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. 2018 Jul 6;13(7):1013-1021.
doi: 10.2215/CJN.13631217. Epub 2018 Jun 14.

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 , Morgan Erika Grams  1   2   4
Affiliations

Soluble Urokinase-Type Plasminogen Activator Receptor in Black Americans with CKD

Shengyuan Luo et al. Clin J Am Soc Nephrol. .

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.

Keywords: African Americans; Alleles; Biomarkers; Black Americans; Demography; Follow-Up Studies; Humans; Iothalamic Acid; Kidney Failure, Chronic; Random Allocation; Receptors, Urokinase Plasminogen Activator; Renal Insufficiency, Chronic; United States; chronic kidney disease; creatinine; glomerular filtration rate; hypertension; kidney; proteinuria; risk factors.

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Figures

None
Graphical abstract
Figure 1.
Figure 1.
The unadjusted cumulative incidences of CKD progression, ESKD, worsening proteinuria, and mortality were higher with higher suPAR quartiles in the African-American Study of Kidney Disease and Hypertension. (A) Levels of baseline serum suPAR concentration and cumulative incidence of CKD progression. (B) Levels of baseline serum suPAR concentration and cumulative incidence of ESKD. (C) Levels of baseline serum suPAR concentration and cumulative incidence of worsening proteinuria. (D) Levels of baseline serum suPAR concentration and cumulative incidence of all-cause mortality. CKD progression was defined as doubling of serum creatinine from baseline or ESKD (requiring dialysis or kidney transplantation). Worsening proteinuria was defined as pre-ESKD doubling of 24-hour UPCR to ≥220 mg/g.
Figure 2.
Figure 2.
The adjusted HRs for CKD progression, ESKD, and mortality increased log-linearly with higher levels of baseline suPAR in the African-American Study of Kidney Disease and Hypertension. Solid lines indicate adjusted HRs. Shaded areas indicate 95% CIs. Dashed lines indicate upper and lower limits of 95% CIs. (A) Adjusted HRs for CKD progression plotted against baseline suPAR concentration on a log-scale. (B) Adjusted HRs for ESKD plotted against baseline suPAR concentration on a log-scale. (C) Adjusted HRs for worsening proteinuria plotted against baseline suPAR concentration on a log-scale. (D) Adjusted HRs for mortality plotted against baseline suPAR concentration on a log-scale. HRs were adjusted for demographics (age and sex), AASK trial arm (BP control goal and trial medication), kidney measures (UPCR and measured GFR), and clinical risk factors (history of heart disease, history of smoking, CRP, and APOL1 risk status) at baseline. CKD progression was defined as doubling of serum creatinine from baseline or ESKD (requiring dialysis or kidney transplantation). Worsening proteinuria was defined as pre-ESKD doubling of 24-hour UPCR to ≥220 mg/g.
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