Fluctuations in Albumin May Forecast Progression of Kidney Disease

A decrease in urinary albumin appears effective as a surrogate biomarker for chronic kidney disease, based on results of meta-analysi, with; implications for research and clinical practice

With Jamie P. Dwyer, MD, and George Bakris, MD

acceptance that a change in albuminuria has strong biological plausibility as a surrogate marker for the progression of chronic kidney disease (CDK). However, empirical evidence to support the validity of this relationship has been lacking.

From this meta-analysis,1 experts with the Chronic Kidney Disease Epidemiology Collaboration concluded that there was a more definitive effect from fluctuations in albuminuria acting as a surrogate endpoint in the progression of CKD. This variability was particularly evident in patients with high baseline albuminuria, said Jamie P. Dwyer, MD, professor of medicine and director of the Nephrology Trials Center at Vanderbilt University Medical Center in Nashville, Tennessee, who led the research.

Renal disease can be assessed with a urinary analysis.

Enhanced Certainty in Renal Disease Endpoint Promises Better Management 

Of note, one of the major challenges in developing therapies for chronic kidney disease has been the limitation of randomized controlled trials, which traditionally have relied on the composite clinical endpoint of end stage kidney disease (ie, estimated glomerular filtration rate (eGFR) of less than 15mL/min per 1.73 m2) and doubling of serum creatine concentrations (equivalent to a 57% decrease in eGFR). The biggest problem is in obtaining a sufficient number of eligible patients who present with a limiting factor restricted to those at end-stage CKD or with a rapid decrease in their GFR.

The major finding, Dr. Dwyer, MD, said, has been that ''there is a good association between albuminuria reduction of a sufficiently large amount (here at least 30%)" and a prediction that the intervention will slow renal disease progression. However, there was one issue of note, he told EndocrineWeb: "This caveat is extremely important though, in that the interventions implemented in our study showed that an albuminuria reduction was along the pathway of protection against CKD progression. So it is still conceivable that a drug or intervention would not reduce proteinuria but could still protect against CKD progression."

For this meta-analysis,1 the team pulled relevant clinical trials listed in PubMed from 1946 through December 15, 2016. They used research terms such as CKD, albuminuria, renal disease, and other pertinent disease-specific terminology. The studies had quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up as well as information on the incidence of end stage renal disease. The researchers requested individual patient data from the authors of eligible studies.

The researchers estimated a treatment effect of significance based on a calculated six-month change in albuminuria and a composite clinical endpoint of treated end stage kidney disease, estimated glomerular filtration rate of less than 15mLmin per 1.73m2, or doubling of serum creatinine. They used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects of albuminuria to those of the identified clinical endpoint across the accepted studies, and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the clinical effects on albuminuria.1

Over all, the studies reflected 29,976 patients, of which 71% has been diagnosed with diabetes. Over a median follow up of 3.4 years, 13% of these patients (n=3,935) reached the composite clinical endpoint.1 Across all studies, for every 30% decrease in geometric mean albuminuria attributed to the treatment relative to the control was linked with an average 27% lower hazard risk for the clinical endpoint (95% Bayesian credible interval 5-45%, median 0.47, 95% BCI 0.02-0.96).

When the researchers looked only at the patients with baseline albuminuria of more than 30 mg/g, the association was strengthened,1 said Dr. Dwyer.

The bottom line for CKD trials was that treatments that decreased the mean albuminuria by 30% relative to the control provided an average HR for the clinical endpoint of 0.68, and 95% of sufficiently large studies would have HRs between 0.47 and 0.95.

Prospects for More Clinically Certain Biomarker in Research for Chronic Kidney Disease

The findings may allow for different designs of research trials in the patient population in the future, Dr. Dwyer said.  From his perspective: "In the broader context of designing trials for CKD progression intervention, trials have ben disappointing, and the disappointment stems in part from the costs of doing CKD progression trials." He noted that they are expensive and lengthy and "working to find earlier endpoints in the progression of kidney disease is a noble goal."

The analysis will need to be reviewed by health authorities such as the Food and Drug Administration (FDA) and the European Medicines Agency ''to see what kind of study designs are feasible using the information from our trial analysis," Dr. Dwyer said. The findings based on this systematic review of the literature strengthen the data with regard to a decrease in urinary albumin of 30% as a surrogate endpoint in drug trials was also presented to the FDA

In the meantime, Dr. Dwyer expects that initially this endpoint will be considered on a ''trial to trial" situation, as experts evaluate the performance of future studies.

This meta-analysis was aimed at refining the design of clinical trials, there are some practical take-home points for clinicians, said George Bakris, MD, professor of medicine and director of the American Heart Association Hypertension Center at the University of Chicago Medicine. He reviewed the study findings for EndocrineWeb.Previously, he  said, there have been  several studies supporting similar results.2

Even so, this review of the literature has many strengths to support moving forward in improving the management of this challenging condition, said Dr. Bakris. It’s extremely insightful that the authors, ''pulled together all of the trials that looked not only at the change in kidney function but also at those who required dialysis."

He also found it beneficial that the investigators looked at the progression of renal disease over the course of years, another strength noted about their findings.1  In addition, ”they went beyond the usual focus of a meta-analysis, by examining patient outcomes from the trials as well as looking at them 'fresh,' using the individual meta-analysis approach,” he said. “That is what made it possible to confirm the finding of a 30% change in albumin as a significant turning point.”

Clinical Takeaway Confirms Role of Albuminuria in Assessing Renal Status

While Dr. Dwyer did not think that the findings would change clinical practice significantly, Dr. Bakris was more optimistic. He believed that we now have the benefit of the amassed data that all appear to be pointing in the same direction, which included multiple events and a long follow-up.  As such, Dr. Bakris said, the results should trigger immediate action among physicians who have not been measuring albumin and tracking it before now.

''The majority of physicians in primary care, general practice, and internal medicine are not measuring albumin in people with diabetes," Dr. Bakris said,  while endocrinologists definitely have been doing so." Patients with a diagnosis of hypertension and kidney disease and/or diabetes should be checked at least once annually for the presence of albuminuria.3 In instances in which serum albumin is above 200 mg/day, blood pressure management strategies should be aimed to reduce albuminuria.

"This paper lends support to the recommendation that a reduction of 30% or more in albumin that is sustained for a period of 2 years translated into dramatically slowed CDK progression,'' Dr. Bakris said. " So, if you don't measure it, how could you know what is going on?"

Following the patient, and tracking the albumin is important in any patient with diagnosed kidney disease to assess whether it is increasing or decreasing over time, Dr. Bakris said, "If you see a 30% decline, you can be confident that it is going in the right direction, and the management strategy in place is effective."

The conclusion reached by the researchers:1 "Future studies are warranted to determine how a change in albuminuria can be best applied in designs for clinical trials of progression of chronic kidney disease while protecting against the risk of a false conclusion of clinical benefit."

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