H1vi / 25B04: Outline the physiological effects of end stage renal dysfunction.

25B04: Exam Report

Outline the physiological effects of end stage renal dysfunction. Changes associated with dialysis as a therapy are NOT required

28% of candidates passed this question.

This question required a structured approach to cover its breadth.

An example of a structure that worked well considered the functions of the kidney (regulation of water, electrolytes and systemic blood pressure; acid-base balance; excretion of metabolic waste; endocrine functions) and then a description of
the consequences of renal failure on each.

Each physiological effect required a reasonably detailed discussion of the mechanism(s) by which it occurs and the consequences on the body.
For example:

  • stating in endocrine dysfunction that “renal failure leads to erythropoietin (EPO) deficiency and anaemia” would score less than stating that “reduced O2 consumption by failing nephrons =>reduced hypoxic stimulation of EPO production by kidneys => reduced RBC production => anaemia.

H1vi / 25B04: Outline the physiological effects of end stage renal dysfunction.

1. Regulation of blood pressure

Reduced Na delivery to juxtaglomerular apparatus or activation of renal stretch receptors due to reduced renal perfusion→ increased RAAS activation → increased ATII formation

Sequelae:

  • Increased ATII release → potent vasoconstriction →  hypertension (also augmented by accelerated atherosclerosis and underlying cause of renal dysfunction e.g. T2DM, HTN)
  • increased sodium and water reabsorption

2. Regulation of total body water

Acute or chronic end stage renal impairment with oligoanuria:

Reduced number of functioning nephrons → reduced filtration surface area → reduced urine formation and oliguria/free water retention

Multiple sequelae including:

  • hyponatraemia
  • congestive cardiac failure, APO
  • oedema (further exacerbated by hypoalbuminaemia and reduced intravascular oncotic pressure per Starling forces)

ATN with polyuria:

  • dysregulation of volume homeostasis – uncontrolled diuresis

3. Electrolytes

Sodium:

  • dysregulation of Na+ balance via increased RAAS activation → increased Na reabsorption and increased circulating volume
  • may progress to hyponatraemia due to impaired free water elimination

Potassium:

  • impaired K elimination due to failure of K secretion in distal tubules → Hyperkalaemia

Phosphate:

Hyperphosphataemia due to:

  • Impaired phosphate elimination: 90% of total daily phosphate load eliminated by kidney → reduced number of functioning nephrons → reduced filtration and elimination
  • Acidaemia → shift of phosphate out of cells into plasma

4. Acid-base balance

Normal individual secretes 60mmol of H+ per day:

  • 50% as ammonia
  • 50% as titratable acid
  • Both processes impaired in renal failure
  • Multifactorial acidaemia:
    1. Reduced ammonium elimination
    2. Hypoalbuminaemia and reduced plasma buffering capacity
    3. Hyperphosphataemia → reduces buffering capacity and titratable acid elimination
    4. Impaired bicarbonate reabsorption → failure of maximal bicarb reabsorption = bicarb loss in urine, exacerbating acidaemia

5. Metabolic wastes

Uraemia – progressive nephron loss → reduced GFR → impaired clearance of urea and other middle-molecular-weight toxins → systemic accumulation of uraemic solutes → multisystem toxicity (e.g. encephalopathy, platelet dysfunction, pericarditis)

6. Endocrine functions

EPO:  Renal cortical atrophy → loss of peritubular interstitial fibroblast-like cells in the renal cortex → ↓ hypoxic sensing and ↓ erythropoietin (EPO) production → ↓ bone marrow erythroid stimulation → ↓ red blood cell production → normocytic, normochromic anaemia of chronic kidney disease

RAAS activation/hypertension/fluid retention: Reduced renal perfusion and nephron loss → activation of juxtaglomerular apparatus → ↑ renin release → ↑ angiotensin II production →

  • systemic vasoconstriction → hypertension
  • ↑ aldosterone secretion → ↑ distal tubular sodium reabsorption → osmotic free water retention → volume expansion and hypertension 

Calcitriol deficiency & hypocalcaemia:  Loss of functioning proximal tubular cells → ↓ 1-α-hydroxylase activity → impaired conversion of 25-hydroxyvitamin D to 1,25-dihydroxycholecalciferol (calcitriol) →. ↓ intestinal calcium absorption and ↓ renal tubular calcium reabsorption → hypocalcaemia → secondary hyperparathyroidism → renal osteodystrophy

7. Immune dysfunction

Impaired PGI release → regulatory effect to counteract ATII, NA, vasopressin by dilating renal cortical arterioles → reduced blood flow and GFR

Impaired Kallekrein release → dysregulation of renal microcirculation and Na excretion

8. Pharmacokinetic effects

  • increased Vd due to increased free water retention
  • hypoalbuminaemia – reduced protein binding capacity/increased free drug
  • alteration of drug metabolism and elimination → e.g. prolonged half life of exogenous insulin in advanced renal failure, increased toxicity of renally eliminated drugs due to reduced clearance e.g. gentamicin, sotalol, digoxin

Author: Sarah Klink