Thursday, May 8, 2014

Endothelin Antagonism for Diabetic Nephropathy: Nephrology Twitter Journal Club

The next Nephrology Twitter Journal Club (@NephJC) will discuss a study in JASN 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 ETs 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 (including the development of fibrosis). ET acts through the activation of G–coupled receptors, with 2 main subtypes. Activation of ET-A receptors cause vasoconstriction and cell proliferation, whereas activation of ET-B causes natriuresis and the release of nitric oxide and prostacyclin, mediating vasodilation. Selective antagonism of the ET-A receptor is therefore an attractive target with combined blockade, perhaps unsurprisingly, appearing to have no beneficial effects. A previous large multicenter RCT of 1392 participants was performed in patients with Type 2 diabetes and CKD 3-4 using Avosentan with RAAS blockers. The study was halted after a median 4 months for cardiovascular safety concerns. Avosentan significantly reduced proteinuria compared to placebo but at the expense of excess fluid overload and congestive cardiac failure. 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 30-75mls/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 a mean of 35% and 38% in the 2 Atrasentan groups respectively. There was no change in renal function or office BP but 24-hour BP, LDL cholesterol and triglycerides decreased significantly in both treatment groups. More patients in the high dose group discontinued due to adverse events and as expected, there was an increase in weight in the Atrasentan group. However, the rates of peripheral edema or congestive heart failure did not differ between groups. The weight gain was presumed to be fluid-related as reflected by small but significant decreases in hemoglobin and hematocrit.

There are two simultaneous basic science publications examining the disparate effects of ET-A & ET-B receptors which I will briefly mention. A KI 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. Moreover, only ET-A blockade therapy reversed renal microvascular rarefaction and was accompanied by markedly decreased renal inflammation and fibrosis. Another study in JASN investigated ET effects in podocytes during experimental diabetic nephropathy. Mice with a podocyte-specific double deletion of ET-AR and ET-BR manifested less albuminuria and were protected from podocyte loss and diabetic nephropathy. Interestingly, this study also provides evidence that dual blockade of the ET-AR and ET-BR may be necessary to achieve maximal benefit in diabetic nephropathy; challenging 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-up 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 follow the live Twitter journal club on May 13th at 9pm Eastern time and feel free to comment using #NephJC.

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