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Pathophysiology of acute
and chronic renal failure
Jianzhong Sheng MD, PhD
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
• 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,
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
• 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
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 (ethylene 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 (Cytomegolovirus)
• 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)
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
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)
• 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
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
The causes of acute rental failure
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
 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
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
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 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
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
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
– 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
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
 erythropoetin
 erythropoesis
 Red blood cell mass
 Red blood
cell survival
Platelet dysfunction
Bleeding tendency
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
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
ill-definedsensations 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
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
?
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
Thanks

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12130957.ppt

  • 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%)
  • 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
  • 20.
  • 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
  • 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