Article

Albuminuria, , 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 as an indicator of progression has not been investigated in Due to the number of children with CKD in the absence of . 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 -to- (UP/C [milligrams per milligram]) and Material. -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 , 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 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 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 , 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 “”) 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]/ 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 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, 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. After agglutination, the antigen-antibody complexes nonwhite), CKD cause (glomerular versus nonglomerular), were measured turbidimetrically by quantifying the loss of hypertension status (systolic or diastolic BP $age-sex-height– intensity of a light beam placed through the solution. The specific 95th percentile, versus systolic and diastolic BP ,age- quantity of albumin (milligrams) was then divided by the sex-height–specific 95th percentile), age-sex–specific body quantity of creatinine (grams) in the urine in order to obtain mass index ($95th percentile versus ,95th percentile), and the ratio, ACR. The total urine protein content of the urine uric acid values (1, 20–22). Pearson correlation coefficients was also determined by a turbidimetric method. The were used to quantify the strength of the cross-sectional linear quantity of protein (milligrams) was divided by the quan- relationship between log(UP/C) and log(ACR), log(UP/C) tity of creatinine (milligrams) in the urine to obtain the ratio, and log(Unon-alb/cr), and log(ACR) and log(Unon-alb/cr) at UP/C. Unon-alb/cr was defined as urine total protein the index visit. (milligrams) minus urine albumin (milligrams) divided by Parametric failure time models assuming a generalized creatinine (grams). Coefficients of variation on the Roche gamma (GG) distribution (23) of event times were used to Hitachi Cobas modular analyzer for within-run and be- assess the independent association of index visit values of tween-run assays were 1.5% and 3.5%, respectively, for UP/C, ACR, and Unon-alb/cr on the time to the composite urine albumin, and 1.5% and 1.5% for urine protein. end-point of either .50% decline in eGFR (compared with eGFR at the index visit) or initiation of RRT. Two sets of Statistical Analyses analyses were performed: one on the basis of clinically Linear regression was used to examine the cross- meaningful UP/C cutoffs and a second set on the basis of sectional relationship between mean eGFR level and both clinically meaningful ACR cutoffs. Because proteinuria is UP/C and ACR in study participants in whom either considered clinically relevant when the UP/C is $0.2 mg/mg proteinuria level was elevated in comparison to the and nephrotic range proteinuria is typically defined as a reference group (UP/C,0.2 mg/mg and ACR,30 mg/g) UP/C.2.0 mg/mg, these values were used as cutoffs in using the following categories: UP/C,0.2 mg/mg and determining categories for UP/C (,0.2, 0.2–2.0, and ACR$30 mg/g; UP/C$0.2 mg/mg and ACR,30 mg/g; .2.0 mg/mg) (19, 24). We then examined the distribution UP/C$0.2 mg/mg and ACR$30 mg/g (5, 17–19), overall, of ACR and Unon-alb/cr and chose cutoffs for these Clin J Am Soc Nephrol 12: 912–920, June, 2017 Albuminuria in Children with CKD, Fuhrman et al. 915

Table 3. Relationship between indicated exposure at index visit and subsequent decline of >50% in GFR or initiation of RRT, n=751

95% No. (%) Regression Exposure No. Relative Time Confidence with Event Modela Interval

Urine protein-to- creatinine, mg/mg ,0.2 287 25 (9) GG (3.553,1.086,0.690) 1 (reference) 0.2–2.0 363 112 (31) GG (2.393,1.086,0.690) 0.31 0.21 to 0.47 .2.0 101 65 (64) GG (0.974,1.086,0.690) 0.08 0.04 to 0.13 Urine albumin-to- creatinineb,mg/g ,56 287 31 (11) GG (3.391,1.024,0.784) 1 (reference) 56–1333 363 104 (29) GG (2.428,1.024,0.784) 0.38 0.26 to 0.55 .1333 101 67 (66) GG (1.031,1.024,0.784) 0.09 0.06 to 0.15 Urine nonalbumin- to-creatinineb,mg/g ,118 287 25 (9) GG (3.593,1.233,0.507) 1 (reference) 118–715 363 112 (31) GG (2.411,1.233,0.507) 0.31 0.20 to 0.46 .715 101 65 (64) GG (0.936,1.233,0.507) 0.07 0.04 to 0.12

GG, generalized gamma. aIncludes the location, scale, and shape parameters of the regression model. bCutoffs for urine albumin-to-creatinine and urine nonalbumin-to-creatinine were chosen to yield same sample sizes as determined by urine protein-to-creatinine cutoffs of 0.2 and 2.0. variables (,56, 56–1333, and .1333 mg/g for ACR; ,118, shown in Table 1. The median age was 12.4 years, 15% of 118–715, and .715 mg/g for Unon-alb/cr) that would participants had stage 1 hypertension or greater, and the yield the same sample sizes (287, 363, and 101) for the median eGFR was 54.6 ml/min per 1.73 m2. A glomerular three different categories across the three sets of analyses. cause for CKD occurred in 30% of the participants. At the Similarly, because ACR is considered moderately in- index visit, 56% of participants were on an ACE inhibitor or creased when $30 mg/g and severely increased when ARB. .300 mg/g, these values were used as cutoffs for ACR categories (,30, 30–300, and .300 mg/g). Cutoffs for Cross-Sectional Analyses UP/C (,0.139, 0.139–0.630, and .0.630 mg/mg) and for Table 2 shows the results of a multivariable linear Unon-alb/cr (,86, 86–273, and .273 mg/g) were chosen regression analysis to quantify the relationship between to yield the same sample sizes (220, 271, and 260) for the mean eGFR level and both UP/C and ACR at the index three different categories across the three sets of analyses. visit. The mean eGFR in the individuals with albuminuria $ Relative times (RTs) were used to quantify the strength of (ACR 30 mg/g) in the absence of overt proteinuria (UP/ , fi the relationship between each of these variables and the C 0.2 mg/mg) did not differ signi cantly from those of the , , composite event. Specifically, RTs represent the time it reference group (UP/C 0.2 mg/mg and ACR 30 mg/g). takes for P%(P can be any percentage between 0% and In contrast, those with both albuminuria and overt pro- $ $ 100%) of the “exposed group” to develop the composite teinuria (UP/C 0.2 mg/mg and ACR 30 mg/g) had a 2 event divided by the time it takes for the same P%ofthe mean eGFR that was 16.0 ml/min per 1.73 m lower (95% fi 2 2 “unexposed group” to develop the composite event. We con dence interval [95% CI], 19.7 to 12.4) than that of chose to use RTs as opposed to relative hazards because the reference group. Importantly, participants with overt $ , time is the unit of measurement of the dependent variable, proteinuria (UP/C 0.2 mg/mg), but ACR 30 mg/g, had a 2 and to quantify the association of UP/C, ACR, and Unon- mean eGFR that was 9.3 ml/min per 1.73 m lower (95% CI, 2 2 , alb/cr on CKD progression in terms of how higher levels of 17.8 to 0.7) than those with UP/C 0.2 mg/mg and , each exposure shorten the time to the event (i.e.,RT,1). We ACR 30 mg/g. utilized regression models under the assumption of pro- We repeated the cross-sectional multivariable linear portional times (i.e., the RTs did not depend on “P”). The regression including only the 289 patients not on an ACE appropriateness of the GG distribution was assessed by and/or ARB at the index visit (Supplemental Table 1). comparing each estimated survival curve on the basis of the Similar results were obtained to the analysis where patients GG parameter estimates with the corresponding nonpara- on an ACE and/or ARB were included; individuals with $ metric Kaplan–Meier survival curve. All analyses used a albuminuria (ACR 30mg/g)intheabsenceofovert , 0.05 level of significance. proteinuria (UP/C 0.2 mg/mg) had a mean eGFR that was not significantly different from the reference group. In com- paring the analyses with and without the restriction of ACE Results inhibitor/ARB use, the magnitude of the difference in means Characteristics at the index visit of the 751 CKiD was greater when comparing those with UP/C$0.2 mg/mg participants included in our time-to-event analyses are and ACR$30 mg/g to those with UP/C,0.2 mg/mg and 916 Clinical Journal of the American Society of Nephrology

Figure 2. | Similar prognostic ability for each of the three methods to quantify proteinuria for characterizing a >50% decline in GFR or need for RRT based on clinically meaningful cutoffs of UP/C (Kaplan–Meier, dashed lines and Generalized Gamma, solid lines). Left panel: UP/C categorized as ,0.2, 0.2–2.0, and .2.0; middle panel: ACR categorized as ,56, 56 to ,1333, and .1333; right panel: Unon-alb/cr categorized as ,118, 118 to ,715, and .715. n=751. ACR, urine albumin-to-creatinine ratio; Unon-alb/cr, urine nonalbumin-to-creatinine ratio; UP/C, urine protein-to-creatinine ratio.

ACR,30 mg/g when the analysis was restricted to those not compared with Unon-alb/cr,100 mg/g (RT=0.14; 95% on an ACE or ARB. CI, 0.08 to 0.24). Figure 1 shows the strong collinearity of ACR and UP/C In order to compare the three methods to quantify (r=0.92), Unon-alb/cr and UP/C (r=0.92), and Unon-alb/cr proteinuria, UP/C, ACR, and Unon-alb/cr were stratified and ACR (r=0.74) at the index visit. into categories on the basis of levels of UP/C (,0.2 mg/mg [n=287], 0.2–2.0 mg/mg [n=363], and .2.0 mg/mg Time-to-Event Analyses [n=101]) as shown (Figure 2, Table 3). Categories of ACR The median follow-up time from the index visit to the and Unon-alb/cr were chosen on the basis of where 0.2 and composite event was 3.4 years (interquartile range, 2.2–5.0) 2.0 fell in the distribution of UP/C so that the lowest levels and 27% of the study population (n=202) were observed to of UP/C, ACR, and Unon-alb/cr would have the same develop the composite event (.50% decline in eGFR or sample sizes but not necessarily the same participants. initiation of RRT). Seventy-seven children had a .50% Similarly, the middle categories (as well as the highest decline in eGFR before undergoing dialysis or transplant categories) of UP/C, ACR, and Unon-alb/cr would have and 37 had a .50% decline in eGFR without subsequent the same number of participants. The lowest category of dialysis or transplant. Eighty-eight children went onto RRT each measure of proteinuria was designated as a reference without first exhibiting a .50% decline in eGFR. As shown group (i.e., UP/C,0.2 mg/mg, ACR,56 mg/g, and Unon- in Table 3, the times to the composite event were 92% alb/cr,118 mg/g). The RTs to a .50% decline in eGFR or shorter for those with UP/C.2.0 mg/mg when compared the initiation of RRT were almost identical for each of the with participants with a UP/C,0.2 mg/mg (RT=0.08; 95% three measures of proteinuria when comparing the middle CI, 0.04 to 0.13). For albuminuria, the times to the category to the reference group (0.31 for UP/C, 0.38 for composite event were 84% shorter for participants with ACR, 0.31 for Unon-alb/cr) and highest category to the ACR.300mg/gwhencomparedwiththosewith reference group (0.08 for UP/C, 0.09 for ACR, 0.07 for ACR,30 mg/g (RT=0.16; 95% CI, 0.10 to 0.26). Similarly, Unon-alb/cr). the times to the composite event were 86% shorter for In order to further explore the subgroup of study participants with a Unon-alb/cr$300 mg/g when participants with UP/C,0.2 mg/mg (n=287), the Clin J Am Soc Nephrol 12: 912–920, June, 2017 Albuminuria in Children with CKD, Fuhrman et al. 917

Figure 3. | Similar prognostic ability for each of the three methods to quantify proteinuria for characterizing a >50% decline in GFR or need for RRT based on clinically meaningful cutoffs of ACR (Kaplan–Meier, dashed lines and Generalized Gamma, solid lines). Left panel: UP/C categorized as ,0.139, 0.139–0.630, and .0.630; middle panel: ACR categorized as ,30, 30–300, and .300; right panel: Unon-alb/cr categorized as ,86, 86–273, and .273. n=751. ACR, urine albumin-to-creatinine ratio; Unon-alb/cr, urine nonalbumin-to-creatinine ratio; UP/C, urine protein-to-creatinine ratio. association between ACR (treated as a continuous variable) and ACR,30 mg/g). Importantly, however, a significant and the composite event was examined. Each log higher in association with lower eGFR was also seen in participants ACR was not associated with any greater risk of reaching with a UP/C$0.2 mg/mg and ACR,30 mg/g. the composite endpoint (P=0.96). To our knowledge, this study is the first to examine the When UP/C, ACR, and Unon-alb/cr were compared on association of albuminuria and renal progression in a the basis of the levels of ACR (,30 mg/g [n=220], 30–300 pediatric CKD population in the absence of diabetes. The mg/g [n=271], and .300 mg/g [n=260]), the RTs to the results of this analysis indicate that ACR and UP/C are event were very similar when comparing the middle and very well correlated (r=0.92) and the discrepancy in their highest categories of each of the three measures of pro- correlation does not yield differential inferences with teinuria to the reference group (Figure 3, Table 4). respect to characterizing the time to .50% decline in eGFR or initiation of RRT in the population studied. The congruence of the results for the analyses whereby methods Discussion of protein quantification were compared on the basis of In this large study of North American children with CKD UP/C as well as ACR categories indicates an equivalent without diabetes, it was found that UP/C, ACR, and Unon- prognostic ability for each of these markers in terms of alb/cr had a similar ability to characterize progression to a characterizing CKD progression. composite event of a .50% decline in eGFR or initiation of It can be argued that screening for albuminuria, which is RRT. The times to the event were significantly shorter for more sensitive than the assay for proteinuria, may detect increasing levels of UP/C, ACR, and Unon-alb/cr. Con- patients with CKD at an earlier point in their chronic sistent with previous studies, higher UP/C values were disease. Prior investigations have supported the belief that significantly associated with lower eGFR values (1–4). Not microalbuminuria in patients with diabetes provides an unexpectedly, when the UP/C was $0.2 mg/mg, there ominous connotation regarding the progression of the was a significant association with lower mean eGFR values diabetes (25–27). However, more recent studies have for individuals with ACR$30 mg/g (i.e.,thosewith shown that microalbuminuria may be a transient finding UP/C$0.2 mg/mg and ACR$30 mg/g had significantly in children and adults with diabetes (28, 29) and is not lower eGFR compared with those with UP/C,0.2 mg/mg consistently a strong predictor of renal disease progression 918 Clinical Journal of the American Society of Nephrology

Table 4. Relationship between indicated exposure at index visit and subsequent decline of >50% in GFR or initiation of RRT, n=751

95% No. (%) Regression Exposure No. Relative Time Confidence with Event Modela Interval

Urine protein-to- creatinineb,mg/mg ,0.139 220 17 (8) GG (3.721,0.935,0.991) 1 (reference) 0.139–0.630 271 46 (17) GG (3.043,0.935,0.991) 0.51 0.30 to 0.86 .0.630 260 139 (53) GG (1.662,0.935,0.991) 0.13 0.07 to 0.22 Urine albumin-to- creatinine, mg/g ,30 220 23 (10) GG (3.469,0.932,0.977) 1 (reference) 30–300 271 46 (17) GG (3.001,0.932,0.977) 0.63 0.40 to 1.00 .300 260 133 (51) GG (1.663,0.932,0.977) 0.16 0.10 to 0.26 Urine nonalbumin-to- creatinineb,mg/g ,86 220 18 (8) GG (3.913,0.336,3.328) 1 (reference) 86–273 271 49 (18) GG (3.166,0.336,3.328) 0.47 0.27 to 0.84 .273 260 135 (52) GG (2.065,0.336,3.328) 0.16 0.09 to 0.28

GG, generalized gamma. aIncludes the location, scale, and shape parameters of the regression model. bCutoffs for urine protein-to-creatinine and urine nonalbumin-to-creatinine were chosen to yield same sample sizes as determined by urine albumin-to-creatinine cutoffs of 30 and 300.

in this patient population (30–32). The cost of measuring content. Additionally, although urine collections were urine albumin is more than the cost of measuring total obtained in the morning of the study visit, specimens protein. Thus, there may be a cost-saving benefitto were not consistently first morning voids, providing the avoiding additional urine protein studies when UP/C is potential for orthostatic proteinuria. Nonalbumin protein already known. However, future cost effectiveness studies was calculated indirectly using urine total protein and are required to make any determinations of the cost-saving albumin measurements. We did not directly measure advantage of one method of urine protein quantification specific larger–molecular weight tubular proteins, which over another in the pediatric CKD population. may have added utility in predicting CKD progression in Although our study demonstrates that albuminuria is children. In adults with primary GN, the fractional excre- not superior to proteinuria in monitoring renal progression tion of both IgG and albumin have been found to be in children with CKD, there may be utility in quantifying significant predictors for the progression to stage 5 CKD or both a urine protein and albumin in certain patient groups. death (33). Notably, albuminuria has been shown in Prior studies in both children and adults with nephrotic multiple studies to be an independent indicator of in- syndrome have shown a significant association of the creased cardiovascular disease risk (37–40), an outcome not selectivity of the proteinuria and prognosis and response to explored in this study. The exact timing of ACE inhibitor therapy (33–36). In order to further explore the role of urine and/or ARB medication initiation could not be determined albumin in this study cohort, UP/C, ACR, and Unon-alb/ from the study data. Given that these medications are cr were dichotomized on the basis of a urine albumin-to- common among the CKD population and can result in a protein ratio (APR [milligrams per milligram] of ,0.4 and stabilization or decline in the degree of proteinuria and $0.4). The 0.4 cutoff value was on the basis of prior study albuminuria (18, 41), patients not on an ACE inhibitor or results showing the utility of an APR for identifying ARB at the index study visit were included in a cross- tubular interstitial disorders in adults (13). The RTs to a sectional multivariable linear regression with similar re- .50% decline or initiation of RRT comparing participants sults to the entire patient cohort. with the highest APR (.0.4 mg/mg), highest UP/C (.0.28 In conclusion, in children with CKD without diabetes, mg/mg), highest ACR(.90 mg/g), and highest Unon-alb/ initial UP/C, ACR, and Unon-alb/cr determinations are cr (.148 mg/g) compared with those with the lowest were well correlated and provide a similar characterization of 0.44, 0.20, 0.23, and 0.20, respectively, suggesting that CKD progression. obtaining an APR may provide somewhat different in- formation regarding progression when compared with Acknowledgments UP/C, ACR, and Unon-alb/Cr. Further studies are needed The authors are grateful to GE Healthcare for providing the to determine if APR is a useful measurement in children Omnipaque 300 for the iohexol GFR studies and to Paula Maier for with CKD. accurate data entry. The study does have limitations. A single random urine The in children prospective cohort specimen was obtained on each participant, not accounting (CKiD) study is funded by the National Institute of Diabetes and for potential intraindividual variability in urine protein Digestive and Kidney Diseases, with additional funding from the Clin J Am Soc Nephrol 12: 912–920, June, 2017 Albuminuria in Children with CKD, Fuhrman et al. 919

Eunice Kennedy Schriver National Institute of Child Health and 9. van der Velde M, Matsushita K, Coresh J, Astor BC, Woodward M, Human Development, and the National Heart, Lung, and Blood Levey A, de Jong P,Gansevoort RT,van der Velde M, Matsushita K, Coresh J, Astor BC, Woodward M, Levey AS, de Jong PE, Institute (U01 DK82194, U01-DK-66143, U01-DK-66174, and U01- Gansevoort RT, Levey A, El-Nahas M, Eckardt KU, Kasiske BL, DK-66116). The CKID website is located at http://www.statepi. Ninomiya T,Chalmers J, Macmahon S, Tonelli M, Hemmelgarn B, jhsph.edu/ckid. 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