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

4. 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%)

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

7. 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

8. 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

9. 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

10. Major causes of prerenal ARF • Low cardiac output • Diseases of myocardium, valves, and pericardium, arrhythmias, 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

11. 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

12. 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

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

14. 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 (ethylene glycol) • Endogenous – rhabdomyolysis, hemolysis, uric acid, oxalate, plasma cell dyscrasia (myeloma)

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

16. 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)

17. 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

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

19. 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

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

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

23. 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

24. 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)

25. 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.

26. 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

27. Postrenal azotemia (postrenal ARF) Major causes • Ureteric calculi, blood clot, cancer 2. Bladder neck neurogenic bladder, prostatic hyperplasia, calculi, blood clot, cancer 3. Urethra stricture

28. 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

29. The causes of acute rental failure

30. 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

31. 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

32. 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+

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

34. Uremia  Is clinical syndrome that results from profound loss of renal function  Cause(s) of it remains unknown  Refers 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

35. 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, creatinine, 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

36. 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

37. 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

38. 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.

39. Transport functions of the various anatomic segments of the nephron

40. 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

41. 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

42. Potassium homeostasis • Most CRF patients maintain normal serum K+ concentrations until the final stages of uremia • 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 pH), can lead to hyperkalemia • Hypokalemia is uncommon • poor dietary K+ intake + excessive diuretic therapy + increased GIT losses

43. 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 NH3 (and therefore HCO3-) that can be generated

44. 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

45. 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

46. Pathogenesis of bone diseases in CRF

47. 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

48. Cardiovascular manifestations

49. Hematologic abnormalities • Normochromic normocytic anemia • Erythropoiesis 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

50. 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