Measures to correct underlying causes of acute kidney injury (AKI) should begin at the earliest indication of renal dysfunction. Serum creatinine does not rise to abnormal levels until a large proportion of the renal mass is damaged, because the relationship between the glomerular filtration rate (GFR) and the serum creatinine level is not linear, especially early in disease. Indeed, the rise of serum creatinine may not be evident before 50% of the GFR is lost. It cannot be overstated that the current treatment for AKI is mainly supportive in nature; no therapeutic modalities to date have shown efficacy in treating the condition. Therapeutic agents (eg, dopamine, nesiritide, fenoldopam, mannitol) are not indicated in the management of AKI and may be harmful for the patient.
Maintenance of volume homeostasis and correction of biochemical abnormalities remain the primary goals of treatment and may include the following measures follows viz.,correction of fluid overload with furosemide, correction of severe acidosis with bicarbonate administration, which can be important as a bridge to dialysis, correction of hyperkalemia and correction of hematologic abnormalities (eg, anemia, uremic platelet dysfunction) with measures such as transfusions and administration of desmopressin or estrogens. Furosemide can be used to correct volume overload when patients are still responsive; this often requires high intravenous (IV) doses. Furosemide plays no role in converting an oliguric AKI to a nonoliguric AKI or in increasing urine output when a patient is not hypervolemic. However, response to furosemide can be taken as a good prognostic sign. Hyperkalemia in patients with AKI can be life-threatening. Approaches to lowering serum potassium include the following viz., decreasing the intake of potassium in diet or tube feeds, exchanging potassium across the gut lumen using potassium-binding resins, promoting intracellular shifts in potassium with insulin, dextrose solutions, beta agonists and instituting dialysis.
In AKI, the kidneys are especially vulnerable to the toxic effects of various chemicals. All nephrotoxic agents (eg, radiocontrast agents, antibiotics with nephrotoxic potential, heavy metal preparations, cancer chemotherapeutic agents, nonsteroidal anti-inflammatory drugs [NSAIDs]) should be avoided or used with extreme caution. Similarly, all medications cleared by renal excretion should be avoided, or their doses should be adjusted appropriately.
A study in 2013 indicated that triple therapy using non-steroidal anti-inflammatory drugs (NSAIDs) with 2 anti-hypertensive medications - a diuretic along with an angiotensin. Nephrology consultation should be sought early in the course of AKI. A nephrologist can help to optimise management and avoid the preventable complications of AKI.
Vasodilators
The rationale for vasodilator therapy in AKI is that improved renal perfusion may reduce renal damage. Strong evidence in support of this approach is lacking. However, a meta-analysis of 16 randomized studies concluded that the vasodilator fenoldopam reduces the need for renal replacement therapy and lowers the mortality rate in patients with AKI. Larger trials need to be conducted before the use of fenoldopam can be recommended. Dopamine in small doses (eg, 1-5 mcg/kg/min) causes selective dilatation of the renal vasculature, enhancing renal perfusion. Dopamine also reduces sodium absorption; this enhances urine flow, which helps to prevent tubular cast obstruction. However, most clinical studies have failed to establish this beneficial role of low-dose dopamine infusion, and one study demonstrated that low-dose dopamine may worsen renal perfusion in patients with AKI. Dietary changes are an important facet of AKI treatment. Restriction of salt and fluid becomes crucial in the management of oliguric renal failure, wherein the kidneys do not adequately excrete either toxins or fluids. Because potassium and phosphorus are not excreted optimally in patients with AKI, blood levels of these electrolytes tend to be high. Restriction of these elements in the diet may be necessary, with guidance from frequent measurements. In the polyuric phase of AKI, potassium and phosphorus may be depleted, so that patients may require dietary supplementation of potassium and phosphorous and IV replacement. Calculation of the nitrogen balance can be challenging, especially in the presence of volume contraction, hypercatabolic states, GI bleeding, and diarrheal disease. Critically ill patients should receive at least 1 g/kg/day protein but should avoid hyperalimentation, which can lead to an elevated blood urea nitrogen (BUN) level and water loss resulting in hypernatremia. Dialysis, especially hemodialysis, may delay the recovery of patients with AKI. Most authorities prefer using biocompatible membrane dialyzers for hemodialysis. Indications for dialysis (ie, renal replacement therapy) in patients with AKI are as follows viz., volume expansion that cannot be managed with diuretics, hyperkalemia refractory to medical therapy,correction of severe acid-base disturbances that are refractory to medical therapy, severe azotemia (BUN >80-100) and uremia. Great controversy exists regarding the timing of dialysis. Older studies suggested decreased mortality with early, versus late, initiation of dialysis, but timing of dialysis initiation has not been assessed in large, randomized, controlled trial approaches vary widely at present.
The acute renal failure trial network (ATN) Study found that increasing the intensity of dialysis (either intermittent or continuous) did not improve clinical outcomes (morbidity/mortality). The best evidence suggests that patients with dialysis-dependent AKI should receive at least 3 hemodialysis treatments per week with a delivered Kt/V value of 1.2, or continuous hemodialysis (continuous venovenous hemodialysis or hemofiltration) of 20 mg/kg/h (prescribed).
There seems to be no difference in outcome between the use of intermittent hemodialysis and continuous renal replacement therapy (CRRT), but this question is currently under investigation. CRRT may have a role in patients who are hemodynamically unstable and who have had prolonged renal failure after a stroke or liver failure. Such patients may not tolerate the rapid shift of fluid and electrolytes caused during conventional hemodialysis. Peritoneal dialysis is not frequently used in patients with AKI. Nevertheless, it can technically be used in acute cases and probably is tolerated better hemodynamically than is conventional hemodialysis. In patients who are at high risk for volume overload - in particular, those with chronic heart failure who have a left ventricular ejection fraction of less than 40% - isotonic NaHCO3 solution should be administered before and after the procedure. It can be prepared by mixing 3 ampules of NaHCO3 in a liter of 5% dextrose in water (D5W) and can be given at a rate of 3 mL/kg/h for one hour prior to the procedure, with the rate decreased to 1 mL/kg/h during the procedure and for 6 hours afterward. Diuretics, non-steroidal anti-inflammatory drugs (NSAIDs), and possibly angiotensin-converting enzyme (ACE) inhibitors should be withheld near the time of the procedure. Despite the significant unmet medical need and associated commercial potential for new treatments of AKI, especially SA-AKI, no pharmacological treatment is currently approved and only a limited number of candidate drugs or biological therapies are in clinical development. The multifactorial pathogenesis of the disease probably necessitates a multifactorial intervention to allow adequate response and durable restoration of kidney function, which limits the number of potentially efficacious treatment options.
The only anti-inflammatory biological with such a dual mechanism of action, which also showed significantly improved kidney function in two phase IIa trials, is alkaline phosphatase (AP). This membrane bound homodimeric enzyme exists in humans as four different isoenzymes referred to as placental, germ cell, intestinal, or tissue non-specific AP. The AP was originally considered as a novel therapy for sepsis because it dephosphorylates and detoxifies endotoxin (lipopolysaccharide, LPS).
Renal recovery in most cases is not complete, with the kidneys remaining vulnerable to the nephrotoxic effects of all therapeutic agents. Therefore, agents with nephrotoxic potential are best avoided. Renal recovery is usually observed within the first 2 weeks, and many nephrologists tend to diagnose patients with end-stage (ie, irreversible) renal failure 6-8 weeks after the onset of AKI. It is always better to check these patients periodically, because some patients may regain renal function much later.
AKI is a devastating disease with high incidence and mortality rates. Sepsis is the most common cause accounting for approximately 50% of cases. Despite the enormous unmet medical need, to date no pharmacological therapy has been licensed to treat or prevent AKI. As a consequence, only supportive care is currently being offered to these critically ill patients, renal replacement therapy being the main option which allows the kidney time to heal but is also associated with a number of problems. New therapies would thus be very welcome. Developing new treatments for this indication is particularly challenging due to the multifactorial pathophysiology of the disease including inflammatory, ischaemic and direct nephrotoxic insults acting simultaneously to rapidly cause functional failure of the kidney. Fortunately, following successful earlier studies, a number of large clinical trials with interesting new approaches are underway.
(Authors are with Manipal College Of Pharmaceutical Sciences, Manipal, Karnataka 576 104)