Reducing End-Stage Kidney Disease Risk More Efficiently

Use of albuminuria level changes as the endpoint to determine need to reduce albumin-to-creatinine ratio.

Rates of fatal chronic kidney disease has increased in the past decade. Clinical research on the kidney is lacking since it has not been the priority, and, as a result, there is a lot of room for chronic kidney disease therapy to advance. Patients may not have been receiving adequate treatment, and many deaths can still be prevented through further research and discoveries.

It has been difficult to conduct randomized clinical trials in phase 3 of the trials because the outcomes would involve risky situations such as end-stage kidney disease. Substitute endpoints have been used to test drug efficacy, such as a decrease

in estimated glomerular filtration rate (eGFR), and an early change in urine albumin-to-creatinine ratio (ACR). The early change in albuminuria was used as the surrogate endpoint in this study, which consisted of two analyses (one with observational data, the other with randomized controlled data of drugs for albuminuria).

In the observational data, even at beginning stages of chronic kidney disease, “for individuals with a baseline ACR of 300 mg/g or greater, a 30% decrease in ACR over 2 years was estimated to confer a more than 1% absolute reduction in 10-year risk of end-stage kidney disease,” researchers said. In the randomized, controlled trial data, “each 30% decrease in geometric mean albuminuria by treatment relative to control was associated with an average 27% lower hazard for the composite clinical endpoint of treated end-stage kidney disease, eGFR of less than 15 mL/min per 1.73 m², or doubling of serum creatinine; the association was strengthened in analyses restricted to patients with baseline albuminuria greater than 30 mg/g.” These analyses demonstrate that if a patient has a high baseline albuminuria, there are statistically significant results to encourage reduction in this patient’s albumin-to-creatinine ratio in order to lessen the risk of end-stage kidney disease.

This study also encourages further use of albuminuria to study changes in outcomes in future research, but more studies are needed to identify specific baseline albuminuria levels for inclusion guidelines for participants, as well as a specific albuminuria level threshold for the endpoint. But at least this study has shown us that the amount of change in the albuminuria endpoint to convey a significant effect from clinical treatment would be about a 30% decrease.

There are additional challenges to be considered in future research on chronic kidney disease. Sex role is one of them. There are differences in the risk of the disease between men and women, women being more at risk. Chronic kidney disease is “more common in women than in men, especially for disease category G3 (GFR 45–59 mL/min per 1·73 m²),” even though, in many countries, men are more likely than women to receive kidney replacement therapy. Furthermore, according to the study, “in addition to slower slopes of progression of chronic kidney disease, women might have less access to kidney replacement therapy in some countries, or be more likely to choose conservative treatment.” Due to this, there is bias in the clinical requirement for kidney replacement therapy outcome, based on the individual’s sex. Potential baseline differences between women and men were also demonstrated in previous studies. Therefore, the effect of sex on the correlation between albuminuria level changes and outcomes should be better analyzed.

Practice Pearls:

• Therapy for chronic kidney disease has not been studied to its full potential and resulting deaths can still be prevented.
• This study found early change in albuminuria to be an agreeable endpoint in analyzing treatment for chronic kidney disease.  
• Results showed a significant effect from chronic kidney disease therapy to be a decreased albuminuria level of 30%.

References:

Dolores Sanchez-Niño, Maria; Fernandez-Fernandez, Beatriz; Ortiz, Alberto. “Working towards novel albuminuria endpoints in chronic kidney disease.” The Lancet Diabetes and Endocrinology. 2019. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(18)30352-8/fulltext. 30 January 2019.

Annahita Forghan, Pharm.D. Candidate 2019, LECOM College of Pharmacy