Summary

Professor Dr. Sundeep Mishra discusses therapy for acute renal failure by,

• reviewing three classes of drugs that are generally recommended- Diuretics, Vasodilators, and Calcium Channel Blockers
• comparing how favourable their effects are on renal function and/or renal blood flow

Acute renal failure(ARF), is an abrupt loss of kidney function that develops within 7 days. It has multiple etiologies but may be a consequence of damage to the kidney tissue caused by decreased kidney blood flow (kidney ischemia) from any cause, exposure to substances harmful to the kidney, an inflammatory process in the kidney, or an obstruction of the urinary tract that impedes the flow of urine.

ARF is generally diagnosed on the basis of characteristic laboratory findings, such as elevated blood urea nitrogen and creatinine, or inability of the kidneys to produce sufficient amounts of urine. It may lead to a number of complications, including metabolic acidosis, high potassium levels, uremia, changes in body fluid balance, and effects on other organ systems leading to an increased risk of death, prolonged hospital stay, and risk of permanent/chronic renal failure (CRF).

In this condition occurrence of uncontrolled hypertension is common but its pharmacologic treatment has been attempted on an empiric basis with varying degree of success. Use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) is generally contra-indicated because they could acutely lead to worsening of renal function. Three classes of drugs are generally recommended based on their favourable effects on renal function and/or renal blood flow.

Diuretics

Although diuretics seem to have no effect on the outcome of established ARF, they appear to be useful in controlling hypertension if there is evidence of fluid overload and are thus used extensively. They have also been used to reduce the requirement for renal replacement therapy.

Loop Diuretics

Furosemide increases the excretion of water by affecting the chloride-binding cotransport system; by inhibiting sodium and chloride reabsorption in the thick ascending loop of Henle and the distal renal tubule. Furosemide is a potent and rapid-acting agent with peak action at 60 minutes and duration of action of 6- to 8-hours.In ARF higher doses may be required for greater diuretic effect; doses as high as 600 mg/day, but the administration of such high doses must be carefully monitored. In emergencies and intensive care settings, IV doses may be needed in ARF in view of the need for quick and predictable action. Furthermore, an IV infusion may be preferred when really large doses are necessary. This method promotes a sustained natriuresis with reduced ototoxicity compared with conventional intermittent bolus dosing.

Thiazide-type of diuretics are longer acting and less potent and therefore they may not be as useful either as a substitute to loop diuretic or in addition to it in an acute setting.

Mineralocorticoid receptor antagonists - Risks of hyperkalemia and worsening acute kidney injury have precluded the use of mineralocorticoid antagonist in this setting (where it is contra-indicated).

Vasodilators

Fenoldopam

Fenoldopam is a selective dopamine-receptor agonist with an additional mechanism of rapid-acting vasodilation; it is 6 times more potent than dopamine in producing renal vasodilation. It decreases systemic vascular resistance and increases renal blood flow to the cortex and medullary regions in the kidney. Thus it is not only found to control severe hypertension by the way of vasodilatation but also improves the renal functions. It increases diuresis and has minimal adrenergic effects.

Calcium Channel Blockers

These drugs have been found effective in several animal models of ARF, but their renal protective action in humans has not been demonstrated (except newer calcium channel blockers like benidipine). Nevertheless, they are effective antihypertensive agents in this situation. The effects of calcium channel blockers (CCBs) are believed to be mediated through vasodilation, and they are increasingly used to enhance the function of transplanted kidneys.

Nifedipine, Amlodipine

Nifedipine relaxes smooth muscle and produces vasodilation, which may improve blood flow and oxygen delivery into the renal system. Earliest available CCBs, nifedipine, nicardipine, verapamil, and diltiazem were short acting. Several reports with short-acting CCBs reported increased mortality. This led to the development of CCBs with a longer duration action and pharmacokinetic profile with enhanced L-type of vascular selectivity like nifedipine SR (slow release), felodipine ER (extended release), diltiazem SR and amlodipine.

Benidipine

Benidipine hydrochloride is another new CCB found to inhibit the T-type as well as L- and N-type calcium channels. Benidipine, via blockade of T-type calcium channels, seems to exert a renoprotective effect. Several studies have demonstrated that benidipine is not only more potent than amlodipine (only L Channel blockade) or cilnidipine (both L and N channel blockade) but also favourably affects the renal function and thus it may be more useful in ARF. Furthermore, it may have added value through its greater attenuation of oxidative stress and the reduction of aldosterone.

Other Drugs

If blood pressure is still uncontrolled other BP reducing agents like beta-blockers, alpha-blockers and alpha 2 agonists (e.g. clonidine) and finally vasodilators (e.g. minoxidil) may be considered to control blood pressure but they have no reno-protective effects per se.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The writer, Dr. Sundeep Mishra is a Professor of Cardiology.