Abstract
Background and objectives Some biomarkers of renal tubular injury are reported to be useful for predicting renal prognosis in the early stage of diabetic nephropathy (DN). Our study compared predictions of the renal prognosis by such biomarkers and by histologic tubulointerstitial damage.
Design, setting, participants, & measurements Among 210 patients with type 2 diabetes and biopsy-proven DN managed from 1985 to 2011, 149 patients with urinary N-acetyl-β-d-glucosaminidase (NAG) and urinary β2-microglobulin (β2-MG) data at the time of renal biopsy were enrolled. The primary outcome was a decline in eGFR of ≥50% from baseline or commencement of dialysis for ESRD.
Results The median follow-up period was 2.3 years (interquartile range, 1.1–5.3), and the primary outcome was noted in 94 patients. Mean eGFR was 46.3±23.2 ml/min per 1.73 m2, and 132 patients (89%) had overt proteinuria at baseline. Cox proportional hazards analysis revealed that the association of urinary NAG and β2-MG with the outcome was attenuated after adjustment for known promoters of progression (+1 SD for log NAG: hazard ratio [HR], 1.14; 95% confidence interval [95% CI], 0.84 to 1.55; +1 SD for log β2-MG: HR, 1.23; 95% CI, 0.94 to 1.62). In contrast, the interstitial fibrosis and tubular atrophy (IFTA) score was still significantly correlated with the outcome after adjustment for the same covariates (+1 for IFTA score: HR, 2.31; 95% CI, 1.56 to 3.43). Moreover, adding the IFTA score to a model containing known progression indicators improved prediction of the outcome (increase of concordance index by 0.02; 95% CI, 0.00 to 0.05; category–free net reclassification improvement by 0.54; 95% CI, 0.03 to 1.05; and relative integrated discrimination improvement by 0.07; 95% CI, −0.08 to 0.22).
Conclusions Adding urinary NAG and β2-MG excretion to known promoters of progression did not improve prognostication, whereas adding the IFTA score did. The IFTA score may be superior to these tubulointerstitial markers for predicting the renal prognosis in advanced DN.
- diabetic nephropathy
- renal pathology
- renal prognosis
- tubulointerstitial lesion
- urinary biomarker
- diabetes mellitus, type 2
- disease progression
- follow-up studies
- humans
- kidney failure, chronic
Introduction
Proteinuria and albuminuria are commonly regarded as sensitive biomarkers of the renal prognosis in patients with diabetic nephropathy (DN) (1,2). However, it has recently been pointed out that these markers have some drawbacks for predicting the renal outcome (3,4). With the aim of achieving more accurate prediction of the renal prognosis, other biomarkers have also been investigated, including markers of renal tubular injury and inflammation (3,5).
N-acetyl-β-d-glucosaminidase (NAG) is a lysosomal brush border enzyme that is localized in the microvilli of renal tubular epithelial cells. Because of its relatively high molecular mass (>130 kD), NAG is not filtered through the glomeruli, and it is only released into the urine after renal tubular injury (6,7). Urinary NAG excretion is also associated with inflammation, such as that related to NF-κB activation, which is important in the pathophysiology of DN (8). On the basis of these reports, urinary NAG may not just be a useful indicator of renal tubulointerstitial damage but also, may be a marker of neuropathy in patients with diabetes (4,9,10).
β2-Microbrobulin (β2-MG) is a low molecular mass protein (11.8 kD) that is produced by all cells expressing the MHC class 1 antigens (6). It is filtered by the glomeruli but then, almost completely reabsorbed and catabolized by the cells of the proximal tubules (11). Therefore, urinary β2-MG is a classic biomarker of renal tubulointerstitial injury along with urinary NAG.
We recently reported that the extent of interstitial fibrosis and tubular atrophy (IFTA) was a significant predictor of the renal prognosis, even after adjustment for urinary protein excretion (UP) (12,13). There have also been some other recent reports that stressed the influence of IFTA on the renal prognosis (14,15). However, it is unclear how closely tubulointerstitial markers, including urinary NAG and β2-MG, actually reflect tubulointerstitial injury. Moreover, the diagnosis of DN was not confirmed by renal biopsy in previous studies of tubulointerstitial markers.
At our institution, a relatively large number of patients with diabetes have had DN confirmed by renal biopsy and have also been followed up for a long period (13). In most of them, urinary NAG and β2-MG were examined at the time of renal biopsy as markers of tubulointerstitial injury. Using our database, we performed this study to investigate the relationship of IFTA with urinary NAG and β2-MG, and we also compared these markers as predictors of the renal prognosis in patients with type 2 diabetes and biopsy-proven DN.
Materials and Methods
Study Design
Among 210 patients with type 2 diabetes who underwent renal biopsy at Toranomon Hospitals (Kanagawa, Japan and Tokyo, Japan) from March of 1985 to June of 2011 and were confirmed to have pure DN, which was defined as DN without other coexisting renal diseases (except nephrosclerosis) or kidney transplantation, 149 patients, in whom urinary NAG and β2-MG were examined at the time of renal biopsy and baseline eGFR was ≥10 ml/min per 1.73 m2, were eligible for enrollment in this study (Figure 1). DN was diagnosed by at least two renal pathologists and/or nephrologists, and the diagnosis was re-evaluated according to the classification of the Renal Pathology Society (RPS) (16). The protocol of this study was approved by the ethics committee of Toranomon Hospital in February of 2015, and procedures fully adhered to the Declaration of Helsinki. This study was registered with the University Hospital Medical Information Network in February of 2015 (identification no. UMIN000016662).
Flowchart of study participants. β2-MG, β2-microglobulin; NAG, N-acetyl-β-d-glucosaminidase.
Laboratory Parameters and Definitions
Urinary NAG levels were determined by an enzymatic assay (Nittobo Medical, Fukushima, Japan), whereas urinary β2-MG levels were determined by latex–enhanced turbidimetric immunoassay (Denka Seiken, Tokyo, Japan). Urinary NAG excretion (units per gram creatinine) was measured in a 24-hour urine specimen at the time of renal biopsy in 137 patients (92%), and urinary β2-MG excretion (micrograms per gram creatinine) was measured in 140 patients (94%). Excretion of NAG and β2-MG was not examined using a 24-hour specimen in the remaining patients (9% and 6%, respectively), but their levels were measured in a spot urine samples (urinary NAG [units per gram creatinine] and urinary β2-MG [micrograms per gram creatinine]). GFR was estimated by using the Japanese coefficient–modified Chronic Kidney Disease Epidemiology Collaboration Equation (17), whereas baseline UP was measured in a 24-hour urine specimen. In this study, the presences of normoalbuminuria, microalbuminuria, and macroalbuminuria were defined as urinary albumin excretion (UAE) <30 mg/g creatinine, UAE≥30 and <300 mg/g creatinine, and UAE>300 mg/g creatinine, respectively, in at least two of three consecutive urine specimens obtained immediately before and after renal biopsy (18), whereas overt proteinuria was defined as macroalbuminuria or UP>1 g/d. Hemoglobin A1c (HbA1c) data are presented as National Glycohemoglobin Standardization Program values according to the recommendations of the Japanese Diabetes Society and the Federation of Clinical Chemistry (19). As in our previous studies, the average annual values of clinical parameters, such as UP, systolic/diastolic BP, Hb, and HbA1c, were calculated (13,20). If data for any of these variables were unavailable during follow-up, the mean value of the observations before and after the missing value was calculated and used instead. We used UP (grams per gram creatinine) if UP (grams per day) was not available during follow-up. These laboratory data obtained during follow-up were only used to illustrate the clinical course and were not used for analyses. Treatment with an angiotensin–converting enzyme inhibitor (ACE-I) or angiotensin II type 1 receptor blocker (ARB) during follow-up was defined as use for more than one half of the follow-up period.
End Point
The primary end point was defined as a decline of eGFR of ≥50% from baseline or commencement of dialysis because of ESRD. None of the patients received kidney transplantation during follow-up.
Renal Biopsy and Pathologic Classification
As described previously, the indications for renal biopsy were UP>0.5 g/d or atypical DN, such as nephritic syndrome with short duration of diabetes and renal involvement without diabetic retinopathy and/or with hematuria, and therefore, all biopsies were for clinical assessment and not for research (21). Tissue was obtained by needle biopsy, and the specimens were processed for light microscopy, immunofluorescence, and electron microscopy. Specimens for light microscopy were stained with hematoxylin and eosin, periodic acid–Schiff, Weigert elastica–van Gieson, Masson trichrome, or periodic acid methenamine silver stain according to routine methods. Classification of DN and determination of histologic scores (including exudative lesions) according to the criteria of the RPS and the criteria used in our previous study (13,16) were done by at least two renal pathologists and/or nephrologists who were unaware of the clinical status of each patient.
Statistical Analyses
Data were summarized as percentages or means±SDs as appropriate. Skewed variables (urinary NAG, urinary β2-MG, UP, triglycerides, and total cholesterol) underwent logarithmic transformation to improve normality before analysis. Categorical variables were analyzed with the chi-squared test, the Fisher exact test, and the two–group proportion test, whereas continuous variables were compared by using the paired t test, the Wilcoxon signed rank test, the Mann–Whitney U test, the Kruskal–Wallis H test, or ANOVA as appropriate. The distribution of each clinical and histopathologic parameter stratified by urinary NAG tertiles, β2-MG tertiles, and the IFTA score was compared using trend analysis. Correlations among urinary NAG, urinary β2-MG, and the IFTA score were evaluated by Spearman correlation analysis for the IFTA score and Pearson correlation analysis for the two urinary markers. Cumulative renal survival was estimated by the Kaplan–Meier method for each urinary NAG tertile, urinary β2-MG tertile, and IFTA score, and renal survival rates were compared among these stratified cohorts by using the log-rank test. The Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the death–censored end point. In Cox model 1, HRs were adjusted for age, sex, body mass index, diabetic retinopathy, and systolic BP at the time of renal biopsy. These covariates were selected as potential confounders on the basis of biologic plausibility and metabolic memory (22,23). In model 2, HRs were adjusted for all of the above covariates plus UP and eGFR at the time of renal biopsy. To examine the best fit of the biomarkers or IFTA score in each Cox regression analysis, fractional polynomial regression analysis was performed. In addition, to investigate the incremental predictive power of the interstitial markers, we compared Harrell concordance index (c index) between multivariate Cox proportional hazards models adjusted for the covariates in model 2 with or without the interstitial markers. Moreover, improvement in discriminating the risk of the outcome at median follow-up (2.3 years) was assessed by analysis of the category–free net reclassification improvement (NRI) and integrated discrimination improvement (IDI) as reported elsewhere (24–26). The median follow-up time was selected as the cutoff point for analysis, because it was previously used in a similar study (3). The 95% CIs for the differences in the c index, category-free NRI, and IDI were computed on the basis of 10,000 bootstrap samples. Two–tailed P values <0.05 were considered to indicate statistically significant differences. Analyses were performed with Stata SE software (version 14.0; StataCorp., College Station, TX).
Results
Of 210 patients screened, 149 met the selection criteria and were enrolled to investigate the usefulness of interstitial lesions (IFTA score), urinary NAG, and urinary β2-MG for predicting the renal prognosis (Figure 1). The median follow-up period was 2.3 years (interquartile range [IQR], 1.1–5.3 years). During follow-up, the primary outcome (decline of eGFR of ≥50% from baseline or initiation of dialysis because of ESRD) occurred in 94 patients, and seven patients died.
The characteristics of 149 patients are shown in Table 1. The age (mean±SD) at the time of renal biopsy was 58±13 years old, 79% of the patients were men, and 70% had diabetic retinopathy. Median baseline urinary NAG and β2-MG excretion were 12.6 U/g creatinine (IQR, 7.3–20.8) and 779 μg/g creatinine (IQR, 124–4001), respectively, whereas the mean baseline eGFR was 46.3±23.2 ml/min per 1.73 m2. Median UP was 2.4 g/d (IQR, 1.2–4.5), and 132 patients (89%) had overt proteinuria. Clinical and histopathologic parameters stratified according to urinary NAG tertiles, urinary β2-MG tertiles, and the IFTA score are shown in Supplemental Tables 1–3. Patients with higher IFTA scores and higher urinary marker concentrations were older; had diabetic retinopathy more frequently; had higher levels of systolic BP, serum creatinine, UP, and serum uric acid; and took more antihypertensive agents. Patients with higher IFTA scores and urinary marker concentrations also had lower creatinine clearances and eGFRs as well as lower serum albumin and Hb levels.
Baseline clinical parameters and histopathologic findings for all patients
Comparison of histopathologic findings among the urinary NAG and β2-MG tertiles revealed that patients with higher grades of pathologic findings and exudative lesions were in higher tertiles for urinary NAG and β2-MG, except that the arteriosclerosis score did not become higher across the β2-MG tertiles (Supplemental Tables 1 and 2).
Differences between major clinical parameters at baseline and during follow-up (or at final assessment) are displayed in Table 2. The mean systolic BP, diastolic BP, HbA1c, and Hb in all declined significantly during follow-up, whereas mean UP was significantly higher than at baseline. Rates of ACE-I and ARB use were significantly higher during follow-up compared with baseline. When the major parameters were stratified according to urinary NAG tertiles, β2-MG tertiles, and the IFTA score, there were significant differences of average annual UP, systolic BP, and Hb and the final use of erythropoietin-stimulating agents among each tertile and score, whereas there were no significant differences of ACE-I or ARB treatment during follow-up among these stratified cohorts (Supplemental Table 4).
Comparison of main clinical parameters between baseline and follow-up (or at final follow-up) in all patients
Relations among the log–converted baseline urinary NAG level (log NAG), the log–converted baseline urinary β2-MG level (log β2-MG), and the IFTA score are shown in Figure 2. There were significant positive correlations among all of these parameters (r=0.47; P<0.001 between log NAG and the IFTA score; r=0.58; P<0.001 between log β2-MG and the IFTA score; and r=0.57; P<0.001 between log NAG and log β2-MG).
Associations among urinary N-acetyl-β-d-glucosaminidase (NAG), urinary β2-microglobulin (β2-MG), and the interstitial fibrosis and tubular atrophy (IFTA) score. (A) Association between urinary NAG and the IFTA score. (B) Association between urinary β2-MG and the IFTA score. (C) Association between urinary NAG and urinary β2-MG. The boxes show interquartile ranges, and the whiskers show 1st and 99th percentiles. Cr, creatinine.
Kaplan–Meier curves for renal survival stratified according to baseline urinary NAG tertiles, urinary β2-MG tertiles, and IFTA score are displayed in Figure 3. There were significant differences of renal survival among the NAG tertiles and β2-MG tertiles. Likewise, there were significant differences of renal survival among the IFTA scores.
Renal survival rate stratified by urinary N-acetyl-β-d-glucosaminidase (NAG), urinary β2-microglobulin (β2-MG), and the interstitial fibrosis and tubular atrophy (IFTA) score. (A) Renal survival curves for urinary NAG tertiles. The estimated 5-year renal survival rate was 68% in NAG tertile 1, 31% in NAG tertile 2, and 12% in NAG tertile 3. (B) Renal survival curves for urinary β2-MG tertiles. The estimated 5-year renal survival rate was 68% in β2-MG tertile 1, 34% in β2-MG tertile 2, and 10% in β2-MG tertile 3. (C) Renal survival curves for IFTA scores. The estimated 5-year renal survival rate was 100% for patients with an IFTA score of zero, 70% for patients with an IFTA score of one, 24% for patients with an IFTA score of two, and 0% for patients with an IFTA score of three. There were significant differences of the renal survival rate between the different NAG tertiles, β2-MG tertiles, and IFTA scores. Outcome was ≥50% decline in eGFR or dialysis because of ESRD. The log-rank test was used for survival analysis. Cr, creatinine; IQR, interquartile range.
The adjusted HRs of urinary NAG, urinary β2-MG, and the IFTA score (as categorical and continuous variables) for the renal end point are shown in Table 3. Cox proportional hazards analysis revealed that urinary NAG and β2-MG were positively associated with the renal end point in both categorical and continuous analyses after adjustment for diabetic retinopathy and baseline systolic BP. However, the association of those urinary markers with the renal prognosis was considerably weaker after adjustment for baseline UP and eGFR. However, the IFTA score still showed a positive correlation with the renal prognosis, even after adjustment for baseline UP and eGFR. Compared with an IFTA score of one, the HRs for the outcomes of IFTA scores of zero, two, and three were 0.05 (95% CI, 0.01 to 0.39), 1.59 (95% CI, 0.82 to 3.08), and 3.82 (95% CI, 1.74 to 8.39), respectively. A one–point higher IFTA score was also significantly associated with a higher risk of the renal end point (HR, 2.31; 95% CI, 1.56 to 3.43). Fractional polynomial comparisons revealed that the best fit for the IFTA score was a trinomial equation, but there was no significant difference between linear and trinomial analysis of the IFTA score (P=0.18).
Univariate and multivariate Cox proportional hazard models incorporating urinary N-acetyl-β-d-glucosaminidase, urinary β2-microglobulin, and the interstitial fibrosis and tubular atrophy score
The difference of Harrell c index between Cox regression models with or without the IFTA score and the NRI and IDI values for predicting the primary outcome at median follow-up obtained by adding IFTA score are summarized in Table 4. Adding the IFTA score to the multivariate model as a categorical variable resulted in a significantly higher c index (increment of 0.02; 95% CI, 0.00 to 0.05). Similarly, adding the IFTA score to the models improved the risk classification and relative integrated discrimination of the outcome at median follow-up (category-free NRI: 0.54; 95% CI, 0.03 to 1.05 and relative IDI: 0.07; 95% CI, −0.08 to 0.22).
Difference of Harrell concordance index between Cox regression models with or without the interstitial fibrosis and tubular atrophy score and the category–free net reclassification improvement and integrated discrimination improvement for predicting the outcome at median follow-up obtained by adding the interstitial fibrosis and tubular atrophy score
When we performed the same analyses in patients with overt proteinuria (n=132) and patients with data on 24-hour urinary excretion of NAG and β2-MG (n=133) as sensitivity analyses, the results that we obtained were similar (data not shown).
Discussion
Recently, it has been suggested that tubulointerstitial lesions are more important for predicting the renal prognosis than other types of lesions, such as glomerular and vascular lesions, in not only patients with DN but also, those with other renal diseases (12,27,28). Therefore, more accurate biomarkers of tubulointerstitial injury and inflammation are needed. A study of the Joslin Diabetes Center showed that urinary NAG and kidney injury molecule 1 were markers of renal tubular injury that could predict regression of microalbuminuria in patients with type 1 diabetes (4). Regarding markers of inflammation, elevated serum levels of TNFα receptors 1 and 2 were reported to be closely related to an increased risk of ESRD in patients with type 2 diabetes (29,30). Another recent investigation performed in American Indians with type 2 diabetes and preserved kidney function showed that measuring the urinary levels of neutrophil gelatinase–associated lipocalin (NGAL) and liver fatty acid–binding protein (L-FABP), two markers of tubular injury, significantly improved prediction of the renal prognosis when combined with conventional prognostic indicators, such as albuminuria and GFR, although the actual size of the improvement was small (3). These investigations were related to important elements of the pathophysiology of DN, such as tubulointerstitial damage in the early stage and the role of inflammation mediated via the TNFα pathway (31–33).
In this study, urinary excretion of NAG and β2-MG was significantly correlated with the severity of tubulointerstitial injury, but there was a distinct difference of predictive power between these urinary markers and histologic detection of tubulointerstitial injury (IFTA score). This difference may be explained by the limited accuracy of urinary markers because of several potential influences on marker levels, such as metal irons, urine pH, and complications (6,34–36). Moreover, recent studies have shown that addition of these markers to known promoters of progression does not significantly improve prediction of the risk of ESRD in patients with relatively early DN (3,37), although both NAG and β2-MG are thought of as early markers of interstitial injury in DN (6). Almost 90% of our subjects had overt proteinuria and a reduced eGFR at baseline, and the influence of these interstitial markers on the primary end point was markedly reduced after adjustment for baseline UP and eGFR. Accordingly, urinary NAG and β2-MG might not be useful independent predictors of the renal prognosis in patients with advanced DN.
In one of the above–mentioned recent studies, urinary NGAL and L-FABP showed a stronger incremental predictive power for the renal prognosis than urinary NAG (3). Therefore, it may be worthwhile comparing these biomarkers with the IFTA score. However, Nielsen et al. (38) reported that urinary NGAL, L-FABP, and kidney injury molecule 1 were not associated with more rapid GFR decline after adjusting for known promoters of the progression of DN, including UAE, in patients with type 1 diabetes and overt nephropathy. Taken together with our results, it seems that the markers of tubular injury reported so far do not provide additional prognostic information beyond that obtained from known promoters of progression in patients with advanced DN. In contrast to the urinary markers of tubular injury, we found that the histologic severity of tubulointerstitial injury (IFTA score) could predict the renal prognosis independently of known indicators of progression, such as UP and eGFR. In addition, adding the IFTA score to the above-mentioned promoters of progression resulted in a significantly higher c index and also, led to higher NRI and IDI values for predicting the renal outcome, although the IDI was not statistically significant. We assessed interstitial injury according to the recent consensus classification of DN in this study, but it is possible that the predictive power of interstitial injury would have been even greater if it had been categorized in more detail. On the basis of these considerations, the IFTA score is considered to be useful for predicting the renal prognosis in patients with advanced DN. When we repeated the same analyses in 132 patients with overt proteinuria, the results were similar, and our conclusions were unchanged. These results suggest that we should pay more attention to pathologic findings on renal biopsy, such as tubulointerstitial injury, and that the IFTA score should be assessed by a renal pathologist, even when the diagnosis is typical DN.
This study had some limitations. First, it was a retrospective cohort study performed at a single center, and urinary NAG and β2-MG levels were not examined in all of the patients with biopsy-proven DN. Also, the indications for renal biopsy were insufficiently standardized, suggesting that there might have been selection bias. Therefore, it may be difficult to generalize our results to patients with type 2 diabetes and CKD, especially those with advanced CKD. However, our study was the first to directly compare urinary markers of tubular injury with the histologic severity of tubular injury as predictors of the renal prognosis. Second, information about 24-hour urinary NAG and β2-MG excretion was not available in some of our subjects, but we obtained similar results when we only analyzed the patients with 24-hour urinary excretion data. Third, the study was performed over a long period (>25 years), suggesting that changes of clinical management during long–term follow-up might have affected the renal prognosis. Unfortunately, treatment factors were not examined sufficiently during follow-up, and our analyses were not adequately adjusted for these factors. However, there were no significant differences of ACE-I or ARB use during follow-up among the urinary NAG tertiles, urinary β2-MG tertiles, and different IFTA scores. There were also no obvious major differences of glycemic control among the NAG or β2-MG tertiles and the different IFTA scores on the basis of comprehensive assessment of the mean HbA1c, mean Hb, and erythropoietin-stimulating agent use (Supplemental Table 4).
In conclusion, assessment of urinary NAG and β2-MG excretion did not add prognostic value to known indicators of renal progression in patients with type 2 diabetes and biopsy-proven DN, whereas the IFTA score improved prognostication. On the basis of this finding, the IFTA score may be more useful for predicting the renal prognosis than classic markers of tubulointerstitial damage, especially in patients with advanced DN. Accordingly, it seems to be important to perform correct evaluation of the IFTA score in patients with DN who undergo renal biopsy.
Disclosures
None.
Acknowledgments
We thank Drs. Shoji Kawatsu (The Institute for Adult Diseases, Asahi Life Foundation), Ayako Hakura, Masafumi Yokota, Yukio Maruyama, Tomio Onuma, and Ai Terai for providing data and treatment after renal biopsy. We also thank Drs. Akiko Endo, Satoshi Hamanoue, Masahiro Kawada, Aya Imafuku, Takashi Iijima, Koichi Kikuchi, Yuta Kogure, Junichi Inenaga, and Koji Takemura for their helpful comments and management of patients. We thank Prof. Shiro Hinotsu (Center for Innovative Clinical Medicine, Okayama University Hospital), Dr. Toshiharu Mitsuhashi (Center for Innovative Clinical Medicine, Okayama University Hospital), and Prof. Ayumi Shintani (Department of Clinical Epidemiology, Osaka University Graduate School of Medicine) for their helpful comments on statistical analyses.
This work was supported in part by a Grant-in-Aid for Practical Research Project for Renal Disease, from the Japan Agency for Medical Research and Development (grant no. 15ek0310003h0001), a grant from Okinaka Memorial Institute for Medical Research, and a grant from The Kidney Foundation, Japan (grant no. JKFB15-16).
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
This article contains supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.04980515/-/DCSupplemental.
- Received May 5, 2015.
- Accepted December 16, 2015.
- Copyright © 2016 by the American Society of Nephrology
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