Soluble Urokinase-Type Plasminogen Activator Receptor in Black Americans with CKD
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Article Soluble Urokinase-Type Plasminogen Activator Receptor in Black Americans with CKD Shengyuan Luo ,1,2 Josef Coresh,1,2,3 Adrienne Tin,1,2 Casey M. Rebholz,1,2 Teresa K. Chen,4 Salim S. Hayek ,5 Melissa Tracy,6 Michael S. Lipkowitz,7 Lawrence J. Appel,1,2,3 Andrew S. Levey,8 Lesley A. Inker,8 Jochen Reiser,9 and Morgan Erika Grams1,2,4 Abstract 1 Background and objectives Black Americans with and without APOL1 kidney disease risk variants face high risk Department of Epidemiology, Johns of ESKD. Soluble urokinase-type plasminogen activator receptor (suPAR), a circulating signaling protein and Hopkins Bloomberg marker of immune activation, constitutes a promising biomarker of CKD-associated risks. We aimed to quantify School of Public the associations between serum suPAR concentration and adverse outcomes in Black Americans with and without Health, Baltimore, 2 APOL1 kidney disease risk variants, over and above iodine-125 iothalamate measured GFR and proteinuria. Maryland; Welch Center for Prevention, Epidemiology, and Design, setting, participants, & measurements Using data from the African-American Study of Kidney Disease Clinical Research, and Hypertension, a multicenter clinical trial followed by a cohort phase with a median total follow-up of 9.7 years 3Division of General (interquartile range, 6.5–10.9 years), we examined the associations of suPAR with CKD progression (defined Internal Medicine, as doubling of serum creatinine or ESKD), ESKD, worsening proteinuria (defined as pre-ESKD doubling of Department of $ Medicine, and 24-hour urine protein-to-creatinine ratio to 220 mg/g), and all-cause death. 4Division of Nephrology, Results At baseline, the median suPAR was 4462 pg/ml, mean measured GFR was 46 ml/min per 1.73 m2,and Department of median 24-hour urine protein-to-creatinine ratio was 80 mg/g. After controlling for baseline demographics, Medicine, Johns Hopkins University, randomization arm, GFR, proteinuria, APOL1 risk status, and clinical risk factors, there was a 1.26-times higher Baltimore, Maryland; risk for CKD progression per SD higher baseline log-transformed suPAR (hazard ratio [HR], 1.26; 95% confidence 5Division of interval [95% CI], 1.11 to 1.43; P,0.001). Higher suPAR was also independently associated with risk of ESKD (HR, Cardiology, Emory , University, Atlanta, 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 6 with worsening proteinuria in patients with two APOLI risk alleles (HR, 1.46; 95% CI, 1.08 to 1.99; P=0.02). Georgia; Division of Cardiology and 9Department of Conclusions Higher suPAR was associated with various adverse outcomes in Black Americans with CKD, with Medicine, Rush and without APOL1 kidney disease risk variants, independently of proteinuria and GFR. University Medical Center, Chicago, Clin J Am Soc Nephrol 13: 1013–1021, 2018. doi: https://doi.org/10.2215/CJN.13631217 Illinois; 7Division of Nephrology, Georgetown University, Introduction Observational studies in primarily European popula- Washington, DC; More than 4% of deaths worldwide are attributable to tions suggest that suPAR may be associated with and 8Division of CKD (1). Despite the extensive resources devoted to incident CKD (7–10). There is less evidence of asso- Nephrology, Tufts CKD treatment, the incidence of ESKD remains high, ciations between suPAR and adverse outcomes in Medical Center, Boston, Massachusetts particularly among Black Americans. Higher ESKD Black Americans with CKD. We recently found faster risk in Black Americans is explained in part by the suPAR-associated eGFR decline in Black Americans Correspondence: Dr. prevalence of a high-risk genotype (two APOL1 risk with two APOL1 risk alleles compared with zero or Morgan E. Grams, alleles), present in 13% of Black Americans; however, one risk allele in two populations (11). However, Welch Center for the majority of ESKD cases occur in people with the evidence of associations of suPAR with eGFR decline Prevention, low-risk genotype (2,3). Novel biomarkers and treat- in Black Americans with the low-risk genotype was Epidemiology, and Clinical Research, ment targets are needed in order to ameliorate adverse mixed, and the associations between suPAR and Room 2-638, 2024 outcomes in CKD among individuals with and with- clinical outcomes, independent of measured GFR East Monument Street, out APOL1 risk alleles. and proteinuria, were not explored. Baltimore, MD 21205. Soluble urokinase-type plasminogen activator re- Using a baseline measurement of suPAR in the Email: mgrams2@ ceptor (suPAR), a cell membrane glycosylphosphati- African-American Study of Kidney Disease and Hy- jhmi.edu dylinositol-anchored protein expressed in many cell pertension (AASK), a clinical trial of Black Americans types (e.g., podocytes and immune, endothelial, and with hypertension-attributed kidney disease, mea- bone marrow cells), is released into the circulation sured GFR, per-protocol proteinuria assessments, during immune activation. Circulating suPAR par- and APOL1 genotyping, we characterized the associ- ticipates in cell adhesion, migration, and survival, ations between suPAR and CKD progression, ESKD, and may mediate podocyte injury in FSGS (4–6). worsening proteinuria, and all-cause death. www.cjasn.org Vol 13 July, 2018 Copyright © 2018 by the American Society of Nephrology 1013 1014 Clinical Journal of the American Society of Nephrology Materials and Methods analyses. By suPAR quartile, continuous variables were Study Design summarized using means with SD (for symmetrically In brief, AASK was a three3two factorial design, distributed variables), or medians and interquartile ranges randomized, controlled trial evaluating the effects of three (for variables with skewed distributions). Categorical antihypertensives (ramipril, metoprolol, and amlodipine) variables were summarized using proportions. Baseline and two BP control goals (mean arterial pressure #92 mm characteristics were compared using tests for linear trends. Hg versus 102–107 mm Hg) in slowing CKD progression Cumulative incidences of CKD progression and ESKD (12,13). Participants were self-identified Black Americans were plotted using competing risks regression accounting (18–70 years of age) with hypertension-attributed CKD for death as the competing event, and for worsening (measured GFR between 20 and 65 ml/min per 1.73 m2). proteinuria, accounting for ESKD and death as competing After completion of the trial (in April of 2002), 691 events. Kaplan–Meier functions were used to plot cumu- participants without ESKD entered the cohort phase (14). lative mortality. Cox proportional hazards regression was Participants were censored at loss to follow-up or the end used to assess the associations of baseline suPAR (log- of study (in June of 2007). Informed consent was obtained transformed and scaled to 1 SD) with outcomes. Multivari- from all participants. The study protocol was approved by able models included baseline demographics (age and sex), the institutional review boards at Johns Hopkins Univer- trial arms (BP control goal and trial medication), baseline sity and all other participating institutions. kidney measures (measured GFR and proteinuria), CRP, APOL1 risk status (modeled as a three-category variable: zero or one risk variant, two risk variants, and not Measurement of Exposure Blood samples were taken at enrollment and stored at genotyped), history of heart disease, and history of smok- 280°C. Serum suPAR concentrations were measured in 955 ing. The assumption of a log-linear relationship between participants with available samples, using an ELISA suPAR and outcomes was tested by modeling suPAR using fi (suPARnostic kit; ViroGates, Copenhagen, Denmark), in cubic splines, and comparing model t with the original 2017. In a blind duplicate study (n=21), the mean coefficient model using Akaike information criterion. Interactions of variation was 3.9% (median, 2.3%), and the correlation between kidney function and suPAR on outcomes were (r) was 0.97. assessed by including an interaction term of baseline GFR and suPAR in the regression models, with Wald test for statistical significance. To assess consistency by APOL1 risk Outcomes, Kidney Function Measures, and Risk Factors status, analyses were repeated with an interaction term by fi The primary outcome was CKD progression, de ned APOL1 risk status (zero or one risk allele versus two risk as doubling of serum creatinine from baseline or ESKD alleles versus not genotyped). The ability of suPAR to (requiring dialysis or kidney transplantation). Secondary improve risk discrimination when added to prediction outcomes included incident ESKD, worsening proteinuria models was assessed using Harrell C-statistic. To assess the (pre-ESKD doubling of 24-hour urine protein-to-creatinine robustness of results, the associations of baseline suPAR $ ratio [UPCR] to 220 mg/g), and all-cause mortality. with CKD progression, worsening proteinuria, and ESKD Baseline GFR was measured by urinary clearance of iodine- were tested using multivariable competing risks regression 125 iothalamate. Serum creatinine was collected every 6 as sensitivity analyses. A two-sided a value of 0.05 was months and measured with an autoanalyzer (AASK Cen- chosen as the cut-off for statistical significance. All statis- tral Biochemistry Laboratory, Cleveland Clinic, Cleveland, tical analyses were performed using Stata 14.0 (StataCorp, OH), 24-hour urine creatinine and protein were measured College Station, TX). yearly using the modified