Anyone in the world
In the last week I have seen 2 patients who have had steroid resistant nephrotic syndrome due to minimal change disease. Both have had various immunosuppressives without success and have continued to have nephrotic range proteinura for 5 years. Despite this they both have normal kidney function!! Thus the obsession with microalbuminuria (MA) as a risk factor for progression in CKD is something I have always found puzzling. There has been a plethora of publications over the last 10 years focussing on the association between microalbuminuria (MA) and adverse renal and cardiovascular outcomes and its likely that MA identfcaton wll be central to the KDIGO approach to CKD. In simple terms there are two schools of thought as regards proteinuria and CKD:
1) proteinuria in itself is nephrotoxic (based predominantly on in vitro and in vivo studies showing evidence of inflammatory and fibrogenic effects on tubular epithelial cells) and cardiotoxic and so reducing proteinuria will positively impact on both cardiovascular and renal endpoints.
2) Proteinuria and MA simply reflecting underlying glomerular and endothelial 'health' and improved levels of proteinuria simply reflect improvements in underlying glomerular or vascular disease.
The Altitude study which was published in NEJM recently
seriously questions whether strategies designed to improve proteinuria per se can in themselves have any impact on cardiovascular and renal outcomes. The Altitude study is a large RCT of 8561 patients studying the impact of combining aliskiren (direct renin inhibitor) with an ACEi\ARB on a range of cardiorenal endpoints. Despite a significant reduction in proteinuria and blood pressure, Aliskiren combined with ACE\ARB had no positive effect on any cardio-renal endpoint. This fits in with data from previous interventional (not observational) studies suggesting a disconnect between MA reduction and cardio-renal outcomes. For example in the ROADMAP
study of olmesartan in type 2 diabetes showed that despite reducing MA, olmesartan had no effect on cardiovascular morbidity, kidney function and there were significantly more deaths in the treatment group. Similarly the huge ACCOMPLISH
study demonstrated significantly superior cardiovascular outcomes with benazepril combined with amlodipine when compared with benazepril combined with a thiazide in hypertensive patients at risk of cardiovascular disease - DESPITE improved MA in the thiazide group..
Taken together the interventional (as opposed to the observational) data clearly shows that proteinuria and MA are little more than biomarkers for renal and cardiovascular disease. Attempts to target MA per se are futile and as a wise colleague of mine once said MA is little more than a urinary ESR......
1. Cardiorenal end points in a trial of aliskiren for type 2 diabetes.Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Persson F, Desai AS, Nicolaides M, Richard A, Xiang Z, Brunel P, Pfeffer MA; ALTITUDE Investigators. N Engl J Med. 2012 Dec 6;367(23):2204-13
3. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. Haller H, Ito S, Izzo JL Jr, Januszewicz A, Katayama S, Menne J, Mimran A, Rabelink TJ, Ritz E, Ruilope LM, Rump LC, Viberti G; ROADMAP Trial Investigators. N Engl J Med. 2011 Mar 10;364(10):907-17.
[ Modified: Thursday, 1 January 1970, 1:00 AM ]