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Pathophysiology of acute and chronic renal failure

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Title: Pathophysiology of acute and chronic renal failure


1
Pathophysiology of acute and chronic renal failure
  • Renata Pécová

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 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

4
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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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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

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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

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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

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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

23
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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

29
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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

33
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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

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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

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43
Sites of renal damage, including factors that
contribute to the kidneys 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
  • 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 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

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 hyperparathyreoidis
    m
  • 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 twitchin
    g 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
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