Late-Breaking Trials Provide New Insights for Improving Clinical Care

The late-breaking clinical trials presented at ASN Kidney Week 2015 featured research that could help advance patient care in a wide range of clinical areas—from uremic pruritus in dialysis patients to acute kidney injury (AKI) in the hospital setting to the next frontier in renal replacement therapy. Although some trial outcomes were unfavorable or unexpected, Lynda Szczech, MD, FASN, told ASN Kidney News they still provide an important contribution to the medical literature and clinical care. “Negative trials have value too. They will prevent patient exposure where there’s no benefit,” said Szczech.

Randomized trials address multiple facets of AKI

Several trials focused on preventive treatments and protocols for reducing AKI incidence in the hospital setting. AKI is estimated to complicate the postoperative course of 20 to 30 percent of patients undergoing cardiac surgery, and is associated with a 5-fold increase in premature death.

Frederic T. Billings, MD, presented results from the Statin AKI Cardiac Surgery trial, a prospective, double-blind, placebo-controlled clinical trial of high-dose perioperative atorvastatin for prevention of AKI associated with cardiac surgery (1). Because statins can affect some underlying mechanisms of AKI, the researchers wanted to determine if a short-term high dose of perioperative atorvastatin would reduce postoperative AKI.

The 820-participant randomized trial was terminated early after researchers determined high-dose perioperative statin use did not decrease postoperative AKI risk following cardiac surgery in patients with chronic kidney disease, and could increase AKI risk in patients naïve to statin therapy. However, the short-term withdrawal or continuation of statins around the time of cardiac surgery did not appear to affect AKI risk.

A substudy of the SIRS (Steroids In caRdiac Surgery) trial—a multinational placebo-controlled, randomized trial of 7286 patients at high risk of perioperative mortality undergoing cardiac surgery—investigated whether corticosteroids could reduce the patient’s AKI risk (2). Because corticosteroids have been successful in treating acute inflammation in the kidney, the authors, led by Amit Garg, MD, PhD, hypothesized they could suppress the systemic inflammatory response syndrome activated by the use of cardiopulmonary bypass pump in cardiac surgery.

The researchers found that high doses of the corticosteroid methylprednisolone did not reduce AKI risk regardless of whether the patient had preexisting CKD. The results would suggest that prophylactic steroids not be used to prevent AKI in patients undergoing cardiac surgery with cardiopulmonary bypass, said Garg.

Another clinical trial investigated contrast-induced AKI, a complication in medical imaging estimated to affect between 2 and 20 percent of patients. Investigators at the Charité Hospital in Berlin led by Eva Schönenberger, MD, conducted the first randomized comparison between CT angiography and invasive contrast-enhanced angiography (the standard test for diagnosing a blocked coronary artery) to determine which method was the most accurate and safest for detecting coronary disease (3).

In the study, 318 patients with suspected coronary disease were randomized to undergo either invasive angiography or CT angiography. Both arms received the same contrast agent administered directly into the coronary arteries for angiography or superficial veins for CT. AKI was 2 to 3 times more likely to occur with invasive angiography compared with CT angiography. “The diagnosis of coronary disease by CT may thus offer two advantages—noninvasiveness and at the same time reduced risk of AKI,” Schönenberger told Kidney News.

New understandings in dialysis care

Researchers led by Ashley Irish, MBBS, MD, conducted the FAVOURED (Fish oils and Aspirin in Vascular access OUtcomes in REnal Disease) trial to investigate ways to potentially overcome the 30 to 50 percent attrition rate of newly created arteriovenous fistulae (AVF), considered the optimal vascular access for hemodialysis (4). Because of the anti-inflammatory, antiplatelet, antihypertensive effects of fish oil and aspirin, investigators conducted a randomized, placebo-controlled trial to determine if they could reduce AVF access failure.

After randomizing 567 hemodialysis patients to fish oil or placebo, with a subset of patients randomized to additionally receive aspirin or placebo, the researchers found that neither omega-3 polyunsaturated fatty acids nor aspirin had any effect in preventing AVF failure. “It’s disappointing we didn’t see a benefit because these therapies are cheap, safe, and readily available,” said Irish. Yet he added that such trials generate a huge amount of knowledge about the natural history of AVFs and other aspects that can inform practice and drive future trials.

Another randomized trial investigated whether nalbuphine, a κ-opioidagonist/μ-opioid antagonist, was safe and effective in reducing the itching intensity of uremic pruritus, a common side effect of hemodialysis that affects a patient’s sleep, quality of life, and social functioning (5). Because κ receptors mediate anti-pruritic effects, researchers led by Vandana Mathur, MD, FASN, hypothesized the opioid nalbuphine could reduce the itching associated with uremic pruritus.

A total of 373 patients on dialysis were randomized to one of two doses of nalbuphine or placebo. After 8 weeks, the high-dose (120 mg) group demonstrated a significant reduction in itch intensity. “Other quality of life measures, such as sleep, also seemed to improve,” said Mathur.

Tacrolimus more effective in steroid-resistant nephrotic syndrome

A new prospective open-label randomized controlled trial found tacrolimus was superior to mycophenolate mofetil (MMF) in maintaining remission in children with steroid-resistant nephrotic syndrome (6). Led by Aditi Sinha, MD, researchers from the All India Institute of Medical Sciences in New Delhi conducted a trial to determine if MMF would enable remission while avoiding the toxicity associated with calcineurin inhibitors, such as tacrolimus.

A total of 60 patients were randomized to either tacrolimus and prednisone or MMF and prednisone. After 12 months, MMF was inferior to tacrolimus with 51.7 percent of patients on MMF experiencing treatment failure (recurrence of steroid resistance, frequent relapses, or more than one serious adverse effect) compared to 9.7 percent in the tacrolimus group. Ninety percent of patients receiving tacrolimus demonstrated a favorable outcome (sustained remission and infrequent relapses) compared with 48 percent in the MMF group. “In patients with steroid-resistant nephrotic syndrome and remission with 6-month therapy with tacrolimus therapy, MMF was associated with a higher risk of treatment failure,” said Sinha.

A new frontier: the Wearable Artificial Kidney (WAK) trial

The first human trial of the WAK, invented by UCLA/Cedars Sinai nephrologist Victor Gura, MD, FASN, demonstrated the proof of concept of the device (7). The WAK is a miniaturized, battery-operated, belt-like device that removes excess salt, water, and accumulated toxins that allows patients to undergo dialysis at a natural rate while ambulating or working and without the customary dietary restrictions required by hemodialysis.

Five of the seven patients in the pilot study completed the 24-hour trial, conducted at the University of Washington at Seattle. The WAK was well tolerated and effective in maintaining electrolyte homeostasis, solute clearance, and volume removal. “The data provides proof of concept that the WAK is an effective and safe dialysis device that will greatly improve quality of life for ESRD patients,” said Gura. “The results suggest that the WAK has the potential to reduce patient mortality and cut the exorbitant cost of treating kidney failure.”

References

1. 

Billings FT, et al. High dose perioperative atorvastatin and acute kidney injury following cardiac surgery [Abstract]. J Am Soc Nephrol 2015; 26(Suppl):B1.

2. 

Garg A, Whitlock RP. Effect of methylprednisolone on acute kidney injury in patients undergoing cardiac surgery with cardiopulmonary bypass [Abstract]. J Am Soc Nephrol 2015; 26(Suppl):B1.

3. 

Schönenberger E, et al. Nephrotoxicity of invasive and noninvasive coronary angiography: randomized controlled study of intracoronary and intravenous contrast agent administration [Abstract]. J Am Soc Nephrol 2015; 26(Suppl):B3.

4. 

Irish AB, et al. The Omega-3 fatty acids (Fish oils) and Aspirin in Vascular Access Outcomes in Renal Disease (FAVOURED) study: a randomised placebo-controlled trial [Abstract]. J Am Soc Nephrol 2015; 26(Suppl):B2.

5. 

Mathur VS, et al. Randomized, double-blind, placebo-controlled, parallel, 3-arm study of safety and anti-pruritic efficacy of nalbuphine HCl ER tablets in hemodialysis patients with uremic pruritus [Abstract]. J Am Soc Nephrol 2015; 26(Suppl):B2.

6. 

Sinha A, Bagga A. Randomized trial on efficacy of mycophenolate mofetil versus tacrolimus in maintaining remission in children with steroid resistant nephrotic syndrome [Abstract]. J Am Soc Nephrol 2015; 26(Suppl):B2.

7. 

A trial assessing use of a Wearable Artificial Kidney (WAK) in patients undergoing maintenance hemodialysis [Abstract]. J Am Soc Nephrol 2015; 26(Suppl):B9.