Article Albuminuria, Proteinuria, and Renal Disease Progression in Children with CKD Dana Y. Fuhrman, Michael F. Schneider, Katherine M. Dell, Tom D. Blydt-Hansen, Robert Mak, Jeffrey M. Saland, Susan L. Furth, Bradley A. Warady, Marva M. Moxey-Mims, and George J. Schwartz Abstract Background and objectives The role of albuminuria as an indicator of progression has not been investigated in Due to the number of children with CKD in the absence of diabetes. contributing authors, the affiliations are Design, setting, participants, &measurementsChildren wereenrolledfrom 49 centersof the CKD in Children study provided in the between January of 2005 and March of 2014. Cross-sectional multivariable linear regression (n=647) was used Supplemental to examine the relationship between urine protein-to-creatinine (UP/C [milligrams per milligram]) and Material. albumin-to-creatinine (ACR [milligrams per gram]) with eGFR (milliliters per minute per 1.73 m2). Parametric Correspondence: time-to-event analysis (n=751) was used to assess the association of UP/C, ACR, and urine nonalbumin-to- Dr.GeorgeJ.Schwartz, creatinine (Unon-alb/cr [milligrams per gram]) on the time to the composite endpoint of initiation of RRT or Department of Pediatrics, Division of 50% decline in eGFR. Pediatric Nephrology, University of Rochester Results The median follow-up time was 3.4 years and 202 individuals experienced the event. Participants with a Medical Center 601 UP/C$0.2 mg/mg and ACR$30 mg/g had a mean eGFR that was 16 ml/min per 1.73 m2 lower than those Elmwood Avenue, Box with a UP/C,0.2 mg/mg and ACR,30 mg/g. Individuals with ACR,30 mg/g, but a UP/C$0.2 mg/mg, had a 777, Rochester, NY 14642. Email: 2 , , mean eGFR that was 9.3 ml/min per 1.73 m lower than those with a UP/C 0.2 mg/mg and ACR 30 mg/g. george_schwartz@ When categories of ACR and Unon-alb/cr were created on the basis of clinically meaningful cutoff values of UP/C urmc.rochester.edu with the same sample sizes for comparison, the relative times (RTs) to the composite end-point were almost identical when comparing the middle (RT=0.31 for UP/C [0.2–2.0 mg/mg], RT=0.38 for ACR [56–1333 mg/g], RT=0.31 for Unon-alb/cr [118–715 mg/g]) and the highest (RT=0.08 for UP/C [.2.0 mg/mg], RT=0.09 for ACR [.1333 mg/g], RT=0.07 for Unon-alb/cr [.715 mg/g]) levels to the lowest levels. A similar trend was seen when categories were created on the basis of clinically meaningful cutoff values of ACR (,30, 30–300, .300 mg/g). Conclusions In children with CKD without diabetes, the utility of an initial UP/C, ACR, and Unon-alb/cr for characterizing progression is similar. Clin J Am Soc Nephrol 12: 912–920, 2017. doi: https://doi.org/10.2215/CJN.11971116 Introduction The 2012 Kidney Disease Improving Global Outcomes Proteinuria is a major prognostic indicator of renal guidelines for staging and predicting the progression of progressioninbothchildrenandadultswithCKD CKD designate a urine albumin-to-creatinine ratio (ACR) (1–4). The Chronic Kidney Disease in Children (CKiD) of ,30 mg/g as “normal-to-mildly increased,” 30– study reported that total urine protein-to-creatinine ratios 300 mg/g as “moderately increased,” and .300 mg/g (UP/C) .2.0 mg/mg in children with glomerular CKD as “severely increased.” (5) Traditionally, in studies of were associated with a 94% reduction in the time to adults with CKD, albuminuria, rather than overall either a 50% decline in eGFR or the initiation of RRT (1). proteinuria, has been utilized in studies of progres- Children with nonglomerular CKD and a UP/C.2.0 sion (2, 6–10). Although the association of normal or mg/mg had a 79% reduction in the time to this same mildly increased levels of albuminuria on worsening endpoint. Indeed, compared with hypoalbuminemia, renal function has been explored in the adult CKD elevated BP, dyslipidemia, and anemia, nephrotic range population, the association of smaller amounts of proteinuria was the strongest risk factor for renal pro- albuminuria (alternatively termed “microalbuminuria”) gression in children with CKD, regardless of glomerular and kidney disease progression in pediatric patients or nonglomerular cause (1). In 2009, the randomized, has largely been confined to studies of patients prospective The Effect of Strict Blood Pressure Control with diabetes mellitus (8, 11). Because of this and ACE Inhibition on the Progression of Chronic Renal difference in urine protein quantification methods Failure in Pediatric Patients (ESCAPE) trial in children in adult versus pediatric studies, we wanted to with CKD demonstrated that higher levels of proteinuria determine whether albuminuria, specifically, has partic- were associated with a more rapid decline in GFR (3). ular importance compared with general proteinuria as 912 Copyright © 2017 by the American Society of Nephrology www.cjasn.org Vol 12 June, 2017 Clin J Am Soc Nephrol 12: 912–920, June, 2017 Albuminuria in Children with CKD, Fuhrman et al. 913 Table 1. Characteristics at the index visit of the 751 CKiD participants Characteristics Median (Interquartile Range) or % (n) Age, yr 12.4 (8.6–15.7) Men 61 (457) White race 65 (491) Systolic or diastolic BP $95th percentilea 15 (108) Current ACE or ARB use 56 (417) eGFRb, ml/min per 1.73 m2 54.6 (39.5–71.8) Glomerular CKD cause 30 (228) Age-sex–specific body mass index $95th percentilec 17 (129) Urine protein-to-creatinine, mg/mg 0.32 (0.12–1.04) Urine albumin-to-creatinine, mg/g 112.0 (20.9–615.0) Urine nonalbumin-to-creatinine, mg/g 167.6 (75.0–400.7) Urine albumin-to-protein, mg/mg 0.44 (0.15–0.65) n, number of participants. aBP percentiles were determined using age/sex/height–specific values; missing for 33 participants. beGFR=0.4133(height [centimeters]/serum creatinine [milligrams per deciliter]). cBody mass index percentiles were determined using age/sex–specific values; missing for 12 participants. an indicator of renal progression in children without diabetes 49 nephrology centers across North America. The study mellitus. design and conduct were approved by an observational Evaluation for albuminuria is currently not part of the study-monitoring board appointed by the National In- routine care of children with CKD without diabetes. stitute of Diabetes and Digestive and Kidney Diseases and Likewise, investigating the amount of nonalbumin proteins by the internal review boards of each participating center. in the urine, whose increased presence indicates tubular Each participating family provided informed consent. The dysfunction, is not routinely done in the evaluation of demographic and clinical characteristics of the cohort as a pediatric patients with CKD (12–14). This study sought to: whole have been published elsewhere (15). Study partic- (1) quantify the cross-sectional relationship between both ipants were seen at annual follow-up visits after their initial UP/C and ACR with eGFR, (2) determine the cross- baseline visit which occurred between January of 2005 and sectional relationships between UP/C, ACR, and urine March of 2014. Beginning in June of 2008, urine albumin nonalbumin-to-creatinine (Unon-alb/cr), and (3)compare was added to the urine panel of tests as part of each annual the association of each of UP/C, ACR, and Unon-alb/cr visit. Of the 891 participants enrolled, 757 had at least one visit with time to RRT or .50% decline in eGFR. with ACR measured; the visit with the first ACR measure- ment was defined as the index visit. Our time-to-event analyses were restricted to the 751 participants who had Materials and Methods follow-up data after the index visit to determine time to first of Study Population .50% decline in eGFR or RRT. eGFR (milliliters per minute The CKiD study is a multicenter, prospective cohort per 1.73 m2) was calculated at each visit using: 0.4133(height study of children with mild-to-moderate CKD conducted at [centimeters]/serum creatinine [milligrams per deciliter]) (16). Table 2. Multivariablea linear regression analysis of index visit values of eGFR on urine protein-to-creatinine (milligrams per milligram) and urine albumin-to-creatinine (milligrams per gram), n=647 Mean eGFR (millilitre per minute per 1.73 m2) 95% Confidence Exposureb No. Relative to Interval Reference Urine protein-to-creatinine 170 0 (reference) ,0.2 and urine albumin-to-creatinine ,30 Urine protein-to-creatinine 86 23.1 28.1 to 1.9 ,0.2 and urine albumin-to-creatinine $30 Urine protein-to-creatinine 21 29.3 217.8 to 20.7 $0.2 and urine albumin-to-creatinine ,30 Urine protein-to-creatinine 370 216.0 219.7 to 212.4 $0.2 and urine albumin-to-creatinine $30 aAdjusted for age, sex, race, CKD cause, hypertension status, body mass index, and uric acid. bFor urine protein-to-creatinine the units are mg/mg; for urine albumin-to-creatinine the units are mg/g. 914 Clinical Journal of the American Society of Nephrology Figure 1. | Collinearity between the three methods to quantify proteinuria at the index study visit, n=751. Thedashedlineshownineachof the panels in Figure 1 is the line on which all of the data would fall if there were perfect agreement between the two variables. Protein Measures and also among those not reporting an angiotensin converting Participants provided a random urine collection on the enzyme (ACE) inhibitor or angiotensin receptor blocker morning of the study. Urine albumin was measured using an (ARB)attheindexvisit.Onthebasisofpreviousstudies immunoturbidimetric assay whereby anti-albumin antibodies showing significant associations with eGFR, the linear re- react with the urine sample to form antigen-antibody com- gression model was adjusted for: age, sex, race (white versus plexes.