Primary Nephrotic Syndrome and Risks of ESKD, Cardiovascular Events, and Death: The Kaiser Permanente Nephrotic Syndrome Study
Authors: Go Alan S. , Tan Thida C. , Chertow Glenn M. , Ordonez Juan D. , Fan Dongjie , Law David , Yankulin Leonid , Wojcicki Janet M. , Zheng Sijie , Chen Kenneth K. , Khoshniat-Rad Farzien , Yang Jingrong , Parikh Rishi V. 
Published: June 2021

Significance Statement
Little population-based data exist about adults with primary nephrotic syndrome and risks of kidney, cardiovascular, and mortality outcomes. In a cohort of 907 adults with nephrologist-confirmed primary nephrotic syndrome attributed to minimal change disease, FSGS, and membranous nephropathy, adjusted rates of ESKD, acute coronary syndrome, heart failure, ischemic stroke, venous thromboembolism, and death were significantly higher than in 89,593 matched adults with no diabetes or known proteinuria. Adults with FSGS had the highest rate of ESKD, followed by adults with membranous nephropathy and adults with minimal change disease. Additional research is needed to understand the mechanisms underlying these excess risks, and population-level identification strategies on the basis of electronic health records should be implemented to identify and optimize personalized care of patients with primary nephrotic syndrome.

Background
Little population-based data exist about adults with primary nephrotic syndrome.

Methods
To evaluate kidney, cardiovascular, and mortality outcomes in adults with primary nephrotic syndrome, we identified adults within an integrated health care delivery system (Kaiser Permanente Northern California) with nephrotic-range proteinuria or diagnosed nephrotic syndrome between 1996 and 2012. Nephrologists reviewed medical records for clinical presentation, laboratory findings, and biopsy results to confirm primary nephrotic syndrome and assigned etiology. We identified a 1:100 time-matched cohort of adults without diabetes, diagnosed nephrotic syndrome, or proteinuria as controls to compare rates of ESKD, cardiovascular outcomes, and death through 2014, using multivariable Cox regression.

Results
We confirmed 907 patients with primary nephrotic syndrome (655 definite and 252 presumed patients with FSGS [40%], membranous nephropathy [40%], and minimal change disease [20%]). Mean age was 49 years; 43% were women. Adults with primary nephrotic syndrome had higher adjusted rates of ESKD (adjusted hazard ratio [aHR], 19.63; 95% confidence interval [95% CI], 12.76 to 30.20), acute coronary syndrome (aHR, 2.58; 95% CI, 1.89 to 3.52), heart failure (aHR, 3.01; 95% CI, 2.16 to 4.19), ischemic stroke (aHR, 1.80; 95% CI, 1.06 to 3.05), venous thromboembolism (aHR, 2.56; 95% CI, 1.35 to 4.85), and death (aHR, 1.34; 95% CI, 1.09 to 1.64) versus controls. Excess ESKD risk was significantly higher for FSGS and membranous nephropathy than for presumed minimal change disease. The three etiologies of primary nephrotic syndrome did not differ significantly in terms of cardiovascular outcomes and death.

Conclusions
Adults with primary nephrotic syndrome experience higher adjusted rates of ESKD, cardiovascular outcomes, and death, with significant variation by underlying etiology in the risk for developing ESKD.