Medical School Renal Review

Urine ProductionSupplements amniotic fluid•Starts 10th weeks•Problem results in oligohydramnios•

Kidney Migration

Failure to ascend results in pelvic kidney○

Kidneys are formed in the pelvis and ascend to lumbar location•

There is progressive revascularization as kidneys ascend•

Renal Development

Lateral to the aorta○

Tissue arises from intermediate mesodermcalled nephrogenic cords

•

Divided into 3 stages:•

Forms first○

Non-functional○

Pronephros•

Forms second○

Functional weeks 6-10○

Cloaca is later partitioned into bladder & urethra and rectum

□

Connects the mesonephros to the cloaca

Mesonephric ducts○

Sproat distally from mesonephric ducts

Induce formation of metanephros

Ureteric buds○

Mesonephros•

Gives rise to final kidney and ureters○

The allantosis forms the urachus (after the lumen is obliterated) and ultimately the median umbilical ligament

○

Metanephros•

Molecular Regulation

Stimulates branching of, and receptability to ureteric bud○

Mesenchyme expresses GDNF, HGF & WT1•

Ureteric bud in turn produces FGF2 & BMP7 which stimulate mesenchyme proliferation

•

Bladder and Urethra Development

Anterior cloaca forms the urogenital sinus, posterior forms the rectum

○

Develop from hindgut endoderm (cloaca)•

Continuous with allantosis

Different embryological origins

However, mesonephric ducts that develop into the ureters are incorporated into the bladder as the trigone

□

Smooth muscle develops from mesoderm

□

Develops into the bladder

Vesical portion○

Develops into membranous urethra (females) or prostatic and membranous urethra (males)

Neck○

Develops into vestible of the vagina (females) or penile urethra (males)

Definitive urogenital sinus○

Urogenital sinus is divided into three parts:•

Renal Development

Embryology

Horseshoe kidneyFusion of the lower lobes•Benign•Predisposition to nephrolithiasis•

Potter's Sequence

Results in bilateral renal agenesis○

Due to a malformation of the ureteric bud•

Fetus is unable to produce urine from swalled amniotic fluid, resulting in oligohydramnios

•

Clubfoot, flipper hands and/or hyperextensible joints

Limb deformities○

Sloping forehead, flattened nose, recessed chin and low floppy ears

Facial deformities○

Pulmonary hypoplasia○

Presentation•

Results in death•

Pelvic KidneyFailure of the kidneys to ascend•

Can lead to pain and infection

Hydronephrosis & vesicoureteric reflux

○

Presentation•

Kidney Cystic Disease

Due to lack of induction of sacral intermediate mesoderm

○

Cysts vary in size○

Abnormal structures and lobe formation○

Multicystic renal dysplasia•

Mutation in PKHD1 gene that encodes fibrocystin

○

Leads to enlarged, sponge-like kidneys○

Childhood polycystic kidney disease•

Cysts contain red/brown fluid

Late onset autosomal dominant disease characterized by bilateral, multiple expanding cysts

○

Leads to renal failure○

PKD1 gene that encodes polycystin-1

PKD2 gene that encodes polycystin-2

Mutation of either:○

Cyst formation

Mutations result in abnormal cilia○

HTN

Polyuria & proteinuria

Berry anuerysms

Mitral valve prolapse

Hematuria□

Renal colic

Presentation○

HTN control

Dialysis

Treatment○

Adult polycystic kidney disease•

Other Cystic Diseases

Cysts are filled with a clear fluid○

Benign○

Simple cysts•

Associated with dialysis○

Histology shows calcium oxalate crystals○

Can lead to renal cell carcinoma○

Aquired cystic disease•

Renal Medullary Cystic Disease

Common○

Multiple cystic dilations in the medullary collecting ducts

○

Medullary sponge kidney•

Medullary cysts located at the corticomedullary junction

○

Cortical & tubular atrophy

Interstitial fibrosis

Hyalinization

Histology○

Small kidneys with granular, contracted surface

Gross○

Polyuria & polydypsia

Tubular acidosis

Liver fibrosis

Motor abnormalities□

Retinal dystrophy□

Ocular problems

Presentation○

Nephronophthisis & adult-onset medullary cystic disease•

Renal Congenital Anomalies

Embryology

Posterior Abdominal Wall LymphaticsLower limbs drain into the deep inguinal nodes, common iliac nodes and finally the lumbar nodes

•

The gluteal region, perineum and posterior abdominal wall drain directly into the lumbar nodes

•

Lumbar nodes drain into lumbar trunks and then the cisterna chyli

•

The inferior surface of the diaphragm drains into the celiac nodes and then the intestinal trunk

•

The GI tract drains directly into the intestinal trunk•Intestinal trunk drains into the cisterna chyli•Cisterna chyli drains into the thoracic duct•

KidneyRight kidney is more palpable and sits lower than the left (T12-L4)

•

Fat In the renal sinus

PerInephric fat○

Fat Around the kidney

PerAnephric fat○

External features•

Segments of the kidney correspond to segmental branches of the renal artery

•

Maintainence of ECF osmolarity○

Regualtion of total body water (TBW)○

Urea (protein metabolism)

Uric acid (nucleic acid metabolism)

Creatinine (muscle breakdown)

Urobilinogen (heme/RBC metabolism)

Metabolized by liver, removed by kidney

□

Hormones & drug excretion

Excretion of metabolic waste○

Endocrine functions○

Gluconeogenesis○

Function•

BladderLocated in the retropubic space•

Forming rugae○

Lined by transitional epithelium•

Innervated by the pudendal nerve

External urethral○

Present in males only

Internal urethral○

Sphincters•

Superior bladder is supplied by the superior vesical arteries from the internal iliac

○

Inferior/posterior bladder is supplied by the inferior vesical arteries in males, and the vaginal arteries in females

○

Vessels•

Parasympathetics from S2-S4 innervate the detrusor muscle

○

Innervation (parasympathetic)•

Fibers from T11-L2○

Innervation (sympathetic)•

Travel with parasympathetics○

Spinal reflex with CNS modification

Stretch receptors are integrated in the spinal cord

1.

Efferent outflow via parasympathetics causes contraction of detrusor muscle

2.

Pontine□

Hypothalamus□

Relexation of pelvic floor muscles, perineal muscles and external urethral sphincter

Cortex□

Modifications can be inhibitory (mid-brain) or facilitory

Micturition○

Afferents•

UretersRetroperitoneal•

Ureters pass under arteries and vas deferens in males

○

Ureters pass under uterine artery and round ligament in females

○

"Water under the bridge"•

Renal Anatomy

Anatomy

Lumbar PlexusMoms In Illinois Get Lucky Frequently On Love

•

Root T12-L4

Nerve to quadratus lumborum○

Root L2-L4

Nerve to psoas major○

Root L1-L2

Nerve to psoas minor○

Muscular branches•

Innervates hypogastric and butt○

Root L1○

Illiohypogastric nerve•

Root L1○

Innervates naterior labia majora

Anterior labial nerve (female)○

Innervates anterior scrotum

Anterior scrotal nerve (male)○

Illioinguinal nerve•

Root L1-L2○

Innervates cremaster muscle and scrotum (male)

Genital branch○

Innervates femoral triangle

Femoral branch○

Genitofemoral nerve•

Root L2-L3○

Innervates lateral thigh○

Lateral femoral cutaneous nerve•

Root L2-L4○

Inervates anterior thigh muscles○

Femoral nerve•

Root L2-L4○

Innervates medial thigh muscles○

Obturator nerve•

Root L4-L5○

Joins sacral plexus○

Lumbosacral trunk•

NephronFunctional unit of the kidney•

Renal corpuscle○

Tubular system○

Composed of:•

Short thin descending limb and do NOT have a thin ascending limb

Located almost entirely in the cortex

Loop of Henle barely penetrates the medulla

Cortical○

Glomerulus is located at the junction between the cortex and medulla

Contain exceptionally long Loop of Henle

Long thin descending and ascending limb

Juxtamedullary○

Types of nephrons•

Kidney Structure I

Anatomy

Renal CorpuscleFilters the plasma•

Fluid moves from the glomerulus into Bowman's space

○

Renal corpuscle is composed of the glomerulus and Bowman's space/capsule

•

Unless (+) charged○

Damage results in proteins crossing and proteinuria

Small proteins can cross, but not large ones (EX: albumin)

○

Organic molecules and proteins cross○

Molecules >8nm will NOT cross•

Creates a leaky capillary

The 1st fluid barrier is composed of endothelial fenestrations in the glomerulus capillaries

○

Collagen IV□

Laminin (glycoprotein)□

Fibronectin/entactin□

Heparin sulfate (proteoglycan)□

Lipid bilayer with a gel-like mesh of glycoproteins

Blood proteins STAY in the blood□

Negative charge aids in protein filtration

2nd fluid barrier is the glomerular basement membrane (GBM)

○

Podocytes contain pedicels (foot projections) along the basement membrane

Filtration occurs between the pedicels through filtration slits

3rd fluid barrier are the podocytes○

Fluid filtration•

Tubular SystemDivided into functional units:•

Continuous with Bowman's capsule○

Surrounded by peritubular capillaries arising from the efferent arterioles

○

Reabsorbs essential substances lost during filtration (EX: glucose)

○

EX: hormones, drugs

Actively secretes substances○

Proximal convoluted tubule (PCT)•

Thin descending limb ends at hairpin turn, then forms;

○

Found only in juxtaglomerular nephrons

Thin ascending limb○

Pumps Na+, K+, and Cl- from the lumen into the cells via NKCC-2 transporter

Pumps ions into the interstitium via Na/K ATPase and K & Cl channelgs

Interstitium is also concentrated by urea

Concentrates the interstitium○

Arise from efferent arterioles

Function is water uptake

Surrounded by capillaries called vasa recta○

Passes between the afferent & efferent arterioles

Location of juxtaglomerular apparatus

Ascending thick limb○

Loop of Henle•

Travels back through the medulla, absorbing water and urea

○

Located distal to juxtaglomerular apparatus○

Surrounded by peritubular capillaries○

Contains principal and intercalated cells○

Forms collecting duct○

Distal convoluted tubule (DCT)•

Final passage of urine towards the renal pelvis○

Collecting duct•

Juxtaglomerular ApparatusComposed of macula densa cells, extraglomerular mesangial cells and juxtaglomerular cells

•

Specialized epithelial cells of the ascending thick limb

○

Sensitive to Na and flow rate through the DCT○

Regulate GFR through paracrine action○

Macula densa•

Specialized myoepithelial cells in the afferent arteriole

○

Act as baroreceptors (monitor BP)○

Maintain normal GFR (via BP control) through release of renin

○

Juxtaglomerular cells (JG cells)•

Contractile cells with receptors for both AG II and natriuretic factor

○

Further regulate GFR○

Extraglomerular mesangial cells•

Kidney Structure II

Anatomy

ECF, ICF & Total Body Water (TBW)Although the osmolarity of ICF and ECF is the same, the composition of each is very different

•

Plasma and interstitial fluid○

Main cation is Na+○

Main anions are Cl- and HCO3-○

75% is interstial fluid, 25% is plasma○

ECF•

Main cations are Mg+ and K+○

Main anions are proteins and PO4-○

ICF•

60% of total weight is water (TBW)○

40% of total weight is ICF (2/3 of TBW)○

20% of total weight is ECF (1/3 of TBW)○

60-40-20 rule•

Infants and children have a higher TBW than adults due to loss proportion of fat

○

Aging and females have more body fat and thus a decreased TBW

○

As body fat percent increases, TBW decreases•

Glomerular Filtration Rate (GFR)

V is urine flow rate (mL/min)□

GFR = Ucreatinine x V / Pcreatinine

Gold standard for GFR measurement is inulin although creatinine is more useful clinically

○

Normal GFR is 120 mL/min○

Decreased GFR causes elevated BUN and creatinine in the blood

BUN is also used to estimate GFR○

Represents renal clearance that is neither reabsorbed nor secreted

•

Hydraulic permeability○

Surface area○

Net filtration pressure○

Filtration depends on•

Favors filtration over the entire capillary due to stronger hydrostatic pressure than oncotic pressure

○

Negligable in Bowman's space□

Usually OPPOSES filtration

Increases along the capillary due to the same protein concentration but reduced water

Altered oncotic pressure in the blood wil change GFR

Net oncotic pressure○

Increased pressure within Bowman's space (kidney stone) will decrease GFR

Opposes filtration within Bowman's space□

Usually FAVORS filtration

Combinations that reduce blood flow will reduce GFR and vice versa

Afferent contraction reduces GFR

Efferent contraction increases the pressure upstream, this increasing GFR

Afferent and efferent arterioles can contract□

Due to BP and arterioles

Net hydrostatic pressure○

Net filtration pressure•

Contraction of mesangial cells in response to vasoactive paracrines

Thickened GBM□

Glomerular, GBM or podocyte damage

Reduced surface area results in reduced GFR○

Surface area•

GFR AutoregulationGoal of the kidney is to minimize changes and keep GFR steady

•

Due to high pressure already within the glomerulus, it is extremely susceptible to pressure changes (HTN) which can cause damage

•

Increased pressure causes stretch of the afferent arteriole

○

Maintains constant RBF

This leads to vasoconstriction of the afferent arteriole

○

Myogenic autoregulation (stretch)•

As BP increases, filtrate increases○

Filtered Na+ is thus increased, resulting in increased Na+ in the DCT

○

Increased Na+ is sensed by the macula densa

○

Macula densa cells secrete paracrines, reducing BP in kidney

○

Tubuloglomerular feedback•

Fluid Dynamics and GFR I

Physiology

Other GFR Regulation Mechanisms

Increases GFR and water excretion○

Via reduced ENaC phosphorylation

Decreases Na+ reabsorption○

Decreases renin secretion○

Produced in response to hypervolume, exercise and caloric restriction

○

Natriuretic peptide•

Decreased RBF and GFR

Activation of α1receptors on renal arterioles (efferent > afferent) causes vasoconstriction

○

Sympathetic stimulation•

Increasing RBF and GFR

PGE2 and PGI1 cause vasodilation of the afferent and efferent arterioles

○

NSAIDs inhibit PGE synthesis nd can interefere with these protective effects in the kidney

○

Prostaglandins/bradykinin •

Vasoconstrictor of the efferent arteriole preferentially

○

Can result in increased GFR if only the efferent arteriole is constricted, or decreased GFR if both arterioles are constricted

○

AG II•

Increased RBF and GFR

Dilates vessels and suppresses Na+ reabsorption in the proximal tubule by inhibiting Na/K ATPase

○

Dopamine•

Types of Transport

Substances travel through tight junctions between cells or cells themselves

○

Passive diffusion○

Paracellular•

Substances or transported through the apical, cytoplasma and basolateral cell surfaces

○

Uses channels and transporters○

Transcellular•

Fluid Dynamics and GFR II

Physiology

Glucose

Overwhelms the glucose transporters

Unless serum glucose is greater than 200 mg/dL ○

Glucose >350 mg/dL results in glucosuria○

Filtered freely and completely reabsorbed in the PCT•

Na+/glucose symporter

Saturated at 200 mg/dL (splay)

Via SGLT-2 co-transporter○

Na+ is pumped out at basolateral membrane

Secondary active transport maintains low Na+ gradient within the cell

○

Glucose is pumped into the interstitial fluid at the basolateral membrane by GLUT-2

○

Reabsorption•

Amino Acids and Proteins

Na+/AA co-transporter○

AAs are freely filtered and completely reabsorbed by secondary active transport and in the PCT

•

Peptides that cross are either degraded into AAs by luminar surface peptidases or reabsorbed via receptor-mediated endocytosis

○

Proteins•

Breakdown product of AA○

Breakdown product of creatine□

Directly reflects amount of muscle in the body

□

Creatinine

Ammonium

Uric acid

Urea

Excreted in several forms:○

Related nitrogen metabolism•

UreaFreely filtered•Secreted in the Loop of Henle via OCT•50% is reabsorbed by urea transporters in the collecting duct

•

Converted from ammonia by the liver○

Can also be converted into glutamine by the liver○

Urea is a waste product from the metabolism of AA•

Glutamine is then converted back into ammonium and bicarb

○

Bicarb is symported back into the blood with Na+○

Ammonium is antiported into the lumen via Na+○

Glutamine is actively pumped into the PCT epithelial cells from the blood and the lumen of the PCT

•

Organic Cations

Endogenous (hormones) and exogenous (drugs) substances

○

Most are freely filtered or actively secreted at the PCT•

Uniporter○

Secretion (basolateral absorption) is via organic cation transporters (OCT)

•

Secretion (into the lumen) is via a H+-antiport•

Organic AnionsActive secretion is via organic anion transporters (OAT) on the basolateral membrane (absorption into PCT epithelial cells)

•

Responsible for majority of drug and metabolite secretion•

Filtered freely○

Reabsorbed in the PCT○

Secreted in late PCT via OAT○

Transport insufficiency results in gout○

Urate•

100% cleared in single pass○

Filtered freely and actively secreted○

Used to estimate renal plasma flow○

PAH (para-aminohippuric acid)•

Phosphate

Slight increase in filtered load produces substantial phosphate loss

○

Filtered load always exceeds transport max•

Reabsorbed via a Na/Pi transporter•

Chloride

Follows Na+ and water○

Paracellular diffusion•

Cl- enters the cell, HCO3- is pumped into the interstium

○

Cl-/HCO3- antiport on the basolateral membrane•

Reabsorption & Secretion

Physiology

General

For secondary active transport○

Each segment of the nephron depends on the action of the basolateral Na/K ATPase to maintain low intracellular Na+ concentration

•

Proximal TubuleMajor site of reabsorption•

Tubular fluid is isosmotic○

Solutes and water are reabsorbed proportionally•

ALL glucose and AA○

60%-70% of filtered electrolytes (including Na+, 60%) and water

○

50% or filtered urea○

Na+ is reabsorbed via cotransport with other substances and countertransport with HCO3-through the Na+/H+ antiporter

○

Na+ is reabsorbed with Cl- in the distal PCT by lumen positive potential difference

○

Reabsorbs:•

Ammonia is secreted to buffer the secreted H+•

ANP blocks Na+ reabsorption○

AG II acts on the proximal tubule to stimulate Na+ reabsorption

•

Precursors are glutamine and lactose○

Significant role during fasting & acidotic states

Contributes 20% of total glucose○

Limited gluconeogenesis•

Loop of HenleMain purpose is to setup the hyperosmolarity of the medulla

•

Reabsorbs 20% of filtered water (water permeable)

○

Thin descending limb•

Impermeable to water and has no reabsorption

○

Actively pumps ions into the interstitium○

Thin ascending limb•

Diluting segment of the tubular system○

Impermeable to water, but reabsorbs solutes (thus diluting the urine)

○

Active transport of Na+ into the interstitium○

Thick ascending limb•

Early DCT

But ADH susceptible○

Impermeable to water and urea•

ANP blocks Na+ reabsorption○

AG II stimulates Na+ reabsorption•

PTH increases Ca+ reabsorption•

Late DCT and Collecting Duct

Reabsorb Na+ and water secrete K+ via Na/K ATPase

○

Principle cells•

Important for acid-base regulation○

Secrete H+ and reabsorb K+ and HCO3-○

Combine CO2 & H2O forming H+ & HCO3-

H+ is secreted into the lumen via either Na+/H+ antiporter or H+-ATPase

HCO3- enters the interstitium

Contain carbonic anhydrase○

Intercalated cells•

Aldosterone stimulates Na+ reabsorption and K+ secretion (principle cells) and H+ secretion (intercalated cells)

•

Water reabsorption is increased○

ADH results in the insertion of aquaporins into the luminal membrane

•

Urea passively diffuses into the interstitium○

But ADH susceptible

Passes through the renal medulla and is impermeable to water

○

Concentrates the urine during low fluid levels (with ADH) and dilutes urine during high fluid levels (lack of ADH)

○

Collectign duct•

Nephron Physiology I

Physiology

Setting Up the Hyperosmotic Renal Medullary Interstitium

Due to extremely high concentration of solutes○

The osmolarity in the medulla can reach 1400 mOsM (normal interstitium is 300 mOsM)•

Active transport of Na+, K+ and Cl- out of the thick ascending limb of the loop of Henle○

Active transport of ion from the collecting ducts○

Passive diffusion of urea from the collecting ducts○

Water transport out of the medulla via the vasa recta and peritubular capillaries○

Major factors that contribute to medullary hyperosmolarity•

Capable of establishing a 200 mOsM difference between the lumen and interstitium

Ascending limb is impermeable to water so gradient is NOT diluted

The most important cause is the active transport of Na+, K+ and Cl - into the interstitium in thethick ascending limb of the loop of Henle

○

Initial set-up starting with 300 mOsM of normal fluid

Creates a 200 mOsM difference (200:lumen, 400:interstitium)i.Active transport of ions into the interstitium in the thick ascending limb of loop of Henle1.

Water is carried away from interstitium by vasa recta, preventing dilution of interstitium1)

As the descending limb of the loop of Henle is permeable to water, water flows out of the tubular fluid into the interstitium

i.

Tubular fluid in the descending limb of loop of Henle is now 400 mOsMii.

Tubular fluid in the descending limb of the loop of Henle equilibrates with interstitium2.

Except now the starting point is 400 mOsM instead of 300 mOsM (result is 300:lumen, 500:interstitium)

1)Again, a concentration gradiant is established by the ion transporter in the thick ascending limbi.

Fluid from the descending limb enters the ascending limb of the loop of Henle3.

Steps are repeated over and over establishing final concentration gradient4.

Setting up the medulla hyperosmotic gradient•

Nephron Physiology II

Physiology

K+ Regulation

Chronic control is via the renal system○

Acute contol is the buffering capacity of intracellular stores○

Control•

98% of K+ is stored intracellularly○

Less K+ is pumped into the cell; more remains outside

◊

Reduces the activity of the Na/K ATPase

Acidosis□

Cell lysis□

Exercise□

As water moves OUT of the cells toward a hyperosmotic ECF, K+ follows

EX: hyperglycemia

Increased ECF osmolarity□

Caused by:

Increased K+ release increases extracellular [K+]○

Insulin□

Release from the adrenal cortex is stimulated by increased plasma [K+]

Aldosterone□

Increases the activity of the Na/K ATPase

Alkalosis□

As water moves INTO the cell, K+ follows

Decreased ECF osmolarity□

Increased cellular uptake counteracts K+ loss due to repeated action potentials during times of stress

Catecholamines (Epi & NE)□

Caused by:

Increased K+ uptake reduces extracellular [K+]○

Storage (Acute control)•

K+ follows water□

Majority (65%) is reabsorbed in the proximal tubulevia osmotic pull of water

Remainder is absorbed in the thick ascending limb of the loop of Henle via NKCC-cotransporter

Reabsorption○

Occurs in the DCT via principal cells

Basolateral Na/K ATPase increases intracellular [K+] which then diffuses into the lumen

Increased tubular flow

Increased Na+ delivery to the distal nephron□

Increases the activity of the basolateral Na/K ATPase

Aldosterone also increases luminal wall permeability

Increased plasma [K+] and aldosterone□

Simulated by:

Secretion/excretion○

Chronic control (kidney regulation)•

Na+ Regulation

Therefore Na+ osmolarity is controlled by the intake and secretion of water (diluting and increasing the osmolarity respectively)

○

Excretion is primarily through the use of ADH

○

Intake is primarily through the thirst mechanism

○

Na+ is the most abundant ion in the ECF and thus is closely linked to the amount of water in ECF

•

Aldosterone increases Na+ reabsorption from the lumen in the distal tubule

•

Electrolyte Regulation I

Physiology

Major Kidney Endocrine Function

Synthesized in the kidneys in response to hypoxia

○

Binds to proerythroblasts, accelerating their maturation

Stimulates RBC proliferation and maturation○

Deficiency of EPO can result from chronic kidney disease, renal malignancy or an AE of chemotherapy

○

RBC production regulation/erythropoietin•

Decreased Ca+ stimulates PTHsecretion from the parathyroid

Converts vitamin D from inactive to active form

□

PTH activates 1-α-hydroxylase in the kidney

Different than PTH alone (stimulates Ca+ reabsorption but inhibits PO4- reabsorption)

□

Active vitamin D facilitates Ca+ and phosphate reabsorption in the kidney and small intestine

Vitamin D is stored in the liver but is dependent on plasma Ca+ for its activation and action

○

Vitamin D synthesis•

Produced and released by the juxtaglomerular cells

○

Production of renin (RAAS)•

Increases GFR and RBF

Required for vasodilation of the afferent arterioles

○

Production of prostaglandins•

Hormones Acting on the Kidney

Released by the atria in response to increased stretch○

Increases GFR (slightly)

Increased natriuresis

Causes vasodilation of afferent arterioles,vasoconstriction of efferent arterioles, and decreases Na+ reabsorption in the DCT & CD

○

Atrial natriuretic peptide (ANP)•

Inhibits Na+/PO4- cotransport

Inhibition of PO4- reabsorption in the PCT○

Stimulation of Ca+ reabsorption in the DCT○

PTH•

Synthesized in the adrenal cortex○

Synthesized and excreted in response to changes in the ECF via RAAS and increased plasma [K+]

○

Increases permeability of apical surface to Na+ and K+

Stimulates mineralocorticoid receptors (MRs) on principle cells

○

Results in increased Na+ reabsorption and K+ excretion○

Stimulates H+secretion by intercalated cells○

Aldosterone•

Also produced in response to AG II

Released from the posterior pituitary in response to high serum osmolarity and diminished blood volume

○

Increased ADH secretion□

Concentrated urine and increased total body water

Increased water reabsorption□

Decreased plasma volume is sensed as decreased BP by baroreceptors

Inhibits firing to supraoptic nuclei

Decreased ADH secretion

Osmoreceptors swell in the hypothalamus□

Dilute urine and decreased total body water

Decreased water reabsorption□

Increased plasma volume results in decreased fluid osmolality

Determines whether the kidney produces dilute or concentrated urine

○

Increases the insertion of aquaporins into the apical membrane

Water moves out of the collecting duct into the interstitium

ADH acts on V2 receptors on the principal cells in the collecting duct

○

Particularly important during hemorrhage to maintain BP

High levels of ADH also act on V1 receptors on arterioles causing vasoconstriction

○

ADH•

Kidney Endocrine Functions

Physiology

Renin-Angiotensin-Aldosterone System (RAAS)Regulates BP•

Results in decreased perfusion

Perceived as decreased stretch by the JG cells

Hypotension○

Increased renal parasympathetic activity○

β1 agonists (isoproterenol) stimulate renin secretion

β1 antagonist (propranolol) inhibit renin secretion

β1 stimulation○

Decreased Na+ delivery to the kidneys○

Renin is released in response to:•

Angiotensinogen is produced by the liver○

Renin cleaves angiotensinogen to angiotensin I (AG I)•

Located in the lung endothelium○

Angiotensin converting enzyme (ACE) converts AGI to AG II•

Increases TPR

Venous constriction increases venous return to the heart

Increased BP

Increased GFR□

Increased constriction of the efferent arterioles

Direct vasoconstriction (fast response)○

Decreased excretion of salt and water□

Increased ECF and blood volume□

Aldosterone promotes Na+ reabsorption in the DCT & CD

Aldosteron synthesis and release from the adrenal cortex (slow response)○

Increased reabsorption of Na+ and HCO3-□

AG II stimulates Na/H exchange in the proximal tubule

Direct action on the kidney○

Increased ECF volume and BP□

Increased water reabsorption

ADH secretion from the posterior pituitary○

Increased sympathetic activity○

AG II has numerous effects:•

RAAS

Physiology

LungsRegulate short term changes in acid-base homeostasis via ventilation

•

Raises the pH

Increases CO2 removal, thus lowering the plasma [H+]

○

Ventilation is triggered by decreased pH•

CO2 ventilation controls pH via the bicarbonate buffer system

•

Lowers plasma [H+] (raises pH)

Decreases amount of CO2 (increased CO2 removal)

○

Metabolic acidosis (loss of HCO3-) increases the respiratory rate

•

Increases plasma [H+] (lowers pH)

Promotes CO2 retention○

Metabolic alkalosis (increased HCO3-) decreases the respiratory rate

•

Buffer Systems

Found in the kidney○

Creates a new bicarb and excretes a H+○

HCO3- is pumped into the interstitium

NH4+ is secreted via the Na+/NH4+ exchanger and excreted in the urine

Ammonia (NH3) can also diffuse into the lumen and combine with H+ (pumped via an H+ ATPase)

Glutamine is metabolised to HCO3- and NH4+○

During acidosis, there is increased NH4+ secretion

pH determines the amount of H+ secreted○

Ammonia buffer system•

Found in the kidney○

Creates a new bicarb and secretes a H+○

Largely responsible for the low acidity and buffering of the urine

○

H+ is secreted and combines with HPO4-forming H2PO4- which is then excreted in the urine

HCO3- is pumped into the interstitium

Carbonic anhydrase creates H+ and HCO3-○

Phosphate buffer system•

Found in lung and kidney○

Process is reversible

Kidney: proximal and distal tubule cells

Bicarb and H+ are formed from CO2 and H2O via carbonic anhydrase

○

Bicarbonate buffer system•

KidneyResponsible for long-term changes in acid-base homeostasis

•

Ammonia and the phosphate buffer system○

Bicarb production•

Most H+ is secreted in the form of either NH4+ & H2PO4-

○

Direct H+ secretion occurs in intercalated cells via H+ ATPase

○

H+ secretion•

H+ ATPase

Via secondary active transport□

Na/H antiporter

HCO3- is filtered freely, H+ is pumped into the lumen by various mechanisms

○

H+ is pumped back into the lumen, HCO3- is pumped into the interstitium

□

Increased plasma pH

Net result is H+ remains in lumen, while HCO3- is reabsorbed

□

CO2 diffuses back into the cells and combines with water, again via carbonic anhydraseforming HCO3- and H+

HCO3 and H+ combine in the lumen via carbonic anhydrase (CA)

○

Lower H+ in the lumen□

Lower amount of available H+ for lumenal secretion

Decreased H+ for HCO3- to combine with via CA

Increased HCO3- excretion

Lowers plasma pH

Metabolic alkalosis○

Compete HCO3- reabsorption□

Increased H+ excretion□

Increased activity of phosphate and ammonia buffer systems

□

Excess H+ results in increased H+ secretion

Increased plasma pH

Metabolic acidosis○

HCO3- filtration and H+ secretion•

Stimulation of the Na/H antiporter leads to an increased in bicarb reabsorption

Increased by CO2 and AG II○

Increased ECF volume causes decreased HCO3-reabsorption and dilutional acidosis

○

Decreased ECF volume causes increased HCO3-reabsorption and contraction alkalosis

○

HCO3- reabsorption•

Acid-Base Homeostasis

Physiology

Hyperkalemia

Addison's disease○

Hemolysis

Rhabdomyolysis

Cell lysis and increased K+ release○

DM

Insulin deficiency○

Decreased urine flow

Renal failure (acute or chronic)

DM□

Sickle cell□

Obstruction□

Transplant□

Renal tubular defects and acidosis

Impaired K+ secretion○

Etiology•

Tingling/parasthesia○

Arrhythmia○

Muscle weakness○

Can lead to V. fib

Wide QRS

Peaked T wave

Flat P wave

EKG abnormalities and arrhythmia○

Clinical•

Dialysis○

IV Ca+ stabalizes the myocardium

Reduce cardiac effects○

Insulin & glucose

Albuterol and epi□

β-Agonsist

Promote K+ movement into cells○

Diuretics (NOT K+ sparing)

Bind K+ in the GI tract, increases excretion

□

Cation-exchange resins (sodium polystyrene sulfonate)

Increase K+ excretion○

Inhibit K+ ○

Treatment•

Hypokalemia

Dehydration○

V/D

Enterocollitis

Increased K+ excretion○

Alkalosis○

Insulin○

Diuretics (loop or thiazide)○

Increased aldosterone levels○

Hypomagnesemia○

Etiology•

Cramps, fatigue and muscle weakness

Ileus

Respiratory paralysis

Neuromuscular○

Arrhythmia

U waves□

Flat/inverted T waves□

ST segment depression□

EKG abnormalities

Cardiac○

Clinical•

IV K+○

Magnesium correction○

Treatment•

Hypernatremia

Tremors and ataxia○

Irritability and confusion○

Seizures○

Coma and death○

General clinical symptoms arise >160mEq and are neurologic

•

Hyperglycemia with diabetic ketoacidosis

Central DI

Nephrogenic DI

Dehydration and water loss○

Etiology•

Treat underlying cause○

IV NS or LR○

Treatment•

Hypomagnesemia

Dietary deficiency with poor absorption○

Etiology•

A/N/V○

Lethargy○

Personality changes○

Hypocalcemia and hypokalemia○

Clinical•

Magnesium sulfate○

Treatment•

Electrolyte Disorders I

Pathology

Hyponatremia

N/V

Irritability and confusion

Seizures

<120mEq?○

Coma and death

<110mEq?○

General clinical symptoms are neurologic•

Treatment is generally hypertonic saline•Different types based on the total volume of fluid in the body

•

Acute viral gastroenteritis□

GI losses

Dehydration

Renal salt wasting

Acute renal failure

Etiology○

Orthostasis

Decreased skin turgor

Hypotension

3rd spacing

Clinical○

Rehydration with NS

Treatment○

Hypovolemic hyponatremia•

Hypothyroidism

Cortisol deficiency

Hypopituitarism

SIADH

Etiology○

Water restriction

Loop diuretics

Treatment○

Euvolemic hyponatremia•

CHF

Cirrhosis/liver failure

Nephrotic syndrome

Etiology○

Edema

Clinical○

Salt and water restriction

Loop diuretics

Treatment○

Hypervolemic hyponatremia•

Electrolyte Disorders II

Pathology

GeneralLab changes in pH, paCO2 & HCO3- will be in the same direction

•

Na - (HCO3 + Cl)○

Normal is 10-12○

Anion gap•

Metabolic Acidosis

1.2 paCO2 / 1 HCO3-

Decreased pH, paCO2 and HCO3- (large)○

Loss of HCO3-

Increased H+

Decreased HCO3- due to:○

Clinical•

Methanolo□

Uremia□

Diabetic ketoacidosis□

Phenformin & Paraldehyde□

Isoniazid, Infection & Iron□

Lactic acidosis□

Ethylene glycol□

Salicylates□

MUDPILES (etiology):

High anion gap metabolic acidosis○

Hyperalimentation□

Acetazolamide, Acid infusion & Addison's

□

Renal tubular acidosis□

Diarrhea□

Ureteroenteric shunt□

Pancreatic fistula□

Spironolactone□

HARDUPS (etiology):

Non/normal anion gap metabolic acidosis○

Types•

IV HCO3-○

Treatment•

Renal Tubular Acidosis

Aquired defect in the acidification of urine○

Sjogren's

Lithium

Sarcoidosis

Obstruction

Amphotericin B

Etiology○

Type I (distal)•

Aquired defect that results in renal loss of HCO3-○

Myeloma

Renal transplant

Etiology○

Type II (proximal)•

Abnormal ammonium excretion○

DM

Chronic kidney disease

Glomerulosclerosis

Associated with:○

Type IV•

Metabolic Alkalosis

0.7 paCO2 / 1 HCO3-

Increased pH, paCO2 and HCO3- (large)○

Clinical•

Contraction (volume)

Licorice & laxatives

Cushing's□

Hyperaldosteronism□

Endocrine

Vomiting

Calcium carbonate or milk and sodium bicarbonate

◊

Excessive ingestion of calcium and absorbable alkali

Milk-alkali syndrome□

Excessive alkali

Refeeding with a carbohydrate rich diet after prolonged fasting

□

Refeeding alkalosis

Potassium reduction (hypokalemia)

Diuretics

CLEVER PD○

Etiology•

IV NaCl, KCl and Mg○

Spironolactone is due to mineralocorticoid excess○

Treatment•

Metabolic Acidosis/Alkalosis

Pathology

General

10 change in paCO2 / 0.08 change in pH○

pH & paCO2 will change in opposite directions•

Respiratory AcidosisOccurs secondary to CO2 retention•

Opiates, sedatives and anesthetics□

Drugs

CNS tumors & trauma

CNS hypoxia

Pickwickian syndrome

Inhibition of medullary respiratory center○

Guillain-Barre syndrome

Myasthenia gravis

Botulinum□

Organophosphates□

Toxins

Muscle relaxants

Scoliosis, myopathy & muscular dystrophy

Weakness of respiratory muscles○

COPD

ARDS

Decreased CO2 exchange○

Etiology•

1 HCO3 / 10 paCO2 increase

Acute○

4 HCO3 / 10 paCO2 increase

Chronic○

Types•

Patent airway○

β-agonist○

Ventilator○

Treatment•

Respiratory AlkalosisOccurs secondary to low plasma CO2 concentration•

Head trauma

Stroke

Anxiety, stress & hyperventilation

Salicylates & sepsis

Progesterone

Central○

Pulmonary embolism

Asthma

Pneumonia

Pulmonary○

Increased RR on mechanical ventilation

Iatrogenic○

Etiology•

2 HCO3 / 10 paCO2 decrease

Acute○

4 HCO3 / 10 paCO2 decrease

Chronic○

Types•

Simplified Acid-Base Problem AnalysisR = Respiratory; M = MetabolicMnemonic --> Ravage Me MaRy

Respiratory Acidosis/Alkalosis

Pathology

General

Primarily a result of increased GBM permeability

Minimal change disease□

Focal segmental glomerulosclerosis (FSGS)□

Membranous glomerulopathy□

MPGN (can present as nephrotic or nephritic)

□

Diabetic nephropathy□

Renal amyloidosis□

SLE□

Diseases:

Nephrotic syndrome○

Direct inflammatory damage to the glomeruli

Poststreptococcal/infectious

Acute proliferative glomerulonephritis□

RPGN, crescentic

Rapidly progressive glomerulonephritis (RPGN)

□

Anti-GBM disease & Goodpasture's□

MPGN□

IgA nephropathy (Berger's disease)□

Alport's syndrome & Thin basement membrane disease

□

Diseases:

Nephritic syndrome○

Divided into two groups based their pathogenesis and clinical manifestions:

•

Focal does not

Diffuse involves all glomeruli○

Segmental involves only part of the glomerulus

Global involves the entire glomerulus○

Classification•

Accumulation of collagenous matrix that contributes to capillary lumen obliteration and fibrous adhesions

Sclerosis○

Accumulation of eosinophilic dense material that also contributes to capillary lumen obliteration

Hyalinosis○

Often due to deposition of immune complexes

Basement membrane thickening○

Due to cellular proliferation, leukocyte infiltration and crescent formation

Hypercellularity○

Histology•

Diagnosis of ALL glomerulopathies is dependent on RENAL BIOPSY

•

Glomerular diseases can ultimately lead to chronic glomerulonephritis and renal failure

•

Glomerulopathy Pathogenesis

Alport syndrome○

Thin basement membrane disease○

GBM thinning•

Diabetic nephropathy (DM)○

Minimal change disease○

FSGS○

Epithelial damage•

Often exhibit granularstaining

SLE□

MPGN□

Renal amyloidosis□

RPGN (Type II)□

Proliferating glomerulonephritis

□

Diseases:

Circulating complex deposition in the kidney○

Exhibit linear staining□

RPGN (Type I)□

Anti-GBM disease□

Goodpasture's□

Anti-GBM antibodies

Exhibit granular staining□

RPGN (Type III)□

Antibodies against Heymann antigen in the subepithelial basement membrane

Heymann nephritis□

Antibodies against fixed antigens

Exhibits granularstaining□

Membranous glomerulopathy□

Antibodies against planted antigens

Intrinsic complex deposition○

Antigen-antibody complex deposition•

Glomerulopathies

Pathology

General

Vitamin D deficiency○

Massive proteinuria○

Due to protein loss

Albumin is the main mediator of serum oncotic pressure

Hypoalbuminemia○

Due to decreased serum oncotic pressure

All these changes lead to increased Na+ and water retention, contributing to further edema

Decreased intravascular volume activates the RAAS, sympathetic system, ADH release and decreased release of ANP

□

Fluid is lost to the interstitial space

Edema○

Due to increased production of serum lipoproteins by the liver in an attempt to maintain oncotic pressure

Hyperlipidemia/lipiduria○

Secondary to loss of anticoagulant factors through the glomeruli

Hypercoagulability○

Due to loss of immunoglobulins through the glomeruli

Particularly staphylococcal and pneumococcal

Increased risk of infection○

Increased GBM permeability leads to a variety of clinical symptoms:

•

Affects the kidney ONLY

Minimal change disease

Membranous glomerulopathy

FSGS

MPGN

Primary○

Systemic diseases that also affect the kidney

SLE

DM

Amyloidosis

Secondary○

Types•

Minimal Change Disease

Frequently follows respiratory infection or immunizations○

Selective proteinuria (mostly albumin lost)○

Leading cause of nephrotic syndrome in children•

Lead to increased permeability□

Electron microscopy reveals effacement (loss) of visceral epithelial foot processes

Glomeruli appear normal under light microscope○

Histology•

Prednisone○

Cyclophosphamide & Chlorambucil

Alkylating agents○

Treatment•

Membranous Glomerulopathy

More common in men○

Leading cause of nephrotic syndrome in adults•

IgG and C3 deposits

Diffuse GBM thickening due to subepithelial deposits○

Histology•

Thyroiditis, SLE & RA

Autoimmune disease○

Penicillamine, gold, NSAIDs & Captopril

Drugs○

Malignancy○

Hepatitis B & C

Syphilis

Schistosomiasis, malaria & leprosy

Infection○

Associated with:•

Steroids are ineffective○

Transplant○

Treatment•

Membranous Glomerulopathy"Spikes" of methenamine silver stain demonstrate increased

GBM synthesis between subepithelial deposits. Diffuse thickening of the capillary wall is also visible.

Nephrotic Syndrome I

Pathology

FSGS

Non-selective proteinuria○

Higher incidence of hematuria & HTN○

Reduced GFR○

Poor corticosteroid response○

Frequently progresses to chronic kidney disease & renal insufficiency

○

Considered to be a more severe form of minimal change disease (similar effacement of foot processes) but with:

•

Causes hemodynamic changes such as HTN

Ultimately leads to sclerosis and hypercellularity

Epithelial damage leads to hypertrophy of affected glomeruli

○

Pathogenesis•

Focal hyalinosis and segmental sclerosis○

Foam cells and microcyst formation○

Collapsing glomerulus○

Histology•

Idiopathic○

Higher incidence of collapsing glomeruli□

Dilation & fibrosis of tubule segments□

More severe

HIV-associated FSGS○

Types•

Oral glucocorticoids (20%-40% effective)○

Cyclophosphamide & cyclosporine○

Treatment•

FSGS

Membranoproliferative Glomerulonephritis (MPGN)

Thickened GBM○

Glomerular cell proliferation○

Leukocyte infiltration○

Crescents○

"Tram-track" GBM appearance due to deposits that separate the GBM (mostly Type II MPGN)

○

Histology•

More common in adults

IgG and C3 deposit location is subendothelial

□

MPGN is secondary to immune complex deposition (Type III hypersensitivity)

Activation of alternative and classical complement pathway

Associated with hepatitis B & C, SLE, HIV, schistosomiasis, malignancy and α1-antitrypsin deficiency

Type I (idiopathic/secondary)○

MPGN is secondary to denseintramembrane immune complex deposition

Binds C3decreasing serum levels□

Associated with C3 nephritic factor (C3NeF)

Deposits are C3 (no IgG)

Can present as either nephrotic OR nephritic

Type II (Dense deposit disease)○

Types•

No effective therapy○

Treatment•

MPGNTram-track appearance of GBM

Nephrotic Syndrome II

Pathology

GeneralPathology is a result of glomerulus inflammation•

Secondary to destruction of glomerular capillaries

Hematuria & RBC casts○

Secondary to inflammatory cell infiltration and immune complex deposition

Oliguria (<400 mL urine output/day)

□

Azotemia (increased BUN and creatinine in the blood) due to inefficient filtering

□

Causes obstruction of the capilary lumen, decreasing GFR and leading to:

Oliguria○

Proteinuria○

Secondary to edema and increased fluid retention due to decreased GFR

HTN○

Clinical•

Renal biopsy○

Diagnosis•

Acute Proliferative Glomerulonephritis (Postreptococcal/Infectious)

Staph and pneumococcal

Malaria & toxoplasmosis□

Parasitic

Hepatitis B & C, mumps, HIV, varicella and mononucleosis

□

Viral

Can also be associated with:○

Appears 2-3 weeks following skin infection and 10 days following pharyngeal infection

○

Most common in children 2-6 Y.O.○

Frequently follows infection with GABHS•

Secondary to immune complex deposition with resulting complement activation and inflammation

○

Pathogenesis•

Hypercellularity and enlarged glomeruli○

IgG and C3 deposits (granular)○

Histology•

"Smoky brown" urine (hematuria) with RBC casts

○

Diagnosis•

Diuretics control HTN○

Penicillin○

Treatment•

Rapidly Progressive (Cresentic) Glomerulonephritis (RPGN)

Rapid loss of renal function (GFR)○

Severe oliguria○

Other nephritic symptoms○

Not a disease per se, but a malignant form of nephritic syndrome

•

Kidneys are enlarged and pale with petechial hemorrhages

○

Gross•

Sclerosis○

Proliferating parietal cells within Bowman's space

Fibrin (due to fibrinogen escape into Bowman's space) accumulates between crescents

Crescents○

Monocytes and macrophages in Bowman's space○

Crescents can lead to glomerular necrosis○

Histology•

Associated with Goodpasture's

Antigen is α-chain of collagen IV□

Linear deposits of IgG and C3 along the GBM

Labs are ANCA-negative

Plasmapheresis□

Cyclophosphamide□

Prednisone□

Treat until anti-GBM antibody is undetectable

□

Treatment

Type I (Anti-GBM antibody disease)○

Henoch-Schonlein Purpura□

IgA nephropathy□

IgGs that reversibly precipitate in the cold

Derm lesions include raised palpable purpura and acral purpura

Cryoglobulinemia□

SLE□

Postreptococcal GN□

Associated with:

Granular deposits

Labs are ANCA-negative

Type II (Immune complex deposition)○

Polyarteritis nodosa□

Wegener's□

Microscopic polyangiitis□

Associated with:

Absence of deposits on the GBM

Labs are ANCA-positive

Type III (Pauci-immune)○

Types•

High dose corticosteroids & underlying cause○

Treatment•

Nephritic Syndrome I

Pathology

RPGNCrescent masses and leukocytes within Bowman's

space

IgA Nephropathy (Berger's Disease)Similar to Henoch-Schonlein Purpura, but without systemic manifestations (renal only)

•

Common in children & young adults•Most common form of glomerulonephritis worldwide•

Gross hematuira 24-48 hours post URI, UTI and GI infection

○

Clinical•

IgA deposits in the mesangium leads to glomerular injury and nephritic symptoms

○

Also shows C3 deposits○

Histology•

Spontaneously resolves only to recur every few months or during other infections

○

20%-50% of cases progress to ESRD within 20 years○

Treatment•

Alport's Syndrome & Thin Basement Membrane Disease

X-linked mutation in α5 chain of type IV collagen

Alport's syndrome○

Mutation in α3 or α4 chain of type IV collagen

Thin basement membrane disease○

Both are hereditary defects associated with type IV collagen

•

More pronounced in men (due to X-linkage)○

Nephritic symptoms○

Deafness○

Cataracts and lens dislocation○

Clinical•

Foam cells○

Produces "basket-weave" appearance

GBM thinning○

Histology•

Ultimately progresses to ESRD•

Dialysis○

Transplant○

Treatment•

Chronic GlomerulonephritisProgressive, end-stage glomerulonephritis•

Nephritic syndromes○

Loss of appetite & vomiting○

Anemia○

Weakness○

Clinical•

Thin cortex○

Increased peripelvic fat○

Gross•

Glomeruli obliteration○

Arterial & arteriolar sclerosis○

Tubule atrophy○

Interstitial fibrosis○

Leukocyte infiltration○

Histology•

Dialysis○

Treatment•

Nephritic Syndrome II

Pathology

Renal Calculi

Severe, colicky flank pain that radiates to the groin

○

Hematuria, hydronephrosis and infection○

Clinical•

Most common

Hyperparathyroidism

Bone disease, multiple myeloma & mets

Sarcoidosis

Milk-alkali syndrome

Hypercalcemia/hypercalciuria□

Primary oxaluria type I□

Etiology

Stones are radiopaque

Calcium oxalate/Calcium phosphate○

Proteus vulgaris or staphylococci□

Common in women□

Due to excessively alkaline urine from UTI caused by urease (+) bacteria

Bacteria convert urea to ammonia, which then precipitates as a stone

Stone are radiopaque

Struvite (ammonium magnesium phosphate)○

Leukemia & myeloproliferative disease

□

Associated with gout (hyperurecemia) or diseases that cause rapid cell turnover

More likely to form in acidic urine

Stones of radiolucent

Carbonic anhydrase inhibitors (acetazolamide)

Alkalinize the urine□

Treatment

Uric acid○

Cystinuria□

Caused by patients with genetic defects in metabolism of cystine

More likely to form in acidic urine

Stones are radiolucent

Alter CYS solubility, reduce CYS intake or increase CYS excretion (IV fluids)

□

Treatment

Cystine○

Types•

Abdominal X-ray○

Diagnosis•

Increased fluid intake○

Pain management○

Extracorporeal shockwave lithotripsy (ESWL)○

Surgery (nephrolithotomy)○

Treatment•

AA Metabolism Disorders

PAH gene

Defect in phenylalanine hydroxylase○

Causes neurologic sequelae such as retardation

□

PHE is converted to phenylpyruvate

Results in PHE buildup in the blood○

Diagnosis is the presence of phenylpyruvate in the urine

○

Detected at birth

PHE restricted diet

Treatment○

Phenylketonuria (PKU)•

HGD gene□

Homogenisate oxidase

Defect in tyrosine pathway○

Can lead to arthritis and kidney & prostate stones○

Diagnosis is dark urine (oxidized)○

Alcaptouria•

AGXT gene

A transaminase defect in alanine-glyoxylate aminotransferaseresults in the inability to convert glyoxylate to glycine

○

Oxalate crystalizes with Ca++ forming radiopaque Ca-oxalate stones

Results in buildup of glyoxylate, which spontaneously oxidizes to oxalate

○

Primary oxaluria type I•

Isoleucine□

Leucine□

Valine□

Such as (I Love Vermont):

BCKD, DBT & DLD genes

Defect in α-keto acid dehydrogenaseresults in the inability to decarboxylate branched chain AA

○

Urine smells like "burnt sugar"○

Results in neurological complications○

Maple syrup urine disease•

Renal Calculi & Amino Acid Disorders

Pathology

AA Transport Disorders

Failure-to-thrive & diarrhea

Photosensitivity & dermatitis

Ataxia, tremor, dementia, psych problems, retardation, psych problems, etc.

Error in neutral AA transporter located in the PCT & intestine results in numerous Pellegra-like symptoms:

○

Hartnup disease•

Errors in basic AA transporters (cysteine) result in dimer formation and cystine stones

○

Cystinuria•

Autosomal recessive deficiency of cystathionine B-synthase

○

Marafanoid habitus

Increased incidence of seizures

Lens dislocation (DOWNWARD)

Increased urinary excretion of homocystine

Clinical○

Dietary restriction of MET

Treatment○

Homocystinuria•

Amino Acid Disorders II

Pathology

Urinary CastsUsually an indication of tubular pathology•

Can also indicate pyelonephritis

Absence of cells (hyaline casts) are seen in normal individuals

○

Cells within the cast reveal an intrarenal source•

Casts are composed of a protein matrix of Tamm-Horsfall mucoprotein

•

Desquamated tubular cells in a protein matrix

Findings○

ATN

Ethylene glycol toxicity

Heavy metal poisoning

Acute transplant rejection

Etiology○

Epithelial cell casts•

Glomerulonephritis

IgA nephropathy

Poststeptococcal glomerulonephritis

Goodpasture's

Malignant HTN

Vasculitis

Renal ishemia

Etiology○

RBC casts•

Casts indicate inflammation in renal interstitium, tubules and glomeruli

WBCs in urine indicate acute cystitis

Findings○

Pyelonephritis

Interstitial nephritis

Lupus

Etiology○

WBC casts•

Derived from renal tubular cells○

Severe renal disease

Nephrotic syndrome

Etiology○

Granular casts•

Fat droplets in a hyaline matrix ○

Often exhibit maltese-cross configuration○

Nephrotic syndrome

Etiology○

Fatty casts•

General Tubulointerstitial Disease

Casts○

Absence of glomerular injury○

Metabolic acidosis

Polyuria/nocturia□

Electrolyte disorders□

Inability to concentrate urine

Tubular defects○

Clinical•

Diffuse cortical necrosis○

Renal papillary necrosis○

UTI & pyelonephritis○

Drug Induced Tubulointerstitial nephritis○

Heavy metals○

Obstruction○

Neoplasms○

Due to high metabolic rate of tubular cells, large amounts of oxygen are required

□

Ischemia results in cortical and tubular infarction

DIC, microscopic polyangiitis, TTP & HUS

Ischemia○

Etiology•

Diffuse Cortical NecrosisDue to infarction of the cortices of the kidney, secondary to ischemia

•

Can progress to ARF•

DIC, microscopic polyangiitis, sepsis, Obstetric complications, TTP & HUS

○

Etiology•

Signs and symptoms of the systemic cause○

Azotemia○

Proteinuria, hematuria, RBC casts○

Granular casts○

Clinical•

Renal Papillary NecrosisResult of ischemic infarct of the renal papillae•

DM, acute pyelonephritis, chronic phenacetin use○

Associated with:•

Polyuria○

Rust-colored urine○

ARF○

Lloyd's sign○

Clinical•

Casts, hematuria and necrotic renal papillae○

X-ray may show nephrocalcinosis○

Diagnosis•

Treat underlying disease•

Tubulointerstitial Disease

Pathology

General UTI

E.coli

Sexually active young females□

Staphylococcus saprophyticus

Outpatient○

E.coli

Inpatient○

Children with recurrent UTIs should be evaluated for vesicoureteral reflux (VUR)

Children○

Etiology•

Dysuria, frequency & urgency○

Suprapubic pain & painful urination○

Hematuria○

Confusion (elderly)○

F/N/V

Positive flank pain (costovertebral angle/CVA tenderness)

□

Lloyd's sign

Progressive symptoms○

Clinical•

Identifies specific bacteria□

Urine culture

Pyuria (PMNs) & bacteriuria□

Urine microscopy

Nitrites□

Leukocyte esterase□

Hematuria□

Urine dipstick

Clean catch or suprapubic tap (Gold Std)○

Voiding cystourethrogram○

Cystourethroscopy○

History○

Diagnosis•

Bacterial virulence○

Elderly women have increased vaginal pH (menopause)

Inefficient voiding

Pregnancy

Increased glucose in the urine□

Diabetics

Altered host defence○

Pathogenesis•

Appropriate antibiotic therapy○

Preschool or pregnant

No treatment is required for asymptomatic bacteriuria except:

○

Treatment•

General Pyelonephritis

UTI is the most common

Route of infection is either hematological or ascending UTI

○

Infection of the upper urinary tract, including the kidneys•

E.coli

Klebsiella

Staphylococcus saprophyticus & epidermis

Proteus

Bacterial○

Mostly in the immunocompromised

CMV

Adenovirus

Polyomavirus

Viral○

Etiology•

UTI leads to tract obstruction & urine stasis, eventually leading to VUR and intrarenal reflux

○

Treatment would be surgery□

Can be due to genetic causes, such as a short ureter

VUR○

Typically affects the tubules, interstitium and renal pelvis

○

Pathogenesis•

WBC casts○

Lloyd's sign○

F/N/V & malaise○

UTI symptoms○

Clinical

Interstitial suppurative inflammation○

Tubular necrosis○

Cortical surface of the kidney shows fibrous depressions

Pyelonephritic scars○

Histology

Papillary necrosis○

Perinephric abscess○

Complications

Appropriate antibiotics○

Treatment

Acute○

Tubular atrophy, hypertrophy and/or dilation

○

Histology

Located corticomedullarly overlying dilated, blunted & deformed calyces

Flattened papillae

Course, irregular renal scarring○

Gross

Chronic○

Types (similar clinical manifestations)•

Urinary Tract Infections (UTI)

Pathology

Acute Drug Induced

Rifampin○

Diuretics○

Allopurinol○

Cimetidine○

Methicillin○

Etiologic agents•

Resulting immunologic response targets tubular cells and basement membranes

Drug acts as a hapten ○

Typically 15 days post-drug administration○

Pathogenesis•

Interstitial edema○

Lymphocytic infiltration○

Giant-cell granulomas○

Tubulointerstitial symptoms○

Histology•

Rash○

Fever○

Eosinophiluria○

ARF○

Clinical•

Discontinue offending drug○

Treatment•

Analgesic Nephropathy

Phenacetin○

APAP○

Caffeine○

Codeine○

Aspirin○

Etiologic agents•

Generation of oxidative metabolites from the drugs results in cortical interstitial nephritis and renal papillary necrosis

○

Pathogenesis•

Depressed cortical areas overlying papillary necrosis○

UTI○

Tubular acidosis○

Clinical•

Drug withdrawl○

Treatment•

NSAID Associated Tubulointerstitial NephritisNSAID use results in decreased prostaglandin synthesis and tubular damage due to ishemia

•

ARF○

Acute hypersensitivity○

Associated with:•

Drug Induced Tubulointerstitial Nephritis

Pathology

Acute Renal Failure (ARF)

<24 hours○

Characterized by an abrupt onset decrease in renal function (GFR)

•

Condition is reversible•

Azotemia○

Oliguria/anuria○

Uremic syndrome○

Hyperkalemia○

Metabolic acidosis○

Clinical•

Problem with the BODY

Sepsis□

Shock□

CHF□

Hypovolemia

Pre-renal○

Problem with the BEAN

Nephritic or nephrotic

Tubulointerstitial

Renal○

Problem with the BLADDER

Obstruction

Post-renal○

Type•

Maintain fluid and electrolyte balance○

Avoid nephrotoxic medications○

Treat cause○

Dialysis○

Treatment•

Chronic Renal FailureCharacterized by a substantial decrease in renal function over a long period

•

Renal artery stenosis○

DM & SLE○

HTN○

Amyloidosis○

Chronic glomerulonephritis○

Tubulointerstitial nephritis○

Adult polycystic kidney disease○

Renal cancer○

Chronic urinary tract obstruction○

Etiology•

GFR is 50% of normali.Asymptomaticii.

Diminished renal reserve1.

GFR is 20%-50% normali.

Azotemia1)Anemia2)HTN3)Polyuria/nocturia4)

Clinicalii.

Renal insufficiency2.

GFR is <25% normali.Regulation failure of volume & solutesii.

Uremia1)Muddy-brown casts2)Confusion3)JVD4)

Clinicaliii.

Dialysis1)Transplant2)Symptomatic3)

Treatmentiv.

Chronic renal failure3.

GFR <5% normali.

Decreased albumin and Ca++1)Elevated K+, phosphate and uric acid2)Pulmonary congestion and CHF3)Pericarditis4)Increased infections5)Bone defects6)

Clinicalii.

Dialysis1)Furosemide2)

Treatmentiii.

End-stage renal disease (ESRD)4.

Stages•

Consequences of Renal Failure

Lethargy, seizures, myoclonus, asterixis & pericardial friction rub

Occurs as BUN rises○

Failure of urea excretion results in gut bacterial conversion to ammonia (hyperammonemia)

○

Uremic syndrome•

Failure to excrete dietary K+○

Hyperkalemia•

Metabolic acidosis•Na+ and water retention•

Failure of EPO production○

Anemia•

HTN•

Glucose, AA, phosphate and bicarb are passed into the urine

○

Fanconi's syndrome•

Renal Failure

Pathology

General

Arises from tubular epithelium○

Most common primary tumor of the kidney•

Common in males, 60-70 Y.O.•

Tobacco○

Obesity○

Heavy metal exposure○

HTN○

Petroleum products○

Epidemiology•

Yellow, often located near the poles○

Gross•

Invades the renal vein and IVC with mets to lung (50%), bones (33%) and regional nodes

•

Hematuria○

Palpable mass○

CVA pain○

Fever○

Clinical•

Clear cell carcinoma○

Papillary renal cell carcinoma○

Chromophobe renal carcinoma○

Bellini duct carcinoma○

Types•

Nephrectomy○

Treatment•

Clear Cell CarcinomaMost common RCC•Originates from the proximal tubular epithelium•

Bizarre nuclei with clear or granular cytoplasm○

Histology•

Necrosis○

Yellow-gray due to lipid presence○

Gross•

Associated with a defect of the VHL tumor suppressor geneon Chr 3p

•

Papillary Renal Cell CarcinomaOriginates from the DCT•

Papillary growth pattern○

Interstitial foam cells○

Rings of calcium

Psammoma bodies○

Histology•

Hemorrhagic and cystic○

Gross•

Associated with a defect in the MET gene on Chr 7•

Chromophobe Renal CarcinomaOriginates from the intercalated cells of the CD•

Darkly staining with a perinuclear halo○

Histology•

Characterized by loss of an entire chromosome•

Bellini Duct CarcinomaOriginates from medullary CD•

"Hobnail" pattern○

Nests of malignant cells in fibrotic stroma

○

Histology•

Renal Cell Carcinoma (RCC)

Pathology

Bladder Cancer

50-70 Y.O.○

Affect men more than women•

SCC is associated and only occurs with schistosomiasis○

Cancer of transitional cells (urothelium) of the bladder (90%)•

Smoking○

Radiation○

β-naphthylamine○

Cyclophosphamide○

Epidemiology•

Painless hematuria○

Urinary frequency○

Hydronephrosis○

Clinical•

Papillary, red and elevated○

Gross•

Frequently mets to the liver, lungs and bone•

Surgical resection○

Cystectomy with radiation & chemotherapy○

Treatment•

Wilms' TumorMost common primary tumor of the kidney in early childhood (2-5 Y.O.)

•

Due to loss of WT1 tumor suppressor gene on Chr 11•

Large, palpable abdominal mass○

Can lead to intestinal obstruction○

Abdominal pain○

Fever○

Hematuria○

Clinical•

Abdominal ultrasound○

Diagnosis•

Tan-gray with hemorrhage and necrosis○

Gross•

Nephrectomy with chemotherapy○

Treatment•

Wilms' tumor

Aniridia

GU malformation

Retardation

WAGR complex○

Gonadal dysgenesis and renal abnormalities

Denys-Drash syndrome○

Beckwith-Wiedemann Syndrome○

Associated with:•

Gitelman's and Bartter's Syndrome

Defective Na+ reabsorption in the distal tubule

Identical presentation as loop diuretic overdose

Gitelman's○

Defective Na+ reabsorption in the thick ascending limb of the loop of Henle

Identical presentation as thiazide diuretic overdose

Bartter's○

Both are the result of defective Na+ reabsorption

•

Presents in adulthood○

Cramps○

Polyuria/nocturia○

Fatigue○

Hypotension○

Mg++ wasting○

Clinical (Gitelman's)•

Presents early○

Ca++ wasting○

Polyuria/polydipsia○

Growth & mental retardation○

Clinical (Bartter's)•

NSAIDs○

Mg++ replacement○

Aldactone

ACEIs

K+ supplementation○

Treatment•

Beckwith-Wiedmann Syndrome

Macroglossia○

Organomegaly or hemihypertrophy•

Neonatal hypoglycemia•Abdominal wall defects•Increased risk of embryonal tumors (Wilms')•

Treatment for neonatal hypoglycemia○

May cause permanent brain damage if unrecognized

○

Treatment•

Other Renal Associated Cancers and Miscellaneous Renal Disease

Pathology

Dialysis

Unresponsive to conservative treatment

Hyperkalemia

Encephalopathy

Pericarditis/pleuritis

Severe metabolic acidosis

Indications○

Calcium oxalate deposition

Aquired cystic disease

Renal

Smooth muscle cell accumulation

Arterial intimal thickening

Dialysis related amyloidosis

Hypotension

Sepsis

Leukopenia

Vascular

Peritonitis

Obesity

Hyperglycemia

Hyperlipidemia

Peritoneal

Complications○

TransplantIndicated when unresponsive to conservative treatment and dialysis complications

•

Active infection○

Malignancy○

HIV○

Hepatitis b surface antigen○

Vascular disease○

Active glomerulonephritis○

Absolute contraindications•

70+ Y.O.○

Psychiatric disease○

Or chronic hepatitis

Hepatitis C with cirrhosis○

Dialysis/treatment non-compliance○

Primary renal disease○

Relative contraindications•

Renal Disease Treatments

Pathology

Medical School Renal Review

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Transcript of Medical School Renal Review