Digging Deeper: RENAAL Reexamined

So I stumbled across this KI paper while watching a great lecture on ukidney given by Phil Mcfarlane at last year's Prevention in Renal Disease Conference in Toronto.

It's a really nice post hoc analysis of the RENAAL data looking at albuminuria's predictive value for events (ESRD, doubling of serum Cr, death).

See the previous post for what RENAAL was all about, patients with DMII and nephropathy who were randomized to ARB or placebo.

Here, de Zeeuw and colleagues asked...

1) Whether baseline albuminuria was predictive of events
2) Whether the degree of reduction was predictive of long term risk reduction for these events and finally
3) Whether the amount of albuminuria remaining after therapy conveyed risk similar to baseline levels.

1) Baseline albuminuria.


No shocker here, the more albumin you had in your urine the more likely you were to reach either the renal end point (ESRD, doubling of serum Cr, death) or ESRD. HRs are multivariate adjusted and calculated using an ACR less than 1.5 g/g as the referent.

What really struck me was that if you had a ACR of greater than 3.0 g/g, almost 100% of folks reached the renal end point at four years and nearly 80% got to ESRD.

2) % reduction of albuminuria at 6 months.

Exciting stuff here and very elegant figures. In terms of reduction in the composite end point you see a drop in risk the greater the reduction in albuminuria.


Around a 60% reduction in risk for those who achieved a drop of 60% or more in their albuminuria at 6 months.

When looking at ESRD in isolation the risk of progression vs protection as predicted by albuminuria is more marked.


Those with greater than a 40% increases in their albuminuria were upwards of two and a half more times more likely to need dialysis or transplantation when compared to those whose values were unchanged.

Likewise those who achieved the most dramatic reductions saw their risk drop by roughly 75% compared to unchanged values.

3) Residual albuminuria.

This is fascinating.


The curves of risk for a renal event at baseline and after six months based on the amount of albuminuria are virtually superimposable with lower levels associated with fewer events.

Interestingly when you subdivide the degree of albuminuria based on whether someone was on ARB or placebo and look at risk both at baseline and at six months you see that at six months for a given amount of albuminuria those on ARB fared no better than those on placebo.


The authors suggest that these findings taken together point towards albuminuria as a specific target for renoprotective therapy and that consideration should be given to further reducing albuminuria in patients on ARBs who continue to have high levels.

I love the idea that we can potentially do more for RENAAL style patients by driving albuminuria down as far as possible. To further lower proteinuria in a patient already on a ARB one could 1) use high dose ARB 2) add an ACEI 3) Add an aldosterone blocker 4) add a renin inhibitor or 5) add a nondihydropyridine CCB.

This is not without some controversy so with that in mind the ONTARGET trial will be next under the spotlight.