Download Pathophysiology of acute and chronic renal failure

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
frequent
output
<400
ml/d)
is
• 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,
arrhytmias, 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
  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
+ 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
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)
•
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
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
• Proximal tubules and thick ascending
limb cells have greater oxygen
requirements than other renal cells
because of high rates of active (ATPdependent) 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
•
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
Pathophysiology of ischemic and toxic ARF
Vasoactive hormones that may be responsible for the
hemodynamic abnormalities in ATN
• 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
•
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
Sites of renal damage, including factors that contribute to the
kidney´s susceptibilty to damage
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)
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
Renal handling of aminoglycosides
•
•
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
Nephrotoxicants may act at different sites in the kidney,
resulting in altered renal function. The site of injury by
selected nephrotoxicants are shown.
Course of ischemic and nephrotoxic
ARF
•
Most cases of ischemic or nephrotoxic ARF
are characterized by 3 distinct phases
1. 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
2. Maintenance phase
(average 7 to 14 days)
- the GFR is depressed, and metabolic
consequences of ARF may develop
3. 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
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
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
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
– Erythropoesis is depressed
• Effects of retained toxins
• Diminished biosynthesis of erythropoietin – more
important
• Aluminium intoxication – microcytic anemia
• Fibrosis of bone marrow due to hyperparathyreoidism
• Inadequate replacement of folic acid
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
azotemia)
(due
 enhanced susceptibility to infection
to
Hematologic abnormalities
Anemia is normochromic and normocytic with a low reticulocyte count
Uremic milieu
Reduction in
renal mass
 Red blood
cell survival
Platelet dysfunction
Bleeding tendency
 erythropoetin
 erythropoesis
 Red blood cell mass
Neuromuscular abnormalities
• CNS
– inability to concentrate
– drowsiness
– insomnia
– mild behavioral changes
early symptoms of uremia
– loss of memory
– errors in judgment
+ neuromuscular irritability including hiccups
cramps
fasciculations
twitching of
muscles
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
early manifestation of uremia
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
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