Shengyuan Luo1,2, Josef Coresh1,2,3, Adrienne Tin1,2, Casey M Rebholz1,2, Teresa K Chen4, Salim S Hayek5, Melissa Tracy6, Michael S Lipkowitz7, Lawrence J Appel1,2,3, Andrew S Levey8, Lesley A Inker8, Jochen Reiser9, Morgan Erika Grams10,2,4. 1. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. 2. Welch Center for Prevention, Epidemiology, and Clinical Research. 3. Division of General Internal Medicine, Department of Medicine, and. 4. Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland. 5. Division of Cardiology, Emory University, Atlanta, Georgia. 6. Division of Cardiology and. 7. Division of Nephrology, Georgetown University, Washington, DC; and. 8. Division of Nephrology, Tufts Medical Center, Boston, Massachusetts. 9. Department of Medicine, Rush University Medical Center, Chicago, Illinois. 10. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; mgrams2@jhmi.edu.
Abstract
BACKGROUND AND OBJECTIVES: Black Americans with and without APOL1 kidney disease risk variants face high risk of ESKD. Soluble urokinase-type plasminogen activator receptor (suPAR), a circulating signaling protein and marker of immune activation, constitutes a promising biomarker of CKD-associated risks. We aimed to quantify the associations between serum suPAR concentration and adverse outcomes in Black Americans with and without APOL1 kidney disease risk variants, over and above iodine-125 iothalamate measured GFR and proteinuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using data from the African-American Study of Kidney Disease and Hypertension, a multicenter clinical trial followed by a cohort phase with a median total follow-up of 9.7 years (interquartile range, 6.5-10.9 years), we examined the associations of suPAR with CKD progression (defined as doubling of serum creatinine or ESKD), ESKD, worsening proteinuria (defined as pre-ESKD doubling of 24-hour urine protein-to-creatinine ratio to ≥220 mg/g), and all-cause death. RESULTS: At baseline, the median suPAR was 4462 pg/ml, mean measured GFR was 46 ml/min per 1.73 m2, and median 24-hour urine protein-to-creatinine ratio was 80 mg/g. After controlling for baseline demographics, randomization arm, GFR, proteinuria, APOL1 risk status, and clinical risk factors, there was a 1.26-times higher risk for CKD progression per SD higher baseline log-transformed suPAR (hazard ratio [HR], 1.26; 95% confidence interval [95% CI], 1.11 to 1.43; P<0.001). Higher suPAR was also independently associated with risk of ESKD (HR, 1.36; 95% CI, 1.17 to 1.58; P<0.001) and death (HR, 1.25; 95% CI, 1.08 to 1.45; P=0.003). suPAR was only associated with worsening proteinuria in patients with two APOLI risk alleles (HR, 1.46; 95% CI, 1.08 to 1.99; P=0.02). CONCLUSIONS: Higher suPAR was associated with various adverse outcomes in Black Americans with CKD, with and without APOL1 kidney disease risk variants, independently of proteinuria and GFR.
BACKGROUND AND OBJECTIVES: Black Americans with and without APOL1kidney disease risk variants face high risk of ESKD. Soluble urokinase-type plasminogen activator receptor (suPAR), a circulating signaling protein and marker of immune activation, constitutes a promising biomarker of CKD-associated risks. We aimed to quantify the associations between serum suPAR concentration and adverse outcomes in Black Americans with and without APOL1kidney disease risk variants, over and above iodine-125 iothalamate measured GFR and proteinuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using data from the African-American Study of Kidney Disease and Hypertension, a multicenter clinical trial followed by a cohort phase with a median total follow-up of 9.7 years (interquartile range, 6.5-10.9 years), we examined the associations of suPAR with CKD progression (defined as doubling of serum creatinine or ESKD), ESKD, worsening proteinuria (defined as pre-ESKD doubling of 24-hour urine protein-to-creatinine ratio to ≥220 mg/g), and all-cause death. RESULTS: At baseline, the median suPAR was 4462 pg/ml, mean measured GFR was 46 ml/min per 1.73 m2, and median 24-hour urine protein-to-creatinine ratio was 80 mg/g. After controlling for baseline demographics, randomization arm, GFR, proteinuria, APOL1 risk status, and clinical risk factors, there was a 1.26-times higher risk for CKD progression per SD higher baseline log-transformed suPAR (hazard ratio [HR], 1.26; 95% confidence interval [95% CI], 1.11 to 1.43; P<0.001). Higher suPAR was also independently associated with risk of ESKD (HR, 1.36; 95% CI, 1.17 to 1.58; P<0.001) and death (HR, 1.25; 95% CI, 1.08 to 1.45; P=0.003). suPAR was only associated with worsening proteinuria in patients with two APOLI risk alleles (HR, 1.46; 95% CI, 1.08 to 1.99; P=0.02). CONCLUSIONS: Higher suPAR was associated with various adverse outcomes in Black Americans with CKD, with and without APOL1kidney disease risk variants, independently of proteinuria and GFR.
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