This document summarizes the pathophysiology of acute and chronic renal failure. It describes how acute renal failure is characterized by a rapid decline in glomerular filtration rate over hours to weeks, leading to retention of waste products and oliguria. The main causes of acute renal failure are prerenal failure due to hypoperfusion, intrinsic renal failure due to direct kidney damage, and postrenal failure due to urinary tract obstruction. Chronic renal failure develops over months to years and is caused by a gradual loss of kidney function, leading to accumulation of waste products and complications like metabolic bone disease, anemia, and cardiovascular disease.

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:
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%)

6. Classification of ARF
1. Prerenal failure
2. Intrinsic ARF
3. 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
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

10. Major causes of prerenal ARF
2. Low cardiac output
• Diseases of myocardium, valves, and pericardium,
arrhythmias, tamponade
• Other: pulmonary hypertension, pulmonary embolus
3. 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
1. Renovascular obstruction
1. Renal artery obstruction: atherosclerotic
plaque, thrombosis, embolism, dissecting
aneurysm)
2. Renal vein obstruction: thrombosis,
compression

14. 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 (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
1. 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

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

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

53. 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

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

55. 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.)

56. 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
?

57. 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

58. Thanks