Positive Results for Transplant Intervention and Liraglutide

A safe, inexpensive pre-transplant intervention can reduce graft loss and mortality, according to late-breaking trial results presented during Kidney Week 2016.

During the late-breakers session at the meeting, the positive results from the REPAIR study of remote ischemic preconditioning (RIPC) were accompanied by reassuring datas on the renal outcomes from the LEADER Trial of Liraglutide in type 2 diabetes. Other preliminary studies presented at the meeting found positive results for medications for lupus nephropathy and focal segmental glomerulosclerosis (FSGS), as well as some positive results for rapid withdrawal of steroids in transplant patients. But a trial of low-sodium dialysate did not find a benefit.

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Transplant protection

Together, the rush of blood that flows into a newly transplanted kidney and the period of reduced oxygen just before transplant may permanently damage the organ. This damage may reduce kidney function and the life of the transplant.

But some evidence has suggested that preconditioning the organ by briefly limiting blood flow prior to the transplant can protect against these injuries by triggering the body’s protective mechanisms (Veighey K and MacAllister R. Pediatr Nephrol 2015; 30:1749–1759). Now, Kristin Veighey, MB, MRCP, a nephrologist and research fellow at the University College London Centre for Nephrology, and her colleagues have shown that using a blood pressure cuff to briefly limit blood flow to the upper arm in the living donor and recipient just before surgery can reduce graft loss and substantially cut recipient mortality.

In the REPAIR study (http://repair.lshtm.ac.uk/), Veighey and her colleagues randomized 406 live donor/recipient pairs to placebo, RIPC just prior to surgery, RIPC 24 hours before surgery, or both. At the meeting, Veighey presented 5-year follow-up data that found sustained improvements in adjusted average eGFRs in patients who received early RIPC compared to placebo at 2, 3, 4, and 5 years, although the overall eGFR difference was not significant. The study also found reduced graft loss in the early RIPC group compared with placebo (5% vs. 6%), and reduced mortality in the early vs. placebo groups (2% vs. 5%). No adverse events were documented in the intervention groups.

“Based on the fact that this is safe, it is easy to deliver, and it is virtually cost-neutral at the point of delivery, we would advocate that this is something we should be offering to our patients as part of routine practice in this setting,” Veighey said.

The potential benefits of RIPC were first shown in cardiology, and we are now starting to see them in nephrology, said Gretchen Brandt, MD, a nephrologist at Kaiser Permanente in Washington, DC. She noted that it is remarkable to see a clinically significant improvement in mortality and graft function in live donor patients, who already tend to do well.

“I’m very excited because this is a very low-tech, low-cost intervention,” Brandt said. “We’ll have to see if [the benefits] hold over the long haul.”

If they do, the intervention could be widely applied even in resource-poor settings.

“It’s on the cutting edge,” said Brandt. “It’s not yet standard of care.”

Diabetes interventions

Diabetes drug Lirgalutide may have beneficial effects on the kidneys as well as the heart, suggest data from the LEADER trial presented by Johannes F. Mann, MD, of the University of Erlangen-Nürnberg in Germany. The cardiovascular outcomes of the LEADER trial, which enrolled 9340 patients with type 2 diabetes with high cardiovascular risk and randomized them to liraglutide or placebo were published in June (Marso SP, et al. N Engl J Med 2016; 375:311–322). The results showed a reduction in deaths from a composite of cardiovascular causes in patients taking the drug compared with placebo (4.7% vs 6%).

Mann and his colleagues found that the risk of a composite of negative renal outcomes was about 22% lower in patients taking liraglutide compared with placebo (HR, 0.787; p=0.003). But this result was driven by reductions in new onset macroalbuminuria alone, while there were no significant reductions in other renal outcomes including persistent doubling of serum creatine, ERSD, or death by renal cause. The eGFRs of liraglutide-treated patients also decreased less than placebo-treated patients, but the benefit was seen only in the subgroup of patients with an eGFR less than 60 mL/min. The drug was not associated with an increase in the risk of renal events.

“Liraglutide reduced the risk of nephropathy, cardiovascular events, and all-cause mortality relative to placebo,” Mann said.

While the cardiovascular benefits were the trial’s primary outcome, Brandt said it is nice to also see a benefit in nephropathy. “That’s a 2-for-1,” she said.

She noted that 3.84 years of follow-up is not a very long time, considering that diabetic nephropathy takes 17 to 20 years to progress. It may be possible that patients with lower eGFRs might show benefit after a longer period of follow-up.

She did, however, note a few drawbacks to liraglutide. It is expensive, requires a daily injection, and is associated with gastrointestinal adverse events. She also noted that there is emerging evidence that cheaper, oral diabetes medications given at higher doses may also be useful for patients with stage 3 or 4 chronic kidney disease (CKD). She noted that in general clinicians are getting better at treating chronic diseases. So, whether switching to a new drug class or tightening up use of the existing armamentarium will be the best approach, “needs to be sorted out in the long haul,” she said.

Other results

Cardiovascular disease is a major cause of death for patients with end stage renal disease (ERSD). It is a particular concern in patients receiving dialysis who often experience left ventricular hypertrophy, which may hasten death, according to Mark Marshall, MD, who is now director of medical affairs, renal, Baxter Healthcare in the Asia-Pacific region. In a single-blind, government-funded study, Marshall and his colleagues tested whether low-sodium dialysate (135 mM) reduced left ventricular hypertrophy in dialysis patients compared with standard dialysate (140 mM) in the phase 2 SoLID Trial. It did not. He and his colleagues have planned a larger trial.

“A lot of nephrologists are moving to low-sodium dialysate without a lot of evidence,” cautioned Marshall. “This needs to be tested in a larger trial.”

The trial was well designed, said Brandt, though she noted the trial used dialysate sodium levels that were on the ends of the spectrum to see a difference. At her institution, for example, she noted that the standard dialysate sodium level is somewhere is in the middle at 137 mM. She also noted that left ventricular mass is a surrogate marker and that it might be difficult to see a difference in a 9-month trial.

I wouldn’t give up hope that there are future studies that see a difference 2 to 5 years out,” Brandt said.

In the meantime, she suggested that clinicians watch for hypotension in patients during dialysis.

“Patients in the low-dialysate arm were often hypotensive,” she explained.

Other studies presented at the meeting suggested benefits to rapid steroid withdrawal in low-risk kidney transplant patients, and provided preliminary evidence for the safety and efficacy of new agents for lupus nephropathy and FSGS.

The HARMONY Trial, which enrolled 615 low-risk Caucasian kidney transplant patients, and tested the effect of rapid steroid withdrawal with standard immunosuppressive therapy, did not meet its primary endpoint of reduced acute rejections at 12 months. But rapid withdrawal did nearly cut diabetes among transplant recipients in half.

The phase 2 AURA-LV trial of calcinurin-inhibitor voclosporin for lupus nephritis (LN) (n=265) met its primary endpoint, with 32.6% of low-dose treated patients and 27.3% of high-dose patients achieving complete remission at 24 weeks compared with 19.3% of the placebo group. It also met its secondary endpoints. But the treatment group also had more adverse events and a higher mortality rate than placebo. A phase 3 trial is planned.

Sparsenta, a dual angiotensin II and endothelin type A receptor antagonist, had more of an effect on proteinuria, a surrogate endpoint, than angiotensin II antagonist with irebsartan in patients with focal segmental glomerulosclerosis in the phase 2 DUET trail, which enrolled 96 patients. Sparsartan was also well tolerated.

December 2016 (Vol 8, Issue 12)