Transcript RENAL FAILURE

RENAL FAILURE
M. Tatár
Dept of Pathophysiology
Definition
• Kidneys lose their ability to mantaine normal volume and
composition of the body fluids (homeostasis) under conditions
of normal dietary intake (~ 0.5 g/kg/day of protein)
• Renal insuficiency – decline in renal functions to about 25% of
normal; GFR of 25-30 ml/min; serum creatinin and urea will be
mildly elevated
• Renal failure – significant loss of renal functions; less than 10%
of renal function remains = end-stage renal failure
• Uremia – elevated blood urea and creatinin levels accompanied
by fatigue, anorexia, mausea, vomiting, pruritus, and neurologic
changes (clinical syndrome)
• Azotemia – increased serum urea levels and frequently
increased creatinine levels
Classification
• Acute renal failure
– rapidly progressive
– may be reversible
– cellular dysfunction
• Chronic renal failure
– progressing over a period of months and years
– irreversible
– reduction of functioning nephrons
Acute Renal Failure (ARF)
• Prerenal
– renal vasoconstriction,  renal blood flow   GFR
– tubular cell function is not disturbed ( reabsorptive capacity is
mantained
– overall kidney function will improve with normalisation of
intravascular fluid volume
• Intrarenal (acute tubular insufficiency)
– primary damage of tubular epithelial cells
– tubular function is disturbed: urinary sodium concentration is
increased above 40 mmol/l
– renal function remains depressed after correction of circulatory
disorders or termination of the insult
– recovery only after tubule cells regeneration (2-3 weeks)
• Postrenal
– obstruction of urine outflow affecting 75% of renal parenchyma
Characteristics of ARF
• Reduction in glomerular and tubular function
–
–
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–
low GFR
high fractional Na excretion
reduced tubular secretory activity (metabolic acidosis)
diminished concentrating ability
• Cellular and molecular basis
– intracellular accumulation of Na and Cl, water influx, cell swelling
– membrane depolarisation, reduction of transport systems
– loss of extracellular fluid, Er aggregation, vascular congestion and
stasis  impairing perfusion  oxygen depletion
– excessive accumulation of Ca2+  cell damage
– cell acidosis inhibits activation of enzymes
– lipid peroxidation – oxidative stress
Heterogeneity of cellular insufficiency along the nephron (1)
Main activities of the tubule cells is the reabsorption of
filtered Na (driving force for the reabsorption of water and for
the coupled transport of organic solutes); Na+,K+,ATP-ase
• Intrarenal heterogenenity of cellular metabolism
effect of ischemia and nephrotoxins on specific cells in the kidney
is related to specific biochemical properties
– enzymes of the glycolytic pathway are abundant throughout
the distal tubule  more resistant to hypoxia
– capacity to transport substances: inward transport of
nephrotoxic substances by normally existing transport systems
increase their intracellular concentrations to levels at which they
become cytotoxic
Heterogeneity of cellular insufficiency along the nephron (2)
• Proximal tubule
– is most pronounced to ischemic cell injury  reduced
reabsorption of Na+, Cl-, HCO3- and glucose
• Thick ascending limb of the loop of Henle
– reduced concentrating capacity
• Distal convolution, collecting duct
– structural derangements resulting from ischemic episodes are
more discrete
Heterogeneity of cellular insufficiency along the nephron (3)
Vascular components of acute renal failure (1)
• Circulatory dysfunction (prerenal failure)
–  GFR  reduction in renal excretory functions (no cell
damage)
– reduction of renal functions is fully reversed when circulation
is normalised
• Persistent decrease in renal excretory function following
normalisation of circulation
– Evidence of kidney damage during the period of circulatory
dysfunction – „prerenal“ renal failure is replaced by an
„intrarenal“ one
Vascular components of acute renal failure (2)
Acute clinical renal failure
• Syndrome
– caused by an abrupt reduction in GFR (frequently to 20% or
less)  progressive rise in blood urea nitrogen and
creatinine over hours, days, or weeks
• Serious condition with substantial morbidity and a high
mortality
– even severe ARF is potentially reversible in most cases if
correctly managed
• Oliguria
– May be the first manifestation of ARF (daily urine output of
< 400ml/24 hours
– but often urine volume is normal (nonoliguric ARF)
ARF due to prerenal failure
• Impaired glomerular perfusion
– in the absence of any structural kidney damage
– GFR is promptly restored to normal if the cause of the renal
hypoperfusion can be corrected
– can be precipitated by: volume depletion, cardiac failure, systemic
vasodilatation
• Activation of the sympathetic and R-A systems and release of
vasopresin cause intrarenal vasoconstriction
• Renal adaptive responses preserve GFR in the early stages of
prerenal failure
– local generation of vasodilator prostaglandins
– angiotensine preferentially constricts the efferent arteriol
• Urine
– is concentrated, sodium concentration is below 40 mmol/l
ARF due to acute tubular necrosis
• Causes of ATN based on the mechanism of injury
– ischemic and toxic ATN
• Ischemic ATN
– more severe and prolonged reduction in renal blood flow
– restoration of renal perfusion will not promptly reverse renal
dysfunction
– Common clinical situations:
postoperative patients, especially with cardiac, aortic, and
gastrointestinal surgery
complication following burns: volume depletion, myoglobinuria,
antibiotic toxicity
fluid loses, severe cardiac failure, sepsis
• ATN due to toxins
– Aminoglycoside antibiotics and radiocontrast media: damage of
mitochondrial function, membrane structire, lysosomal integrity
Clinical course of ATN
• Initiating phase
– patients are subject to factors causing ATN but have not yet
developed frank parenchymal injury
– may last hours or days
– with development of tubular necrosis, GFR falls abruptly to very
low levels (typically below 5-10 ml/min)
• Maitenance phase
– GFR remains markedly depressed
– may last a few days or as long as several weeks
– characterized by progressive accumulation of nitrogenous wastes
and by development of the manifestation of uremia
• „Recovery phase“
– cellular repair and regeneration ultimately leads to a progressive
rise in GFR
Chronic renal failure (CRF)
• The degree of the reduction in functional mass
– rather than the underlying disease, was generally to blame for the
clinical manifestation of patients with CRF
• The degree of reduction in glomerular filtration rate
– is good determinant or predictor of the clinical manifestations
• Rate of progression of CRF and possible mechanisms
– role of proteinuria: increased protein flux through glomerular
basement membrane cause mesangial cell injury and
proliferation, increased production of mesangial matrix, and
glomerular sclerosis
– glomerular capillary hyperperfusion and hypertension of the
remaining nephrons: kidney may be protected from glomerular
injury by the ACE inhibitors (reduce glomerular capillary
hypertension)
Renal failure progresses particularly when GFR falls
below 25% of its normal level
Water handling in CRF
• Ability to excrete a concentrated urine becomes impaired as
nephron number declines
• mechanisms:
– remaining nephrons must increase their capacity to excrete water
– single-nephron GFR rises, but it cannot compensate overall GFR
falls
– solute load to the distal nephron is increased  volume of water
removed from the filtrate is less than normal
– transfer of osmotically active solute to the medullary interstitium
is reduced  decreased water reabsobtion
– under normal circumstances (urine osmolality of 1200 mosm/kg)
man can excrete 600 mmol of solute in 500 ml of water; in CRF
(urine osmolality of 500 mosm/kg) excretion of 500 mmol require
1000 ml of water
Ability to excrete a concentrated urine
Sodium excretion in CRF
• Remain surprisingly controlled, despite the progressive
nephron damage
• Sodium balance is maintained until GFR falls below 10%
of the control value
Abnormalities of acid-base balance
• Formation of hydrogen ions
– metabolism of sulfur-containing amino acids, nucleic acids, and
the incomplete oxidation of carbohydrates and fats
• Kidney final task
– Excretion of the acid and regeneration of bicarbonates to
replenish the organism buffering capacity
• Metabolic acidosis appears when GFR falls to 20-30%
of normal
a) initially is hyperchloremic MA with a normal anion gap
Defect in H+ excretion resulting in decresed bicarbonate reabsorption
Sodium is reabsorbed with chloride as an accompanying anion
b) As CRF progresses and GFR falls below 10-20 ml/min it becomes
a high anion gap MA
retention of anions increases the anion gap
diminished ammonium (NH4+) excretion
Proximal tubule
Distal nephron
Anion gap
[ Na+ ] - ( [Cl-] + [ HCO3-] ) = 10 - 12 mmol.l-1
140 - ( 104 + 24 )
= 12 mmol.l-1
Nervous system
• Uremic encephalopathy
– electrolytes derangements, vitamin deficiency, drug intoxication,
subdural hematoma
– depressed cerebral oxygen consumption:  brain uptake of
glutamine, brain uses less ATP, calcium overload of mitochondria
– symptomatology: fatigability, daytime drowsiness and insomnia,
variable disorders of speech, confusion, hallucinations, delirium,
and coma
• Severe polyneuropathy
– predominantly afflicts the autonomic system: postural
hypotension and impotence
Gastrointestinal disturbances
• Nausea, vomiting, hiccups, and diarrhea
Hematologic disturbances
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
Renal osteodystrophy
Alterations in plasma calcium and phosphate concentration
 altered parathyroid gland function
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–
1.
2.
classic theory: secondary hyperparathyroidism in renal failure,
phosphate retention causes a small decrease in plasma
calcium  stimulates PTH secretion  osteitis fibrosa cystica
other factors:
cell from parathyroid tissue of CRF patient with secondary
hyperparathyroidism have shown that higher Ca
concentrations are required to suppress PTH secretion
calcitriol deficiency: metabolic inhibitors of 1--hydroxylase
in kidney
- decreased intestinal calcium absorption
- calcitriol may directly inhibit PTH secretion
Cardiovascular manifestations
Pulmonary manifestations
• „Uremic lung“
– mechanisms: metabolic acidosis, volum overload, left ventricular
dysfunction
– degenerative changes of the capillary endothelium, focal
accumulation of interstitial edema fluid, altered alveolocapillary
basement membrane
Lipid metabolism disturbances
• Incresed risk of atherosclerosis
– hypertriglyceridemia, elevated VLVD (reduced activity of the
major lipolytic enzymes)
– decrease in HDL cholesterol