Author + information
- Received October 14, 2015
- Revision received December 7, 2015
- Accepted December 14, 2015
- Published online March 15, 2016.
- LaTonya J. Hickson, MDa,b,∗ (, )
- Sara M. Negrotto, MDc,
- Macaulay Onuigbo, MDa,
- Christopher G. Scott, MSd,
- Andrew D. Rule, MDa,
- Suzanne M. Norby, MDa,
- Robert C. Albright, DOa,
- Edward T. Casey, DOa,
- John J. Dillon, MDa,
- Patricia A. Pellikka, MDe,
- Sorin V. Pislaru, MD, PhDe,
- Patricia J.M. Best, MDe,
- Hector R. Villarraga, MDe,
- Grace Lin, MDe,
- Amy W. Williams, MDa and
- Vuyisile T. Nkomo, MD, MPHe
- aDivision of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
- bRobert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota
- cDepartment of Medicine, Mayo Clinic, Rochester, Minnesota
- dDivision of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
- eDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
- ↵∗Reprint requests and correspondence:
Dr. LaTonya J. Hickson, Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905.
Background Cardiovascular disease among hemodialysis (HD) patients is linked to poor outcomes. The Acute Dialysis Quality Initiative Workgroup proposed echocardiographic (ECHO) criteria for structural heart disease (SHD) in dialysis patients. The association of SHD with important patient outcomes is not well defined.
Objectives This study sought to determine prevalence of ECHO-determined SHD and its association with survival among incident HD patients.
Methods We analyzed patients who began chronic HD from 2001 to 2013 who underwent ECHO ≤1 month prior to or ≤3 months following initiation of HD (n = 654).
Results Mean patient age was 66 ± 16 years, and 60% of patients were male. ECHO findings that met 1 or more and ≥3 of the new criteria were discovered in 87% and 54% of patients, respectively. Over a median of 2.4 years, 415 patients died: 108 (26%) died within 6 months. Five-year mortality was 62%. Age- and sex-adjusted structural heart disease variables associated with death were left ventricular ejection fraction (LVEF) ≤45% (hazard ratio [HR]: 1.48; confidence interval [CI]: 1.20 to 1.83) and right ventricular (RV) systolic dysfunction (HR: 1.68; CI: 1.35 to 2.07). An additive of higher death risk included LVEF ≤45% and RV systolic dysfunction rather than neither (HR: 2.04; CI: 1.57 to 2.67; p = 0.53 for test for interaction). Following adjustment for age, sex, race, diabetic kidney disease, and dialysis access, RV dysfunction was independently associated with death (HR: 1.66; CI 1.34 to 2.06; p < 0.001).
Conclusions SHD was common in our HD study population, and RV systolic dysfunction independently predicted mortality.
- chronic kidney disease
- heart failure
- left ventricle
- right ventricle
- structural heart disease
Heart failure (HF) contributes significantly to morbidity in patients with end-stage renal disease (ESRD) requiring dialysis (1–5). However, the causes of HF and HF symptoms in dialysis patients are often poorly defined and/or misclassified. Dyspnea or volume overload can be multifactorial and may not be related to underlying structural heart disease (SHD) (6). The Acute Dialysis Quality Initiative (ADQI) XI Workgroup recently proposed a new classification of HF in patients with ESRD that specifically excludes patients with volume overload and a normal heart and focuses on those with underlying SHD as defined by echocardiography (ECHO). The goal of the classification was to optimize diagnostic and therapeutic approaches to HF and address the unique complexities associated with nonphysiological periodic volume removal (6). The 3 elements of the proposed staging system included: 1) standardized ECHO evidence of structural and/or functional heart abnormalities; 2) dyspnea occurring in the absence of primary lung disease, including isolated pulmonary hypertension; and 3) response of congestive symptoms to dialysis/ultrafiltration. Standardized ECHO criteria, adapted from the American Society of Echocardiography (ASE) and European Association of Echocardiography (EAE) consensus guidelines (7–10), assess 8 ECHO abnormalities, of which at least 1 must be present to fulfill the diagnosis of SHD.
The prevalence of SHD based on the proposed criteria and its impact on overall survival in dialysis patients are unknown, and the ADQI XI Workgroup called for research focused on the epidemiology and prognosis of dialysis patients classified with this new scheme. Our study was undertaken to ascertain prevalence of SHD based on the proposed ADQI criteria and to examine prognostic implications of SHD in ESRD patients who were starting maintenance hemodialysis (HD) therapy.
Mayo Clinic Dialysis Services provides all HD in the Mayo Clinic Health System, a comprehensive integrated healthcare network for 395,000 residents in southeastern Minnesota, northern Iowa, and southwestern Wisconsin, through 8 community-based outpatient HD facilities as previously described (11,12). This study included patients ≥18 years of age who began chronic outpatient HD therapy between January 1, 2001, and May 31, 2013 (n = 1,357), who remained on dialysis ≥30 days (n = 1,187), and who underwent ECHO examination at Mayo Clinic ≤1 month prior to or ≤3 months after initiation of HD (n = 654). Primary outcome was all-cause mortality by study end (December 31, 2013). Minnesota research authorization was provided for all participants. The Mayo Clinic Institutional Review Board approved this study.
Baseline characteristics, comorbidities, and laboratory test results were collected through review of the electronic medical record. Data included cause of ESRD, type of initial dialysis access, and initial dialysis location. First dialysis access was categorized as arteriovenous fistula, arteriovenous graft, or central venous catheter. Catheters were further classified as temporary (nontunneled, noncuffed) or tunneled (cuffed). HF diagnosis included congestive HF, systolic HF, diastolic HF, or cardiomyopathy based on manual review of medical records. The Charlson comorbidity index score, consisting of 19 comorbid conditions, was obtained by a previously validated automatic note-search strategy (automated digital algorithm) (13). HD initiation was categorized as occurring before or after the release of the 2005 Kidney Disease Outcomes Quality Initiative clinical practice guidelines (14).
ECHOs performed ≤1 month prior to or ≤3 months after dialysis initiation were identified through the Mayo Clinic Echocardiographic Laboratory database. Indications for ECHO are included in Online Table 1. ECHO was performed according to ASE and EAE guidelines for assessment of valves and chamber size and function (7–10). SHD was defined according to the proposed criteria from the ADQI XI Workgroup (6), except for left ventricular (LV) regional wall motion abnormalities (RWMA). The 16-segment model was used for RWMA assessment, and any RWMA was included (instead of >10% of the myocardium); and right ventricular (RV) systolic dysfunction included semiquantitative assessment. Measurement definitions matched the proposed ADQI XI criteria. Left ventricular hypertrophy (LVH) was defined as LV mass index >110 g/m2 for women and >130 g/m2 for men or LV mass index >47 g/m2.7 for women and >50 g/m2.7 for men. Increased LV volume index was defined as >86 ml/m2 end diastolic volume or >37 ml/m2 end systolic volume. RV systolic dysfunction was defined as lateral tricuspid annulus velocity (S′) <9.5 cm/s or abnormal systolic function by semiquantitative assessment and LV systolic dysfunction as left ventricular ejection fraction (LVEF) ≤45%. Other ADQI XI criteria included left atrial (LA) enlargement (volume index ≥34 ml/m2), diastolic dysfunction grade ≥2, and mitral and/or aortic valvular disease with moderate to severe stenosis or regurgitation. Methods and references for quantitation of the above ECHO variables are provided in the supplemental Materials section in the Online Appendix.
Continuous variables were reported as mean ± SD or median with interquartile ranges (IQR) for non-normally distributed variables. Categorical variables were expressed as count (percent). Comparison of proportions between groups was made using the chi-square test. Continuous variables were compared using 2-sample Student t test or Wilcoxon rank sum test. Primary outcome was all-cause mortality between dialysis start and study period end. Subjects were censored at time of kidney transplantation, transfer to a non-Mayo Clinic dialysis services facility, transition to home dialysis therapies such as peritoneal dialysis or home HD, and study period end. Kaplan-Meier methods were used to summarize event rates, and comparison between groups was done using log-rank test. Age- and sex-adjusted survival curves were created using a semiparametric approach, assuming age and sex followed the proportional hazards assumption, whereas proportional hazards were not required for the grouping variables (15). The association of SHD with mortality was assessed by Cox proportional hazards regression models for long-term outcomes after adjustment for age and sex. Additional models further adjusted for other predictors of mortality (race, diabetes as cause of ESRD, type of dialysis access). For SHD variables with missing values, a missing value indicator was included to estimate the effect of missing values. Multivariate models included only SHD variables that were statistically significant after age and sex adjustment. SHD variables significant in multivariate analysis were simplified into groups for ease of interpretation.
We conducted a series of additional analyses to further evaluate parameters beyond the ADQI proposed criteria. To determine whether pulmonary hypertension (pulmonary artery systolic pressures >35 mm Hg) was also a predictor of survival, Cox regression analyses were performed in those with available pulmonary artery systolic pressures. To minimize the confounding effect of nonphysiological volume overload either prior to start of dialysis or between treatments, Cox regression analyses were repeated among those who had ECHO performed after dialysis initiation and who were further subgrouped to those undergoing dialysis within 24 h before ECHO. Statistical significance was set at a p value of <0.05 (2-sided), and statistical analyses were performed with SAS version 9.4 software (SAS Institute Inc., Cary, North Carolina).
Overall incident dialysis cohort
From January 2001 to May 2013, N = 1,187 patients started and remained on HD ≥1 month. Among these patients, 654 (55%) underwent ECHO ≤1 month prior to or ≤3 months after HD initiation. Baseline demographic characteristics of patients without ECHOs meeting study entry criteria (n = 533 [45%]) are shown in Table 1 and are compared to the study population. Patients without ECHOs had fewer comorbidities including coronary artery disease (48% vs. 56%, respectively, p = 0.003), HF (36% vs. 56%, respectively, p < 0.001), and Charlson score ≥8 (45% vs. 52%, respectively, p = 0.02) but were more likely to have an AV fistula or graft dialysis access present at first dialysis treatment (39% vs. 20%, respectively, p < 0.001) (Online Table 2). Overall survival also differed between groups (Figure 1A). Study patients who underwent ECHOs and did not have SHD had survival rates similar to those of patients without ECHOs who were not included in the study (p = 0.97) (Figure 1B). However, patients with SHD had worse overall survival than those without ECHOs (p < 0.001).
For patients with ECHOs who met study inclusion criteria (n = 654 [55%]), baseline demographics are shown for the overall study group and also were divided by the presence or absence of SHD (Table 1). Mean age of the study was 66 ± 16 years (median 68 years; IQR: 56 to 78 years), and 56% had HF. The mean ± SD Charlson comorbidity index score was 7.5 ± 3.4 (median 8; IQR: 5 to 10). The most common causes of kidney disease were diabetes mellitus (29%), hypertension (15%), and glomerulonephritis (12%). One or more ECHO findings of SHD were present in 567 patients (87%). Compared to those without SHD, patients with ≥1 ECHO finding of SHD at baseline were older (66.7 ± 15.8 years of age vs. 58.5 ± 16.4 years of age, respectively, p < 0.001), had higher prevalence of coronary artery disease (60% vs. 34%, respectively, p < 0.001) and HF (60% vs. 26%, respectively, p < 0.001), and a higher Charlson comorbidity score (7.7 ± 3.3 vs. 6.1 ± 3.4, respectively, p < 0.001).
Echo findings and SHD
Baseline ECHO findings among patients with SHD are shown in Table 2. Median time between ECHO and HD initiation was 0 days (IQR: −4 to 8 days). Most patients (85%) had ≥5 baseline SHD variables documented, and 53% had 7 or 8. A total of 266 patients (44%) had other ECHOs performed within the year preceding the index ECHO that met inclusion criteria, which indicates that repeated acquisition of data for some SHD variables may not have been performed. Within available data, the prevalence of SHD, defined by the presence of ≥1 SHD finding, was high (87% [n = 567]). Among patients with SHD, the most common abnormalities were LA volume index ≥34 ml/m2 (81%), diastolic dysfunction ≥grade 2 (78%), LVH by g/m2 (49%) and by g/m2.7 (71%), and RWMA (50%). Of patients with valvular SHD (16%), mitral regurgitation was the most common (13%), followed by aortic stenosis (3%). RV systolic dysfunction was present in 34% of patients by semiquantitative assessment and 28% by S′ criteria.
Over a median follow-up of 2.4 years (IQR: 0.9 to 4.9 years), 239 subjects were censored, of whom 61 (26%) underwent kidney transplantation, 46 (19%) were transferred to an outside dialysis unit, 32 (13%) had renal recovery, 4 (2%) were transitioned to home HD or PD, and 96 (40%) were alive at the end of the study. Overall, 415 patients died; 108 (26%) of these deaths occurred within 6 months. Cumulative death rates were 17%, 38%, and 62% at 6 months, 2 years, and 5 years, respectively. Causes of death were sudden cardiac arrest (29%), dialysis withdrawal (inpatient or outpatient) leading to death (25%), other causes (10%), sepsis (7%), trauma (0.2%), and unknown causes (28%). In unadjusted analysis, compared to patients with 0 to 1 SHD abnormalities, survival was reduced by the presence of >1 abnormality at baseline (p = 0.002). However, this association was no longer significant following adjustment for age and sex (0 to 1 SHD vs. 2 to 3 SHD, p = 0.75; 0 to 1 SHD vs. >3 SHD, p = 0.13; and 2 to 3 SHD vs. >3 SHD, p = 0.05, with p trend = 0.12). The 2 age- and sex-adjusted SHD variables significantly associated with mortality were LVEF ≤45% (hazard ratio [HR]: 1.48; confidence interval [CI]: 1.20 to 1.83; p < 0.001) and RV systolic dysfunction (HR: 1.68; CI: 1.35 to 2.07, p < 0.001) (Table 3). RV systolic dysfunction was an important predictor of mortality, with the absence of RV dysfunction among SHD patients conferring no evident difference in survival to patients with no SHD at baseline (Central Illustration). In age- and sex-adjusted analyses using patients with no SHD as the reference group, patients with SHD but without RV dysfunction experienced no difference in survival (HR: 0.84; CI: 0.61 to 1.14, p = 0.25), whereas SHD patients with RV dysfunction had reduced survival (HR: 1.41; CI: 1.01 to 1.96, p = 0.04). The combination of RV and LV systolic dysfunction was also a strong determinant of survival. Age- and sex-adjusted relationships among RV systolic function, LVEF, and survival were further explored (Figure 2, Table 4). Patients with impaired LV function (LVEF: ≤45%) and RV systolic dysfunction had an increased risk of death (HR: 2.0; CI: 1.6 to 2.7, p < 0.001) compared to patients with LVEF ≥45% and normal RV systolic function. The combination of these 2 SHD factors was simply additive (test for interaction, p = 0.53). We further assessed RV systolic dysfunction in a model with age, sex, race, diabetic kidney disease, and AV fistula access. RV dysfunction remained associated with death by study end (HR: 1.66; CI: 1.34 to 2.06; p < 0.001).
Sensitivity analyses examined whether our findings were supported among patients who started dialysis prior to ECHO (n = 358). In that cohort, Cox regression analyses revealed 3 important SHD predictors of death, including moderate diastolic dysfunction (HR: 1.49; CI: 1.03 to 2.17, p = 0.04), RV dysfunction (HR: 1.75; CI: 1.30 to 2.36, p < 0.001), and LV systolic dysfunction (HR: 1.74; CI: 1.29 to 2.33, p < 0.001). Analyses were further limited to patients undergoing dialysis treatments ≤24 h prior to their ECHO (n = 190) and revealed similar findings to the original study cohort wherein both RV and LV systolic dysfunction remained the only predictors of death. Separate analyses examined the relationship between pulmonary hypertension and death. Among those with measured pulmonary artery systolic pressure (n = 530), the mean pressure was 46.8 ± 14.8 mm Hg, and 75% of patients had evidence of pulmonary hypertension (pulmonary artery systolic pressure >35 mm Hg). Compared to those without any SHD, those with ≥1 SHD abnormality had higher pulmonary artery systolic pressure (47.9 ± 14.7 vs. 35.0 ± 10.3, respectively, p < 0.001) and higher prevalence of pulmonary hypertension (78% vs. 44%, respectively, p < 0.001). Pulmonary hypertension was associated with reduced survival after adjusting for age and sex (HR: 1.41; CI: 1.08 to 1.84, p = 0.01) but was not independently associated with overall survival when adjusted for RV systolic dysfunction and LVEF ≤45% (HR: 1.26; CI: 0.96 to 1.66, p = 0.09).
In our study cohort, SHD was common, with a substantial majority of the patients having ≥1 baseline ECHO abnormality and more than one-half having ≥3. The presence of SHD was also associated with more comorbidities. Patients with impaired LVEF and RV dysfunction had a 2-fold increased risk of death compared to patients with LVEF >45% and normal RV function. Overall, RV dysfunction appeared to have the strongest association with mortality in this cohort.
The prevalence of underlying SHD is influenced by patient demographics and associated comorbidities, such as higher prevalence of LVH in patients with long-standing or poorly controlled hypertension, either contributing to or a result of their kidney disease. Patients with ESRD have a demonstrated substrate for rapid progression of many SHD subtypes (e.g., calcific valvular lesions) and known risks for ischemic cardiac dysfunction (16).
Left ventricle and mortality
Several studies have shown impaired LVEF, diastolic dysfunction, and LVH as predictors of mortality in dialysis patients (17–25). Yamada et al. (23) found that, in 1,254 incident HD patients of similar age to those in the present study (62 ± 14 years) and who were followed for 7 years, reduced LVEF was present in 13% and was a strong predictor of death from cardiovascular events as well as all-cause mortality. Progressive decline of LVEF was associated with increasing risk of death. We also found LV dysfunction was prevalent and associated with higher risk of mortality.
Diastolic dysfunction of grade 2 or higher was not independently associated with excess mortality in the age- and sex-adjusted analyses of our entire study cohort. However, an association with diastolic dysfunction and mortality was seen in patients who initiated dialysis before an ECHO was performed. Barberato et al. (20) examined a somewhat younger patient group (52 ± 16 years) with no previous cardiovascular disease such as HF, myocardial infarction, or valvular disease. That study found that advanced diastolic dysfunction was independently and significantly predictive of cardiovascular events (including sudden death, acute myocardial infarction, and decompensated HF requiring hospitalization), as well as increased mortality compared to those with normal diastolic function or mild diastolic dysfunction. Han et al. (21) found a strong impact of diastolic dysfunction on cardiovascular events in dialysis patients, although that study included only patients with preserved LV systolic function and defined diastolic dysfunction based on Doppler criteria (mitral early inflow velocity to early mitral annular velocity ratio of E:E′ >15). Dubin et al. (26) demonstrated in a study of 40 patients that E:E′ but not conventional measures of diastolic dysfunction (i.e., classification into impaired relaxation, pseudonormal, and restrictive filling patterns) was associated with elevated N-terminal pro–B-type natriuretic peptide and high-sensitivity troponin. This suggests that Doppler-based data may have greater utility in evaluating cardiac function in the ESRD population. The aforementioned discordant findings may be explained by different patient populations and suggest that further evaluation of how to define diastolic function in ESRD and its impact on patient outcomes is needed.
Silberberg et al. (25) found that LVH (LV mass index >125 g/m2) upon HD initiation was an independent determinant of all-cause mortality in 91 patients (55 ± 15 years of age) followed for ≤5 years. However, that study excluded patients with pre-existing malignancy and those with valvular disease. Paoletti et al. (24) also showed LVH to be predictive of subsequent sudden cardiac death in 123 patients (range: 29 to 79 years of age) who were on HD therapy for at least 6 months and followed for more than 10 years. Our study confirmed the link between impaired LV systolic function but not LVH or diastolic dysfunction and poor outcome.
Right ventricle and mortality
In this study, RV systolic dysfunction was relatively common (27%), and a minority of patients (10%) had moderate to severe dysfunction. RV systolic dysfunction was independently associated with poor survival even when modeled with age, sex, diabetes, ESRD cause, and AV fistula access in a multivariate analysis. RV dysfunction in HD patients is thought to result from chronic volume overload and is exacerbated by AV fistula access, especially in the brachial position (27,28). RV dysfunction in turn leads to an impaired LV. This was shown by Paneni et al. (27) in 120 patients undergoing chronic dialysis, who had preserved LVEF (>50%) in which RV systolic dysfunction correlated with indices of LV systolic and diastolic function and was independently associated with reduced LVEF. The RV-to-LV interdependence and impact of RV dysfunction are known in several cardiac diseases (29–35): RV systolic dysfunction is associated with poor outcomes in severe native aortic valve stenosis (29), is an independent predictor of short- and long-term mortality in patients with HF (31), predicts transplant-free survival in patients with dilated cardiomyopathy (32), is predictive of outcomes in patients who have undergone primary percutaneous coronary intervention for acute myocardial infarction (34), and is associated with clinical and ECHO evidence of more advanced HF predictive of poorer outcomes (36). Our study supports the interdependent relationship between RV and LV, as biventricular failure was associated with a significantly increased risk of death.
This was a retrospective study of ECHO examinations performed over a several-year timeframe in which practice patterns and guidelines changed, including the recommendation for more quantitative RV functional assessment (37,38). However, while semiquantitative RV assessment has limitations (31,37,39), it does afford useful information about RV size and function, provided the ECHO is sufficiently detailed (40,41). Semiquantitative RV assessment correlated well with quantitative assessment in our study. Referral for ECHO <1 month prior to or ≤3 months after HD initiation was not systematic, as shown by the different survivorship between those who had an ECHO and those that did not. Our study nonetheless provides insight into the need for a standardized approach to SHD assessment, emphasizing the position of the ADQI to adopt consistent methodology for collection and documentation of ECHO data in dialysis patients. The predominantly white population of our study may limit generalizability, and a lack of data regarding dialysis-specific factors (adequacy, bone and mineral metabolism, anemia, hypoalbuminemia, and AV fistula duration) may have affected the association of SHD with mortality.
SHD is common among incident HD patients. Both the impaired LV and RV systolic functions were associated with poor outcomes and death. RV systolic dysfunction appears to have important prognostic implications, however additional studies are needed to confirm these findings. Implementation of a standardized comprehensive screening ECHO examination to completely evaluate all SHD variables may help identify HD patients at highest risk of death, inform the need for early intervention to improve patient outcomes, and generate critical conversations with patients related to their prognosis.
COMPETENCY IN PRACTICE-BASED LEARNING: Guidelines recommend screening ECHO to evaluate cardiac structure and function in patients with end-stage renal disease after initiating dialysis.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Patients with end-stage renal disease and RV dysfunction, as assessed by ECHO, are at higher risk of death during the first 6 months after dialysis was initiated than patients with normal RV function.
TRANSLATIONAL OUTLOOK: Additional research is needed to understand the prevalence of SHD and identify predictors of early mortality in patients who start dialysis.
This project was supported by a Mary Kathryn and Michael B. Panitch Career Development Award (to Dr. Hickson); a Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery award (to Dr. Hickson); a Mayo Clinic Rochester-Mayo Clinic Health System Integration award (to Dr. Hickson and Dr. Onuigbo); a Division of Cardiovascular Diseases research grant (to Drs. Hickson, Nkomo, and Scott); and National Center for Advancing Translational Sciences (NCATS) grant UL1 TR000135. Study contents are the sole responsibility of the authors and do not necessarily represent the official views of National Institutes of Health. Dr. Williams is a member of the American Society of Nephrology Public Policy Board. Dr. Pellikka is funded through a research grant from the Intersocietal Accreditation Commission. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
This study was presented in abstract form at: Kidney Week Annual Meeting of the American Society of Nephrology; November 14, 2014; Philadelphia, Pennsylvania.
- Abbreviations and Acronyms
- Acute Dialysis Quality Initiative
- American Society of Echocardiography
- European Association of Echocardiography
- end-stage renal disease
- heart failure
- left ventricular ejection fraction
- left ventricular hypertrophy
- right ventricle
- regional wall motion abnormalities
- standard deviation
- structural heart disease
- Received October 14, 2015.
- Revision received December 7, 2015.
- Accepted December 14, 2015.
- American College of Cardiology Foundation
- ↵U.S. Renal Data System. USRDS 2014 Annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States. National Institute of Diabetes and Digestive and Kidney Diseases, 2014. Available at: http://www.usrds.org/2014/view/Default.aspx Accessed January 17, 2015.
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