Immunoglobulin A nephropathy (IgA nephropathy or IgAN) is the third most common type of chronic kidney disease (CKD). It progresses to end-stage kidney disease (ESKD) in one of four patients within 20 years of diagnosis, yet approved therapies for IgAN are lacking.

To remedy the scarcity of therapies, researchers looked at whether or not proteinuria, the presence of high levels of protein in the urine, could be a surrogate endpoint in studies to understand the clinical benefits of future therapies.* 

Proteinuria as a surrogate endpoint

A surrogate endpoint predicts what a clinical benefit might be, whereas a biomarker is “an indicator of normal biologic processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions,” as stated in the study.

Researchers sought to find out whether proteinuria could be used as a reliable predictor of proteinuria on kidney outcomes and a treatment’s effect on long-term kidney outcomes in IgAN patients. Sustained proteinuria and a decrease in estimated glomerular filtration rate (eGFR) are considered risk factors for the progression of IgAN to ESKD. 

According to the researchers, “In IgAN, sustained proteinuria, typically greater than 1 g/day, has been strongly associated with poorer kidney outcomes.” Patients with decreased GFR at diagnosis of IgAN (an eGFR of less than 60 ml/min per 1.73 m2) are at higher risk of progression to ESKD.

What they found

Previous data indicates a consistent and robust connection between the level and duration of proteinuria and loss of kidney function in patients with IgAN. 

Data from 13 randomized controlled trials also shows a connection between treatment effects on proteinuria and treatment effects on the time it takes to reach a doubling of serum creatinine level, ESKD, or death. 

The populations studied had the following characteristics:

• The mean of proteinuria at baseline was 1.8 g/day, with two-thirds of patients included in these trials having a value in the range of 1.0 to 3.2 g/day.
• The mean estimated glomerular filtration rate (eGFR) baseline was 63 ml/min. per m2 with two-thirds of patients having a value in the range 47 to 86 L/min. per m2.
• The age range across studies was 31.6±11.5–46.4±13.4 years. (No study included children over the age of 14 years old.)

This data supports the use of proteinuria reduction as a surrogate endpoint for a treatment’s effect on the loss of kidney function and the progression to ESKD in future trials that enroll a similar population. The clinical benefit of therapies approved under this program should be verified in a confirmatory trial.

*Thompson, A., Carroll, K., Inker, L.A., Floege, J., et al. (2019, Mar. 7). Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy. Clinical Journal of the American Society of Nephrology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419287/