Losartan May Protect Renal Allografts from Progressive Fibrosis

BERLIN—Treatment with an angiotensin receptor blocker (ARB) may prevent the rate at which fibrosis of transplanted kidneys develop, according to a study presented at the 24th International Congress of The Transplantation Society.

Hassan Ibrahim, MD, MSc, Professor of Medicine at the University of Minnesota in Minneapolis, showed in his five-year, randomized, double-blind, placebo-controlled trial that, compared with placebo, losartan (Cozaar, Merck) had a statistically modest benefit for a significant reduction in rate of doubling of the interstitium or end-stage renal disease (ESRD) from interstitial fibrosis or tubular atrophy (IF/TA), but its use slows the rate of expansion of the renal interstitium.

With losartan, a 10% increase in the volume fraction of the interstitial tissue per glomerular cortex (Vvint/c) was associated with a loss of GFR of 3 mL/min./1.73 m over a five-year period. With placebo, the GFR loss was 18 mL/min./1.73 m2. “This difference is clinically relevant. It conveys a strong signal for this therapy being important,” Dr. Ibrahim told Renal & Urology News after his presentation. “Only 20% of transplant recipients in the U.S. receive this therapy by six months post-transplant. These results should ease some of the concerns about using this drug in transplant patients.”

“At the end of the study the event rate was much lower than we expected, and that limits the conclusions of the study,” Dr. Ibrahim said. “However, I would argue that in a low-power situation we were able to show some benefit, although it's far from definitive.”

Dr. Ibrahim was the principal investigator in this $5 million study, which was largely funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Merck provided $150,000 as well as the losartan and placebo tablets.

The researcher randomized 77 adult kidney recipients to 100 mg/day losartan and another 76 to placebo. The patients were non-pregnant recipients of a first or second renal transplant. They did not have a known hypersensitivity to losartan, documented renal artery stenosis, hyperkalemia, primary oxalosis, dense-deposit disease, focal and segmental glomerulosclerosis or hemolytic uremic syndrome. They also were not recipients of a kidney from an HLA-identical sibling and did not require ACE inhibitors or ARBs for a cardiovascular condition.

Forty-seven recipients in the losartan group and 44 taking placebo had both baseline and exit biopsies or ESRD from IF/TA. The investigators also ascertained the baseline and exit biopsy information from patients in the two groups who developed ESRD or have died before the end of the study.

The primary endpoint was a reduction of the combined endpoint of the doubling of (Vvint/c) and graft loss from IF/TA over the five years of the trial. A total of only 16 graft losses occurred, 12 from IF/TA and four from other causes. Losartan did not significantly reduce the rate of the primary endpoint, Dr. Ibrahim said possibly, because of the low number of events or the lack of true benefit.  Likewise, losartan did not show a statistically significant effect on death, ESRD, or doubling of interstitium volume. A significant effect of losartan was the reduction in the rate of decline of GFR concomitant with slowing interstitial expansion.

The University of Minnesota Investigators showed losartan to be safe as they observed only one case of serious hyperkalemia, “which was readily reversible,” he said.

An ongoing Canadian study with ramipril,an ACE inhibitor, will shed more light on the power of this class of agents to improve renal outcomes and patients survival, he said.

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