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Renal function

Glomeruli

  • In the kidney cortex
  • 200L of plasma are filtered daily
  • Production of ultrafiltrate depends upon the blood flow through the glomerulus as well as the hydrostatic and oncotic pressure across the membranes
  • Sodium, potassium, urea, glucose and calcium are readily filtered but protein and protein bound substances and only filtered in small amounts and most are reabsorbed

 

Proximal convoluted tubules

  • Also in the cortex
  • Receive filtrate from the glomerular spaces
  • Here the majority of NaCl reabsorption occurs
  • At the same time reabsorption of water occurs – isosmotic process
  • Here occurs the reabsorption of almost all the potassium, calcium and magnesium and 70% of the sodium
  • Here reabsorption of 70-80% of water occurs

 

Loops of Henle

  • Extend down into the renal medulla
  • Due to the isosmotic reabsorption that has occurred in the proximal convoluted tubule, the fluid entering the loop of Henle is still isosmotic
  • Countercurrent multiplication is an active process occurring in the Loops of Henle whereby a high  osmolality is achieved in the renal medulla and urine osmolality is reduced
  • Based on the fact that the descending limb is permeable to water and the ascending limb is impermeable to water and solute and chloride is actively pumped from the ascending limb to the descending limb with chloride following

 

Distal convoluted tubules

  • Situated in the cortex
  • Lie near the afferent arterioles with the juxtaglomerular apparatus in between
  • Where fine adjustment takes place via ion exchange mechanisms e.g Na+ absorbed in exchange for K+ or H+

 

Collecting ducts

  • Progress through the medulla to open into the renal pelvis
  • Via the action of ADH water without solute is reabsorbed into the ascending vasa recta along the osmotic gradient created by countercurrent multiplication. This produces a more concentrated urine

 

  • In addition to its excretory function and acid-base control, the kidney also has an endocrine role;
    • Production of 1,25-dihydroxyvitamin D, the active metabolite of Vitamin D
    • Erythropoietin
    • Renin

 

Homeostatic control of water excretion

 

Water restriction

  • By increasing plasma osmolality, water restriction increases ADH secretion allowing countercurrent exchange and enhanced water reabsorption

Water load

  • High water intake results in reduced plasma osmolality reducing ADH secretion
  • This results in the production of a dilute urine and the maintenance of a high osmolality within the medulla. Blood from the meduallry vessels flows back into the circulation helping to correct the fall in systemic osmolality

Osmotic diuresis

  • An excess of unabsorbable solute in the proximal tubule impairs water reabsorption by its osmotic effect
  • The unabsorbed solute concentration rises progressively as water is reabsorbed with other solutes during passage through the proximal tubule and this inhibits further water reabsorption
  • Therefore the Loop of Henle encounter high volumes which have a low sodium concentration which thereby inhibits the pumps which set up the countercurrent multiplication gradient
  • There is therefore no increase in the osmolality in the medulla and therefore there is inhibition of distal water reabsorption under the influence of ADH from the collecting ducts
  • This results in a diuresis
  • This is achieved therapeutically using mannitol and pathologically in diabetes mellitus when the active transport mechanisms of glucose reasborption of glucose is exceeded or in uraemia as urea can diffuse back into the tubule passively

 

Renal disorders

  • Uraemia is the term used to describe a raised plasma urea concentration and is almost always accompanied by a raised creatine
  • Biochemical findings and urine output depend on the relative contributions of glomerular and tubular dysfunction

 

Reduced glomerular filtration rate with normal tubular function

  • Increased plasma phosphate and urate as filtration fails. What is filtered is reabsorbed and the capacity for secretion is impaired by the reduced volume
  • A large proportion of the reduced amount of filtered sodium is reabsorbed meaning there is less available for exchange with H+ and K+. this results in;
  • Reduced H+ secretion which results in reduced reabsorption of bicarbonate and plasma bicarbonate levels fall
  • Reduced K+ secretion and K+ retention
  • If the low GFR is accompanied by low renal blood flow;
  • Aldosterone secretion will be maxed and any sodium reaching the distal tubule will be exchanged for K+ or H+. Urinary sodium concentration will therefore by low
  • ADH secretion will be increased resulting in a reduced urine volume and increased urinary osmolality
  • In summary the following plasma findings will be found;
    • Uraemia and increased creatinine concentrations
    • Low bicarbonate concentration with a low pH (acidosis)
    • Hyperuricaemia and hyperphosphataemia
  • Urine findings would be;
    • Reduced volume – oligouria
    • Low sodium concentration (only if renal blood flow is reduced to stimulate aldosterone)
    • High urea concentration and therefore high osmolality  - only if ADH is stimulated

 

Reduced tubular function with normal GFR

  • Plasma findings
    • Normal urea and creatinine concentrations as the GFR is normal
    • Due to proximal or distal tubular failure;
      • Low bicarbonate concentration and acidosis
      • Hypokalaemia due to reduced potassium reabsorption
    • Due to proximal tubular failure;
      • Hypophosphataemia
      • Hypomagnesaemia
      • Hypouricaemia
  • Urine
    • Due to proximal or distal tubular failure;
    • Increased volume
    • High pH
    • Due to proximal tubular failure;
      • Aminoaciduria
      • Phosphaturia
      • Glycosuria
      • Proteinuria
    • Distal tubular failure;
      • High sodium concentration – due to inability to respond to aldosterone
      • Low osmolality – due to inability to respond to ADH

 

 

Acute renal failure

 

  • Oligouria (urine output of less than 400ml/day or 15ml/hr) usually indicates a low GFR and acute renal failure

 

Causes of acute renal failure;

Prerenal

  • Acute oligouria with a reduced GFR
  • Caused by factors which reduced the hydrostatic pressue between the renal capillaries and the tubular lumen
  • May be due to;

o       Intravascular depletion of whole blood (haemorrhage) or plasma volume (GI loss) or reduced intake

o       Reduced pressure due to vascular dilation caused by ‘shock’ e.g. MI, cardiac failure, intravascular haemolysis (due to mismatched blood transfusion)

  • Patient is normally hypotensive
  • If reversed within a few hours the condition is reversible
  • As the tubules are not affected and only the glomeruli are involved, biochemical findings are as described above
  • Increased tissue breakdown may exacerbate hyperkalaemia, hyperuricaemia and hyperphosphataemia

 

Acute oligouria due to intrinsic renal damage

  • May be due to;
    • Prolonged renal circulatory insufficieny
    • Acute glomerulonephritis – usually in children
    • Septicaemia
    • Various drugs/poisons
    • Myoglobinuria
    • Bence-Jones proteinuria
  • Difficult to distinguish between renal circulatory insufficiency and intrinsic renal damage that may follow it
  • Following renal circulatory insufficiency, there is oligouria due to reduced GFR and back pressure on the glomerulus due to obstruction of tubular flow by oedema
  • Tubular damage results in an inappropriately dilute urine for the degree of hypovolaemia
  • Fluid must be given with caution as there is a danger of overloading the circulation
  • During recovery oligouria is followed by polyuria
  • As cortical blood flow increased, tubular oedema subsides and GFR is restored
  • Eventually biochemical findings start to look like this of ‘pure’ tubular dysfunction

 

Acute oligouria due to renal outflow obstruction (post-renal)

  • Oligouria or anuria (absence of urine) may occur
  • Causes include;
    • Intrarenal obstruction with blockage of the tubular lumen with haemoglobin, myoglobin and rarely urate or calcium. Obstruction caused by casts of tubular oedema is usually the result of true renal damage
    • Extrarenal obstruction due to calculi, neoplasms, urethral strictures or prostatic hypertrophy
  • Early correction may rapidly increase urine output but the longer it is untreated the greater the damage of ischaemic and pressure damage to renal tissue

 

Summary of causes of acute renal failure

  • Pre-renal
    • Hypotension
    • Hypovolaemia
    • Renal artery stenosis plus an ACEi
    • Hepatorenal syndrome
  • Renal or intrinsic renal disease
    • Acute tubular necrosis
    • Vasculitis
    • Glomerulonephritis
    • Nephrotoxic drugs
    • Sepsis
    • Thrombotic microangiopathy
    • Hypercalcaemia
    • Hyperuricaemia
    • Bence-Jones proteinuria
  • Post-renal
    • Calculi
    • Retroperitoneal fibrosis
    • Prostate hypertrophy/malignancy
    • Carcinoma of the cervix of bladder

 

Investigations of acute renal dysfunction

  • History for possibly nephrotoxic drugs
  • Hypovolaemia/hypotension?
  • If you are considering post renal urinary tract obstruction renal tract imaging may be useful
  • Monitor urine output, plasma urea and creatinine, electrolytes and acid-base status
  • Hyperkalaemia, hypermagnesaemia, hyperphosphataemia, hyperuricaemia and metabolic acidosis may occur in the oligouric phase of acute renal failure
  • Urine microscopy showing granular casts supports the diagnosis of acute tubular necrosis
  • If the urinary:plasma urea ratio is greater than 10 this suggests pre-renal pathology
  • The fractional excretion of sodium (FENa%) can be measured using a simultaneous blood sample and spot urine;
  • FENa% = urine[sodium]/plasma[sodium] x plasma[creatinine]/urine[creatinine] x 100%
  • An FENa% of less than 1% is typical of pre-renal failure
  • Bloods should be taken for FBS, coagulation screen and culture
  • Look for Bence-Jones proteins
  • In obscure cases renal biopsy may be required

 

Lab tests to investigate acute renal failure

 

Pre-renal failure

Intrinsic renal failure/acute tubular necrosis

Urine sodium (mmol/L)

< 20

>40

FENa%

<1

>1

Urine:plasma creatinine ratio

>40

<20

Urine:plasma osmolality ratio

>1.2

<1.2

Urine:plasma urea ratio

>10

<10

 

 

Chronic renal failure

  • Defined as being of more than 3months duration
  • Causes;
    • Diabetes mellitus
    • Nephrotoxic drugs
    • Hypertension
    • Glomerulonephritis
    • Chronic pyelonephritis
    • Polycytic kidneys
    • Urinary tract obstruction
    • Severe urinary infections
    • Amyloid and paraproteins
    • Progression from acute renal dysfunction
  • There is generally a patchy distribution of damage with some nephrons being destroyed and others being normal
  • Although there is a loss of renal function, homeostasis is initially preserved at the expense of various adaptations such as glomerulotubular changes and secondary hyperparathyroidism
  • Chronic renal dysfunction may pass through 2 main phases;
  • Initially a polyuric phase
  • Subsequent oligouria or anuria, sometimes needing dialysis or renal transplantation

 

Polyuric phase

  • At first glomerular function may be adequate to maintain plasma urea and creatinine concentrations within reference range but as more glomeruli are involved the urea excretion falls and the plasma concentration increases causing osmotic diuresis
  • This and tubular dysfunction causes polyuria
  • This stage is usually accompanied by a metabolic acidosis

 

Oligouric phase

  • As nephron destruction continues, glomerular function decreases and urine output falls
  • Oligouria results in a steep rise in plasma urea, creatinine and potassium concentrations and metabolic acidosis becomes more severe

 

Other abnormal findings in chronic renal failure

  • Plasma phosphate concentrations rise and plasma total calcium concentrations fall
  • Although the raised H+ concentration increased the proportion of free ionised calcium, total calcium levels fall as the raised phosphate concentration and impaired renal tubular function inhibits the conversion of Vitamin D to its active metabolite which contributes to the fall in calcium
  • Hypocalcaemia should only be treated after correction of hyperphosphataemia
  • After several years of chronic renal failure, secondary hyperparathyroidism may cause decalcification of bone with a rise in plasma alkaline phosphatase activity
  • Plasma urate concentration rises in parallel with plasma urea
  • Hypermagnesaemia can occur
  • Normochromic, normocytic anaemia due to EPO deficiency is common. Because haemopoiesis is impaired it doesn’t respond to iron therapy
  • One of the commonest causes of death in patients with chronic renal failure is cardiovascular disease in part due to dyslipidaemia, hypertriglyceridaemia and low HDL cholesterol. Some of these affects may be due to reduced activity of lipoprotein lipase
  • There may be abnormal endocrine function such as hyperprolacinaemia, insulin resistance, low plasma testosterone and abnormal thyroid function
  • Some of these features may be explained by the presence of ‘middle molecules’ which the kidney would normally excrete. These compounds of relatively small molecular weight may have toxic effects on tissues
  • The presence of increasing proteinuria may be the best indicator of disease progression

 

 

 

 

 

 

 

Stages of renal dysfunction

 

Stage

Description

GFR (ml/min)

Metabolic features

1

Normal

>90

Normal

2

Early renal insufficiency

60-89
  • Plasma urea and creatinine rise
  • PTH starts to rise

3

Chronic renal failure

30-59
  • Calcium absorption decreased
  • Lipoprotein lipase decreased
  • Malnutrition
  • Anaemia

4

Severe renal failure (pre-end stage)

15-29
  • Hypertriglyceridaemia
  • Hyperphosphataemia
  • Metabolic acidosis
  • Hyperkalaemia

5

End-stage renal failure

<15
  • Uraemia and marked elevation of creatinine

 

  • A slight rise in urea and creatinine is a common finding particularly in the elderly. It suggests some degree of renal damage but if not progressive doesn’t need treatment
  • Congestive cardiac failure may impair renal circulation enough to cause mild uraemia

 

Nephrotic syndrome

  • Caused by increased glomerular basement membrane permeability resulting in protein loss (>3g/day)
  • The consequences of this are;
    • Hypoproteinaemia
    • Hypoalbuminaemia
    • Peripheral oedema
  • It is also associated with a hyperlipidaemia and a hyperfibrinogenaemia
  • Uraemia only occurs in later disease when the glomeruli cease to function

 

Diagnosis of renal dysfunction

 

Glomerular function tests

 

Measurement of plasma concentrations of urea and creatine

  • As glomerular function deteriorates, substances that are normally cleared by the kidneys such as urea and creatinine accumulate in the plasma
  • An elevated plasma urea concentration above 15mmol/L indicates impaired glomerular function
  • Creatinine can be measured to assess renal function but levels depend upon the recent intake of a high protein meal and the assay is prone to analytic interference by substances such as bilirubin, ketone bodies and certain drugs

 

Clearance as an assessment of GFR

  • GFR = urinary [S] x urine volume per unit time / plasma [S]
  • GFR thus measured is referred to as clearance, the volume of plasma that could be theoretically cleared of substance S in one minute
  • Only substances freely filtered by glomeruli and not acted on by the tubules can be used to measure the GFR
  • There is no such endogenous substance but inulin can be used as can radiolabelled EDTA
  • For endogenous substances such as creatinine, the following equation can be used to calculate a clearance that is approximately the GFR

 

  • Creatinine clearance ml/min =
  • Urinary[creatinine] x urine vol (ml) / plasma[creatinine] x collection period (min)

 

  • The Cockcroft –Gault equation can be used to assess GFR indirectly. This method doesn’t require urine collection

 

  • In men;
    • Creatinine clearance ml/min =
    • (140 – age (years)) x weight (kg) / 72 x plasma creatinine (μmol/L)
    • In women this equation has to be multiplied by 0.85

 

  • Creatinine clearance is higher than inulin clearance as some creatinine is secreted by the tubules
  • Urea clearance is lower that in inulin as some urea is reabsorbed into the tubules
  • Other factors that make creatinine clearance inaccurate;
    • The fact that both urine and plasma is assayed means that there is more scope for inherent imprecision in lab assays
    • Inaccurate urine collection
    • Both creatine and urea may be partly destroyed by bacterial action in old or infected urine

 

  • The plasma creatinine concentration may not exceed the upper limit of the reference range until the GFR has been reduced by approximately 60%

 

  • Clearance values will be low whether the reduced GFR is due to renal circulatory insufficiency, intrinsic renal damage or post-renal causes and cannot be used to distinguish between them

 

Cystatin C

  • Cystatin C is another endogenous substance that can be used as a marker for GFR
  • It is a member of the family of cysteine proteinase inhibitors
  • Unlike creatinine it is not secreted by the renal tubules and does not return to the circulation after filtration
  • Blood concentration is independent of sex and age
  • Possibly an ideal endogenous marker for GFR?

 

Renal tubular function tests

  • Can be divided into those that predominantly identify proximal tubular dysfunction and those that identify distal dysfunction

 

Proximal tubular function tests

  • Plasma;
    • Normal urea and creatinine concentrations
    • Low bicarbonate concentration with metabolic acidosis
    • Hypokalaemia, hypophosphataemia, hypomagnesaemia and hypouricaemia
  • Urine;
    • Increase volume
    • High pH compared with plasma
    • Phosphaturia, glucosuria, uricosuria
    • Generalised aminoaciduria
  • Tubular proteinuria can be diagnosed by measuring specific LMW proteins such as;
    • Retinol binding protein
    • N-acetyl-β-D-glucosamine
    • α1-microglobulin

 

  • Fanconi syndrome – when there is detectable glycosuria, phosphaturia and non-selective aminoaciduria

 

Distal tubular function tests

  • Plasma;
    • Low bicarbonate and high chloride concentration with a low pH
    • Hypokalaemia
  • Urine;
    • Increased volume
    • pH high compared with plasma
    • Inappropriately high sodium concentration
    • Inappropriately low osmolality

 

  • The water deprivation test may be used if tubular damage is suspected
  • The ability to form concentrated urine in response to fluid deprivation depends on normal tubular function and the presence of ADH
  • If diabetes insipidus is suspected do the test after giving synthetic ADH

 

Urine sodium estimation

  • Can be used to differentiate acute oligouria due to renal damage from that due to renal circulatory insufficiency
  • Alsosterone secretion will only be maximal if renal blood flow is reduced resulting in sodium reabsorption by the distal tubules
  • If urinary sodium concentration is less than 20mmol/L then tubular function is assumed not to be impaired

 

Treatment

 

Acute renal failure

  • Make sure you don’t give nephrotoxic drugs
  • In oligouric acute renal failure, fluid intake is restricted to a volume which equals the urine output plus insensible losses
  • Treat any hyperkalaemia
  • Dialysis may improve fluid and electrolyte imbalances
  • During the polyuric phase there may be hypokalaemia, hypomagnesaemia and hypovolaemia that requires correcting
  • Pre-renal acute failure can sometimes be treated by prompt treatment of hypovolaemia
  • Sometimes frusemide with mannitol or dopamine infusion may re-establish normal urine flow
  • If oligouria is due to intrinsic damage some clinicians restrict fluid and sodium intake, giving only enough fluid to replace losses and provide a low protein diet to minimise aggravation of uraemia
  • In post renal failure, promptly relieve the obstruction

 

Chronic renal failure

  • Dietary modification – increased calorie intake along with reduced protein intake may slow the decline in GFR by reducing protein catabolism
  • Water intake should only be restricted if the plasma sodium concentration is not being maintained
  • Similarly sodium intake shouldn’t be restricted unless there is hypertension and oedema
  • It is essential to monitor plasma potassium levels and potassium restricted may be necessary if hyperkalaemia occurs
  • Tissue precipitation of calcium phosphate may occur which may be reduced by adequate fluid intake
  • Dietary phosphate is restricted in the early stages of chronic renal dysfunction
  • If the plasma phosphate level is raised phosphate binding agents may be indicated such as calcium acetate or carbonate
  • Oral calcitriol can be used to treat hypocalcaemia, suppress PTH concentrations and help avoid renal osteodystrophy
  • Recombinant EPO can be used to treat anaemia when the Hb is less than 11g/dL
  • Optimisation of glycaemic control in diabetics is important as is treating hypertension

 

Dialysis

  • Removes urea and other toxins from the plasma and corrects electrolyte balance by dialysing the patients blood against fluid containing no urea and appropriate concentrations of electrolytes, free ionised calcium and other plasma constituents
  • Types of dialysis;
  • Haemofiltration  - where large volumes of fluid and solute can be removed through a highly permeable membrane. Dialysis is dependant primarily on the blood pressure. Fluid is replaced intravenously
  • Haemodialysis – blood is passed through an extracorporeal circulation and dialysed across an artifial membrane with a solution of low solute concentration before being returned to the body. Negative pressure on the dialysate side of the membrane can be varied to adjust the amount of water removed
  • Intermittent and continuous ambulatory peritoneal dialysis – fold of the peritoneum are used as the dialysing membrane with capillaries on one side and an appropriate fluid of high osmolality is infused into the peritoneal cavity on the other. After a suitable time to allow for equilibriation of diffusible solutes, the peritoneal cavity is drained and the cycle repeated

 

  • Dialysis can be used in some cases of acute renal failure until renal function improves or as a regularly repeated process in cases of chronic renal failure
  • It may also be used to prepare patients for transplantation

This entry was posted on Sunday, January 13th, 2008 at 3:25 pm and is filed under Endocrine. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.

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Disclaimer: These notes are my own personal study aid - DO NOT use them for medical advice!