Pathophysiology of acute and chronic renal failure

1. Pathophysiology of acute and chronic renal failure Jianzhong Sheng MD, PhD

2. Acute renal failure (ARF) • Rapid decline in glomerular filtration rate (hours to weeks) • Retention of nitrogenous waste products • occurs in 5% of all hospital admission and up to 30% of admission to intensive care units

3. 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

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

7. Classification of ARF • Prerenal failure • Intrinsic ARF • Postrenal failure (obstruction)

9. 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

10. 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

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

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

14. 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

16. 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

17.   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, PGE2) and nitric oxide is also enhanced  dilatation of afferent arterioles

18. +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

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

21. Major causes of intrinsic renal ARF • Diseases of glomeruli • Glomerulonephritis and vasculitis • 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)

22. 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

24. 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)

25. 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 frequently inaccurate (even in ischemic or nephrotoxic ARF) because tubule cell necrosis may not be present in  20 to 30 % of cases

26. 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

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

28. 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

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

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

32. 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

34. Proximal tubules and thick ascending limb cells have greater oxygen requirements than other renal cells because of high rates of active (ATP-dependent) 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

35. 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

36. Pathophysiology of ischemic and toxic ARF

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

38. 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

40. 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

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

44. 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)

45. 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

46. Renal handling of aminoglycosides

47. 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.

48. 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

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

50. Course of ischemic and nephrotoxic ARF • Most cases of ischemic or nephrotoxic ARF are characterized by 3 distinct phases • 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