The Endothelin Antagonist Atrasentan Lowers Residual Albuminuria in Patients with Type 2 Diabetic Nephropathy.

de Zeeuw DColl BAndress DBrennan JJTang HHouser MCorrea-Rotter RKohan DLambers Heerspink HJMakino HPerkovic VPritchett YRemuzzi GTobe SWToto RViberti GParving HH.

PMID: 24722445

An editorial providing useful context can be found here. (HTML free, PDF for $)

Live TweetChat: May 13th at 9PM Eastern

The next Nephrology Twitter Journal Club (@NephJC) will discuss a recently published study describing the use of Atrasentan, a selective Endothelin-A receptor blocker, in diabetic kidney disease. This is the latest attempt to resurrect this class of agents in CKD. Within the last year, the big diabetic nephropathy stories have been the Bardoxolone saga and the VA Nephron D study so it's about time we had some good news. We can perhaps be cautiously optimistic after this Endothelin (ET) antagonist study.

There are many endothelins with ET-1 being the predominant isoform. They are produced by many cells in the kidney and have a wide variety of biologic actions including the regulation of vascular resistance, fluid and electrolyte transport, and cell proliferation (they have an important role in the development of renal fibrosis). Endothelins acts through activation of G-coupled receptors, with 2 main subtypes:

  • Activation of ET-A receptors cause vasoconstriction and cell proliferation
  • ET-B causes natriuresis and the release of nitric oxide and prostacyclin, mediating vasodilation

Selective antagonism of the ET-A receptor is the therapeutic target. Combined blockade, unsurprisingly, has no beneficial effects in human trails. The ASCEND Trial was a large multicenter RCT of 1,392 participants was performed in patients with Type 2 diabetes and CKD 3-4 using the Endothelin A receptor antagonist, Avosentan. The study was halted after a median 4 months due to excess CV events, primarily CHF and fluid overload. Avosentan did significantly reduce proteinuria compared to placebo. It should be noted that Avosentan is a less ET-A selective antagonist than Atrasentan, the agent in the current JASN study.

The current study was a placebo-controlled RCT involving 211 patients with diabetic nephropathy, overt proteinuria and eGFR 30-75 ml/min. The mean age was 65 years and 70-80% were male. Two doses of Atrasentan were studied, 0.75mg/day and 1.25mg/day. There was a significant improvement seen in albuminuria with albumin/creatinine ratios decreasing by 35% and 38% with 0.75 and 1.25 mg of atrasentan. There was no change in renal function or office BP but 24-hour BP, total cholesterol, LDL cholesterol and triglycerides significantly decreased with either dose of study drug. The total number of adverse events and serious adverse events looked similar across the groups (68, 71, and 74% for total adverse events, 8, 9 and 7% for serious adverse events with placebo 0.5 and 1.25 mg of atrasentan respectively), but more patients in the 1.25 mg dose group discontinued study drug due to adverse events. The high dose group also had more weight gain, than the low dose or placebo group. The 0.5 mg group initially gained 1 kg but returned to baseline weight by week 10. The weight gain was presumed to be fluid-related as reflected by a small but significant decreases in hemoglobin and hematocrit. However, the rates of peripheral edema or congestive heart failure did not differ between groups. All of the biochemical and physiologic changes reversed after 30 days of washout.

There are 2 simultaneous basic science publications examining the disparate effects of ET-A & ET-B receptors which I will briefly mention. A Kidney International paper reported on pigs with unilateral renovascular disease treated with either ET-A or ET-B antagonists. Renal blood flow and GFR were significantly improved after ET-A but not ET-B blockade. ET-A blockade therapy reversed renal microvascular rarefaction and markedly reduced renal inflammation and fibrosis. Another study investigated ET effects in podocytes during experimental diabetic nephropathy. Mice with a podocyte-specific double deletion of ET-A receptor and ET-B receptor manifested less albuminuria and were protected from podocyte loss and diabetic nephropathy. Interestingly, the results of this study challenges the belief that ET-B antagonism is detrimental.

So, is it time for ET antagonists to enter the mainstream? These agents have been around for quite some time but the adverse events reported with previous agents looked like it had buried these drugs for good. This study is welcome and obviously encouraging. However, the short follow and lack of hard endpoints mean further data is needed and longer studies warranted. Also, it is obvious that we have much still to learn regarding the ET system and how to manipulate it for gain in our CKD patients. The Nephrology community is well used to false dawns, particularly in diabetic nephropathy. Will ET antagonists prove to be the first clinically useful agents since the introduction ACE inhibitors/ARBs?

We would like to hear what you think. Please join the live Nephrology Journal Club on Twitter on Tuesday May 13th. Use the hashtag #NephJC so everyone can find your comments.

Paul Phelan and Joel Topf

The Tweet Chat

The live journal club went off last night and we had a spirited discussion of the trial. A PDF of the transcript is available hereYou can see the highlights in the following four stories.

Here is the Google Hangout we conducted to summarize and extend the journal club discussion.

The future of atrasentan will be determined by the definitive trial now being conducted. This is a four year, placebo controlled trial to determine if the reduction in albuminuria translates to a reduction in death, dialysis or doubling of serum creatinine. The differences between the current trial, RADAR and SONAR are summarized below:

Nice summary of the trial put together by Nephrology On-Demand can be found here.