Nephrotoxic medications

Nephrotoxic medications as triggers and risk factors for AKI:

ACEI/ARB

Treatment with an ACEI prior to admission has been shown to be an independent risk factor for AKI (8, 27).  However, it is perhaps a misnomer to consider a fall in GFR as a ‘side effect’ as these drugs act within the kidney in exactly the way they are designed to: they block intra-renal production (ACEI) or action (ARB) of angiotensin II.  In chronic kidney disease this is a desirable effect, correcting the glomerular hyperperfusion believed to be responsible for progressive loss of kidney function. This is a difficult balancing act as, although some reduction in perfusion pressure may be desirable or at least ‘tolerated’, excessive reduction in perfusion pressure leads to AKI.  Thus, if the balance of factors affecting glomerular perfusion alters acutely e.g. due to sepsis or hypovolaemia, renin-angiotensin system blockade may become inappropriate.  Once the acute insult is removed, treatment may be restarted in most cases.

The additive effect of dual ACEI and ARB blockade is of interest.  Albuminuria is a marker of intraglomerular hypertension and reduction of albuminuria has been suggested to be a therapeutic endpoint in it’s own right in CKD.  The increased efficacy of dual ACEI and ARB blockade on reduction in albuminuria led to this becoming an accepted therapeutic regimen in CKD.  However, benefit in terms of preventing progression of CKD has not been proven and an increased risk of AKI has been demonstrated in T2DM (36).  Accordingly, recent joint European Society for Hypertension/European Society for Cardiology Guidelines document ‘dual blockade’ as specifically contraindicated (37).  This can be understood in terms of a potential benefit that increases the risk of AKI too much to make it a safe regimen to use widely.

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 (8, 38) 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 (39).  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 (3).  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 (40).  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 (41), 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 (42).

The ‘At Risk Patient’: Summary

Thus, the ‘at risk’ patient profile is typified by the elderly patient (>65 years) with T2DM receiving an ACEI.  Acute insults might include an intercurrent infective illness, such as cellulitis, or administration of a NSAID, including over the counter preparations.  Such patients are common in primary care emphasising how important it is for GPs to understand the pathophysiology, diagnosis and management of AKI.

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