Diuretics can act as a double-edged sword in AKI, so it is essential to understand the pharmacology, benefits and harms of using diuretics. This article will help to acquire that knowledge for your daily practice.

Introduction

Acute kidney injury (AKI) is a frequent complication seen in intensive care units (ICUs), significantly elevating mortality risk, particularly when renal replacement therapy (RRT) is required. In managing AKI, patients commonly receive diuretics, with loop diuretics being the preferred choice among physicians.

Pharmacology of loop diuretics

Loop diuretics, classified as weak organic acids, hinder the sodium/potassium chloride cotransporter found in the tubular epithelial cells of the thick ascending loop of Henle. Normally, this segment of the nephron reabsorbs approximately 30–40% of the filtered sodium load. By impeding this cotransporter, loop diuretics diminish the oxygen consumption of tubular cells, potentially shielding them from ischemic damage.

Furosemide causes a greater loss of water than sodium loss, resulting in the production of hypotonic urine. Loop diuretics also cause increased urinary excretion of potassium, calcium, and magnesium by inhibiting the passive reabsorption of these ions. Additional organic acids such as cephalosporin, ciprofloxacin, oseltamivir, and others could potentially compete with loop diuretics, leading to a reduction in their effectiveness.

Over 95% of the loop diuretics are bound to albumin. Therefore, they do not undergo glomerular filtration. They reach their target site by active secretion from the blood into the urine by the organic acid transporters present in the proximal tubules. Hypoalbuminemia (which is common in patients with AKI in the ICU) leads to a decreased secretion into the tubules and an increased clearance of loop diuretics. The diuretic effect of loop diuretics is therefore considerably reduced in the presence of hypoalbuminemia.

In the presence of renal dysfunction, the transport of loop diuretics into the tubules is impaired. This impairment is exacerbated by reduced renal blood flow, a common occurrence in AKI patients. Additionally, metabolic acidosis diminishes the tubular secretion of loop diuretics. Consequently, higher-than-normal doses of diuretics may be necessary to induce diuresis in AKI patients.

Many hold the belief that administering loop diuretics through continuous infusion may be more efficacious compared to intermittent boluses. Numerous studies have shown that while continuous furosemide infusion facilitates maintaining a consistent diuresis, it does not impact renal function, electrolyte balance, or mortality rates.

It's crucial to recognise that loop diuretics have a minimum threshold dose below which they are ineffective and a maximum ceiling dose beyond which no further benefit is achieved. Once this ceiling dose is reached, additional diuretics acting on different nephron sites, such as thiazide diuretics, may be considered to enhance the effect.

Potential benefits of loop diuretics in AKI

1. Loop diuretics may reduce oxygen consumption in the thick ascending limb of Henle, potentially protecting it from ischemic damage.
2. By inhibiting prostaglandin dehydrogenase, loop diuretics can lead to decreased breakdown of prostaglandin E2, a renal vasodilator, potentially increasing renal blood flow.
3. Sustaining urine flow can help prevent tubular obstruction and subsequent backflow of glomerular filtrate by clearing any debris blocking the tubules.
4. Some research suggests that oliguric AKI carries a poorer prognosis compared to nonoliguric AKI. Loop diuretics may be administered to convert oliguric AKI to nonoliguric AKI.
5. Patients in the ICU with AKI and oliguria often receive substantial fluid volumes for administering antibiotics, vasopressors, and nutrition, risking fluid overload. Diuretics can aid in simplifying fluid management in these cases.

Potential harm caused by loop diuretics

1. Loop diuretics reduce effective circulating volume either through venodilation or diuresis, potentially leading to decreased renal blood flow and glomerular filtration rate via renin.
2. Despite the common belief that loop diuretics clear tubular obstruction, some studies suggest they may actually worsen tubular blockage by acidifying the urine and increasing Tamm-Horsfall protein aggregation in the tubules.
3. Loop diuretics can induce electrolyte imbalances and metabolic alkalosis. High doses in AKI patients pose a significant risk of ototoxicity and may impair respiratory mucociliary clearance, potentially exerting immunosuppressive effects.
4. Increased urine output following loop diuretic administration might mistakenly be interpreted as improved renal function, delaying diagnosis and treatment of underlying AKI causes.
5. Loop diuretics can induce hypovolemia, hypokalemia, hypophosphatemia, hypomagnesemia, and metabolic alkalosis.
6. Their use may limit the reliability of urinary sodium concentrations in differentiating between hypovolemia and normovolemia.
7. Delaying renal replacement therapy due to loop diuretic administration may heighten mortality risks.
8. High doses of loop diuretics can lead to ototoxicity in patients with reduced renal furosemide clearance.
9. They may induce systemic vasoconstriction at high doses.
10. Loop diuretics inhibit Na-K-Cl2 cotransporters in the respiratory tract, reducing mucociliary transport and sputum clearance.
11. Loop diuretics acidify urine, reducing the solubility of myoglobin and haemoglobin in patients with conditions like rhabdomyolysis and intravascular hemolysis, which may promote free radical formation by radiocontrast agents.

Drug interactions

1. Loop diuretics decrease the elimination of substances like theophylline, gentamicin, and various organic acids such as benzylpenicillin, cephalosporins, oxypurinol, bumetanide, and the active metabolite of oseltamivir.
2. They elevate the risk of amphotericin-induced hypokalemia and potentiate the antiepileptic effect of valproate, as well as the hypotensive effect of angiotensin-converting enzyme inhibitors.
3. Loop diuretics diminish the therapeutic efficacy of warfarin, although warfarin reciprocally reduces the diuretic effect of furosemide.

Discussion

The urine output might increase with diuretics. Evidence that loop diuretics decrease mortality, reduce the need for dialysis, or limit the length of ICU stay is lacking. In the management of patients with AKI, the priority lies in identifying and addressing reversible factors contributing to renal injury, discontinuing potential nephrotoxic substances, optimising hemodynamic stability, and rectifying electrolyte imbalances.

Critically ill patients frequently receive substantial fluid volumes, and loop diuretics are often administered in these cases to mitigate fluid overload and potentially simplify patient management. Based on the current evidence, therefore, the use of diuretics should be limited to the management of volume overload and/or hyperkalemia. Patients should undergo dialysis promptly when indicated and the use of diuretics should not delay the institution of dialysis.

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

About the author of this article: Dr Bhavin Mandowara is a practising nephrologist at Zydus Hospital, Ahmedabad.