ASCEND trial terminated prematurely

Endothelin antagonist Avosentan showed promising results in reduction of proteinuria and prevention of progressive renal disease in animal studies. Please see images above that showed improvement in renal histology after administration of endothelin antagonist in animal studies. ASCEND trial (Mann et al, JASN 2010) is a multicenter, multinational, double-blind, placebo-controlled trial of 1392 patients that evaluated addition of Avosentan to ACEi/ARB in diabetic nephropathy. Trial was terminated prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events (esp.CHF) with avosentan. During this short follow-up, no difference was detected in the frequency of time to doubling of serum creatinine, ESRD or death between groups. However, Avosentan significantly reduced proteinuria by about 50%.

New transplant medicine on the horizon

Recent focus in transplant pharmacology has been T cell co-stimulation. Here is a nice graphic from Nature Reviews in Immunology on interaction between T cell and Antigen Presenting Cell(APC). As you can see in the picture, both CD28 and CTLA-4 on T cells interact with same receptor CD80/CD86(B7-1/B7-2) on antigen presenting cells. While CD28 is co-stimulatory, CTLA-4 is required for immune regulation and inhibition. While Belatacept blocks CD80/86, thus interfering with both CD28 and CTLA-4 pathways, a newly identifiied true CD28 antagonist was shown to be preserve CTLA-4 dependent immune regulation and improve allograft survival in primates (Poirier et al, Science Translational Medicine 2010).

Confirmation of adverse outcomes with proteinuria

In a recently published study (Hemmelgarn et al, JAMA 2010), the adverse outcomes of proteinuria were confirmed by studying almost a million patients. In this mammoth study of 920928 adults in Canada, it was demonstrated that prognosis associated with a given level of eGFR varies substantially based on the presence and severity of proteinuria. In fact, patients with heavy proteinuria but without overtly abnormal eGFR appeared to have worse clinical outcomes than those with moderately reduced eGFR but without proteinuria. Adjusted mortality rates were more than 2-fold higher among individuals with heavy proteinuria measured by urine dipstick and eGFR of 60 mL/min/1.73 m(2) or greater, as compared with those with eGFR of 45 to 59.9 mL/min/1.73 m(2) and normal protein excretion (rate, 7.2 [95% CI, 6.6-7.8] vs 2.9 [95% CI, 2.7-3.0] per 1000 person-years, respectively; rate ratio, 2.5 [95% CI, 2.3-2.7]). Similar results were observed for the outcomes of hospitalization with acute myocardial infarction, end-stage renal disease, and doubling of serum creatinine level. Authors proposed that future revisions of the classification system for CKD should incorporate information on proteinuria. The main limitation of this study is that it is an observational study.

Welcome to Nephrology World

It is with great pleasure that I created this blog. Dr.Nathan Hellman of Renal Fellow Network is an inspiration for me to create this blog. The main intention of this blog is to share knowledge among various renal communities around the world. The renal pathology that we see in US and the rest of the world is diverse. So it is rewarding for everyone to discuss interesting cases and new literature.