1. Pathophysiology of acute and chronic renal failure
Renata Péčová

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 admissions and up to 30% of admissions 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 esistance 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. Intraluminal precipitation of protein or uric acid crystals
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

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

52. 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

53. 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

54. 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

55. 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

56. 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

57. 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+

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

59. 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

60. 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

61. 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

62. 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

63. 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

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

65. 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

66. 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

67. 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

68. 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

69. 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

70. 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

71. Pathogenesis of bone diseases in CRF

72. 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

73. Cardiovascular manifestations

74. 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

75. 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

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

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

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

79. Neuromuscular abnormalities
asterixis
myoclonus
chorea
stupor
seizures
coma
terminal uremia

80. 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 ill-definedsensations of discomfort in the feet and lower legs and frequent leg movement
later motor nerve involvement follow ( deep tendon reflexes, etc.)

81. Gastrointestinal abnormalities
anorexia
hiccups
nausea
vomiting
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
early manifestation of uremia ?

82. 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