Pathophysiology of acute and
chronic renal failure
Renata Péčová
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
• 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,
arrhytmias, tamponade
Other: pulmonary hypertension, pulmonary embolus
3. Increased renal systemic vascular esistance 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)
oxide is also enhanced
 dilatation of afferent arterioles
and
nitric
+ 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 (ethylen 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
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
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
consequences of ARF may develop
metabolic
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
calculi, blood clot, cancer
3. Urethra
stricture
hyperplasia,
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
 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
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
concentrations until the final stages of uremia
K+
– 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 1,25dihydroxyvitamin 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 (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
 Red blood
cell survival
Platelet dysfunction
Bleeding tendency
 erythropoetin
 erythropoesis
 Red blood cell mass
Neuromuscular abnormalities
• CNS
– inability to concentrate
– drowsiness
– insomnia
early symptoms of uremia
– mild behavioral changes
– 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 illdefinedsensations 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