Pathophysiology of acute and chronic renal failure Renata

Pathophysiology of acute and chronic renal failure Renata Péčová

Acute renal failure (ARF) • rapid decline in glomerular filtration rate (hours to weeks) • retention of nitrogenous waste products – occurs in 5% of all hospital admissions and up to 30% of admissions to intensive care units

• Oliguria (urine output < 400 ml/d) is frequent • ARF is usually asymptomatic and is diagnosed when screening of hospitalized patients reveals a recent increase in serum blood urea nitrogen and creatinine

ARF • may complicate a wide range of diseases which for purposes of diagnosis and management are conveniently divided into 3 categories: 1. disorders of renal perfusion – kidney is intrinsically normal (prerenal azotemia, prerenal ARF) (~55%) 2. diseases of renal parenchyma – (renal azotemia, renal ARF) (~40%) 3. acute obstruction of the urinary tract – (postrenal azotemia, postrenal ARF) (~5%)

Classification of ARF 1. Prerenal failure 2. Intrinsic ARF 3. Postrenal failure (obstruction)

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

ARF – etiology and pathophysiology • Prerenal azotemia (prerenal ARF) – due to a functional response to renal hypoperfusion – is rapidly reversible upon restoration of renal blood flow and glomerular ultrafiltration pressure – renal parenchymal tissue is not damaged – severe or prolonged hypoperfusion may lead to ischemic renal parenchymal injury and intrinsic renal azotemia

Major causes of prerenal ARF 1. Hypovolemia 1. Hemorrhage (e. g. surgical, traumatic, gastrointestinal), burns, dehydration 2. Gastrointestinal fluid loss: vomiting, surgical drainage, diarrhea 3. Renal fluid loss: diuretics, osmotic diuresis (e. g. DM), adrenal insufficiency 4. Sequestration of fluid in extravascular space: pancreatitis, peritonitis, trauma, burns, hypoalbuminemia

Major causes of prerenal ARF 2. Low cardiac output • • Diseases of myocardium, valves, and pericardium, arrhytmias, tamponade Other: pulmonary hypertension, pulmonary embolus 3. Increased renal systemic vascular esistance ratio • • • Systemic vasodilatation: sepsis, vasodilator therapy, anesthesia, anaphylaxis Renal vasoconstriction: hypercalcemia, norepinephrine, epinephrine Cirrhosis with ascites

• Prerenal azotemia (prerenal ARF) – due to a functional response to renal hypoperfusion hypovolemia mean arterial pressure detection as reduced stretch by arterial (e. g. carotid sinus) and cardiac baroreceptors trigger a series of neurohumoral responses to maintain arterial pressure: • • • activation of symptahetic nervous system RAA releasing of vasopresin (AVP, ADH) and endothelin

• Prerenal azotemia (prerenal ARF) – is rapidly reversible upon restoration of renal blood flow and glomerular ultrafiltration pressure norepinephrine angiotensin II ADH endothelin vasoconstriction in musculocutaneous and splanchnic vascular beds reduction of salt loss through sweat glands thirst and salt appetite stimulation renal salt and water retention

cardiac and cerebral perfusion is preserved to that of other less essential organs renal responses combine to maintain glomerular perfusion and filtration : stretch receptors in afferent arterioles trigger relaxation of arteriolar smooth muscle cells + biosynthesis of vasodilator renal prostaglandins (prostacyclin, PGE 2) and nitric oxide is also enhanced dilatation of afferent arterioles

+ angiotensin II induces preferential constriction of efferent arterioles (by density of angiotensin II receptors at this location) intraglomerular pressure is preserved and filtration fraction is increased during severe hypoperfusion these responses prove inadequate, and ARF ensues

Intrinsic renal azotemia (intrinsic renal ARF) • Major causes 1. Renovascular obstruction 1. Renal artery obstruction: atherosclerotic plaque, thrombosis, embolism, dissecting aneurysm) 2. Renal vein obstruction: thrombosis, compression

Major causes of intrinsic renal ARF 2. Diseases of glomeruli • Glomerulonephritis and vasculitis 3. Acute tubular necrosis • • Ischemia: as for prerenal azotemia (hypovolemia, low CO, renal vasoconstriction, systemic vasodilatation) Toxins: • • exogenous – contrast, cyclosporine, ATB (aminoglycosides, amphotericin B), chemotherapeutic agents (cisplatin), organic solvents (ethylen glycol) Endogenous – rhabdomyolysis, hemolysis, uric acid, oxalate, plasma cell dyscrasia (myeloma)

Major causes of intrinsic renal ARF 4. Intersitial nephritis • • Allergic: ATB (beta-lactams, sulfonamides), cyclooxygenase inhibitors, diuretics Infection • • • bacterial – acute pyelonephritis viral – CMV Fungal – candidiasis Infiltration: lymphoma, leukemia, sarcoidosis Idiopathic

• Renal azotemia (renal ARF) – Most cases are caused either by ischemia secondary to renal hypoperfusion ischemic ARF – or toxins nephrotoxic ARF Ischemic and nephrotoxic ARF are frequently associated with necrosis of tubule epithelial cells – this syndrome is often referred to as acute tubular necrosis (ATN)

• Terms intrinsic ARF and ATN are often used interchangeably, but this is inappropriate because some parenchymal disease (vasculitis, glomerulonephritis, interstitial nephritis) can cause ARF without tubule cell necrosis • The pathologic term ATN is inaccurate (even in ischemic or ARF) because tubule cell necrosis present in 20 to 30 % of cases frequently nephrotoxic may not be

Ischemic ARF – Renal hypoperfusion from any cause may lead to ischemic ARF if severe enough to overwhelm renal autoregulatory and neurohumoral defence mechanisms – It occurs not frequently after cardiovascular surgery, trauma, hemorrhage, sepsis or dehydration

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

Ischemic ARF • Mechanisms by which renal hypoperfusion and ischemia impair glomerular filtration include – Reduction in glomerular perfusion and filtration – Obstruction of urine flow in tubules by cells and debris (including casts) derived from ischemic tubule epithelium – Backleak of glomerular filtrate through ischemic tubule epithelium – Neutrophil activation within the renal vasculature and neutrophil-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 tubule cells particularly the terminal straight portion of proximal tubule (pars recta) and the thick ascending limb of the loop of Henle • These segments traverse corticomedullary junction and outer medulla, regions of the kidney that are relatively hypoxic compared with the renal cortex, because of the unique counterurrent arrangement of the vasculature

• Proximal tubules and thick ascending limb cells have greater oxygen requirements than other renal cells because of high rates of active (ATPdependent) sodium transport • Proximal tubule cells may be prone to ischemic injury because they rely exclusively on mitochondrial oxidative phosphorylation (oxagen -dependent) for ATP synthesis and cannot generate ATP from anerobic glycolysis

• Cellular ischemia causes alteration in – – – energetics ion transport membrane integrity cell necrosis: - depletion of ATP - inhibition of active transport of sodium and other solutes - impairment of cell volume regulation and cell swelling - cytoskeletal disruption - accumulation of intracellular calcium - altered phospholipid metabolism - free radicals formation - peroxidation of membrane lipids

Pathophysiology of ischemic and toxic ARF

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

• Necrotic tubule epithelium • may permit backleak of filtered solutes, including creatinine, urea, and other nitrogenous waste products, thus rendering glomerular filtration ineffective • may slough into the tubule lumens, obstruct urine flow, increase intratubular pressure, and impair formation of glomerular filtrate

• Epithelial cell injury per se cause secondary renal vasoconstriction by a process termed tubuloglomerular feedback: – specialized epithelial cells in the macula densa region of distal tubule detect increases in distal tubule salt delivery due to impaired reabsorption by proximal nepron segments and in turn stimulate constriction of afferent arterioles

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

Nephrotoxic ARF – The kidney is particularly susceptible to nephrotic injury by virtue of its • Rich blood supply (25 % of CO) • Ability to concentrate toxins in medullary interstitium (via the renal countercurrent mechanism) • Renal epithelial cells (via specific transporters)

• ARF complicates 10 to 30 % of courses of aminoglycoside antibiotics and up to 70 % of courses of cisplatin treatment • Aminoglycosides are filtered accross the glomerular filtration barrier and accumulated by proximal tubule cells after interaction with phospholipid residues on brush border membrane. They appear to disrupt normal processing of membrane phospholipids by lysosomes. • Cisplatin is also accumulated by proximal tubule cells and causes mitochondrial injury, inhibition of ATPase activity and solute transport, and free radical injury to cell membranes

Renal handling of aminoglycosides

• • Radiocontrast agents Mechanisms: intrarenal vasoconstriction and ischemia triggered by endothelin release from endothelial cells, direct tubular toxicity Intraluminal precipitation of protein or uric acid crystals • Rhabdomyolysis and hemolysis can cause ARF, particularly in hypovolemic or acidotic individuals – Rhabdomyolysis and myoglobinuric ARF may occur with traumatic crush injury • Muscle ischemia (e. g. arterial insufficiency, muscle compression, cocaine overdose), seizures, excessive exercise, heat stroke or malignant hyperthermia, alcoholism, and infections (e. g. influenza, legionella), etc.

• ARF due to hemolysis is seen most commonly following blood transfusion reactions • The mechanisms by which rhabdomyolysis and hemolysis impair GFR are unclear, since neither hemoglobin nor myoglobin is nephrotoxic when injected to laboratory animals • Myoglobin and hemoglobin or other compounds release from muscle or red blood cells may cause ARF via direct toxic effects on tubule epithelial cells or by inducing intratubular cast formation; they inhibit nitric oxide and may trigger intrarenal vasoconstriction

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

Course of ischemic and nephrotoxic ARF • Most cases of ischemic or nephrotoxic ARF are characterized by 3 distinct phases 1. Initial phase - the period from initial exposure to the causative insult to development of established ARF - restoration of renal perfusion or elimination of nephrotoxins during this phase may reverse or limit the renal injury

2. Maintenance phase (average 7 to 14 days) - the GFR is depressed, and metabolic consequences of ARF may develop 3. Recovery phase in most patients is characterized by tubule cell regeneration and gradual return of GFR to or toward normal - may be complicated by diuresis (diuretic phase) due to excretion of retained salt and water and other solutes continued use of diuretics, and/or delayed recovery of epithelial 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) Major causes 1. Ureteric calculi, blood clot, cancer 2. Bladder neck neurogenic bladder, prostatic hyperplasia, calculi, blood clot, cancer 3. Urethra stricture

Mechanisms: • During the early stages of obstruction (hours to days), continued glomerular filtration lead to increase intraluminal pressure upstream to the obstruction, eventuating in gradual distension of proximal ureter, renal pelvis, and calyces and a fall in GFR

Chronic renal failure (CRF) • many forms of renal injury progress inexoraly to CRF • Reduction of renal mass causes structural and functional hypertrophy of remaining nephrons • This compensatory hypertrophy is due to adaptive hyperfiltration mediated by increases in glomerular capillary pressures and flows

Chronic renal failure (CRF) - causes • Glomerulonephritis – the most common cause in the past • Diabetes mellitus • Hypertension • Tubulointerstitial nephritis – are now the leading causes of CRF

Consequences of sustained reduction in GFR • GFR – sensitive index of overall renal excretory function • GFR retention and accumulation of the unexcreted substances in the body fluids – A – urea, creatinine – B – H+, K+, phosphates, urates – C – Na+

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

Uremia is clinical syndrome that results from profound loss of renal function cause(s) of it remains unknown rerers generally to the constellation of signs and symptoms associated with CRF, regardless of cause presentations and severity of signs and symptoms of uremia vary and depend on the magnitude of reduction in functioning renal mass rapidity with which renal function is lost

Uremia – pathophysiology and biochemistry • the most likely candidates as toxins in uremia are the by–products of protein and amino acid metabolism – Urea – represents some 80% of the total nitrogen excreted into the urine – Guanidino compunds: guanidine, creatin, guanidin-succinic acid) – Urates and other end products of nucleic acid metabolism – Aliphatic amines – Peptides – Derivates of the aromatic amino acids: tryptophan, tyrosine, and phenylalanine

Uremia – pathophysiology and biochemistry • the role of these various substances in the pathogenesis of uremic syndrome is unclear • uremic symptoms correlate only in a rough and inconsistent way with concentrations of urea in blood • urea may account for some of clinical abnormalities: anorexia, malaise, womiting, headache

Tubule transport in reduced nephron mass • loss of renal function with progressive renal disease is usually attended by distortion of renal morphology and architecture • despite this structural disarray, glomerular and tubule functions often remain as closely integrated (i. e. glomerulotubular balance) in the normal organ, at least until the final stages of CRF • a fundamental feature of this intact nephron hypothesis is that following loss of nephron mass, renal function is due primarily to the operation of surviving healthy nephrons, while the diseased nephrons cease functioning

Tubule transport in reduced nephron mass • despite progressive nephron destruction, many of the mechanisms that control solute and water balance differ only quantitatively, and not qualitatively, from those that operate normally

Transport functions of the various anatomic segments of the nephron

Tubule transport of sodium and water -1 • In most patients with stable CRF, total-body Na+ and water content are increased modestly, although ECF volume expansion may not be apparent • Excessive salt ingestion contributes to – congestive heart failure – hypertension – ascites – edema • Excessive water ingestion – hyponatremia – weight gain

Tubule transport of sodium and water - 2 • Patient with CRF have impaired renal mechanisms for conserving Na+ and water • When an extrarenal cause for fluid loss is present (vomiting, diarrhea, fever), these patients are prone to develop ECF volume depletion – depletion of ECF volume results in deterioration of residual renal function

Potassium homeostasis • most CRF patients maintain normal serum concentrations until the final stages of uremia K+ – due to adaptation in the renal distal tubules and colon, sites where aldosteron serve to enhance K+ secretion • oliguria or disruption of key adaptive mechanisms (abrupt lowering of arterial blood p. H), can lead to hyperkalemia • Hypokalemia is uncommon – poor dietary K+ intake + excessive diuretic therapy + increased GIT losses

Metabolic acidosis • Metabolic acidosis of CRF is not due to overproduction of endogenous acids but is largely a reflection of the reduction in renal mass, which limits the amount of NH 3 (and therefore HCO 3 -) that can be generated

Phosphate, calcium and bone • Hypocalcemia in CRF results from the impaired ability of the diseased kidney to synthesize 1, 25 dihydroxyvitamin D, the active metabolite of vitamin D • Hyperphosphatemia due to GFR

Phosphate, calcium and bone • PTH • disordered vitamin D metabolism • chronic metabolic acidosis - bone is large reservoir of alkaline salts –calcium phospate, calcium carbonate; dissolution of this buffer source probably contributes to: renal and metabolic osteodystrophy: a number of skeletal abnormalities, including osteomalcia, osteitis fibrosa, osteosclerosis

Pathogenesis of bone diseases in CRF

Cardiovascular and pulmonary abnormalities • Hypertension • Pericarditis (infrequent because of early dialysis) • Accelerated atherosclerosis – – – HT Hyperlipidemia Glucose intolerance Chronic high cardiac output Vascular and myocardial calcifications

Cardiovascular manifestations

Hematologic abnormalities • Normochromic normocytic anemia – Erythropoesis is depressed • • • Effects of retained toxins Diminished biosynthesis of erythropoietin – more important Aluminium intoxication – microcytic anemia Fibrosis of bone marrow due to hyperparathyreoidism Inadequate replacement of folic acid

Hematologic abnormalities • Abnormal hemostasis – Tendency to abnormal bleeding • From surgical wounds • Spontaneously into the GIT, pericardial sac, intracranial vault, in the form of subdural hematoma or intracerebral hemorrhage – Prolongation of bleeding time • platelet factor III activity – correlates with plasma levels of guanidinosuccinic acid

Hematologic abnormalities • Leucocyte function impairment – – – uremic serum coexisting acidosis hyperglycemia protein-calorie malnutrition serum and tissue hyperosmolarity (due to azotemia) enhanced susceptibility to infection

Hematologic abnormalities Anemia is normochromic and normocytic with a low reticulocyte count Uremic milieu Reduction in renal mass Red blood cell survival Platelet dysfunction Bleeding tendency erythropoetin erythropoesis Red blood cell mass

Neuromuscular abnormalities • CNS – inability to concentrate – drowsiness – insomnia early symptoms of uremia – mild behavioral changes – loss of memory – errors in judgment + neuromuscular irritability including hiccups cramps fasciculations twitching of muscles

Neuromuscular abnormalities – – – asterixis myoclonus chorea stupor seizures coma terminal uremia

Neuromuscular abnormalities • Peripheral neuropathy – sensory nerve involvement exceeds motor, lower extremities are involved more than the uppe, and the distal portions of the extremities more than proximal – the restless legs syndrome is characterized by illdefinedsensations of discomfort in the feet and lower legs and frequent leg movement – later motor nerve involvement follow ( deep tendon reflexes, etc. )

Gastrointestinal abnormalities – – anorexia hiccups nausea vomiting early manifestation of uremia Uremic fetor, a uriniferous odor to the breath, derives from the breakdown of urea in saliva to ammonia and is associated with unpleasant taste sensation Uremic gastroenteritis (late stages of CRF) Peptic ulcer gastric acidity hypersecretion of gastrin ? Secondary hyperparathyreoidism

Lipid metabolism • Hypertriglyceridemia and high-density lipoprotein cholesterol are common in uremia, whereas cholesterol levels in plasma are usually normal • whether uremia accelerates triglyceride production by the liver and intestine is unknown • the enhancement of lipogenesis by insulin may contribute to increased triglyceride synthesis • the rate of removal of triglycerides from the circulation, which depends in large part on enzyme lipoprotein lipase, is depressed in uremia • the high incidence of premature atherosclerosis in patients on chronic dialysis