Pathophysiology of acute and chronic renal failure

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Pathophysiology of acute and chronic renal failure

• Renata Pécová

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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

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• Oliguria (urine output lt 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

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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)

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Classification of ARF

• Prerenal failure
• Intrinsic ARF
• Postrenal failure (obstruction)

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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

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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

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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

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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

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• 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

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• 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

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• ? ? 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

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• 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

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

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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)

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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

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• 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)

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• 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

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• 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

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

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Mechanisms of proximal tubule cell-mediated
reduction of GFR following ischemic injury
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Fate of an injured proximal tubule cell after an
ischemic episode depends on the extent and
duration of ischemia
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• 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

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• 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

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• 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

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Pathophysiology of ischemic and toxic ARF
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Vasoactive hormones that may be responsible for
the hemodynamic abnormalities in ATN
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• 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

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• 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

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Sites of renal damage, including factors that
contribute to the kidneys susceptibilty to damage
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• 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)

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• 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

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Renal handling of aminoglycosides
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• 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.

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• 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

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

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• 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

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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
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• 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

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• 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

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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

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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

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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

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

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Uremia pathophysiology and biochemistry

• the most likely candidates as toxins in uremia
  are the byproducts 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

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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

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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

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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

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Transport functions of the various anatomic
segments of the nephron
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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

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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

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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

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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

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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

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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

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Pathogenesis of bone diseases in CRF
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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

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Cardiovascular manifestations
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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 hyperparathyreoidis
  m
• Inadequate replacement of folic acid

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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

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Hematologic abnormalities

• Leucocyte function impairment
• uremic serum
• coexisting acidosis
• hyperglycemia
• protein-calorie malnutrition
• serum and tissue hyperosmolarity (due to
  azotemia)
• ? enhanced susceptibility to infection

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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
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Neuromuscular abnormalities

• CNS
• inability to concentrate
• drowsiness
• insomnia
• mild behavioral changes
• loss of memory
• errors in judgment
• neuromuscular irritability including hiccups
• cramps fasciculations twitchin
  g of muscles

early symptoms of uremia
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Neuromuscular abnormalities

• asterixis
• myoclonus
• chorea
• stupor
• seizures
• coma

terminal uremia
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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.)

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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
?
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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