Pathophysiology of acute and chronic renal failure

Pathophysiology of acute Pathophysiology of acute and chronic renal failureand chronic renal failure

Jianzhong Sheng MD, PhDJianzhong Sheng MD, PhD

Acute renal failure (ARF)Acute renal failure (ARF)

• RRapid decline in glomerular filtration rate apid decline in glomerular filtration rate (hours to weeks)(hours to weeks)

• RRetention of nitrogenous waste productsetention of nitrogenous waste products

– occurs in 5% of all hospital admission and occurs in 5% of all hospital admission and up to 30% of admission to intensive care up to 30% of admission to intensive care unitsunits

• Oliguria Oliguria (urine output (urine output <<400 ml/d) is 400 ml/d) is frequentfrequent

• ARF is usuallyARF is usually asymptomatic asymptomatic and is and is diagnosed when screening of hospitalized diagnosed when screening of hospitalized patients reveals apatients reveals a recent increase in recent increase in serum blood urea nitrogen and creatinineserum blood urea nitrogen and creatinine

ARFARF• MMay complicate a wide range of diseases ay complicate a wide range of diseases

which for purposes of diagnosis and which for purposes of diagnosis and management are conveniently divided into 3 management are conveniently divided into 3 categories:categories:

1.1. DDisorders of renal perfusionisorders of renal perfusion– kidney is intrinsically normal (kidney is intrinsically normal (prerenal azotemia, prerenal azotemia,

prerenal ARFprerenal ARF) () (~~55%)55%)

2.2. DDiseases of renal parenchymaiseases of renal parenchyma– ((renal azotemia, renal ARFrenal azotemia, renal ARF) () (~~40%)40%)

3.3. AAcute obstruction of the urinary tract cute obstruction of the urinary tract – (post(postrenal azotemia, postrenal ARFrenal azotemia, postrenal ARF) () (~~5%)5%)

Classification of ARFClassification of ARF

1.1. Prerenal failurePrerenal failure

2.2. Intrinsic ARFIntrinsic ARF

3.3. Postrenal failure (obstruction)Postrenal failure (obstruction)

ARFARF• usually usually reversiblereversible

• a major cause of in-hospital morbidity a major cause of in-hospital morbidity and mortality due to the serious nature and mortality due to the serious nature of the underlying illnesses and the high of the underlying illnesses and the high incidence of complicationsincidence of complications

ARF – etiology and pathophysiologyARF – etiology and pathophysiology

Prerenal azotemia (prerenal ARF)Prerenal azotemia (prerenal ARF)– DDue to a functional response to renal ue to a functional response to renal

hypoperfusionhypoperfusion– IIs rapidly reversible upon restoration of s rapidly reversible upon restoration of

renal blood flow and glomerular renal blood flow and glomerular ultrafiltration pressureultrafiltration pressure

– RRenal parenchymal tissue is not damagedenal parenchymal tissue is not damaged– SSevere or prolonged hypoperfusion may evere or prolonged hypoperfusion may

lead to ischemic renal parenchymal injury lead to ischemic renal parenchymal injury and intrinsic renal azotemiaand intrinsic renal azotemia

Major causes of prerenal ARFMajor causes of prerenal ARF

1.1. HypovolemiaHypovolemia1.1. Hemorrhage (e.g. surgical, traumatic, Hemorrhage (e.g. surgical, traumatic,

gastrointestinal), burns, dehydrationgastrointestinal), burns, dehydration

2.2. Gastrointestinal fluid loss: vomiting, Gastrointestinal fluid loss: vomiting, surgical drainage, diarrheasurgical drainage, diarrhea

3.3. Renal fluid loss: diuretics, osmotic Renal fluid loss: diuretics, osmotic diuresis (e.g. DM), adrenal insufficiencydiuresis (e.g. DM), adrenal insufficiency

4.4. Sequestration of fluid in extravascular Sequestration of fluid in extravascular space: pancreatitis, peritonitis, trauma, space: pancreatitis, peritonitis, trauma, burns, hypoalbuminemiaburns, hypoalbuminemia

Major causes of prerenal ARFMajor causes of prerenal ARF

2.2. Low cardiac outputLow cardiac output• Diseases of myocardium, valves, and pericardium, Diseases of myocardium, valves, and pericardium,

arrhytmias, tamponadearrhytmias, tamponade• Other: pulmonary hypertension, pulmonary embolusOther: pulmonary hypertension, pulmonary embolus

3.3. Increased renal systemic vascular Increased renal systemic vascular rresistance esistance ratioratio

• Systemic vasodilatation: sepsis, vasodilator therapy, Systemic vasodilatation: sepsis, vasodilator therapy, anesthesia, anaphylaxisanesthesia, anaphylaxis

• Renal vasoconstriction: hypercalcemia, Renal vasoconstriction: hypercalcemia, norepinephrine, epinephrinenorepinephrine, epinephrine

• Cirrhosis with ascitesCirrhosis with ascites

• Prerenal azotemia (prerenal ARF)Prerenal azotemia (prerenal ARF)

– DDue to a functional response to renal ue to a functional response to renal hypoperfusionhypoperfusion

hypovolemia hypovolemia

mean arterial pressure mean arterial pressure

detection as reduced stretch by arterial (e.g. detection as reduced stretch by arterial (e.g. carotid sinus) and cardiac baroreceptors carotid sinus) and cardiac baroreceptors

trigger a series of neurohumoral responses to trigger a series of neurohumoral responses to maintain arterial pressure:maintain arterial pressure:• activation of symptahetic nervous systemactivation of symptahetic nervous system• RAARAA• releasing of vasopresin (AVP, ADH) and endothelinreleasing of vasopresin (AVP, ADH) and endothelin

• Prerenal azotemia (prerenal ARF)Prerenal azotemia (prerenal ARF)

– IIs rapidly reversible upon restoration of renal s rapidly reversible upon restoration of renal blood flow and glomerular ultrafiltration blood flow and glomerular ultrafiltration pressurepressure

norepinephrinenorepinephrineangiotensin IIangiotensin IIADHADHendothelin endothelin vasoconstriction in musculocutaneous vasoconstriction in musculocutaneous and and splanchnic vascular bedssplanchnic vascular beds

reduction of salt loss through sweat reduction of salt loss through sweat glandsglands

thirst and salt appetite stimulationthirst and salt appetite stimulationrenal salt and water retentionrenal salt and water retention

CCardiac and cerebral perfusion is preserved to ardiac and cerebral perfusion is preserved to that of other that of other less essentialless essential organs organs

RRenal responses combine to maintain enal responses combine to maintain glomerular perfusion and filtrationglomerular perfusion and filtration

: stretch receptors in afferent arterioles : stretch receptors in afferent arterioles trigger relaxation of arteriolar trigger relaxation of arteriolar

smooth smooth muscle cellsmuscle cells

+ BBiosynthesis of vasodilator renal iosynthesis of vasodilator renal prostaglandins (prostacyclin, PGEprostaglandins (prostacyclin, PGE22) and nitric ) and nitric

oxide is also enhancedoxide is also enhanced

dilatation of afferent arteriolesdilatation of afferent arterioles

+ AAngiotensin II induces preferential ngiotensin II induces preferential constriction of efferent arterioles (by constriction of efferent arterioles (by density of density of angiotensin II receptors at this location)angiotensin II receptors at this location)

intraglomerular pressure is preserved and filtration intraglomerular pressure is preserved and filtration fraction is increasedfraction is increased

DDuring uring severe hypoperfusionsevere hypoperfusion these these responses prove inadequate, and responses prove inadequate, and ARF ARF ensuesensues

Intrinsic renal azotemia (intrinsic renal ARF)Intrinsic renal azotemia (intrinsic renal ARF)

• Major causes Major causes

1.1. Renovascular obstruction Renovascular obstruction

1.1. Renal artery obstruction: atherosclerotic Renal artery obstruction: atherosclerotic plaque, thrombosis, embolism, dissecting plaque, thrombosis, embolism, dissecting aneurysm)aneurysm)

2.2. Renal vein obstruction: thrombosis, Renal vein obstruction: thrombosis, compressioncompression

Major causes of intrinsic renal ARFMajor causes of intrinsic renal ARF

2.2. Diseases of glomeruliDiseases of glomeruli• Glomerulonephritis and vasculitisGlomerulonephritis and vasculitis

3.3. Acute tubular necrosisAcute tubular necrosis• Ischemia:Ischemia: as for prerenal azotemia (hypovolemia, as for prerenal azotemia (hypovolemia,

low CO, renal vasoconstriction, systemic low CO, renal vasoconstriction, systemic vasodilatation)vasodilatation)

• ToxinsToxins: : • exogenous exogenous – contrast, cyclosporine, ATB – contrast, cyclosporine, ATB

(aminoglycosides, amphotericin B), chemotherapeutic (aminoglycosides, amphotericin B), chemotherapeutic agents (cisplatin), organic solvents (ethylen glycol)agents (cisplatin), organic solvents (ethylen glycol)

• Endogenous – Endogenous – rhabdomyolysis, hemolysis, uric acid, rhabdomyolysis, hemolysis, uric acid, oxalate, plasma cell dyscrasia (myeloma)oxalate, plasma cell dyscrasia (myeloma)

Major causes of intrinsic renal ARFMajor causes of intrinsic renal ARF

4.4. Intersitial nephritisIntersitial nephritis

• Allergic:Allergic: ATB (beta-lactams, sulfonamides), ATB (beta-lactams, sulfonamides), cyclooxygenase inhibitors, diureticscyclooxygenase inhibitors, diuretics

• InfectionInfection• bacterial bacterial – acute pyelonephritis– acute pyelonephritis• viral viral – CMV– CMV• Fungal Fungal – candidiasis– candidiasis

• Infiltration: Infiltration: lymphoma, leukemia, sarcoidosislymphoma, leukemia, sarcoidosis• IdiopathicIdiopathic

• Renal azotemia (renal ARF)Renal azotemia (renal ARF)

– Most cases are caused either by ischemia Most cases are caused either by ischemia secondary to renal hypoperfusion secondary to renal hypoperfusion ischemic ARFischemic ARF

– or toxins or toxins nephrotoxic ARFnephrotoxic ARF

Ischemic and nephrotoxic ARF are Ischemic and nephrotoxic ARF are frequently associated with necrosis of frequently associated with necrosis of tubule epithelial cells – this syndrome is tubule epithelial cells – this syndrome is often referred to as often referred to as acute tubular necrosis acute tubular necrosis (ATN)(ATN)

• Terms intrinsic ARF and ATN are often used Terms intrinsic ARF and ATN are often used interchangeably, but this is inappropriate interchangeably, but this is inappropriate because some parenchymal disease because some parenchymal disease (vasculitis, glomerulonephritis, interstitial (vasculitis, glomerulonephritis, interstitial nephritis) can cause ARF without tubule cell nephritis) can cause ARF without tubule cell necrosisnecrosis

• The pathologic term ATN is frequently The pathologic term ATN is frequently inaccurate (even in ischemic or nephrotoxic inaccurate (even in ischemic or nephrotoxic ARF) because tubule cell necrosis may not ARF) because tubule cell necrosis may not be present in be present in 20 to 30 % of cases 20 to 30 % of cases

Ischemic ARFIschemic ARF

– Renal hypoperfusion from any cause may Renal hypoperfusion from any cause may lead to ischemic ARF if severe enough to lead to ischemic ARF if severe enough to overwhelm renal autoregulatory and overwhelm renal autoregulatory and neurohumoral defence mechanismsneurohumoral defence mechanisms

– It occurs not frequently after It occurs not frequently after cardiovascular surgery, trauma, cardiovascular surgery, trauma, hemorrhage, sepsis or dehydrationhemorrhage, sepsis or dehydration

Ischemic ARF. Flow chart illustrate the cellular basis of ischemic ARF.

Ischemic ARFIschemic ARF

• Mechanisms by which renal hypoperfusion and Mechanisms by which renal hypoperfusion and ischemia impair glomerular filtration includeischemia impair glomerular filtration include

– Reduction in glomerular perfusion and filtrationReduction in glomerular perfusion and filtration

– Obstruction of urine flow in tubules by cells and debris Obstruction of urine flow in tubules by cells and debris (including casts) derived from ischemic tubule (including casts) derived from ischemic tubule epitheliumepithelium

– Backleak of glomerular filtrate through ischemic tubule Backleak of glomerular filtrate through ischemic tubule epitheliumepithelium

– Neutrophil activation within the renal vasculature and Neutrophil activation within the renal vasculature and neutrophil-mediated cell injury may contributeneutrophil-mediated cell injury may contribute

Mechanisms of proximal tubule cell-mediated reduction of GFR following ischemic injury

Fate of an injured proximal tubule cell after an ischemic episode depends on the extent and duration of ischemia

• Renal hypoperfusion leads to ischemia of Renal hypoperfusion leads to ischemia of renal tubule cells particularly the terminal renal tubule cells particularly the terminal straight portion of proximal tubule (pars recta)straight portion of proximal tubule (pars recta) and the and the thick ascending limb of the loop of thick ascending limb of the loop of HenleHenle

• These segments traverse corticomedullary These segments traverse corticomedullary junction and outer medulla, regions of the junction and outer medulla, regions of the kidney that are relatively hypoxic compared kidney that are relatively hypoxic compared with the renal cortex, because of the unique with the renal cortex, because of the unique counterurrent arrangement of the vasculaturecounterurrent arrangement of the vasculature

• Proximal tubules and thick ascending Proximal tubules and thick ascending limb cells have limb cells have greater oxygen greater oxygen requirementsrequirements than other renal cells than other renal cells because of high rates of because of high rates of active (ATP-active (ATP-dependent) sodium transportdependent) sodium transport

• Proximal tubule cells may be prone to Proximal tubule cells may be prone to ischemic injury because they rely ischemic injury because they rely exclusively on mitochondrial oxidative exclusively on mitochondrial oxidative phosphorylation (oxagen-dependent) phosphorylation (oxagen-dependent) for ATP synthesis and for ATP synthesis and cannot generate cannot generate ATP from anerobic glycolysisATP from anerobic glycolysis

• Cellular ischemia causes alteration inCellular ischemia causes alteration in– energeticsenergetics– ion transportion transport– membrane integritymembrane integrity cell necrosis:cell necrosis:

- depletion of ATP- depletion of ATP- inhibition of active transport of sodium and other - inhibition of active transport of sodium and other

solutessolutes- impairment of cell volume regulation and cell impairment of cell volume regulation and cell

swellingswelling- cytoskeletal disruptioncytoskeletal disruption- accumulation of intracellular calciumaccumulation of intracellular calcium- altered phospholipid metabolismaltered phospholipid metabolism- free radicals formationfree radicals formation- peroxidation of membrane lipidsperoxidation of membrane lipids

Pathophysiology of ischemic and toxic ARF

Vasoactive hormones that may be responsible for the hemodynamic abnormalities in ATN

• Necrotic tubule epithelium Necrotic tubule epithelium

• may permit may permit backleak of filtered solutesbackleak of filtered solutes, , including creatinine, urea, and other including creatinine, urea, and other nitrogenous waste products, thus nitrogenous waste products, thus rendering glomerular filtration rendering glomerular filtration ineffectiveineffective

• may may slough into the tubule lumensslough into the tubule lumens, , obstruct urine flow, increase obstruct urine flow, increase intratubular pressure, and impair intratubular pressure, and impair formation of glomerular filtrateformation of glomerular filtrate

• Epithelial cell injury per se cause Epithelial cell injury per se cause secondary secondary renal vasoconstrictionrenal vasoconstriction by a process termed by a process termed tubuloglomerular feedback:tubuloglomerular feedback:

– SSpecialized epithelial cells in the macula densa pecialized epithelial cells in the macula densa region of distal tubule detect increases in distal region of distal tubule detect increases in distal tubule salt delivery due to impaired reabsorption tubule salt delivery due to impaired reabsorption by proximal nepron segments and in turn by proximal nepron segments and in turn stimulate constriction of afferent arteriolesstimulate constriction of afferent arterioles

Sites of renal damage, including factors that contribute to the kidney´s susceptibilty to damage

Nephrotoxic ARFNephrotoxic ARF

– The kidney is particularly susceptible to The kidney is particularly susceptible to nephrotic injury by virtue of itsnephrotic injury by virtue of its• Rich blood supply (25 % of CO)Rich blood supply (25 % of CO)• Ability to concentrate toxins in medullary Ability to concentrate toxins in medullary

interstitium (via the renal countercurrent interstitium (via the renal countercurrent mechanism)mechanism)

• Renal epithelial cells (via specific transporters)Renal epithelial cells (via specific transporters)

ARF complicates 10 to 30% of courses of ARF complicates 10 to 30% of courses of aminoglycoside antibioticsaminoglycoside antibiotics and up to 70% of and up to 70% of courses of courses of cisplatin cisplatin treatmenttreatment

• Aminoglycosides Aminoglycosides are filtered accross the are filtered accross the glomerular filtration barrier and accumulated by glomerular filtration barrier and accumulated by proximal tubule cells after interaction with proximal tubule cells after interaction with phospholipid residues on brush border membrane.phospholipid residues on brush border membrane.They appear to disrupt normal processing of They appear to disrupt normal processing of membrane phospholipids by lysosomes.membrane phospholipids by lysosomes.

• Cisplatin Cisplatin is also accumulated by proximal tubule is also accumulated by proximal tubule cells and causes mitochondrial injury, inhibition of cells and causes mitochondrial injury, inhibition of ATPase activity and solute transport, and free ATPase activity and solute transport, and free radical injury to cell membranesradical injury to cell membranes

Renal handling of aminoglycosides

• Radiocontrast agentsRadiocontrast agents• Mechanisms: intrarenal vasoconstriction and Mechanisms: intrarenal vasoconstriction and

ischemia triggered by endothelin release from ischemia triggered by endothelin release from endothelial cells, direct tubular toxicityendothelial cells, direct tubular toxicityIntraluminal precipitation of protein or uric acid Intraluminal precipitation of protein or uric acid crystalscrystals

• Rhabdomyolysis and hemolysis Rhabdomyolysis and hemolysis can cause ARF, can cause ARF, particularly in hypovolemic or acidotic individualsparticularly in hypovolemic or acidotic individuals

– Rhabdomyolysis and myoglobinuric ARF Rhabdomyolysis and myoglobinuric ARF may occur with may occur with traumatic crush injurytraumatic crush injury• Muscle ischemia (e.g. arterial insufficiency, muscle Muscle ischemia (e.g. arterial insufficiency, muscle

compression, cocaine overdose), seizures, excessive compression, cocaine overdose), seizures, excessive exercise, heat stroke or malignant hyperthermia, exercise, heat stroke or malignant hyperthermia, alcoholism, and infections (e.g. influenza, legionella), alcoholism, and infections (e.g. influenza, legionella), etc.etc.

• ARF due to hemolysis ARF due to hemolysis is seen most commonly is seen most commonly following blood transfusion reactionsfollowing blood transfusion reactions

• The mechanisms by which rhabdomyolysis and The mechanisms by which rhabdomyolysis and hemolysis impair GFR are unclear, since neither hemolysis impair GFR are unclear, since neither hemoglobin nor myoglobin is nephrotoxic when hemoglobin nor myoglobin is nephrotoxic when injected to laboratory animalsinjected to laboratory animals

• Myoglobin and hemoglobin or other compounds Myoglobin and hemoglobin or other compounds release from muscle or red blood cells may cause release from muscle or red blood cells may cause ARF via ARF via direct toxic effects on tubule epithelial direct toxic effects on tubule epithelial cellscells or by or by inducing intratubular cast formationinducing intratubular cast formation; ; they they inhibit nitric oxideinhibit nitric oxide and may trigger intrarenal and may trigger intrarenal vasoconstrictionvasoconstriction

Nephrotoxicants may act at different sites in the kidney, resulting in altered renal function. The site of injury by selected nephrotoxicants are shown.

Course of ischemic and nephrotoxic Course of ischemic and nephrotoxic ARFARF

• Most cases of ischemic or nephrotoxic ARF Most cases of ischemic or nephrotoxic ARF are characterized by 3 distinct phasesare characterized by 3 distinct phases

1.1. Initial phaseInitial phase

- the period from initial exposure to the - the period from initial exposure to the causative insult to development of causative insult to development of established ARFestablished ARF

-- restoration of renal perfusion or restoration of renal perfusion or elimination of nephrotoxins during this elimination of nephrotoxins during this phase may reverse or limit the renal injuryphase may reverse or limit the renal injury

2.2. Maintenance phaseMaintenance phase(average 7 to 14 days)(average 7 to 14 days)-- the GFR is depressed, and metabolic the GFR is depressed, and metabolic consequences of ARF may developconsequences of ARF may develop

3.3. Recovery phaseRecovery phasein most patients is characterized by tubule in most patients is characterized by tubule cell regeneration and gradual return of GFR cell regeneration and gradual return of GFR to or toward normalto or toward normal- may be complicated by diuresis (diuretic - may be complicated by diuresis (diuretic phase) due to excretion of retained salt and phase) due to excretion of retained salt and water and other solutes continued use of water and other solutes continued use of diuretics, and/or delayed recovery of diuretics, and/or delayed recovery of epithelial cell functionepithelial cell function

Growth regulation after an acute insult in regenerating renal tubule epithelial cells. Under the influence of growth-stimulating factors the damaged renal tubular epithelium is capable of regenerating with restoration of tubule integrity and function

Postrenal azotemia (postrenal ARF)Postrenal azotemia (postrenal ARF)

Major causes Major causes

1.1. UretericUretericcalculi, blood clot, cancercalculi, blood clot, cancer

2.2. Bladder neckBladder neckneurogenic bladder, neurogenic bladder, prostatic hyperplasiaprostatic hyperplasia, , calculi, blood clot, cancercalculi, blood clot, cancer

3.3. UrethraUrethrastricturestricture

Mechanisms:Mechanisms:• During the early stages of obstruction (hours During the early stages of obstruction (hours

to days), continued glomerular filtration lead to days), continued glomerular filtration lead to increase intraluminal pressure upstream to increase intraluminal pressure upstream to the obstruction, eventuating in gradual to the obstruction, eventuating in gradual distension of proximal ureter, renal pelvis, distension of proximal ureter, renal pelvis, and calyces and a fall in GFRand calyces and a fall in GFR

Chronic renal failure (CRF)Chronic renal failure (CRF)

• MMany forms of renal injury progress inexoraly any forms of renal injury progress inexoraly to CRFto CRF

• Reduction of renal massReduction of renal mass causes structural causes structural and functional hypertrophy of remaining and functional hypertrophy of remaining nephronsnephrons

• This This compensatorycompensatory hypertrophy is due to hypertrophy is due to adaptive hyperfiltration mediated by adaptive hyperfiltration mediated by increases in glomerular capillary pressures increases in glomerular capillary pressures and flowsand flows

Chronic renal failure (CRF) - causesChronic renal failure (CRF) - causes

• GlomerulonephritisGlomerulonephritis – the most common – the most common cause in the pastcause in the past

• Diabetes mellitusDiabetes mellitus

• HypertensionHypertension

• Tubulointerstitial nephritisTubulointerstitial nephritis– are now the leading causes of CRFare now the leading causes of CRF

Consequences of sustained reduction in Consequences of sustained reduction in GFRGFR

• GFR – sensitive index of overall renal GFR – sensitive index of overall renal excretory functionexcretory function

GFR GFR retention and accumulation of retention and accumulation of the unexcreted substances in the body the unexcreted substances in the body fluidsfluids

– A – urea, creatinineA – urea, creatinine– B – HB – H++, K, K++, phosphates, urates, phosphates, urates– C – NaC – Na++

Representative patterns of adaptation for different types of solutes in body fluids in CRF

UremiaUremia

IIs clinical syndrome that results from profound loss s clinical syndrome that results from profound loss of renal functionof renal function

CCause(s) of it remains unknownause(s) of it remains unknown

RReeffers generally to the constellation of signs and ers generally to the constellation of signs and symptoms associated with CRF, regardless of symptoms associated with CRF, regardless of causecause

PPresentations and severity of signs and symptoms resentations and severity of signs and symptoms of uremia vary and depend onof uremia vary and depend on

the magnitude of reduction in functioning renal the magnitude of reduction in functioning renal massmass

rrapidity with which renal function is lostapidity with which renal function is lost

Uremia – pathophysiology and Uremia – pathophysiology and biochemistrybiochemistry

• TThe most likely candidates as toxins in uremia he most likely candidates as toxins in uremia are the are the by–products of protein and amino acid by–products of protein and amino acid metabolismmetabolism– Urea – Urea – represents some 80% of the total nitrogen represents some 80% of the total nitrogen

excreted into the urineexcreted into the urine– Guanidino compunds: Guanidino compunds: guanidine, creatinine, guanidine, creatinine,

creatin, guanidin-succinic acid)creatin, guanidin-succinic acid)– Urates Urates and other end products of nucleic acid and other end products of nucleic acid

metabolismmetabolism– Aliphatic aminesAliphatic amines– PeptidesPeptides– Derivates of the aromatic amino acids: Derivates of the aromatic amino acids: tryptophan, tryptophan,

tyrosine, and phenylalaninetyrosine, and phenylalanine

Uremia – pathophysiology and Uremia – pathophysiology and biochemistrybiochemistry

• TThe role of these various substances in the he role of these various substances in the pathogenesis of uremic syndrome is unclearpathogenesis of uremic syndrome is unclear

• UUremic symptoms correlate only in a rough remic symptoms correlate only in a rough and inconsistent way with concentrations of and inconsistent way with concentrations of ureaurea in blood in blood

• UUrea may account for some of clinical rea may account for some of clinical abnormalities: abnormalities: anorexia, malaise, womiting, anorexia, malaise, womiting, headacheheadache

Tubule transport in reduced nephron Tubule transport in reduced nephron massmass

• LLoss of renal function with progressive renal disease is oss of renal function with progressive renal disease is usually attended by distortion of renal morphology and usually attended by distortion of renal morphology and architecturearchitecture

• DDespite this structural disarray, glomerular and tubule espite this structural disarray, glomerular and tubule functions often remain as closely integrated (i.e. functions often remain as closely integrated (i.e. glomerulotubular balanceglomerulotubular balance) in the normal organ, at least ) in the normal organ, at least until the final stages of CRFuntil the final stages of CRF

• AA fundamental feature of this fundamental feature of this intact nephron hypothesisintact nephron hypothesis is that following loss of nephron mass, renal function is is that following loss of nephron mass, renal function is due primarily to the operation of surviving healthy due primarily to the operation of surviving healthy nephrons, while the diseased nephrons cease functioningnephrons, while the diseased nephrons cease functioning

Tubule transport in reduced nephron Tubule transport in reduced nephron massmass

• DDespite progressive nephron destruction, many of the espite progressive nephron destruction, many of the mechanisms that control solute and water balance mechanisms that control solute and water balance differ only quantitatively, and not qualitatively, from differ only quantitatively, and not qualitatively, from those that operate normallythose that operate normally

Transport functions of the various anatomic segments of the nephron

Tubule transport of sodium and water -1Tubule transport of sodium and water -1

• In most patients with stable CRF, total-body NaIn most patients with stable CRF, total-body Na++ and and water content are increased modestly, although ECF water content are increased modestly, although ECF volume expansion may not be apparentvolume expansion may not be apparent

• Excessive salt ingestion contributes to Excessive salt ingestion contributes to – congestive heart failurecongestive heart failure– hypertensionhypertension– ascitesascites– edemaedema

• Excessive water ingestion Excessive water ingestion – hyponatremiahyponatremia– weight gainweight gain

Tubule transport of sodium and water - 2Tubule transport of sodium and water - 2

• Patient with CRF have impaired renal mechanisms Patient with CRF have impaired renal mechanisms for conserving Nafor conserving Na++ and water and water

• When an extrarenal cause for When an extrarenal cause for fluid loss is present fluid loss is present (vomiting, diarrhea, fever), these patients are prone (vomiting, diarrhea, fever), these patients are prone to develop ECF volume depletionto develop ECF volume depletion– depletion of ECF volume results in deterioration of depletion of ECF volume results in deterioration of

residual renal functionresidual renal function

Potassium homeostasisPotassium homeostasis

• MMost CRF patients maintain ost CRF patients maintain normal serum Knormal serum K++ concentrationsconcentrations until the final stages of uremia until the final stages of uremia– due to adaptation in the renal distal tubules and colon, sites due to adaptation in the renal distal tubules and colon, sites

where aldosteron serve to enhance Kwhere aldosteron serve to enhance K++ secretion secretion

• OOliguria or disruption of key adaptive mechanisms liguria or disruption of key adaptive mechanisms (abrupt lowering of arterial blood pH), can lead to (abrupt lowering of arterial blood pH), can lead to hyperkalemiahyperkalemia

• HypokalemiaHypokalemia is uncommon is uncommon– poor dietary Kpoor dietary K++ intake + excessive diuretic therapy + intake + excessive diuretic therapy +

increased GIT lossesincreased GIT losses

Metabolic acidosisMetabolic acidosis

• Metabolic acidosis of CRF is not due to Metabolic acidosis of CRF is not due to overproduction of endogenous acids but is overproduction of endogenous acids but is largely a reflection of the largely a reflection of the reduction in renal reduction in renal massmass, which limits the amount of NH, which limits the amount of NH33 (and (and

therefore HCOtherefore HCO33--) that can be generated) that can be generated

Phosphate, calcium and bonePhosphate, calcium and bone

• HypocalcemiaHypocalcemia in CRF results from the in CRF results from the impaired ability of the diseased kidney to impaired ability of the diseased kidney to synthesize 1,25-dihydroxyvitamin D, the synthesize 1,25-dihydroxyvitamin D, the active metabolite of vitamin Dactive metabolite of vitamin D

• HyperphosphatemiaHyperphosphatemia due to due to GFR GFR

Phosphate, calcium and bonePhosphate, calcium and bone

PTH PTH • disordered vitamin D metabolismdisordered vitamin D metabolism• chronic metabolic acidosis - chronic metabolic acidosis - bone is large reservoir bone is large reservoir

of alkaline salts –calcium phospate, calcium carbonate; of alkaline salts –calcium phospate, calcium carbonate; dissolution of this buffer source probably contributes to:dissolution of this buffer source probably contributes to:

renal and metabolic osteodystrophy:renal and metabolic osteodystrophy:

a number of skeletal abnormalities, a number of skeletal abnormalities, includingincluding osteomalcia, osteitis fibrosa, osteomalcia, osteitis fibrosa, osteosclerosisosteosclerosis

Pathogenesis of bone diseases in CRF

Cardiovascular and pulmonary Cardiovascular and pulmonary abnormalitiesabnormalities

• HypertensionHypertension• Pericarditis Pericarditis (infrequent because of early (infrequent because of early

dialysis)dialysis)• Accelerated atherosclerosisAccelerated atherosclerosis

– HTHT– HyperlipidemiaHyperlipidemia– Glucose intoleranceGlucose intolerance– Chronic high cardiac outputChronic high cardiac output– Vascular and myocardial calcificationsVascular and myocardial calcifications

Cardiovascular manifestationsCardiovascular manifestations

Hematologic abnormalitiesHematologic abnormalities

• Normochromic normocytic anemiaNormochromic normocytic anemia– Erythropoesis is depressedErythropoesis is depressed

• Effects of retained toxinsEffects of retained toxins• Diminished biosynthesis of erythropoietinDiminished biosynthesis of erythropoietin – more – more

importantimportant• Aluminium intoxication – Aluminium intoxication – microcytic anemiamicrocytic anemia• Fibrosis of bone marrow due to hyperparathyreoidismFibrosis of bone marrow due to hyperparathyreoidism• Inadequate replacement of folic acidInadequate replacement of folic acid


• Abnormal hemostasisAbnormal hemostasis– Tendency to abnormal bleedingTendency to abnormal bleeding

• From surgical woundsFrom surgical wounds• Spontaneously into the GIT, pericardial sac, intracranial Spontaneously into the GIT, pericardial sac, intracranial

vault, in the form of subdural hematoma or intracerebral vault, in the form of subdural hematoma or intracerebral hemorrhagehemorrhage

– Prolongation of bleeding timeProlongation of bleeding time platelet factor III activity – correlates with platelet factor III activity – correlates with plasma plasma

levels of guanidinosuccinic acidlevels of guanidinosuccinic acid


• Leucocyte function impairmentLeucocyte function impairment– uremic serumuremic serum– coexisting acidosiscoexisting acidosis– hyperglycemiahyperglycemia– protein-calorie malnutritionprotein-calorie malnutrition– serum and tissue hyperosmolarity (due to serum and tissue hyperosmolarity (due to

azotemia)azotemia)

enhanced susceptibility to infectionenhanced susceptibility to infection


Anemia is normochromic and normocytic with a low reticulocyte count

Uremic milieu

Reduction inrenal mass

erythropoetin

erythropoesis

Red blood cell mass

Red blood cell survival

Platelet dysfunction

Bleeding tendency

Neuromuscular abnormalitiesNeuromuscular abnormalities

• CNSCNS– inability to concentrateinability to concentrate– drowsinessdrowsiness– insomniainsomnia– mild behavioral changesmild behavioral changes– loss of memoryloss of memory– errors in judgmenterrors in judgment

++ neuromuscular irritability neuromuscular irritability including including hiccups hiccups

crampscramps

fasciculationsfasciculations twitching of twitching of

musclesmuscles

early symptoms of uremia


– asterixisasterixis– myoclonusmyoclonus– choreachorea– stuporstupor– seizuresseizures– comacoma

terminal uremia


• Peripheral neuropathyPeripheral neuropathy

– SSensory nerveensory nerve involvement exceeds motor, lower involvement exceeds motor, lower extremities are involved more than the uppe, and extremities are involved more than the uppe, and the distal portions of the extremities more than the distal portions of the extremities more than proximalproximal

– TThe he restless legs syndromerestless legs syndrome is characterized by is characterized by ill-definedsensations of discomfort in the feet and ill-definedsensations of discomfort in the feet and lower legs and frequent leg movementlower legs and frequent leg movement

– LLaterater motor motor nervenerve involvement follow ( involvement follow ( deep deep tendon reflexes, etc.)tendon reflexes, etc.)

Gastrointestinal abnormalitiesGastrointestinal abnormalities

– anorexiaanorexia– hiccupshiccups– nauseanausea– vomitingvomiting

Uremic fetorUremic fetor, a uriniferous odor to the breath, derives , a uriniferous odor to the breath, derives from the breakdown of urea in saliva to ammonia and is from the breakdown of urea in saliva to ammonia and is associated with unpleasant taste sensationassociated with unpleasant taste sensation

Uremic gastroenteritis Uremic gastroenteritis (late stages of CRF)(late stages of CRF)

Peptic ulcerPeptic ulcer

gastric aciditygastric acidity

hypersecretion of gastrinhypersecretion of gastrin

Secondary hyperparathyreoidismSecondary hyperparathyreoidism

early manifestation of uremia

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Lipid metabolismLipid metabolism

• HypertriglyceridemiaHypertriglyceridemia and and high-density lipoprotein high-density lipoprotein cholesterolcholesterol are common in uremia, whereas cholesterol are common in uremia, whereas cholesterol levels in plasma are usually normallevels in plasma are usually normal

• WWhether uremia accelerates triglyceride production by hether uremia accelerates triglyceride production by the liver and intestine is unknownthe liver and intestine is unknown

• the enhancement of lipogenesis by insulin may the enhancement of lipogenesis by insulin may contribute to increased triglyceride synthesiscontribute to increased triglyceride synthesis

• TThe rate of removal of triglycerides from the circulation, he rate of removal of triglycerides from the circulation, which depends in large part on enzyme which depends in large part on enzyme lipoprotein lipoprotein lipaselipase, is depressed in uremia, is depressed in uremia

• TThe he high incidence of premature atherosclerosishigh incidence of premature atherosclerosis in in patients on chronic dialysispatients on chronic dialysis

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Pathophysiology of acute and chronic renal failure

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