Blog entry by Meguid El Nahas

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by Meguid El Nahas - Thursday, 6 September 2012, 2:16 PM
Anyone in the world

An interesting article in the BMJ by Prof Yudkin and colleagues in London is entitled:

"The Idolatry of Surroagtes"

http://www.ncbi.nlm.nih.gov/pubmed/22205706

In this article, the authors raise serious and justified concern about the use of surrogate markers as substitutes for hard endpoints in clinical research and trials. They quote a number of examples whereby reduction in surrogate markers are not associated with changes or diverge from expected hard endpoints. 

They comment specifically on albuminuria and raise concern about its disconnect with hard renal and cardiovascular endpoints.

This concern is supported by data showing that a reduction of albuminuria can be associated with imporved renal function (RENAAL), unchanged renal function (ACCORD study) or worse stilll worsening of renal function (ONTARGET). Clearly, reduction of albuminuria can also be misleading if considered a CV endpoint as the ROADMAP study showed  that prevention/reduction of Microalbuminuria with Olmesartan in DM was in fact associated with increased CVD morbidity. 

So lets stop being obssessed with reduction of proteinuria in CKD and focus of the true hard endpoints of death and ESRD. 

I despair when I hear senior nephrologists argue that reduction of proteinuria should take precedent over declining kidney function or starting ESRD....thus continuing to poison their patients with ACE inhibitors and ARBs and accelerating the time to ESRD in the name of reducing proteinuria and preventing CVD....!!!!

Care should be taken in clinical trials, but also in daily practice, not to treat the markers/symptoms of disease on the assumption that we treat the underlying disease or its cause.

This explains why the FDA rightly continues to reject albuminuria as a surrogate marker for ESRD, or even the progression of CKD. The FDA has also recently become more stringent in its requirements that drugs under development are shown to affect favourably hard endpoints at the risk of prolonging the cost and duration of drug development. Better be safe than sorry later...

For the Pharmaceutical industry to steamroll drug developments and marketing using surrogate markers of mortality, CVD, CKD progression or ESRD as albuminuria is unacceptable and potentially dangerous. Even serum creatinine, and the asociated eGFR, should be looked upon with caution when we investigate an intervention aimed at slowing the progression of CKD, delaying ESRD or preventing Death. Serum creatinine is a marker of a number of confounders including protein intake, metabolism, muscle mass and tubular secretion of creatinine; it is NOT a hard enpoint for progression of CKD. For that, MEASURED GFR is the gold standard!

http://www.ncbi.nlm.nih.gov/pubmed/22393413

It is high time the nephrological community discern soft surrogate markers from hard endpoints.

Nephrologists need to realise that hard end points are essential for the practice of true patients centered medicine.

 

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