Pam Harrison

November 11, 2015

SAN DIEGO — Statins, steroids, and fish oils did not live up to expectations, according to results from three highly anticipated trials presented here at Kidney Week 2015, which investigators had hoped would shed light on the relation between vascular complications and kidney disorders.

"Negative trials are sometimes disappointing, but I'm pleased that these trials were rigorously conceived and rigorously conducted. They actually give us answers to important clinical questions," session cochair Sushrut Waikar, MD, from Brigham and Women's Hospital in Boston, told Medscape Medical News.

The first study evaluated the use of high-dose atorvastatin to protect the kidneys of patients undergoing cardiac surgery.

The second study, the Steroids in Cardiac Surgery (SIRS) trial, assessed the effect of methylprednisolone on acute kidney injury in patients undergoing cardiopulmonary bypass surgery.

The third study, the FAVOURED trial, evaluated the role of omega-3 fatty acids and aspirin in vascular access outcomes in patients with renal disease.

"I applaud these investigators for undertaking clinical research with all of its attendant challenges and on doing an excellent job in terms of conducting these difficult studies," Dr Waikar said.

Statins Fail to Protect Kidneys

In their study, Frederic Billings, MD, from the Vanderbilt University School of Medicine in Nashville, Tennessee, and his colleagues tracked acute kidney injury in 820 patients — randomized to either high-dose atorvastatin or placebo — undergoing cardiac surgery.

"Statins affect several mechanisms underlying acute kidney injury," Dr Billings told reporters attending a news conference.

The team hypothesized that the mechanisms that lead to acute kidney injury would be reversed if statin-naive patients started therapy with high-dose atorvastatin a day before surgery and continued until hospital discharge, and if statin users started high-dose atorvastatin the day of surgery and continued until hospital discharge.

However, the hypothesis was not supported; there was no difference in the rate of kidney injury between the atorvastatin and placebo groups (20.8% vs 19.5%; P = .75)

Table. Kidney Injury in Patients Undergoing Cardiac Surgery

Patients Atorvastatin Group (%) Placebo Group (%)
Statin users    
   With chronic kidney disease 35.7 32.8
Statin-naïve patients    
   With kidney disease 52.9 15.8
   Without kidney disease 21.6 13.4


In statin-naïve patients with kidney disease, the numbers were small. However, the magnitude of the negative effect of high-dose atorvastatin on kidney injury was "striking," said Dr Billings, and increased the risk for kidney injury.

In statin-naïve patients without kidney disease, the difference in kidney injury was not significant "but it was clinically important; an 8% difference in acute kidney injury is clinically relevant," Dr Billings explained.

Steroids Fail to Protect Kidneys

The SIRS trial evaluated the effect of methylprednisolone on acute kidney injury in 7286 patients undergoing cardiopulmonary bypass surgery (Lancet. 2015;386:1243-1253).

Patients were randomly assigned to intravenous methylprednisolone — 250 mg on induction of anesthetic and another 250 mg at the start of cardiopulmonary bypass — or placebo.

"Cardiopulmonary bypass initiates a systemic inflammatory response, which activates complement inflammatory cytokines and other inflammatory mediators. This, in turn, increases endothelial permeability, organ damage, and morbidity and mortality, including acute kidney injury," said investigator Amit Garg, MD, from the London Health Sciences Centre in Ontario, Canada. "We were interested in corticosteroids because they suppress this inflammatory response."

However, there was no difference between the methylprednisolone and placebo groups.

Table. Change in SIRS Outcomes From Baseline

Acute Kidney Injury End Point Methylprednisolone Group (%) Placebo Group (%)
14 days after surgery    
   ≥50% increase in creatinine 40.9 39.5
   ≥100% increase in creatinine 9.9 9.9
   ≥200% increase in creatinine 4.0 4.5
30 days after surgery    
   Acute dialysis 2.6 2.4


"There was also no benefit of steroids in those with or without preoperative chronic kidney disease," Dr Garg reported.

Because of the adverse-effect profile of the dose of steroids used in this trial, the investigators make the grade 1 recommendation that steroids not be used in this setting.

Fish Oils Fail to Improve Vascular Access in Renal Disease

For patients on hemodialysis, "an arteriovenous fistula is considered the optimal route for vascular access," said investigator Ashley Irish, MD, from Fiona Stanley Hospital in Perth, Australia. "But they are the hardest ones to get going because arteriovenous fistulas have very high rates of thrombosis, and they often fail to mature so you can't actually use them."

In the FAVOURED trial, known as the Omega-3 Fatty Acids (Fish Oils) and Aspirin in Vascular Access Outcomes in Renal Disease study, the investigators hypothesized that the pleiotropic effect of fish oil on inflammation and platelet function might help turn this situation around.

The 567 patients with stage 4 or 5 chronic kidney disease were randomly assigned to 3 months of high-quality fish oil 4 g daily or placebo, and were followed for 12 months. A subset of patients also received daily aspirin 100 mg or placebo.

The end point was a composite of arteriovenous fistula thrombosis, arteriovenous fistula abandonment, and the unreliable cannulation of a patent arteriovenous fistula.

"Nearly half of all patients in this trial had no useable arteriovenous fistula 12 months after surgery," Dr Irish reported.

Table. FAVOURED Trial Outcomes

Arteriovenous Fistula End Point Fish Oil (%) Placebo (%)
Thrombosis 22 23
Abandonment 19 22
Cannulation failure 40 39


In the subset of patients randomized to aspirin, the rate of arteriovenous fistula failure was similar in the fish oil and placebo groups (45% vs 43%).

"It didn't matter whether you were old or young, had vascular disease, or were diabetic or not," Dr Irish said. "Fish oil didn't help. Nor, for that matter, did aspirin."

The statin study was funded by the National Institutes of Health. SIRS was paid for by the Canadian Institutes of Health Research. The FAVOURED trial was funded by the National Health and Medical Research Council of Australia. Dr Waikar, Dr Billings, Dr Irish and Dr Garg have disclosed no relevant financial relationships.

Kidney Week 2015: American Society of Nephrology Annual Meeting. Presented November 7, 2015.


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