Is albuminuria an appropriate therapeutic target in CKD?
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Yes, the greater the reduction in albuminuria, the better the long-term outcome.
One of the first studies I was involved with when I started in diabetes and kidney disease was looking at the predictors of a good outcome when you start therapy. What we use as endpoints in trials is stopping of creatinine decline and end-stage kidney disease. It takes a while to reach these endpoints. It would be ideal, before a patient is at that late stage of disease, to have an indication of whether you are on the right track.
We use albuminuria to diagnose kidney disease, to find those who should be initiating treatment. Then the question is, can we use albuminuria or other markers to determine if we are on the right track after starting therapy?
Data from a small study demonstrated that out of many markers — changes in blood pressure, change in estimated glomerular filtration rate, change in albuminuria — the best predictor of outcomes was drop in albuminuria. The bigger the reduction in albuminuria in 3 to 6 months, the better your long-term outcomes, which in that study was change in kidney function over 3 years. That concept was confirmed in larger studies.
The RENAAL study, testing the effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy, showed those who had a large reduction in albuminuria did better in terms of progression of chronic kidney disease or cardiovascular disease, and had less mortality.
Meta-analyses of trials show albuminuria has been a fantastic predictor of kidney and CV outcomes.
The data suggest that albuminuria is first, a diagnostic test, and secondly, it is a target in the sense that you should get it down. If albuminuria does not go down, you know something else needs to be done. Either intensify therapy or find a new therapy.
Some have argued that albuminuria may not be an appropriate target for therapies that work in a different, non-hemodynamic way, perhaps with anti-inflammatory effects. Perhaps there you would not see a reduction in albuminuria, or it would take longer to observe a change. However, so far, it has worked with all the therapies that have been successful. Data from the finerenone trial presented at Kidney Week this year also show the importance of lowering albuminuria.
With the caveat that reduction in albuminuria may not be the ideal target for every therapy to come, it works so far in all the successful therapies for CKD.
Peter Rossing, MD, is head of diabetes complications research at the Steno Diabetes Center in Gentofte, Denmark.
Albuminuria is an important risk factor, but is not a surrogate endpoint.
A variety of new drugs are changing the landscape of CKD, including SGLT2 inhibitors and the nonsteroidal mineralocorticoid receptor antagonist finerenone. There is a lot that we as clinicians can do — earlier in the course of disease — to help our patients from going down the slippery slope of worsening CKD.
A recent commentary published in November in The Lancet Diabetes & Endocrinology states the field is moving toward using eGFR slope, and not albuminuria, as a potential outcome for clinical trials, especially for interventions at earlier stages of CKD, when occurrence of clinical kidney disease events as endpoints is less feasible. There are several reasons for this.
Although guidelines call for annual monitoring of urinary albumin in type 2 diabetes, it is just not done routinely outside of clinical trials. Endocrinologists do it, but most people with type 2 diabetes are not cared for by endocrinologists. Consequently, many people with CKD are undiagnosed — something we want to change.
Albuminuria is a widely used biomarker for CKD prognosis and response to therapeutic interventions; however, there is large intra-individual day-to-day variability, up to 40%. That renders albuminuria less useful as an outcome than eGFR.
As an example, an analysis using data from the Japan Chronic Kidney Disease Database assessed whether the presence or absence of proteinuria and the rate of eGFR decline prior to SGLT2 inhibitor initiation vs. other glucose-lowering drugs modified treatment efficacy among more than 2,000 patients with type 2 diabetes and CKD. The findings demonstrated that, in routine clinical practice, people with type 2 diabetes prescribed SGLT2 inhibitors had significantly better kidney outcomes than those who received other glucose-lowering drugs, irrespective of the presence or absence of proteinuria. In other words, protein may or may not be present, but our patients still fare well with the use of SGLT2 inhibitors. A negative urinary microalbumin does not imply that eGFR is necessarily great. I am not dismissing the importance of urinary microalbumin. It is important, but it is not superseding the importance of frequently monitoring eGFR.
- References:
- Nagasu H, et al. Diabetes Care. 2021;doi:10.2337/dc21-1081.
- Tuttle KR. Lancet Diabetes Endocrinol. 2021;doi:10.1016/S2213-8587(21)00265-5.
Helena W. Rodbard, MD, FACP, MACE, is medical director of Endocrine and Metabolic Consultants in Rockville, Maryland, and a past president of the American Association of Clinical Endocrinology and the American College of Endocrinology.
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