End Stage Renal Failure

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• End Stage Renal Failure

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• Glomerular Filtration in Renal Failure
•  
• Renal failure / renal insufficiency is generally
  applied to
• one renal function GFR.
• GFR is equal to the sum of the filtration rates
  of all
• functioning nephrons.
• The total GFR is an index of the functioning
  renal mass.
• A fall in GFR can be due to intrinsic, pre-renal
  or post-renal disease.

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• Reduced GFR results in impaired ability to
• - Excrete nitrogenous waste
• - Regulate pH
• - Regulate electrolyte and water balance.
• Retention of toxic substances accounts for many
  of the signs and symptoms associated with
  end-stage renal disease.

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• These uraemic symptoms include
• Oedema
• Hyperkalaemia, Hypokalaemia, Hypernatraemia
• Peripheral neuropathy
• Altered mental status.
• At this time GFR can fall from 90-125 ml/min to
  5-10ml/min.

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• Acute Renal Failure
• - Sudden onset
• - Rapid cessation of renal function
• - Dramatic and sudden fall in GFR and urine
  production.
• - Oliguria (100-400ml/day)
• - Anuria (0-100ml/day)
• - Potentially reversible

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• Typically the person either recovers from acute
  renal failure or they do not!
• Causes of acute renal failure can be divided into
  three main categories.
• Prerenal failure.
• Usually caused by abnormal blood supply to the
  kidney.
• Intrarenal failure.
• Usually associated with abnormalities associated
  with the nephron or blood flow within the kidney.
• Postrenal failure.
• Usually an obstruction to the flow of urine
  within the urinary tract (e.g. due to kidney
  stones).

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• Prerenal Failure.
• Ultrafiltration is usually maintained by a small
  positive pressure which operates across the
  glomerular membranes.
• If these small positive pressure is reduced or
  lost the GFR is often reduced in consequence.
• Causes of prerenal failure are therefore
  associated with factors that reduce the blood
  pressure within the glomeruli, for example
• Heart failure hypovolaemic/circulatory shock.

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• Pre Renal Causes Of Reduced GFR
•  
• Reduced renal perfusion
• Due to low cardiac output
• Shock, dehydration, haemorrhage, thrombi,
  congestive heart failure, renal artery stenosis.
• Stimulation of the SNS in these cases causes
  afferent constriction, reducing CHBP (to divert
  blood to other organs).

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• Intrarenal Failure.
• Acute intrarenal failure associated with
  abnormalities/ damage within the kidney. Two
  examples given below.
• Damage to the glomerulus.
• e.g. glomerulonephritis.
• Tubular necrosis.
• May result in the death of epithelial cells
  lining the nephron for example due to
• a lack of adequate supply of oxygen nutrients
  etc.. for example following severe ischaemia of
  kidney
• Ingestion of a toxin which is filtered into the
  nephron.
• Epithelial cells may slough off and block the
  nephron, even after an adequate blood supply is
  restored.
• If the basement membrane of the epithelium
  remains intact epithelial cells may grow back.

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• Intrinsic Renal Causes
• Tubular obstruction
• Damage to the glomerulus
• Ischaemia / necrosis of the tubular epithelia
  causes them to slough off.
• This increases the hydrostatic pressure in
  Bowmans capsule and tubule (as flow of filtrate
  is interrupted).
• Causes may include inflammation / infection
  (glomerulonephritis), reduced oxygen supply or
  ingestion of toxins which are filtered into the
  nephron.
• Epithelial damage can also allow fluid to leak
  from the tubules causing oliguria.
• If the basement membrane remains intact,
  epithelial cells may grow back.

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• Postrenal Failure.
• Many factors can occur either singly or in
  combination to either partially obstruct or
  totally block the flow of urine in the urinary
  tract.
• It is worth noting that if the flow of urine is
  blocked from just one kidney the renal function
  will not be impaired since a single functioning
  kidney is sufficient.
• Causes of obstruction include kidney stones, most
  frequently are found in the renal pelvis or
  ureters, and consist of precipitated calcium
  salts, urate or cystine.
• Blood clots may also produce obstruction.
• The bladder and/or urethra may also become
  obstructed (e.g. due to enlargement of the
  prostate gland in men)

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• Post Renal Causes
• Obstruction of urine flow
• Prostate hypertrophy
• Renal stones
• Compression of the ureter and bladder generates
  back-pressure, increasing hydrostatic pressure in
  Bowmans capsule.
• If the flow of urine from one kidney is blocked,
  renal function is not necessarily impaired a
  single functioning kidney is sufficient.

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• General Effects Of Acute Renal Failure.
• If acute renal failure is moderate in magnitude
  than fluid retention within the blood and ECF
  maybe seen.
• In addition, since the excretory function of the
  kidney is impaired then there may also be
  retention of waste products, sodium and
  potassium. This can result in oedema and
  hypertension.
• Generally a person may require longer to restore
  their homeostatic balance.
• Retention of potassium can prove fatal due to its
  effect on the heart (i.e. producing fibrilation
  if its concentration in ECF rises relatively
  little).

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• Chronic Renal Failure
• - Slow progressive fall in GFR, over months and
  years.
• - Irreversible loss of nephrons.
• - Initial polyuria (gt2L/day), due to inability to
  produce concentrated urine, followed by oliguria
  / anuria.
• - Symptoms may not appear until GFR is severely
  reduced and dialysis may be necessary.

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• Chronic renal failure
• The kidney has a large residual capacity of
  nephrons and consequently problems of maintaining
  homeostasis do not occur until about 30 of the
  nephrons have been lost.
•  
• Many diseases can result in chronic renal
  failure by creating physiological conditions that
  result in a further loss of nephrons, in a
  viscous cycle culminating in renal failure.

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• Examples Of Disease That May Result In Chronic
  Renal Failure.
• Immunological disorders e.g. glomerulonephritis
  (GN), Lupus erythmatosus.
• Metabolic disorders, e.g. diabetes mellitus.
• (Renal) vascular disorders, e.g.
  arteriosclerosis.
• Infections, e.g. tuberculosis (infection may also
  precipitate GN).
• Urinary tract obstruction, e.g. kidney stones
  obstruction of the urethra.
• Congenital disorders, e.g. polycystic disease or
  a congenital absence of the kidney.

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• It Is Hypothesized That The Loss Of Some
  Nephrons May Accelerate The Loss Of More Renal
  Nephrons.
• Currently this remains highly speculative since
  mechanisms are not known.
• This may involve physiological consequences of
  compensatory actions such as increases in blood
  pressure and glomerular pressures, leading to
  faster GFRs.
• The higher blood pressures may lead to the
  deposition of connective tissue proteins within
  the glomerulus (producing sclerosis) which
  impairs and eventually may stop GFR (leading to
  the loss of that nephron).
• ACE inhibitors are sometimes used in an attempt
  to control/delay this process

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• The Loss Of Nephrons Requires That Surviving
  Nephrons Perform More Work.
• Essentially this means that surviving nephrons
  must excrete water solutes at faster rates to
  maintain homeostasis.
• This has logical consequences.
• Glomerular filtration within the surviving
  nephrons would be increased.
• e.g. due to hypertrophy of renal glomerular
  blood vessels.
• The flow rate of filtrate through surviving
  nephrons would also be increased.
• Due to increased GFR.

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• Examples Of Consequences Of Increased Flow Rates
  Of Filtrate Through Surviving Nephrons.
• The maximum degree of urine concentration is
  reduced.
• Increased flow rates of urine through the reduced
  number of collecting ducts does not allow
  sufficient time for water reabsorption (in the
  presence of ADH).
• Rapid flow rates through the loop of Henle also
  reduces the extent to which sodium can be
  actively transported into the renal medulla ().
• Rates of potassium excretion may also be
  increased.
• Due to the rapid removal of K ions from the
  lumenal surface of the DCT principal cells
  increasing the rate of diffusion of K ions out
  of these cells.

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• The Loss Of Very Large Numbers Of Nephrons Leads
  To End Stage Renal Failure.
• Previously (e.g. 1980s) this was primarily
  thought to be due to glomerulonephritis,with its
  variety of causes.
• Today other diseases such as diabetes mellitus
  hypertension are also thought to be responsible
  for many of these cases.
• Estimates for cases of end stage renal failure
  (ESRF) where no definitive cause can be easily be
  identified may still be as high as 20 of the
  total number of cases.

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• Compensatory mechanisms to increase GFR may
  increase glomerular pressures that causes
  deposition of connective tissue.
• Sclerosis may impair and eventually stop
  filtration leading to the loss of the nephron.
• Surviving nephrons must then excrete water and
  solutes at faster rates to maintain homeostasis.
• This would become more obvious if the person was
  under physiological stress (large excess
  ingestion of water or solutes).
• This overloading of the remaining nephrons may
  make them more prone to fail in the future,
  creating a vicious cycle.
• The loss of very large numbers of nephrons leads
  to end stage renal failure.

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• Consequences of increased flow rates through
  surviving nephrons, reduced GFR and renal
  failure 
• Inability to concentrate urine
• There is insufficient time for water
  reabsorption through a reduced number of
  collecting ducts. 
• 2. Failure to maintain electrolyte balance
• Hypokalaemia, Hypernatraemia through activation
  of the Na/K pump etc.
• 3. Oedema
• If ingestion gt excretion salt and water may be
  retained.
• Ischaemia may stimulate the RAA pathway and
  exacerbate hypertension.

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• 4. Uraemia
• Reduced urea and other nitrogenous waste
  excretion (creatinine).
• The degree of elevation of levels of these
  chemicals can be indicative of the degree of
  renal impairment as a whole.
• Results in nervous system, skin and GI
  irritation confusion, drowsiness, coma, muscle
  cramps, gastric bleeding
•  
• High energy, low protein diets aim to minimise
  tissue catabolism and renal workload.

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• 5. Metabolic acidosis
• Secretion and excretion of acidic metabolites is
  reduced or arrested, limiting control of blood
  pH.
• Acidification of blood plasma and ECF can lead to
  coma and death.
• 6. Anaemia
• Kidneys fail to produce and secrete
  erythropoietin, reducing erythropoiesis.

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• 7. Osteolmalacia
• Bone demineralisation reduces its mechanical
  strength.
• The kidneys normally convert vitamin D to its
  active form. Renal failure will reduce vitamin
  D activity and calcium reabsorption from the gut.
•  
• Reduced GFR will reduce phosphate excretion,
  increasing plasma levels.
• Phosphate binds with free calcium ions, reducing
  plasma Ca2.
• This stimulates PTH secretion, causing further
  bone demineralisation.

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• CHRONIC RENAL FAILURE
•  
• Reduction in GFR
•  
• Deposition of connective tissue
•  
• Sclerosis of nephrons
•  
• Further reduction in GFR
•  
• Further loss of nephrons
•  
• Increases workload of remaining nephrons
•  
• Increased loss of nephrons
•  
• End stage renal failure

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Inability to concentrate urine
Failure to maintain electrolyte balance
Oedema
Consequences of renal failure
Anaemia
Osteomalacia
Metabolic acidosis
Uraemia