Visual Overview
Abstract
Background and objectives The relationship between mineral and bone disorders and survival according to residual kidney function status has not been previously studied in patients on hemodialysis. We hypothesized that residual kidney function, defined by renal urea clearance, modifies the association between mineral and bone disorder parameters and mortality.
Design, setting, participants, & measurements The associations of serum phosphorus, albumin-corrected calcium, intact parathyroid hormone, and alkaline phosphatase with all-cause mortality were examined across three strata (<1.5, 1.5 to <3.0, and ≥3.0 ml/min per 1.73 m2) of baseline residual renal urea clearance using Cox models adjusted for clinical characteristics and laboratory measurements in 35,114 incident hemodialysis patients from a large United States dialysis organization over the period of 2007–2011.
Results A total of 8102 (23%) patients died during the median follow-up of 1.3 years (interquartile range, 0.6–2.3 years). There was an incremental mortality risk across higher serum phosphorus concentrations, which was pronounced among patients with higher residual renal urea clearance (Pinteraction=0.001). Lower concentrations of serum intact parathyroid hormone were associated with higher mortality among patients with low residual renal urea clearance (i.e., <1.5 ml/min per 1.73 m2), whereas higher concentrations showed a higher mortality risk among patients with greater residual renal urea clearance (i.e., ≥1.5 ml/min per 1.73 m2; Pinteraction<0.001). Higher serum corrected total calcium and higher alkaline phosphatase concentrations consistently showed higher mortality risk (Ptrend<0.001 for both) irrespective of residual renal urea clearance strata (Pinteraction=0.34 and Pinteraction=0.53, respectively).
Conclusions Residual kidney function modified the mortality risk associated with serum phosphorus and intact parathyroid hormone among incident hemodialysis patients. Future studies are needed to examine whether taking account for residual kidney function into the assessment of mortality risk associated with serum phosphorus and intact parathyroid hormone improves patient management and clinical outcomes in the hemodialysis population.
- Mortality
- chronic kidney failure
- hemodialysis
- end stage kidney disease
- mineral metabolism
- renal function
- Albumins
- Alkaline Phosphatase
- calcium
- Follow-Up Studies
- Humans
- Minerals
- parathyroid hormone
- Phosphorus
- Phosphorus, Dietary
- Proportional Hazards Models
- renal dialysis
- Risk
- urea
- Urinary Tract Physiological Phenomena
Introduction
Mineral and bone disorder (MBD), characterized by abnormal serum concentrations of calcium, phosphorus, intact parathyroid hormone (PTH), and alkaline phosphatase (ALP), are a common complication in patients with CKD, especially in those with ESRD (1). The above MBD abnormalities may lead to high mortality risk due to adverse cardiovascular or infection-related pathways (2–5). However, those abnormalities may be attenuated in patients on hemodialysis with substantial residual kidney function (RKF) who maintain greater solute clearance (6). Preserved RKF also offers other clinical benefits, including lower ultrafiltration volume, less intradialytic hypotension, and lower prevalence of anemia as well as decreased progression rate of malnutrition, inflammation, erythropoietin resistance, and ventricular hypertrophy (6–8). Therefore, the associations of such clinical parameters with mortality and the effect of interventions on patient survival may differ depending on RKF levels among patients on hemodialysis. Indeed, several studies have suggested that frequent hemodialysis is beneficial to those with little or no RKF but may be detrimental to those with substantial RKF (9–11).
However, few studies have taken RKF levels into account when evaluating associations between MBD markers and mortality in patients on hemodialysis, although up to 45% of patients in the United States initiate maintenance dialysis at eGFRs>10 ml/min per 1.73 m2 (12,13). Hence, we hypothesized that RKF levels modify the associations of serum phosphorus, calcium, intact PTH, and ALP with all-cause mortality in patients on hemodialysis.
Materials and Methods
Patients
We retrospectively extracted, refined, and examined data from all incident hemodialysis patients who initiated treatment between 2007 and 2011 and were treated for ≥60 consecutive days in facilities operated by a large dialysis organization in the United States. Patients were followed up from their first dialysis date to December 31, 2011. Of the 133,162 incident ESRD patients who were treated with in-center thrice-weekly hemodialysis as their initial dialysis modality, we excluded 21,125 patients who were ever treated with other modalities; 3012 who had missing data on MBD parameters, such as serum phosphorus, calcium, intact PTH, or ALP, at baseline (i.e., the first quarter or 91 days of dialysis); and 73,911 who had missing data on baseline residual renal urea clearance (rCLurea) (Supplemental Figures 1). Our final study population consisted of 35,114 incident hemodialysis patients. This study was approved by the University of California Irvine Medical Center and the University of Washington with the exemption of obtaining written consent given the large sample size, anonymity of the patients studied, and nonintrusive nature of the research.
Demographic, Clinical, and Laboratory Measures
Information on all-cause death, race/ethnicity, primary insurance, vascular access type, comorbidities, and laboratory variables were obtained from the electronic database of the dialysis provider.
Blood samples were drawn using uniform techniques in all dialysis clinics and transported to the central laboratory in Deland, Florida, typically within 24 hours. All laboratory values were measured by automated and standardized methods. Most laboratory values were measured monthly, including serum urea nitrogen, creatinine, albumin, calcium, phosphorus, and bicarbonate. Serum ferritin and intact PTH were measured at least quarterly. Hemoglobin was measured at least monthly in all patients and weekly to biweekly in most patients. Most blood samples were collected predialysis, with the exception of the postdialysis urea that was obtained to calculate urea kinetics.
We used rCLurea as the index of RKF in all analyses. The average serum urea concentrations during collection were assumed to be 90% of the predialysis concentrations according to the approach by Daugirdas et al. (14), and thus, rCLurea was calculated as follows:
where serum urea nitrogen was obtained on the closest day within ±28 days of urine collection. Urine collected time was reported as 1440 minutes in 98% of measurements, ranging from 720 to 2880 minutes. We then adjusted rCLurea for body surface area and expressed it as milliliter per minute per 1.73 m2 (15,16). Normalized protein catabolic rate (nPCR) was calculated accounting for rCLurea (17,18).
To minimize measurement variability, averaged values of laboratory variables, including rCLurea, during the first patient-quarter (or the first 91 days of dialysis) within each patient served as baseline data and were used in all models.
Statistical Analyses
Differences in baseline characteristics between included versus excluded patients were compared by standardized differences (19,20). Patients were categorized into three groups according to baseline rCLurea strata (<1.5, 1.5 to <3.0, and ≥3.0 ml/min per 1.73 m2), and associations of patient characteristics with rCLurea categories were evaluated by nonparametric trend tests. The cutoff value of 3.0 ml/min per 1.73 m2 was selected on the basis of the definition of substantial RKF in the previous studies and guidelines (11,21,22). To evaluate trends across rCLurea levels, we also used an additional cutoff point at 1.5 ml/min per 1.73 m2, so that all groups maintained reasonable sample sizes, even after being stratified by each MBD parameter. MBD parameters were treated as categorical variables, and their association with all-cause mortality was examined by Cox proportional hazard models.
For each analysis, we used hierarchical adjustment with three models as follows: (1) unadjusted models that included the a priori–defined categories of each one of the exposures (i.e., phosphorus, uncorrected or albumin-corrected calcium, intact PTH, or ALP); (2) case mix–adjusted models that included the above variables plus age, sex, race/ethnicity, primary insurance, central venous catheter use, hypertension, diabetes, history of cardiovascular disease (i.e., congestive heart failure, atherosclerotic heart disease, cerebrovascular disease, or other cardiovascular disease), rCLurea, and single-pool Kt/V; and (3) case mix– plus malnutrition-inflammation cachexia syndrome (MICS)–adjusted models that included all covariates in the case mix model plus body mass index, nPCR, hemoglobin, serum albumin, creatinine, ferritin, and the use of medications, including vitamin D receptor activators (i.e., calcitriol, paricalcitol, or doxercalciferol either oral or intravenous), calcium-containing phosphorus binders, and noncalcium-containing phosphorus binders (i.e., sevelamar and lanthanum), as well as MBD parameters other than the exposure of interest (i.e., phosphorus, uncorrected calcium, and natural log–transformed intact PTH and ALP).
We defined the fully adjusted model (i.e., case mix– plus MICS–adjusted models) as the primary model. Hazard proportionality was confirmed by Schoenfeld residuals. Associations of MBD markers with mortality were also evaluated across strata of rCLurea. Effect modification of the association between each MBD parameter and mortality by rCLurea was evaluated by creation of interaction terms and use of the Wald test. We also categorized patients into a total of 12 or 15 groups according to combined baseline levels of rCLurea and each MBD parameter and examined their associations with mortality. Consistent results were observed in sensitivity analyses using restricted cubic spline functions with four knots (Supplemental Figures 2–6) or excluding patients with rCLurea>15 ml/min per 1.73 m2 (data not shown).
The frequency of missing data was low (<1% for most laboratory tests, except for nPCR [6%] and creatinine [4%]), and multiple imputation methods with five datasets were used in all regression analyses. Analyses were conducted using STATA MP, version 13.1 (StataCorp, College Station, TX).
Results
Baseline Characteristics
The cohort included 35,114 incident hemodialysis patients, in whom the mean±SD age was 62±15 years old; there were 63% men, 55% non-Hispanic white, and 27% non-Hispanic black, and 59% of patients had diabetes. Mean or median serum baseline phosphorus, albumin-corrected calcium, intact PTH, and ALP levels were 5.0±1.1 mg/dl, 9.1±0.5 mg/dl, 312 (interquartile range [IQR], 201–477) pg/dl, and 84 (IQR, 67–110) U/L, respectively. The prevalence rates of patients with low (<1.5 ml/min per 1.73 m2), middle (1.5 to <3.0 ml/min per 1.73 m2), and high (≥3.0 ml/min per 1.73 m2) rCLurea levels were 20%, 28%, and 52%, respectively. Median urine volume was 300 (IQR, 200–450), 600 (IQR, 500–900), and 1200 (IQR–850, 1675) ml/d in the low, middle, and high rCLurea groups, respectively. Patients with greater rCLurea tended to have higher albumin and uncorrected calcium levels and had lower creatinine, phosphorus, intact PTH, and ALP levels (Table 1). A total of 8102 (23%) patients died during the median follow-up of 1.3 years (IQR, 0.6–2.3 years), with an incidence of 15.0 deaths per 100 patient-years. The leading cause of death was cardiovascular disease (40%) followed by withdrawal from dialysis/uremia (10%), infection (7%), and malignancy (4%).
Baseline characteristics of 35,114 incident hemodialysis patients stratified by baseline residual renal urea clearance
Compared with 76,923 excluded patients who lacked data on baseline rCLurea, phosphorus, albumin-corrected calcium, intact PTH, or ALP, the 35,114 included patients were more likely to be men, non-Hispanic white, and vitamin D receptor activator users; had higher levels of body mass index, Kt/V, hemoglobin, and albumin; and had lower levels of ALP and ferritin (standardized difference >0.1) (Supplemental Table 1). Associations of these MBD parameters with all-cause mortality were found to be similar between included versus excluded patients in the fully adjusted models without adjustment for rCLurea and nPCR, the missingness of which was the most common reason for exclusion (>95%) (Supplemental Figure 7).
Association of Phosphorus and All-Cause Mortality according to rCLurea Strata
In the unadjusted model, higher serum phosphorus was associated with better survival. This association was attenuated in the case mix model and even reversed in the MICS model (fully adjusted model) across all rCLurea strata (Figure 1, A–C). Fully-adjusted mortality risk associated with serum phosphorus was significantly modified by rCLurea (Pinteraction=0.001), in which the association of higher serum phosphorous with mortality was more pronounced across higher levels of rCLurea: adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) of the highest phosphorous group (≥7.0 mg/dl) versus the second lowest group (4.0 to <5.0 mg/dl) were 1.31 (95% CI, 1.05 to 1.64), 1.77 (95% CI, 1.45 to 2.17), and 1.93 (95% CI, 1.59 to 2.33) among patients in the low, middle, and high rCLurea strata, respectively (Figure 1, A–C). When categorizing patients into 15 groups according to combined baseline levels of serum phosphorus and rCLurea (reference: serum phosphorous =4.0–5.0 mg/dl and rCLurea≥3.0 ml/min per 1.73 m2), a trend toward lower mortality risk was observed across higher rCLurea within given serum phosphorus categories <6.0 mg/dl (Ptrend<0.001) but was not observed within the higher categories (Figure 1D).
Higher mortality risk associated with higher serum phosphorus was observed across the three strata of renal urea clearance (rCLurea) but pronounced among patients with greater rCLurea. Association of baseline serum phosphorus with all-cause mortality in 35,114 incident hemodialysis patients with baseline rCLurea of (A) <1.5, (B) 1.5 to <3.0, and (C) ≥3.0 ml/min per 1.73 m2 and (D) the mortality risk of 15 groups stratified by baseline rCLurea and serum phosphorus in the case mix and malnutrition-inflammation cachexia syndrome (MICS) model (phosphorus of 4.0 to <5.0 mg/dl with rCLurea≥3.0 ml/min per 1.73 m2 as the reference).
Association of Calcium and All-Cause Mortality according to rCLurea Strata
The overall mortality risk associated with higher albumin-corrected calcium was higher in all models (Ptrend≤0.002 for all models). Compared with the middle corrected calcium group (i.e., 8.8 to <9.2 mg/dl), aHR was 1.08 (95% CI, 1.01 to 1.16) in the highest group (i.e., ≥9.6 mg/dl) overall (Supplemental Figure 7B). The association between corrected calcium and mortality was not significantly modified by rCLurea in the fully adjusted model (Pinteraction=0.34), and the trend in the adjusted association between corrected calcium and mortality seemed consistent across rCLurea strata (Figure 2, A–C). Higher rCLurea was consistently associated with lower mortality risk across serum calcium categories in models evaluating 15 groups of combined rCLurea and corrected calcium levels (reference: corrected calcium =8.8 to <9.2 mg/dl and rCLurea≥3.0 ml/min per 1.73 m2; Ptrend<0.001 for all)(Figure 2D). Consistent patterns were observed in the association between uncorrected calcium and mortality (Supplemental Figure 8).
The association between higher baseline albumin-corrected serum calcium and higher mortality was consistent across the three strata of renal urea clearance (rCLurea). Association of baseline albumin-corrected serum calcium with all-cause mortality in 35,114 incident hemodialysis patients with baseline rCLurea of (A) <1.5, (B) 1.5 to <3.0 2, and (C) ≥3.0 ml/min per 1.73 m2 and (D) the mortality risk of 15 groups stratified by baseline rCLurea and albumin-corrected calcium in the case mix and malnutrition-inflammation cachexia syndrome (MICS) model (albumin-corrected calcium of 8.8 to <9.2 mg/dl with rCLurea≥3.0 ml/min per 1.73 m2 as the reference).
Association of PTH and All-Cause Mortality according to rCLurea Strata
Higher serum intact PTH levels were associated with lower risk of mortality in the unadjusted models across all three rCLurea groups. In the fully adjusted model, this association was attenuated but still significant in the lowest rCLurea group (P=0.004), but it reversed in the middle and highest rCLurea groups (P=0.05 and P<0.01, respectively; Pinteraction<0.001) (Figure 3, A–C). Compared with the second lowest PTH group (150 to <300 pg/ml), the aHRs of the lowest group (<150 pg/ml) were 1.05 (95% CI, 0.92 to 1.19), 0.94 (95% CI, 0.83 to 1.07), and 0.99 (95% CI, 0.90 to 1.09) among patients in the low, middle, and high rCLurea groups, respectively, whereas the aHRs of the highest intact PTH group (≥600 pg/ml) versus the reference were 0.93 (95% CI, 0.79 to 1.09), 1.11 (95% CI, 0.96 to 1.29), and 1.12 (95% CI, 0.99 to 1.26) among patients in the low, middle, and high rCLurea groups, respectively. Models using spline functions yielded consistent results (Supplemental Figure 5). When categorizing patients into 12 groups according to baseline levels of intact PTH and rCLurea, the mortality risk in the high rCLurea group versus the low rCLurea group was attenuated to some extent in higher intact PTH levels but consistently lower across PTH categories (reference: intact PTH =150 to <300 pg/ml and rCLurea≥3.0 ml/min per 1.73 m2) (Figure 3D).
Lower serum intact parathyroid hormone (PTH) showed a higher mortality risk among patients with low renal urea clearance (rCLurea), whereas higher serum PTH was associated with higher mortality among patients with high rCLurea. Association of baseline serum intact PTH with all-cause mortality in 35,114 incident hemodialysis patients with baseline rCLurea of (A) <1.5, (B) 1.5 to <3.0, and (C) ≥3.0 and (D) the mortality risk of 12 groups stratified by baseline rCLurea and serum intact PTH in the case mix and malnutrition-inflammation cachexia syndrome (MICS) model (intact PTH of 150 to <300 pg/ml with rCLurea≥3.0 ml/min per 1.73 m2 as the reference).
Association of ALP and All-Cause Mortality according to rCLurea Strata
Higher ALP was associated with higher mortality irrespective of adjustment models overall. Compared with the middle ALP group (i.e., 60 to <80 IU/L), the highest group (i.e., ≥120 IU/L) was associated with higher mortality risk with aHR of 1.36 (95% CI, 1.28 to 1.45) (Supplemental Figure 7D). The association between ALP and mortality was not significantly modified by rCLurea in the fully adjusted models (Pinteraction=0.53). Trends in the adjusted association between ALP and mortality were consistent across rCLurea strata (Figure 4, A–C), which was also supported in models using restricted cubic splines (Supplemental Figure 6). When categorizing patients into 15 groups according to baseline levels of ALP and rCLurea, higher rCLurea was consistently associated with lower mortality risk across serum ALP categories (reference: ALP=60 to <80 U/L and rCLurea≥3.0 ml/min per 1.73 m2; Ptrend<0.001) (Figure 4D).
The association between higher baseline alkaline phosphatase (ALP) and higher mortality was consistent across the three strata of renal urea clearance (rCLurea). Association of baseline serum ALP with all-cause mortality in 35,114 incident hemodialysis patients with baseline rCLurea of (A) <1.5, (B) 1.5 to <3.0, and (C) ≥3.0 ml/min per 1.73 m2 and (D) the mortality risk of 15 groups stratified by baseline rCLurea and serum ALP in the case mix and malnutrition-inflammation cachexia syndrome (MICS) model (ALP of 60 to <80 U/L with rCLurea≥3.0 ml/min per 1.73 m2 as the reference).
Discussion
This study examined the modification of the association of several MBD parameters with mortality by RKF among incident hemodialysis patients and found several novel observations. RKF levels modified the association of phosphorus and intact PTH with all-cause death. The relative mortality risk associated with high serum phosphorus concentrations was stronger in patients with higher rCLurea levels. As for serum intact PTH, lower concentrations showed a higher mortality risk among patients with low rCLurea, whereas higher concentrations were associated with higher mortality among patients with high rCLurea levels. In contrast, higher concentrations of calcium and ALP were associated with all-cause death irrespective of rCLurea levels. Of note, higher rCLurea was associated with better survival across MBD marker categories, with the exception that patients with serum phosphorus ≥7.0 mg/dl showed comparable mortality risk irrespective of rCLurea levels.
Mortality risk associated with high serum phosphorus concentrations was pronounced in the high rCLurea group versus the low rCLurea group. Serum phosphorus was lower among patients on hemodialysis with higher rCLurea levels, which is consistent with the observation that RKF, even at such low levels, contributes to substantial clearance of phosphorus in patients with ESRD (23). High serum phosphorus levels among patients with high RKF may indicate nonadherence to diet, hemodialysis prescription, and/or medications, including phosphorus binders and cinacalcet, as well as high-turnover bone disease. High dietary phosphorus loading has been shown to induce inflammation, malnutrition, vascular calcification, and premature death in rodent CKD models (24,25), and nonuse of phosphorus binders has also been linked to higher mortality (26).
Previous studies have shown a U-shaped or linear association between serum calcium and mortality in patients on hemodialysis depending on the calcium categorizations, assays used, variables accounted for, statistical models, and the underlying study population (12,27–31). Our results also confirmed that higher serum calcium levels were associated with higher mortality risk in the overall analysis, which could be explained by several mechanisms, including vascular calcification, hypertension, and infection (32). Meanwhile, in contrast to the interaction between serum phosphorus and rCLurea, the association of serum calcium with all-cause mortality was not significantly modified by rCLurea. This finding may be explained by the fact that calcium is less likely to be affected by RKF than phosphorus. Recent calcium balance studies have consistently shown that calcium loads resulted in little or no increase in urinary calcium excretion, even in patients with CKD stages 3 and 4 (33,34). Calcium may be excreted into the urine at even lower levels in patients with ESRD and low RKF, and indeed, we did not observe significant differences in albumin-corrected calcium across rCLurea strata.
There have been mixed data on the PTH-mortality association in patients on hemodialysis (1), and these inconsistent findings may be explained by unmeasured or residual confounding by their RKF. Several-fold higher concentrations of intact PTH are required to maintain normal bone turnover among patients with ESRD (35), known as skeletal resistance to PTH (36). This phenomena is partly due to the diminished PTH receptor expression of osteoblast in the uremic milieu (37,38). Also, accumulated bioinactive 7–84 PTH fragment in patients with ESRD interferes with the second generation intact PTH assay, resulting in falsely higher values of PTH (39). However, these abnormalities in the uremic milieu are likely to be less severe among patients with substantial RKF compared with those with little or no RKF (6,40–42). Our study showed for the first time that higher intact PTH levels were associated with lower mortality among patients on hemodialysis with low RKF, whereas higher intact PTH levels showed a higher mortality risk among patients with substantial RKF. Additionally, the effect of impaired capacity of the bone to buffer mineral loads due to low bone turnover may be accentuated among patients with little or no RKF, resulting in accelerated cardiovascular calcification (43,44). In contrast, we observed a consistent association between higher ALP and higher mortality across rCLurea levels. Although PTH affects bone metabolism, ALP is excreted from the bone and arteries with calcification (45), and hence, it is a useful marker of bone metabolism and active osteochondrogenesis (46–48).
Our results can be interpreted from the other viewpoint of the effect modification of the association between RKF levels and mortality by MBD parameters. The association of higher RKF with better survival was attenuated among patients with higher levels of phosphorus and intact PTH. Nevertheless, patients with greater RKF consistently showed better survival even after rigorous adjustment, supporting the recently highlighted importance of RKF in the hemodialysis population (6,20).
Strengths of our study include its large sample size of patients on hemodialysis with RKF data and use of uniform laboratory measurements. However, several limitations should be noted. First, as with other observational studies, our study cannot prove causality. There may also be residual confounding or unmeasured confounders on the basis of vitamin D deficiency, inflammatory status, elevated fibroblast growth factor–23, treatment adherence, and inadequate predialysis care (49–54). Second, RKF may not be accurate given the use of rCLurea, the difficulties in punctual and complete collection of urine samples, and the use of factor 0.9 for estimating average predialysis serum urea. Nevertheless, the population-level associations can be estimated from an adequate number of patients if such errors are not associated with the outcome, and a recent study has shown that change in rCLurea used in this study was closely related to all-cause mortality (20). Third, the reason for urine being collected (or not collected) was not available in this administrative database, and potential selection bias may exist, because patients with limited RKF are less likely to have undergone urine collections. However, similar patterns of association between all MBD markers and mortality were observed between included and excluded patients, suggesting the independence of the eligibility criteria of this study from those associations. Fourth, we included exclusively incident hemodialysis patients, and it is unclear whether our findings can be extrapolated to prevalent hemodialysis patients. Fifth, cause-specific death was not examined given a limited number of each event, even with, so far, the largest number of patients on hemodialysis with data on rCLurea.
In conclusion, our study showed that RKF modified the association of serum phosphorus and intact PTH with all-cause mortality among incident hemodialysis patients, whereas serum calcium and ALP showed consistent associations with mortality irrespective of RKF. Future studies with a long-term follow-up period are needed to explain the underlying mechanisms of those associations and examine whether taking account for RKF in the assessment of mortality risk associated with serum phosphorus and intact PTH improves patient management and clinical outcomes among patients on hemodialysis.
Disclosures
K.K.-Z. has received honoraria from Abbott (Abbott Park, Illinois), Abbvie (North Chicago, Illinois), Alexion (New Haven, Connecticut), Amgen (Thousand Oaks, California), Astra-Zeneca (Wilmington, Delaware), Aveo (Cambridge, Massachusetts), Chugai (Berkeley Heights, New Jersey), DaVita (Denver, Colorado), Fresenius (Waltham, Massachusetts), Genentech (South San Francisco, California), Haymarket Media (Bute Gardens, London, UK), Hospira (Lake Forest, Illinois), Kabi (Lake Zurich, Illinois), Keryx (Boston, Massachusetts), Novartis (New York, New York), Pfizer (New York, New York), Relypsa (Redwood City, California), Resverlogix (Calgary, Alberta, Canada), Sandoz (Princeton, New Jersey), Sanofi-Aventis (Bridgewater, New Jersey), Shire (Lexington, Massachusetts), Vifor (Glattbrugg, Zurich, Switzerland), UpToDate (Waltham, Massachusetts), and ZS Pharma (Coppell, Texas).
Acknowledgments
The work in this manuscript was performed with the support of National Institute of Diabetes, Digestive and Kidney Disease (NIDDK) of the National Institutes of Health research grants R01-DK095668 (to K.K.-Z.), K24-DK091419 (to K.K.-Z.), and R01-DK078106 (to K.K.-Z.). Y.O. is supported by the Uehara Memorial Foundation Research Fellowship for Research Abroad. E.S. is supported by Department of Veterans Affairs grant IK2-CX001266-001. C.M.R. is supported by NIDDK grant K23-DK102903. C.P.K. is supported by NIDDK grants R01-DK096920 and U01-DK102163. K.K.-Z. is supported by philanthropic grants from Mr. Harold Simmons, Mr. Louis Chang, Dr. Joseph Lee, and Aveo.
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.11931116/-/DCSupplemental.
- Received November 21, 2016.
- Accepted April 4, 2017.
- Copyright © 2017 by the American Society of Nephrology
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