Question

1) Explain why chemically induced changes in renal function may not be detected immediately after toxic exposure.

2) Explain the reasons for the susceptibility of kidney to toxicity.

3) Give two examples of nephrontoxicants and their mechanism of action.

Answer 1

• The kidney contributes to total body homeostasis via its role in the excretion of metabolic wastes, the synthesis and release of renin and erythropoietin, and the regulation of extracellular fluid volume, electrolyte composition, and acid–base balance.

• Xenobiotics in the systemic circulation will be delivered to the kidney in relatively high amounts.

• The processes that concentrate urine also serve to concentrate potential toxicants in the tubular fluid.

• Renal transport, accumulation, and biotransformation of xenobiotics contribute to the susceptibility of the kidney to toxic injury.

• Numerous nephrotoxicants cause mitochondrial dysfunction via compromised respiration and ATP production, or some other cellular process, leading to either apoptosis or necrosis.

• Consequently, chemically induced changes in renal function may not be detected until these grow in more number ... After a population of renal cells are exposed to a toxicant, a fraction of the cells will start interrupting renal function and only then the symptoms are seen.

• NSAID
  Afferent glomerular arteriolar dilatation is mediated in part by prostaglandin E2, production of which is inhibited by NSAIDs, including selective COX-2 inhibitors. These drugs will therefore prevent glomerular vascular reflexes increasing inflow by afferent arteriolar dilatation. This will prevent the glomerulus ‘protecting itself’ if glomerular perfusion is reduced. This effect will be additive with the effects of ACEI/ARB on the efferent arteriole.

  Thus, NSAID other than aspirin, including selective COX-2 inhibitors, are clearly associated with AKI and should be avoided in people at risk of AKI and stopped if being taken by someone who develops AKI.

  Aspirin is an importance exception. Aspirin inhibits prostaglandin synthesis through a mechanism similar to NSAID and COX-2 inhibitors. It is indicated at low dose in many patients with T2DM and ischaemic heart disease who are also at risk of AKI. Although definitive evidence is lacking, studies showing benefit of aspirin in secondary prevention do not document an increase in AKI. Low dose aspirin required for anti-platelet effects most probably does not impact on renal blood flow and can be continued in patients at risk of AKI.

• Diuretics
  Loop diuretics are contraindicated in ‘treatment’ of AKI in almost all cases, particularly if urine volume is decreased Understanding of the haemodynamic challenges to kidney function most often underlying AKI explains this. Simply establishing a urine flow is not equivalent to achieving waste product removal. Loop diuretics achieve increased urine flow through effects on the renal tubule with no direct impact on glomerular filtration. Thus, the diuresis induced is not associated with increased GFR and may exacerbate the situation if hypovolaemia is a significant contributory cause, potentially to a critical level such that the autoregulatory mechanisms can no longer compensate. Overall, loop diuretics will usually worsen the situation in AKI.

  Rarely, when the primary clinical problem associated with AKI is fluid overload (i.e. biochemistry is abnormal but safe), high doses of furosemide may achieve a diuresis, preventing the need for fluid removal by dialysis. However, given the potential to exacerbate AKI, this decision should always be made by the nephrology team.

  Hypovolaemia as a trigger for AKI
  Hypovolaemia is recognised as an important risk factor for AKI, inadequate assessment of hypovolaemia being flagged up as contributing to poor care in many patients in the NCEPOD AKI study. In a retrospective cohort study of patients admitted to a VA hospital, hypovolaemia was found to be more common in community acquired AKI than hospital acquired AKI. In keeping with this, in a community based study, Ali et al demonstrated hypovolaemia to be the precipitating factor for AKI in 32% of cases studied (10). However, hypovolaemia can be difficult to assess. In this context hypovolaemia almost always refers to ‘salt and water’ depletion rather than blood loss. McGee et al reviewed published literature on clinical assessment of hypovolaemia. finding clinical assessment of hypovolaemia due to causes other than blood loss to be unreliable. Most importantly, recognising the poor sensitivity of clinical assessment of hypovolaemia, these authors argue for a low threshold for measurement of creatinine, urea and electrolytes in clinical scenarios where hypovolaemia may be expected. These findings were reiterated by Sinert