• If the MCDK is causing HTN in the child

• Small risk of malignancy (Wilm’s Tumor [1:333])

• The MCDK normally regresses. If instead the kidney is growing it may be a indicate

malignancy

• Patients should be observed with periodic sonography to monitor for neoplastic

change

PCK vs. MCDK

• PCK

• Genetic

• Kidneys develop before the generation of cysts

• ADPKD - 1:500 to 1:1,000

• ARPKD - 1:10,000 to 1:40,000

• Bilateral

• Portal hypertension, systemic hypertension, berry aneurysm, MVP

• Start as functional

• MCDK

• Developmental

• Kidneys start as cysts and never form correctly and eventually regress

• 1:2,000

• Unilateral (bilateral form is incompatible with life)

• Cyst rupture, infection, calcification, and malignancy

• Never functional

Serum Creatinine

• Serum creatinine

• Newborns (Day 1): Not a good indicator of kidney function because

it only reflects the mother’s kidney function

• Infants: Creatinine is dependent on muscle mass and renal

perfusion, which are both lower in infants than adults.

• Not the best indicator of GFR or kidney function because only a

serious decrease in nephron number will cause a detectable

creatinine increase.

Postnatal US

• Useful in detecting any vascular or anatomic abnormalities. • Cysts (ARPKD, ADPKD)

• Unilateral renal agenesis

• Kidney stones

• Hydronephrosis

• Kidney size

• Echogenicity

• Ureters and bladder

• If US is done before significant compensatory hypertrophy occurs, nephron number does correlate with kidney size so ultrasound is a good surrogate.

• In adulthood: When nephron number decreases, the cells can undergo hypertrophy and tubules dilate, so ultrasound is NOT a good surrogate for nephron number.

Renal US

Normal

Echogenicity

Ability to see the renal pyramids

Our patient’s initial RUS

Hyperechoic, lack of pyramids

Measurements:

Right: 7.4 cm x 4.3 cm x 4.2

Left: 7.8 cm x 4.6 cm x 3.6 cm

Nephrogenesis• Normal nephrogenesis: week 5 - 32nd through 36th week.

• 4 stages of development• Renal vesicle

• S-shaped body

• Capillary loop

• Maturing nephron

• The mesenchymal cells release signals which cause the ureter bud to branch out.

• A subset of nephron progenitor cells are induced to undergo mesenchymal to epithelial transition to form renal vesicles.

• The rest of the nephron progenitor cells proliferate to continue nephrogenesis.

• Any error in the 4 steps may cause multicystic dysplastic kidney (MCDK)• Ectopic ureteric bud may cause hydronephrosis due to backup pressure from the dead end

• Failure in ureteric bud to form may lead to unilateral or bilateral renal agenesis

• Defects in renal tube diameter can cause tube dilation, which may lead to cysts in the kidney

• Cell cilium is responsible for sensing fluid shear force. Defects in cell cilium – PKD

• Prematurity significantly impacts nephrogenesis since 60% of nephrogenesisoccurs in the 3rd trimester.

Etiology of reduced nephron number?

• Genetic defects

• In utero compromise

• Intrauterine growth restriction

• Low maternal protein, calories, iron or vitamin A deficiency

• Exposures

• Maternal alcohol, corticosteroids

• Ex utero compromise

• Prematurity

• Altered hemodynamics, infections, nephrotoxic medications, AKI

• Acute kidney injury

Risk Factors in Nephron Development

• The total number of nephrons a person has (nephron endowment) varies from 210,000 to 2.7 million. No new nephrons can be formed after birth.

• Prenatal risk factors:• NSAID use

• Low protein diet

• Low calorie diet

• Vitamin A deficiency

• Iron deficiency

• Alcohol

• Steroids

• Postnatal: • Premature birth

• Nephrotoxic drugs

• Acute kidney injury

• UTIs

Congenital Nephrotic Syndrome

• Nephrotic Syndrome = massive proteinuria, hypoalbuminemia,

edema, and hypercholesterolemia

• Congenital nephrotic syndrome is defined as nephrotic syndrome

manifesting at birth or within the first 3 months of life

• Primary:

• Variety of syndromes inherited as autosomal recessive disorders

• Secondary:

• Due to a number of etiologies such as in-utero infections (cytomegalovirus,

toxoplasmosis, syphilis, hepatitis B and C, HIV), infantile systemic lupus

erythematosus, or mercury exposure.

Other clinical manifestations

• Hypothyroidism-loss of TBG

• Increase susceptibility to infections

• Increased risk of thrombotic events

Rx: Congenital Nephrotic Syndrome

• The management of primary congenital nephrotic syndrome includes intensive supportive care with:• Intravenous albumin and diuretics

• Regular administration of intravenous gamma-globulin

• Aggressive nutritional support (often parenteral).

• Pharmacologically decrease urinary protein loss with:• Angiotensin-converting enzyme inhibitors

• Angiotensin II receptor inhibitors

• Prostaglandin synthesis inhibitors

• Unilateral nephrectomy

• If conservative management fails, and patients suffer from persistent anasarca or repeated severe infections. • Bilateral nephrectomies are performed and chronic dialysis is initiated.

• Renal transplantation is the definitive treatment of congenital nephrotic syndrome, though recurrence of the nephrotic syndrome has been reported to occur after transplantation.

Prognosis of Cystic Kidney Disease

• ARPKD: mortality has improved

• 30% die in the neonatal period due to lung complications

• 15 year survival: 70-80%

• ESRD in >50% during first decade of life

• ADPKD:

• Although neonatal ADPKD may be fatal, long-term survival of the patient and the kidneys is possible for children surviving the neonatal period. ADPKD that occurs initially in older children has a favorable prognosis, with normal renal function during childhood seen in >80% of children.

• Intracranial aneurysms, which appear to cluster within certain families, have an overall prevalence of 5% and are an important cause of mortality in adults but are rarely reported in children

• MKD:

• Patients have solitary kidney so increased risk of HTN, chronic kidney disease and ESKD

RENAL

TRANSPLANTATION

Benefits

• Transplant is the preferred modality of renal replacement therapy and

all patients approaching end stage renal disease (ESRD) should be

considered for transplant.

• The two main benefits of kidney transplant are increased survival and

improved quality of life as compared to dialysis.

• There are few absolute contraindications to kidney transplant.

Anticipated additional

years of life without a

transplant (n=23 275)

Anticipated additional

years of life with a

transplant (n=46 164)

20-39, no DM 20 31

20-39, with DM 8 25

40-59, no DM 12 19

40-59, with DM 8 22

60-74, no DM 7 12

60-74, with DM 5 8

Patients may be added to the transplant

list when their GFR falls below 20 mL/min.

Evaluation and Testing for Transplant• Routine labs

• CBC,CMP, LFTs, coagulation studies

• Immunologic survey:• ABO type, HLA typing, cross reaction and donor specific antibodies

• Cardiovascular and peripheral arterial disease screening:• Screen for unstable or flow limiting coronary artery disease and assess cardiac function

• Age appropriate cancer screening:• Colon cancer screening

• Prostate Cancer Screening: digital rectal exam (DRE) + PSA for men >50

• Pap Smear: women >18yo

• Mammogram: women >40 or earlier if strong family history

• Infection:• Latent or active TB: PPD +/- CXR, serology (e.g. Interferon-gamma release assay)

• Active viral infection: hepatitis B, hepatitis-C, HIV

• Immunity/Exposure: VZV, HSV, EBV, CMV

• Dental evaluation (if indicated)

• Psychological testing

• Social Work

• Financial Evaluation

• Update vaccinations: Hep-B, pneumococcus, VZV (live vaccines contraindicated after)

Absolute Contraindications

• Life expectancy less than 5 yrs

• Active or metastatic malignancy (excepting non-melanoma skin

cancer)

• Unstable of flow limiting coronary artery disease

• Active infection or unresolved chronic infection

• Uncontrolled psychiatric disease

• Active substance abuse

Post Transplant Infection

• Risks: surgery, indwelling catheters, and exposures to hospital and

donor derived pathogens.

• Related to the induction immunosuppression with increased risk for

opportunistic infection

• Trimethoprim sulfamethoxazole (6 mos): decreases risk of

pneumocystis carinii pneumonia and common UTIs

• Valgancyclovir (used for 3-6 months) decreases risk of CMV infection

• After the first six months, infection is more often caused by

community acquired pathogens

Post Transplant Malignancy

• Malignancy:• Increased risk of colon, lung, prostate, and breast cancers, and an even higher

risk of testicular and renal cancers

• Highest increased risk of skin cancer: 50-100 fold increased risk of squamous cell cancers

• Post-transplantation lymphoproliferative disorder (PTLD)• Occurs in 3-10% of solid organ transplant recipients

• Highest risk for pts who have never been exposed to EBV prior to transplant

• Clinical presentation:

• Fever of unknown origin

• Mononucleosis-like syndrome (fever, malaise, pharyngitis, tonsillitis)

• GI bleeding, obstruction, perforation; hepatic or pancreatic dysfunction

• Abdominal mass

• Infiltrative disease of the allograft

• CNS disease

Calcineurin inhibitors induce renal

vasoconstriction.

Kidney susceptible to volume depletion

and thus pre-renal azotemia

Common cause of transient rises in

creatinine, and over time can lead to CKD

Organ Matching

• ABO

• Need to be compatible blood types (i.e. recipient antibodies do not attack donor blood cells; type O blood has antibodies against A & B, etc). If incompatible, hyperacute rejection.

• HLA (As many of these should match as possible)

• Most important thing to have match (other than blood type of course). 6/6 match = perfect (essentially only in identical twins);

• Crossmatching (Indicates incompatibility)

• Mix donor serum and recipient blood. Cells lysing indicate positive crossmatching and rule out donation.

• Donor Specific Antibodies (Indicates incompatibility)

• Positive result if recipient has antibodies for donor HLAs.

Presensitization

• Pre-sensitization (present in > 30% of pts on waitlist) is the

development of anti-HLA antibodies due to past exposure to foreign

HLA

• It can occur following blood transfusion, pregnancy, or prior transplant

• A panel-reactive antibody (PRA) is used to screen for pre-

sensitization- a higher PRA (in percentage points) indicates a higher

level of pre-sensitization and a likely decreased chance of being

matched with a suitable organ

Risks to Donor

• Immediate surgical risks:

• Pneumothorax

• Pneumonia

• Ileus

• Urinary tract infection

• Wound complication

• Deep vein thrombosis +/- pulmonary embolism

• Death (surgical mortality 3.1 per 10,000 donors)

Alloimmune Response

• Signal 1: Antigen presenting cell (APC) presents an Ag triggering a T

cell receptor, signal transduced through the CD3 complex

• Signal 2: Non-Ag specific co-stimulation of the T-cell by the APC

• Signal 1 and Signal 2 activate intracellular pathways that express IL-2

• Calcineurin NFAT

•

• Signal 3: stimulation of IL-2 receptor (CD25) activates mTOR

• Signal 3 stimulates cell proliferation

Rejection of the Renal Allograft

Clinical Presentation:

• Typically presents with asymptomatic rise in serum creatinine

• May be associated with decrease in urine output

• Rarely associated with fevers, hematuria, allograft tenderness

• Diagnosis can only be made based on biopsy and pathology (!) and

treatment depends on type and severity of rejection.

• If clinical suspicion for rejection is high, and no contraindications are

present, then high dose IV corticosteroids are usually given

preemptively.

Increased Serum Creatinine

Pre-Renal Intra-renal Post-renal

•Volume depletion

•Renal vein or artery

thrombosis

• Compression of

vessels from hematoma

or other fluid collection

• Renal artery stenosis

• Calcineurin inhibitor

toxicity

• ATN

• Recurrent primary disease

• Rejection

• Pyelonephritis

• BK virus nephropathy

• Chronic allograft

nephropathy

• de novo renal disease

• Ureteral stenosis or

compression

• Urine leak

• Prostatic obstruction

• Bladder dysfunction (e.g. neurogenic bladder,

particularly in diabetics)

Basic Workup

• Volume resuscitate, check serum creatinine again

• Check calcineurin inhibitor level

• Tremor is a sign of calcineurin inhibitor toxicity

• Urine studies/culture

• Renal US

• Targeted serologic workup if indicated

• Renal transplant biopsy

Hyperacute Acute

Cellular

Acute

Humoral*

ChronicT

imin

g Minutes to days after

vascular anastomosis

Early AR – weeks to 6 months post-tx

Late AR – more than 6 months post tx

Years post-tx

Etio

log

y

Humorally mediated due to

pre-formed antibodies (anti-

ABO or anti-HLA)

Mediated by lymphocytes

activated against donor

antigens in the allograft

Mediated by antibody and

complement. Assoc with

donor specific antibody

Both antibody-

and T-cell-

mediated

Pa

tho

log

y

Antibody-antigen

complexes activate

complement systems and

attack endothelial cells

massive thrombosis in the

allograft

Tubulitis (mononuclear

cellular infiltrate of the

tubular basement

membrane), interstitial

infiltrate, arteritis

Tubular injury,

IF: C4d positive staining in

the peritubular capillaries

Fibrosis and and

glomerulopathy

Tre

atm

ent

Urgent allograft

nephrectomy, stabilize

patient

Mild-mod: 3-5 days pulse

steroids (methylprednisolone

250-500 mg daily)

Mod-severe or steroid

resistant: 3-5 days of pulse

steroids and polyclonal

antibody (e.g.

thymoglobulin®)

Plasmapheresis

Pooled human IV

immunoglobulin

Rituximab (anti-CD 20)

↑ maintenance IS

For mixed acute cellular and acute humoral mediated

rejection treat with combination of above therapies

* humoral =antibody mediated

Immunosuppression

• Induction therapy: Powerful biologics and antilymphocyte globulins

used at the time of transplant to minimize risk of early acute rejection.

Allows for minimization of calcineurin inhibitor exposure during initial

renal recovery.

• ex: thymoglobulin (rabbit anti-thymocyte globulin)

• Maintenance immunosuppression: chronic immunosuppressive

therapy to maintain allograft function

• Treatment of rejection: increase in immunosuppression with goal of

suppressing the alloimmune response

Transplant drug Mechanism of Action Adverse effects

Prednisone Inhibits multiple steps in immune activation

due to ubiquitous expression of

corticosteroid receptors (decreased

cytokine production, inhibits T-cell activity,

anti-inflammatory)

Acne, Na+ retention, htn,

hyperglycemia, psychosis,

cataracts, osteoporosis, Cushing

syndrome

Azathioprine Precursor to 6-mercaptopurine, acts as a

purine analogue that interferes with DNA

synthesis, inhibits proliferation of quickly

growing cells

Leukopenia, bone marrow

suppression, skin cancer,

alopecia, pancreatitis

Mycophenolate mofetil Anti-metabolite that inhibits de novo purine

synthesis, inhibits inosine monophosphate

dehydrogenase (IMPDH)

Diarrhea, nausea/vomiting,

leukopenia, anemia

Cyclosporine,

Tacrolimus

Binds to cytosolic biding protein and

inhibits calcineurin (decrease cytokine

production, inhibits lymphocyte

proliferation)

Acute/chronic nephrotoxicity, htn,

neurotoxicity, diabetes

Sirolimus Binds FKBP12, complex inhibits mTOR,

inhibits cell cycle progression

Hyperlipidemia, proteinuria,

impaired wound healing, non-

infectious pneumonitis

Belatacept Selective blockade of T cell costimulation

(signal 2)

Increased risk of PTLD in EBV

neg pts

“Standard” Triple Therapy

Calcineurin inhibitor

Anti-metabolite

Prednisone

HYPERTENSION AND

DIURETICS

Anything that causes increased delivery of

sodium to the collecting tubules will cause

hypokalemia (metabolic alkalosis will

follow)

Metabolic Alkalosis due to Diuretics

• Like hypokalemia, metabolic alkalosis is the consequence of

increased Na delivery to the CCT and a negative luminal potential but

H+ is secreted from the intercalated cells whereas K is secreted from

the principal cells. Aldosterone is also activated by volume loss

(contraction alkalosis).

• The key steps are:

• Increased Na delivery

• Luminal depolarization caused by increased Na influx into the principal cells

through ENaC

• Activation of the stimulates the electrogenic proton pump (ATPase) located in

the intercalated cells causing increased H+ excretion and bicarbonate

retention.

Thiazide Diuretics

• Blockade of the Na-Cl cotransporters hyperpolarize these cells.

• Hyperpolarization of the luminal membrane activates the voltage dependent calcium channels and increased Ca reabsorption from the lumen.

• Thiazides cause low urinary calcium, but may not cause hypercalcemia, since elevated serum Ca would reduce PTH secretion and also acts on renal CaSR.

• Thiazides cause reduction of ECF and this would result in more Na and Ca reabsorption in the proximal tubules. At the same time hypercalcemia causes polyuria.

• If volume depletion is severe enough, hypercalcemia may develop in these patients.

Treatment of hypercalcemia regardless of

the cause is hydration with sodium

chloride solution.

INTEGRATION

Churg Strauss• Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) is a multisystem disorder

characterized by chronic rhinosinusitis, asthma, and prominent peripheral blood eosinophilia

• Lungs: Asthma is the cardinal feature of EGPA

• Ear, nose, and throat involvement, including serous otitis media, allergic rhinitis, nasal obstruction, recurrent sinusitis, and nasal polyposis

• Nervous: Peripheral neuropathy, usually mononeuritis multiplex, is often seen

• Skin: Palpable purpura to subcutaneous nodules seen

• Renal: Acute Glomerulonephritis - RPGN

• Cardiac: Clinical manifestations include clinical signs of heart failure or pericarditis and cardiac rhythm abnormalities

• Antineutrophil cytoplasmic antibodies (ANCAs) are noted in 40 to 60 percent of EGPA patients. The majority of ANCAs associated with EGPA are p-ANCA/MPO.

• The diagnosis of EGPA is suggested by the presence of asthma, rhinosinusitis, and eosinophilia and then confirmed by lung biopsy or biopsy of other clinically affected tissues

Be careful with hypertensive patients and

hydrochlorothiazide and hypercalcemia

(hydrochlorothiazide can cause

hypercalcemia)

Chronic kidney disease and a large

KIDNEY multiple myeloma and HIV

nephropathy, diabetic nephropathy,

infiltrative: lymphoma and amyloidosis

Anemia, hypercalcemia, Chronic Kidney

disease and large kidney: Multiple

Myeloma

• Bone pain with lytic lesions discovered on routine skeletal films

• An increased total serum protein concentration and/or the presence of a

monoclonal protein in the urine or serum

• Systemic signs or symptoms suggestive of malignancy, such as

unexplained anemia

• Hypercalcemia, which is either symptomatic or discovered incidentally

• Acute renal failure with a bland urinalysis or rarely the nephrotic syndrome

due to concurrent primary amyloidosis.

Multiple myeloma can present with an

acute, subacute or chronic kidney disease

Light cast Nephropathy: Tubulointerstitial

Amyloidosis: Mesangium

Light Chain Deposition Disease: GBM

Palpable purpura Vasculitis

Vasculitides

• Large vessel vasculitis• Takayasu arteritis

• Giant cell arteritis

• Medium vessel vasculitis• Polyarteritis nodosa

• Kawasaki disease

• Primary central nervous system vasculitis

• Small vessel vasculitis• Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) ANCA

• Granulomatosis with polyangiitis (Wegener’s) – ANCA pr3

• Microscopic polyangiitis – ANCA MPO

• Henoch-Schönlein purpura (IgA vasculitis)

• Cryoglobulinemic vasculitis – Low C3/C4

• Hypersensitivity vasculitis

• Vasculitis secondary to connective tissue disorders

• Vasculitis secondary to viral infection

Don’t forget about drug induced vasculitis!

Allopurinol

Phenytoin

NSAIDs

ANA will be positive at some level

Henoch-Schönlein Purpura

• Henoch-Schönlein purpura (HSP), also called IgA vasculitis (IgAV) is the most common form of systemic vasculitis in children. Ninety percent of cases occur in the pediatric age group. In contrast to many other forms of systemic vasculitis, HSP (IgAV) is self limited in the great majority of cases. The disease is characterized by a tetrad of clinical manifestations:

• Palpable purpura in patients with neither thrombocytopenia nor coagulopathy

• Arthritis/arthralgia

• Abdominal pain• Bowel angina

• Gastrointestinal bleeding

• Renal disease• Hematuria

• Palpable purpura

• Age at onset ≤20 years lesion

• No new medications

Hepatitis C is related to cryoglobinemia

and membranous nephropathy.

Circulating immune complexes cause low

complement while in situ immune

complexes present with normal

complement

Bisphosphonates can cause FSGS

URINARY TRACT

MALIGNANCY

Angiomyolipoma

• Hamartoma composed of mixed adipose, smooth muscle and

hyalinized blood vessels

• Due to loss of function mutations in TSC1 and TSC2 genes

• Occur at young age in patients with tuberous sclerosis; (often

multifocal and bilateral in this setting)

• Tuberous sclerosis is characterized by lesions of the cerebral cortex that produce

epilepsy and mental retardation, a variety of skin abnormalities, and unusual benign

tumors at other sites, such as the heart.

• 50% of cases are not associated with Tuberous Sclerosis

• Female predominance

• Picked up on imaging (same density as fat)

• Can occur anywhere in the kidney

• Hemorrhage in large tumors poses a risk

Wilm’s Tumor

• Malignant kidney tumor comprised of blastema, primitive glomeruli and tubules and stromal cells.

• Epidemiology – 1:8000 children, 98% <10 yrs., 85% of all pediatric tumors are nephroblastomas.• 5-10% of cases occur in association with dysmorphic syndromes: WAGR,

Denys-Drash, hemihypertrophy, familial nephroblastoma and Beckwith-Wiedemann syndromes

• Presentation • Abdominal mass with hematuria and hypertension

• ¼ have metastasized at presentation to lymph nodes, lungs, or liver

• Histopathology• Primitive tubules

• Islands of hyperchromatic undifferentiated cells (blastema)

• Stroma filled with spindle shaped cells.

Wilm’s Tumor Prognosis

• Most cases are low stage with favorable histology and excellent

prognosis

• Considerations:

• Clinical Stage

• Low stage is extremely sensitive to chemotherapy, so good prognosis. (Most cases)

• Precursor lesions (bilateral tumors)

• Cellular anaplasia

• Primary Tissue type

• Blastema is susceptible to chemotherapy

WAGR Syndrome:

Wilm’s Tumor

Aniridia

Genital Abnormalities

Mental and motor Retardation

(WT1 deletion)

Denys Drash

Wilm’s tumor

Progressive glomerular disease

(Congenital nephrotic syndrome)

Male pseudohermaphroditism

(WT1)

Beckwith-Wiedemann

Wilm’s tumor

Neonatal hypoglycemia

Muscular hemihypertrophy

Organomegaly

(WT2)

Renal Cell Carcinoma

• Epidemiology

• Most common malignant renal tumor in adults

• Higher incidence in developed countries

• Risk factors

• Obesity

• Tobacco use

• HTN

• Unopposed estrogen therapy

• Exposure to occupational toxins

• Asbestos, petroleum, heavy metals

• Hereditary predispositions

• Von Hippel-Lindau syndrome,

• Hereditary Leiomyomatosis and Renal Cancer syndrome

• Hereditary Papillary Carcinoma

• Birt-Hogg-Dube syndrome

Syndrome Gene/Protein Chr Kidney Other

von Hippel-Lindau VHL/pVHL 3p25 Multiple, bilateral

CCC*, renal cysts

Hemangioblastomas,

pheochromocytomas

and pancreatic cysts

Hereditary papillary

renal carcinoma

c-MET/HGF-R$ 7q31 Multiple, bilateral

Type 1 papillary RCC

None

Hereditary

leiomyomatosis and

RCC

FH/FH# 1q42-43 Papillary RCC Type 2 Skin and uterine

leiomyomas and uterine

leiomyosarcomas

Birt-Hogg-Dubé BHD/folliculin 17p11.2 Multiple RCC of all

subtypes; hybrid

oncocytomas/chromo-

phobe RCC

Lung cysts,

spontaneous

pneumothorax, facial

fibrofolliculomas

Constitutional Chr 3

translocation

Unknown Multiple, bilateral

CCC

None

Tuberous sclerosis TSC1/Hamartin or

TSC2/Tuberin

9q34

16p13

Multiple, bilateral

angiomyolipomas,

lymphangioleiomyo-

matosis and kidney

cysts

Cardiac rhabdomyomas,

small gut adenomas,

lung cysts, cortical

tubers and

subependymal giant cell

astrocytomas

RCC Presentation

• 3 different types of RCC• Clear cell RCC (70-85%)

• Papillary RCC (10%)

• Chromophobe RCC (5%)

• Hematuria, costovertebral pain, and palpable mass• All 3 rarely occur, hematuria is most common

• Often picked up incidentally on imaging

• Often asymptomatic until >10cm• Generalized sx (fever, malaise, weakness, weight loss)

• Abnormal hormone production: polycythemia (EPO), hypercalcemia(PTHrP), HTN (renin), hepatic dysfunction, feminization/masculinization, Cushing syndrome (ACTH), eosinophilia, leukemoid reactions, amyloidosis

• May present with left sided varicocele

• Metastasis most often to lungs (50% of metastases) and bones (33%)

Imaging is the only reliable way to detect

suspected RCC.

Clear Cell RCC• 98% with p3 mutation

• Gross:

• Most likely arise from proximal tubular

epithelium, and usually occur as solitary

unilateral lesions

• Yellow mass

• Microscopic

• Cleared out cytoplasm contains fat and

glycogen

• High grade vascularity (hemorrhagic

grossly)

• Non papillary pattern.

• Prognosis dependent on tumor size and

extent of involvement and histologic

grade.

Type 1 and 2 Papillary RCC• Gross:

• Thought to arise from distal tubules

• Multifocal and bilateral, hemorrhagic

• Better prognosis than CCC

• Type 1

• Small bland cells in papillary pattern

• Foamy macrophages, Psammoma bodies

• Type 2

• Larger, stratified, eosinophilic cells

• Prominent nucleoli, Psammoma bodies

• Younger patients, worse prognosiss

Type 1 and 2 Papillary RCC

Chromophobe RCC

• Gross

• Solid brown/tan, resembles oncocytoma

• Thought to grow from intercalated cells of collecting ducts

• Excellent prognosis compared with that of the clear cell and papillary cancers.

• Microscopic

• Pale eosinophilic cells

• Perinuclear halo from microvesicals

• Well defined cell borders, arranged in solid sheets

• Concentration of the largest cells around blood vessels

• Prominent nucleoli

Chromophobe RCC

Hale’s Colloidal Iron differentiates

oncocytoma from Chromophobe RCC

Large variation in cell appearance

(pleomorphism) makes Fuhrman nuclear

grading difficult.

All RCCs can become sarcomatoid

Von Hippel Lindau syndrome associated

with renal cysts and multiple bilateral clear

cell carcinomas

Urothelial Carcinoma

• Malignant tumor arising from urothelial lining of renal pelvis, ureter,

bladder or urethra

• Highest rates in developed countries

• Risks

• Cigarette smoking

• Napthylamine

• Azo dyes

• Long term cyclophosphamide/phenacetin use

• Presentation

• Seen in older adults

• Classically: painless hematuria

• 2 distinct precursor lesions

• Noninvasive papillary tumors and Flat Noninvasive Urothelial Carcinoma (CIS)

• Flat is associated with early p53 mutations

Urothelial Carcinoma

• Known to be multifocal and recurrent - “field effect”

STAGING

Ta Noninvasive, papillary

Tis Carcinoma in situ (noninvasive, flat)

T1 Lamina propria invasion

T2 Muscularis propria invasion

T3a Microscopic extravesicle invasion

T3b Gross extravesicle invasion

T4 Invades adjacent structures

Flat

Papillary

The most common symptom of bladder

cancer is painless hematuria.

NEPHROLITHIASIS

Formation of Stones

• 1) Supersaturation:

• When the urine becomes supersaturated with crystal-forming substances, a seed

crystal may form through the process of nucleation.

• Low urine volume favors supersaturation

• 2) Crystallization:

• Spontaneous formation of crystal substrate or nuclei is uncommon

• Formation of crystals on pre-existing substrate occurs more commonly.

• Common substrates:

• Uric acid

• Apatite crystals

• Calcium phosphate (Randall) plaques, which originate in renal papillae

• Urine pH may affect crystallization

Risk Factors• Dietary

• Low fluid intake

• High animal protein intake, sodium, refined sugars, oxalate

• Grapefruit juice, apple juice, colas

• Medical• Previous stones (50% of stone formers will have recurrence within 10 years)

• Primary hyperparathyroidism

• UTI Alkaline urine Calcium phosphate and Magnesium ammonium phosphate

• Increased oxalate absorption (IBD, gastric bypass)

• Ileostomy acidic urine, low urine volume due to bicarb loss

• Prolonged immobilization hypercalciuria and urinary stasis

• Insulin resistant states decreased ammoniagenesis, decreased pH

• Genetic disorders• Primary hyperoxaluria

• Dent’s disease

• Bartter’s syndrome

• Distal (type I) RTA (dRTA)

• Cystinuria

Clinical Presentation

• Asymptomatic diagnosed on imaging

• Symptomatic

• Pain that comes in waves

• Flank pain: renal pelvis, upper ureter

• Groin: lower ureter, bladder, urethra

• Hematuria

• Nausea and vomiting

• Dysuria and urgency (distal ureter)

• Complications

• Obstructive Uropathy

• Renal failure

• Staghorn calculi loss of function

Imaging

• CT (non-contrast)

• Highly sensitive and specific (for kidney stones, CT is preferred)

• 95% sensitivity, 98% specifity

• Can diagnose obstruction and alternative abdominal pathology

• Ultrasound

• Used for radiation concerns/pregnancy

• Can miss small stones

• X-ray (KUB)

• Finds calcium stones (because radiopaque) or mixed stones containing calcium, but

not pure uric acid stones (because radiolucent)

• Intravenous pyelogram (IVP)

• Increased contrast toxicity and higher radiation

• MRI

• Used with concerns about radiation exposure as a follow-up to a non-diagnostic

ultrasound

Work Up

• History and physical exam

• Urinalysis w/ culture

• Laboratory evaluation

• Basic metabolic panel to assess for renal function

• Calcium and phosphorus

• PTH

• Urine spot for cysteine

• Urine pro/Cr ratio

• CBC if concern for infection

• Imaging (CT preferred)

Indications for Metabolic Evaluation

• Multiple Stones

• Bilateral Stones

• Uric Acid Stones

• Staghorn calculi

• Nephrocalcinosis

• Solitary Kidney

• Recurrent stones

• Renal transplant

• Age younger than 25

• CKD

High Risk Workup

• 24 Hour Urine collection

• Volume

• Calcium

• Oxalate

• Uric Acid

• Sodium

• Citrate

• 3 Collections must be done to rule out abnormalities

Factors affecting stone formation

• Favors

• Hypercalciuria

• Low urine volume

• Hyperoxaluria

• Hyperuricosuria

• Hypocitraturia

• Opposes

• High urine citrate

• High urine volume

• Low urine calcium

• Low urine oxalate

• Low uric acid

Urinary Citrate

• Inhibitor of crystallization of calcium salts

• Low UCitrate increases calcium oxalate stone formation

• Causes of hypocitraturia

• Metabolic acidosis

• Distal/type 1 RTA

• Chronic K depletion

• High dietary animal protein

Calcium Oxalate Stones

• Most common

• Idiopathic calcium oxalate stones: hypercalciuria

• 2 categories:• Hyperabsorptive hypercalciuria

• Renal hypercalciuria

• High dietary sodium intake can worsen hypercalciuria

• Other etiologies must be ruled out: • Primary hyperparathyroidism

• Excess vitamin D

• Milk-alkali syndrome

• Myeloma

• Malignancy

• Sarcoid

• Due to higher [Ca2+]: decreasing urinary oxalate will have greater effect on stone risk

Prevention of Calcium-containing Stones

• Increase urine volume to reduce calcium concentration

• Dietary protein restriction decrease oxalate excretion

• Moderation of calcium intake

• Restriction of sodium intake

• Administer potassium citrate reduces Ca excretion and increases

Ca solubility

• Administer thiazide diuretics

• Watch out for hypokalemia

Urinary oxalate can affect stone formation

especially in malabsorption due to IBD,

and following gastric surgeries

Struvite stones

• Composed of magnesium ammonium phosphate

• Formed largely after infections by urea-splitting bacteria (e.g., Proteus

and some staphylococci) that convert urea to ammonia.

• Alkaline urine causes the precipitation of magnesium ammonium

phosphate salts.

• Form some of the largest stones, as the amount of urea excreted

normally is very large

• Staghorn Calculi

• Treatment

• Removal of existing stones and treatment with antibiotics

Uric acid stones

• Normal uric acid excretion is <800mg/d in the healthy adult

• Common in individuals with hyperuricemia, such as patients with gout, and diseases involving rapid cell turnover, such as the leukemias (Tumor lysis syndrome).

• The most important factor involved is a fall in urine pH below 6.0 (urate is 10 times as soluble as uric acid)

• In contrast to the radiopaque calcium stones, uric acid stones are radiolucent.

• CT or IVP are required for diagnosis

• Treatment• Acetazolamide or alkali to increase pH

• Decrease protein intake

• Diuresis

• Allopurinol

Cysteine Stones

• Cystinuria is a rare autosomal recessive disorder that usually

develops in childhood

• Impaired transport of amino acids in proximal tubule

• Leads to excretion ranges of 480-3600

• Treatment:

• Increase urine volume

• Maintain urine pH above 7

• Penicillamine, topronin, captopril solubilize cysteine

Drugs that induce stones:

Triamterene

Indinavir

Lopinavir

Topamax

Acute Management

• Acute treatment focuses on:• Diagnosis of severity of stone burden, presence of obstruction or other

complications

• Supportive care, symptom management

• Urologic evaluation if needed based on severity of complications or failure to pass stone with conservative care

• Medical management• Pain control, hydration

• Diet modifications

• Assess for presence of infection• If infection present: urologic evaluation for possible removal

• None: evaluate stone size

• Stone size• >10mm: urologic evaluation

• <10mm: symptomatic management, alpha blockers, hydration, pain control

• Chronic Treatment = dietary, pharmacologic, lifestyle

Cysteine and uric acid stones require

alkalization of urine, while calcium

phosphate stones require acidification

Chronic Management

• Nutritional assessment:• Fluid intake: Recommendation 2 liters or more, mainly water

• Dietary calcium: Low dietary calcium can increase stone risk and urinary oxalate

• Low oxalate diet (avoid spinach and nuts)

• Low fat diet (decreases oxalate excretion)

• Reduced animal protein beneficial in calcium oxalate and uric acid stones

• Reduction in animal protein should be met with increase in vegetable protein intake

• Increased vegetable protein also serves to alkalinize urine

• Beer increases urate excretion, wine has a lesser effect. Beer is bad, wine is fine

• Lifestyle modification• Lower socioeconomic status associated with increase in urinary calcium

• Increased education (high school education or higher) associated with decreased stone risk, lower urinary calcium, and decrease in supersaturationof calcium oxalate and calcium phosphate

• Lower annual family income in patients with stone disease

Surgical Intervention

• Reasons for urologic evaluation:

• Acute Renal Failure

• Pyelonephritis, Sepsis of urinary origin

• Stone greater than 10 mm

• Stone less than 10 mm failing to pass with symptomatic management/supportive

care

• Pain unable to be controlled with medical therapy

URINARY TRACT

OBSTRUCTION

Kidney and Bladder Development

Kidney Development

• The pronephros forms and degenerates during the fourth through

sixth weeks, but the pronephric duct persists, and connects later-

developing kidneys to the cloaca.

• The mesonephros develops from the pronephric duct, which then is

named the mesonephric duct, and persist until development of the

metanephros.

• The metanephros develops at about five weeks, and forms ureteric

buds that give rise to the ureters, renal pelvises, calyces, and

collecting ducts.

• The cloaca subdivides to form the future rectum, anal canal, and the

urogenital sinus, which gives rise to the bladder and urethra.

Nephrogenesis

• Once the mesonephric duct comes in contact with the cloaca at the caudal aspect of the embryo, it grows cranially as the ureteric bud until it comes in contact with the metanephric mesenchyme.

• The ureteric bud and metanephric mesenchyme reciprocally induce growth, forming the kidney. The ureteric bud progressively enlarges and divides to form the renal pelvis, infundibula, collecting ducts, and 8-12 major and minor calyces

• The collecting tubules invaginate metanephric mesoderm to form metanephric vesicles, which subsequently elongate to form metanephrictubules.

• As the metanephric tubules are invaginated by capillaries (glomeruli), nephrons are formed.

• This process continues until the 32nd gestational week. At birth, approximately 750,000 to 1 million nephrons are present in each kidney

Kidney Migration

• With differential longitudinal growth of the embryo, the kidney

“ascends” from its initial location in the pelvis to its final location in the

upper retroperitoneum.

• During ascent, transient blood vessels serially arise and degenerate;

these arteries persist in ectopic kidneys as well as in some orthotopic

renal units.

• Concurrently, the kidneys rotate around their vertical and horizontal

axes so that their final orientation is one in which the upper poles are

slightly more medial and anterior than the lower poles

Horseshoe Kidney

• A horseshoe kidney is formed by fusion across the midline of two

distinct functioning kidneys. The normal ascent of the kidneys is

impaired by they inferior mesenteric artery (IMA) which hooks over

the isthmus.

• Risks:

• Hydronephrosis, secondary to pelviureteric junction obstruction

• Infection and pyeloureteritis cystica

• Renal calculi

• Increased incidence of malignancy

• Wilms tumour

• Transitional cell carcinoma (TCC)

• Increased susceptibility to trauma

Bladder

• Until gestational week 7, the embryo has a cloaca, a single orifice at the caudal aspect. During gestational week 7, the urogenital membrane grows caudally, dividing the cloaca into ventral (urogenital sinus) and dorsal (rectum) components

• With continued caudal growth of the embryo, the proximal (bladder) end of the mesonephric duct is progressively absorbed caudally, such that the common portion of the mesonephric duct is absorbed into the bladder trigone and urogenital sinus.

• The discrete “branches” of the mesonephric duct destined to become the male genital ducts and ureters are now distinct entities attached to the urogenital sinus

• The nonepithelial layers of the detrusor (non-trigone) portion of the bladder arise from condensations of splanchnic mesenchyme.

• The lumen of the allantois, which connects the bladder and the anterior abdominal wall, closes over time, yielding the urachus. Over time, the urachus becomes more fibrotic and becomes the median umbilical ligament

Blood Supply to Bladder

Main Supply: Anterior trunk

of the Internal Iliac artery

Superior, Middle and

Inferior Vesical Arteries

Smaller branches: Obturator

artery and inferior gluteal

artery

Blood Supply to Prostate

Inferior vesical artery,

Internal pudendal artery

and middle rectal artery

Micturition

Micturition

• Storage• 1. During the storage of urine, distention of the bladder produces low-

level vesical afferent firing.

• 2. This stimulates the sympathetic outflow in the hypogastric nerve to the bladder outlet and the pudendal outflow to the external urethral sphincter.• These responses occur by spinal reflex pathways and represent guarding

reflexes, which promote continence.

• 3. Sympathetic firing also inhibits contraction of the detrusor muscle and modulates neurotransmission in bladder ganglia

• Voiding reflexes• 1. During the elimination of urine, intense bladder-afferent firing in the

pelvic nerve activates spinobulbospinal reflex pathways that pass through the pontine micturition centre.

• 2. This stimulates the parasympathetic outflow to the bladder and to the urethral smooth muscle and inhibits the sympathetic and pudendaloutflow to the urethral outlet

Hypogastric Plexus

• The hypogastric plexus receives contributions from both the lumbar

and sacral regions of the spinal cord.

• Innervates the pelvic viscera and contains both sympathetic and

parasympathetic nerves.

• It carries afferent and efferent nerve fibers that are critical for the

control of micturition.

Injuries Affecting Bladder Function

• Injury above T12 may cause Spastic/Reflex bladder: Reflex

action to empty the bladder

• Injury below T12 may cause Flaccid bladder: Bladder will not

contract when full due to an areflexic detrusor

• If the lumbar spinal cord is injured, the patient will demonstrate

symptoms of urinary frequency, urgency, and urge incontinence

but will be unable to completely empty the bladder.

• If the sacral spinal cord is injured, urinary retention due to

detrusor areflexia develops; the detrusor muscle cannot

contract to empty the bladder.

Neurotransmitters

• Parasympathetic• Contraction of detrusor

• S2-S4 preganglionics via pelvic splanchnic nerves: Ach

• Postganglionic neurons (nAChR) – nicotinic

• Detrusor smooth muscle (mAChR) – muscarinic

• Inhibition to outflow region and urethra: NO

• Sympathetic• Contract internal urethral sphincter and urethra

• Intermediolateral nuclei in T10-L2 preganglionics via hypogastricsplanchnic nerves: Ach

• Inferior mesenteric ganglia (nACh)

• Lumbosacral sympathetic chain ganglia (nACh)

• Postganglionics to detrusor muscle: norepinephrine

• Somatic• Pudendal nerve: ACh

Pharmacology of Micturition

• Anti-cholinergics• M3 Receptor Antagonists

• Where are M3 receptors? Detrusor

• Effect: Relaxes Detrusor and Decreased Urgency

• Drugs = oxybutynin

• Highly selective M3 agents like darifenacin and solifenacin are available with equal efficacy and decreased side effect profile.

• Sympathomimetics• ß2-adrenergic receptor agonist

• Where? Detrusor

• Effect: Detrusor Relaxation, increased bladder capacity

• Alpha-1 adrenergic receptor• Where? Detrusor, prostate (in men)

• Effect: Contraction IUS, decreased micturition pressure

• Drugs: Prazosin, Terazosin, Doxazosin

Bladder Compensation: Irritability

• During the initial phase of compensation called irritability

• Detrusor muscle hypertrophies to try to maintain normal urine flow despite increase

resistance from the overgrown prostate.

• The muscular hypertrophy results in a bladder that is hypersenstitive,

• Patient notes the urge to void earlier in the filling phase.

• If the patient cannot suppress these urges, he will note urinary

frequency both day and night.

• If the urge overwhelms his voluntary control of his urethral sphincter,

he may experience urgency incontinence.

Trabeculations and Diverticulae

Bladder Compensation: Stiffening• As the hypertrophy progresses large muscle bundles, called

trabeculations appear.

• With increasing bladder pressures, some of the trabeculations may

form cellules as the bladder epithelial lining is pushed out between

muscle bundles.

• Collagen deposition and fibrosis in bladder wall cause decreased

compliance. The stiff bladder is unable to completely empty.

• With sustained high pressures, cellules may continue to enlarge,

completely losing their muscular backing and develop into a bladder

diverticulum

Bladder Compensation: Stasis• Urinary frequency develops into

urinary hesitancy as bladder slowly develops contractions strong enough to overcome resistance at bladder outlet

• Loss of force and size of urinary stream

• Post void dribbling due to detrusor exhaustion at the end of contraction phase

• Stasis (UTI and stones) and urinary retention are seen.

Bladder Decompensation: Retention

• With continued outlet resistance, the patient’s bladder can no longer

generate a strong enough contractions.

• If the patient undergoes an acute insult to his ability to void, he may

be completely unable to empty, called acute urinary retention.

• Causes for urinary retention may be a high fluid intake , a voluntary delaying of

voiding, or medication which interferes with detrusor function (anticholinergics)

or sphincter relaxation (alpha-adrenergics).

• Immediate treatment: decompress the bladder with foley catheter.

Overview of Stages

• Early: Bladder outlet obstruction causes higher detrusor voiding pressures and compensatory bladder muscle hypertrophy. Urgency, frequency, and nocturia.

• Mid: Increased resistance at the ureteral orifice is transmitted back to the ureter, causing ureteral dilation. Trabeculations and diverticula appear. Collagen deposition and fibrosis lead to hesistancy, retention.

• Late: Stasis (UTI and stones) and urinary retention are seen. The ureter continues to dilate and becomes tortuous. The pressure is transmitted back to the kidney, which results in loss of the fornicealangle and flattening of renal papilla.

• End stage: Finally, the kidney undergoes severe hydronephrosis and renal atrophy. Post renal AKI.

Lower Tract Obstruction

Congenital Acquired Intrinsic Acquired Extrinsic

Bladder neck obstruction Benign prostatic hyperplasia Carcinoma of cervix or colon

Ureterocele Cancer of prostate/bladder Trauma

Posterior urethral valves Calculi

Anterior urethral valves Diabetic neuropathy

Stricture Spinal cord disease

Meatal stenosis Anticholinergic drugs and alpha-

adrenergic antagonists

Phimosis Stricture/Tumor/Trauma

Failure to Store6

• Detrusor Instability (Overactive Bladder)

• Cauda Equina Syndrome

• Neurogenic bladder

• Central Nervous System

• Flaccid: below T12

• Spastic: above T12

• Pelvic floor failure

• Pelvic prolapse/stress incontinence

675

Failure to Empty

• Detrusor muscle failure:

• Diabetic cystopathy, medications (sympathomimetics, anticholinergic)

• Peripheral nerve injury:

• Radical pelvic surgery, neurologic disorder

• Bladder outlet obstruction:

• BPH, urethral stricture, cancer, stone, infection, inflammation

BPH

Overgrowth of the prostate in the transitional zone (periurethral)

Affects the glands and fibromuscular stroma

Prostate normal size: 20 gm

BPH: 30-300 gm

Direct mechanical effect on urine outflow.

Outlet obstruction causes changes in bladder.

Dynamic process:

Ball valving mechanism of obstruction

Changes over time

BPH: treatment

• Acute Obstuction: Drainage

• Watchful waiting: Mild symptoms

• Medical therapy:

• Bladder neck and prostate:

• α-1 adrenergic blockers

• Prazosin, Terazosin, Doxazosin

• Tamsulosin, Alfuzosin

• Prostate:

• 5-α reductase inhibitors

• Finasteride and Dutasteride

• Detrusor:

• Anti-muscarinic agents

• Oxybutynin, Tolterodine, etc.

Upper Tract Obstruction

Intrinsic Extrinsic

Congenital Ureteropelvic junction obstruction Crossing vessel

Ureterovesical junction obstruction Retrocaval ureter

Vesicoureteral reflux

Acquired Stone Abdominal Mass

Stricture Retroperitoneal fibrosis

Mass (tumor, fungus ball, blood clot)

Hemodynamic

Effects

Tubule Effects Clinical Effects

Acute

↑Renal blood flow

(compensation)

↑ Ureteral and tubule

pressures

Pain (capsule distention)

↓GFR ↑Reabsorption of Na+, urea,

water

Azotemia

↓Medullary blood flow Oliguria or anuria

↑Vasodilator prostaglandins,

nitric oxide

Chronic

↓Renal blood flow ↓Medullary osmolarity Azotemia

↓↓GFR ↓Concentrating ability Hypertension

↑Vasoconstrictor

prostaglandins

Structural damage;

parenchymal atrophy

AVP-insensitve polyuria

↑Renin-angiotensin production ↓Transport functions for Na+,

K+, H+

Natriuresis

Hyperkalemic, hyperchloremic

metabolic acidosis

Hemodynamic Effects Tubule Effects Clinical Features

Release of obstruction

Slow ↑ in GFR (variable) ↓Tubule pressure Postobstructive diuresis

↑Solute load per nephron (urea,

NaCl)

Potential for volume depletion and electrolyte

imbalance due to losses of Na+, K+, PO4²,

Mg²+, and water

Natriuretic factors present

Perinephric Stranding

UTI

Term Definition

Urinary tract

infection (UTI)

Bacteria isolated in urine indicative of an infection in the lower

urinary tract, with or without involvement of the upper tract or the

presence of symptoms.

Bacteriuria Bacteria in the urine; “significant” if quantified growth exceeds 105

colony-forming units (CFU)

Asymptomatic

bacteriuria (ABU)

Significant bacteriuria in the absence of local or systemic symptoms

referable to the urinary tract

Cystitis Symptomatic bladder infection

Acute

pyelonephritis

Acute suppurative inflammation of the kidney caused by bacteria,

spread hematogenously or directly via ascending UTI

Prostatitis Inflammation of the prostate gland

Risk Factors

• Children and young adults• Female predominance (30:1 F:M ratio for PCP office visits)

• Older Adults• Gender gap narrows (increased prevalence among men)

• Males > 50 have increased prevalence due to prostatic hypertrophy causing urinary obstruction

• Postmenopausal women are at risk due to changes in vaginal flora caused by changes in hormonal balance

• Women• Up to 40 % have a UTI in their lifetime

• Up to a quarter of women with UTIs have recurrent UTIs

Host Factors Predisposing to UTI

• Anatomic abnormalities: • Ureteral reflux

• Neurologic abnormalities: • Neurogenic bladder, spinal cord injury → urinary stasis → fosters bacterial growth

• Urinary obstruction• Prostatic hypertrophy, obstructing stones

• Hormonal flux:• Pregnancy, Postmenopausal, Change in hormonal balance alters vaginal flora

• Pregnancy is associated with ureteral relaxation, increasing risk of ureteral reflux of bacteria

• Immunocompromised states• Diabetes Mellitus

• Renal transplant: immunosuppressive drugs, post-surgical bladder dysfunction (stasis), incompetent ureterovesical valve (reflux)

• Genetic factors• ABO blood group

• Type B

• Non secretors: unable to produce water soluble forms of the ABO antigens

• First degree female relative with recurrent UTIs

Environmental Factors

• Intercourse

• Mechanical introduction of bacteria into urethra

• Catheters/stents/other FBs

• Introduce pathogens to urinary tract and provide nidus for growth

• Recent use of antimicrobials, diaphragms, or spermicide

• Alters urogenital flora overgrowth of pathogenic bacteria

• Altered mental/functional status

• Can lead to incomplete voiding and urinary stasis

Infecting Organisms

• Majority of infecting organisms are derived from fecal flora.

• > 80% of UTIs are caused by enteric Gram negative rods

• E. Coli is the most common

• Proteus spp, Klebsiella spp, Enterobacter spp, and Enterococcus spp

• Fungal (Candida spp)

• Seen in hospitalized patients with indwelling catheters and/or recent Abx

use

• Mycobacterial (disseminated TB)

• Rarely seen in the U.S. but is fairly common worldwide

• Viral (much less common)

• Adenovirus

• BK virus (common in renal transplant population)

• Consider hematogenous spread

• S. aureus (endocarditis, etc.)

• Salmonella spp

Outpatient vs. Inpatient

Similar flora and incidence, with the

exception of decreased incidence of E.

coli and increased incidence of

Enterococcus and Candida infections in

the inpatient setting.

Pathogenesis

• Common Pathogenesis: Vaginal or fecal bacteria colonize the

periurethral mucosa and ascend to the bladder.

• From there, bacteria can continue ascent to kidneys (aided by

vesicouretal reflux).

• Pyelonephritis can more rarely result from hematogenous spread

• Sepsis

• Infective endocarditis

• More likely with ureteral obstruction

• ICU patients

• Immunosuppression

• Commonly non-enteric organisms

• Staphylococcus aureus

CLASSIFICATION SCHEMA

• All Males, some

Females

• Anatomic abnormality

• Neurologic dysfunction

• Urinary obstruction

• Immunocompomised

• Indwelling

catheters/stents

• Ambulatory Females

• Pre-menopausal

• Non-pregnant

• No indwelling GU

hardware

• No antibiotic use within

2 weeks

Uncomplicated infection Complicated infection

Complications of Pyelonephritis

• Sepsis of urinary origin

• Perinephric abscess

• Papillary necrosis

• Emphysematous pyelonephritis(rare): associated with diabetes

Cystitis

• Dysuria

• Frequency/urgency/nocturia

• Hesitancy

• Suprapubic discomfort

• Gross hematuria

Prostatitis

• Dysuria

• Frequency

• Pain in prostatic/perineal areas

• Fevers & chills

Pyelonephritis

• Fever & malaise

• Sudden onset

• CVA tenderness

• Dysuria

• Frequency/urgency

• Pyuria:

• Nausea/Vomiting

• High fevers/rigors

Clinical Manifestations

Cystitis: Lower abdominal tenderness

Pyelonephritis: CVA tenderness

Prostatitis: prostate tenderness

Urinalysis and Culture

• Pyuria- Leukocyte esterase

• Bacteriuria- Nitrites

• Nitrite production commonly assocated with Enterobacteriaceae

(not with Pseudomonas spp, Enterococcus spp or S.saprophyticus)

• pH: if elevated (>7.5) consider Proteus spp

• Gram stain can help identify causative agent

• Helpful for inpatients

• Not always necessary in outpatients with uncomplicated UTIs

• Should be pursued if patient not responding to empiric treatment or

if UTI was nosocomially acquired

Normal Abnormal

Urinalysis

+

Microscop

y

No Leukocyte Esterase

No nitrites

<5 WBC

Positive Leukocyte Esterase

Positive nitrites

>5-10 WBC

Presence of Bacteria

Urine

Culture

No bacteria or <1000

CFU/mL

105 bacteria

(& asymptomatic)

102-104 bacteria

(& symptomatic or partially

treated)

Lower vs. Upper UTI

• Lower UTI -urethritis, cystitis, prostatitis

• Urinary frequency and pain on urination

• Burning/pain on urination, frequency/urgency and bladder spasm

• Lower abdominal tenderness to palpation and potential urethral

discharge

• Upper UTI- pyelonephritis

• Flank pain (usually unilateral) and constitutional symptoms

• Fever and malaise

• Possible abnormal vital signs, costo-vertebral angle to palpitation

• Radiographic studies (US and CT scan) may suggest peri-nephric

stranding as a marker of inflammation

• May present with or without symptoms related to lower tract UTI

Treatment for ABU

• Asymptomatic Bacteriuria generally does not need treatment. May be

harmful because it will cause recurrent infections and antimicrobial

resistance.

• Exceptions include:

• Pregnant women- These patients are at 20-30% increased risk of

pyelonephritis which can cause pre-term delivery and low birth weight babies.

• Screening for ABU usually done at 12-15 week gestation mark

• Patients who are about to undergo genitourinary tract procedures associated

with mucosal bleeding such as Transurethral resection of the prostate (TURP)

• Screen for ABU and treat with periprocedural antibiotics and longer for patients

with indwelling hardware in place.

TreatmentDrug/Dose/Duration Clinical Efficacy % Common Side Effect

First-line options

Nitrofurantoin,

100mg BID X 5d

84-95 N, HA

TMP-SMX,

1 DS BID x 3d

90-100 Rash, urticaria, N/V,

hematologic abnormalities

Fosfomycin,

3gm single dose

70-91 N/D, HA

Second-line options

Ciprofloxacin,

500mg BID x 3d

85-95 N/V/D

HA, drowsiness

B-lactams, doses vary

3-7d

79-98 N/V/D

Rash, urticaria

Management

Diagnosis Length of

Tx

Exception

Asymptomatic

Bacteriuria (ABU)

Generally,

no need to

treat

Exceptions: patients with ABU who benefit from

treatment:

1) Pregnant women

2) Patients who are about to undergo genitourinary

tract procedures (TURP, mucosal bleeding)

Acute Cystitis 3 day Avoid TMP/SMX if regional rate or resistance are 20%

Complicated UTI 7 day May extend tx to 10-14d if delayed response

May stop after 5 days if early symptom resolution

Acute

Pyelonephritis

Non-hospitalized

hospitalized

7 days

10-14 days

7 days = Fluoroquinolones

14 days= TMP/SMX

10-14 days= B-lactams

Prostatitis 3-4 wks

The detection of S. aureus or Salmonella

in urine culture warrants a search for

bloodstream source.