Rajiv Saran

Chronic kidney disease: global dimension and perspectives

Chronic kidney disease is defined as a reduced glomerular filtration rate, increased urinary albumin excretion, or both, and is an increasing public health issue. Prevalence is estimated to be 8-16% worldwide. Complications include increased all-cause and cardiovascular mortality, kidney-disease progression, acute kidney injury, cognitive decline, anaemia, mineral and bone disorders, and fractures. Worldwide, diabetes mellitus is the most common cause of chronic kidney disease, but in some regions other causes, such as herbal and environmental toxins, are more common. The poorest populations are at the highest risk. Screening and intervention can prevent chronic kidney disease, and where management strategies have been implemented the incidence of end-stage kidney disease has been reduced. Awareness of the disorder, however, remains low in many communities and among many physicians. Strategies to reduce burden and costs related to chronic kidney disease need to be included in national programmes for non-communicable diseases.

Facility Hemodialysis Vascular Access Use and Mortality in Countries Participating in DOPPS: An Instrumental Variable Analysis

BACKGROUND Previously, the Dialysis Outcomes and Practice Patterns Study (DOPPS) has shown large international variations in vascular access practice. Greater mortality risks have been seen for hemodialysis (HD) patients dialyzing with a catheter or graft versus a native arteriovenous fistula (AVF). To further understand the relationship between vascular access practice and outcomes, we have applied practice-based analyses (using an instrumental variable approach) to decrease the treatment-by-indication bias of prior patient-level analyses. STUDY DESIGN A prospective observational study of HD practices. SETTING & PARTICIPANTS Data collected from 1996 to 2004 from 28,196 HD patients from more than 300 dialysis units participating in the DOPPS in 12 countries. PREDICTOR OR FACTOR Patient-level or case-mix-adjusted facility-level vascular access use. OUTCOMES/MEASUREMENTS: Mortality and hospitalization risks. RESULTS After adjusting for demographics, comorbid conditions, and laboratory values, greater mortality risk was seen for patients using a catheter (relative risk, 1.32; 95% confidence interval, 1.22 to 1.42; P < 0.001) or graft (relative risk, 1.15; 95% confidence interval, 1.06 to 1.25; P < 0.001) versus an AVF. Every 20% greater case-mix-adjusted catheter use within a facility was associated with 20% greater mortality risk (versus facility AVF use, P < 0.001); and every 20% greater facility graft use was associated with 9% greater mortality risk (P < 0.001). Greater facility catheter and graft use were both associated with greater all-cause and infection-related hospitalization. Catheter and graft use were greater in the United States than in Japan and many European countries. More than half the 36% to 43% greater case-mix-adjusted mortality risk for HD patients in the United States versus the 5 European countries from the DOPPS I and II was attributable to differences in vascular access practice, even after adjusting for other HD practices. Vascular access practice differences accounted for nearly 30% of the greater US mortality compared with Japan. LIMITATIONS Possible existence of unmeasured facility- and patient-level confounders that could impact the relationship of vascular access use with outcomes. CONCLUSIONS Facility-based analyses diminish treatment-by-indication bias and suggest that less catheter and graft use improves patient survival.

Prevalence of Chronic Kidney Disease in US Adults with Undiagnosed Diabetes or Prediabetes

BACKGROUND AND OBJECTIVES Prevalence of chronic kidney disease (CKD) in people with diagnosed diabetes is known to be high, but little is known about the prevalence of CKD in those with undiagnosed diabetes or prediabetes. We aimed to estimate and compare the community prevalence of CKD among people with diagnosed diabetes, undiagnosed diabetes, prediabetes, or no diabetes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The 1999 through 2006 National Health and Nutrition Examination Survey is a representative survey of the civilian, noninstitutionalized US population. Participants who were aged > or =20 years; responded to the diabetes questionnaire; and had fasting plasma glucose (FPG), serum creatinine, and urinary albumin-creatinine ratio measurements were included (N = 8188). Diabetes status was defined as follows: Diagnosed diabetes, self-reported provider diagnosis (n = 826); undiagnosed diabetes, FPG > or =126 mg/dl without self-reported diagnosis (n = 299); prediabetes, FPG > or =100 and <126 mg/dl (n = 2272); and no diabetes, FPG <100 mg/dl (n = 4791). Prevalence of CKD was defined by estimated GFR 15 to 59 ml/min per 1.73 m(2) or albumin-creatinine ratio > or =30 mg/g; adjustment was performed with multivariable logistic regression. RESULTS Fully 39.6% of people with diagnosed and 41.7% with undiagnosed diabetes had CKD; 17.7% with prediabetes and 10.6% without diabetes had CKD. Age-, gender-, and race/ethnicity-adjusted prevalence of CKD was 32.9, 24.2, 17.1, and 11.8%, for diagnosed, undiagnosed, pre-, and no diabetes, respectively. Among those with CKD, 39.1% had undiagnosed or prediabetes. CONCLUSIONS CKD prevalence is high among people with undiagnosed diabetes and prediabetes. These individuals might benefit from interventions aimed at preventing development and/or progression of both CKD and diabetes.

Peripheral Arterial Disease in Patients With End-Stage Renal Disease Observations From the Dialysis Outcomes and Practice Patterns Study (DOPPS)

Background— Patients with end-stage renal disease are at high risk for cardiovascular morbidity and mortality. The aims of the present study were to describe the prevalence of peripheral arterial disease (PAD) and its effects on prognosis and health-related quality of life (HRQOL) in an international cohort of patients on hemodialysis. Methods and Results— Data from the Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective, international, observational study of hemodialysis patients (n=29 873), were analyzed. Associations between baseline clinical variables and PAD were evaluated by logistic regression analysis. Cox regression models were used to test the association between PAD and risk for all-cause mortality, cardiac mortality, and hospitalization. PAD was diagnosed in 7411 patients (25.3%) with significant geographic variation. Traditional cardiovascular risk factors including age, male sex, diabetes, hypertension, and smoking were identified, together with the duration of hemodialysis, as significant correlates of PAD. Diagnosis of PAD was associated with increased all-cause mortality (hazard ratio [HR]=1.36; P<0.0001), cardiac mortality (HR=1.43; P<0.0001), all-cause hospitalization (HR=1.19; P<0.0001), and hospitalization for a major adverse cardiovascular event (HR=2.05; P<0.0001). HRQOL questionnaires revealed physical health scores that were significantly lower in PAD compared with non-PAD patients (P<0.0001). Conclusions— PAD is common in hemodialysis patients and is associated with increased risk of cardiovascular mortality, morbidity, and hospitalization and reduced HRQOL.

The survival advantage for haemodialysis patients taking vitamin D is questioned: findings from the Dialysis Outcomes and Practice Patterns Study

BACKGROUND Retrospective studies of haemodialysis patients from large dialysis organizations in the United States have indicated that intravenous vitamin D may be associated with a survival benefit. However, patients prescribed vitamin D are generally healthier than those who are not, suggesting that treatment by indication may have biased previous findings. Additionally, no survival benefit associated with vitamin D has been shown in a recent meta-analysis in CKD patients. Because treatment-by-indication bias due to both measured and unmeasured confounders cannot be completely accounted for in standard regression or marginal structural models (MSMs), this study evaluates the association between vitamin D and mortality among participants in the Dialysis Outcomes and Practice Patterns Study (DOPPS) using standard regression and MSMs with an expanded set of covariates, as well as by instrumental variable models to minimize potential bias due to unmeasured confounders. METHODS Data from 38 066 DOPPS participants from 12 countries between 1996 and 2007 were analysed. Mortality risk was assessed using standard baseline and time-varying Cox regression models, adjusted for demographics and detailed comorbidities, and MSMs. In models similar to instrumental variable analysis, the facility percentage of patients prescribed vitamin D, adjusted for the patient case mix, was used to predict patient-level mortality. RESULTS Vitamin D prescription was significantly higher in the USA compared to other countries. On average, patients prescribed vitamin D had fewer comorbidities compared to those who were not. Vitamin D therapy was associated with lower mortality in adjusted time-varying standard regression models [relative ratio (RR) = 0.92 (95% confidence interval: 0.87-0.96)] and baseline MSMs [RR = 0.84 (0.78-0.98)] and time-varying MSMs [RR = 0.78 (0.73-0.84)]. No significant differences in mortality were observed in adjusted baseline standard regression models for patients with or without vitamin D prescription [RR = 0.98 (0.93-1.02)] or for patients in facility practices where vitamin D prescription was more frequent [RR for facilities in 75th versus 25th percentile of vitamin D prescription = 0.99 (0.94-1.04)]. CONCLUSIONS Vitamin D was associated with a survival benefit in models prone to bias due to unmeasured confounding. In agreement with a meta-analysis of randomized controlled studies, no difference in mortality was observed in instrumental variable models that tend to be more independent of unmeasured confounding. These findings indicate that a randomized controlled trial of vitamin D and clinical outcomes in haemodialysis patients are needed and can be ethically conducted.

Physical exercise among participants in the Dialysis Outcomes and Practice Patterns Study (DOPPS): correlates and associated outcomes

BACKGROUND Levels of physical exercise among haemodialysis patients are low. Increased physical activity in this population has been associated with improved health-related quality of life (HRQoL) and survival. However, results of previous studies may not be applicable to the haemodialysis population as a whole. The present study provides the first description of international patterns of exercise frequency and its association with exercise programmes and clinical outcomes among participants in the Dialysis Outcomes and Practice Patterns Study (DOPPS). METHODS Data from a cross section of 20,920 DOPPS participants in 12 countries between 1996 and 2004 were analysed. Regular exercise was defined as exercise frequency equal to or more than once/week based on patient self-report. Linear mixed models and logistic regression assessed associations of exercise frequency with HRQoL and other psychosocial variables. Mortality risk was calculated in Cox proportional hazard models using patient-level (patient self-reported exercise frequency) and facility-level (the dialysis facility percentage of regular exercisers) predictors. RESULTS Regular exercise frequency varied widely across countries and across dialysis facilities within a country. Overall, 47.4% of participants were categorized as regular exercisers. The odds of regular exercise was 38% higher for patients from facilities offering exercise programmes (adjusted odds ratio = 1.38 [95% confidence interval: 1.03-1.84]; P = 0.03). Regular exercisers had higher HRQoL, physical functioning and sleep quality scores; reported fewer limitations in physical activities; and were less bothered by bodily pain or lack of appetite (P <or= 0.0001 for all). Regular exercise was also correlated with more positive patient affect and fewer depressive symptoms (P <or= 0.0001). In models extensively adjusted for demographics, comorbidities and socio-economic indicators, mortality risk was lower among regular exercisers (hazard ratio = 0.73 [0.69-0.78]; P < 0.0001) and at facilities with more regular exercisers (0.92 [0.89-0.94]; P < 0.0001 per 10% more regular exercisers). CONCLUSIONS Results from an international study of haemodialysis patients indicate that regular exercise is associated with better outcomes in this population and that patients at facilities offering exercise programmes have higher odds of exercising. Dialysis facility efforts to increase patient physical activity may be beneficial.

Longer dialysis session length is associated with better intermediate outcomes and survival among patients on in-center three times per week hemodialysis: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS)

BACKGROUND Longer dialysis session length (treatment time, TT) has been associated with better survival among hemodialysis (HD) patients. The impact of TT on clinical markers that may contribute to this survival advantage is not well known. METHODS Using data from the international Dialysis Outcomes and Practice Patterns Study, we assessed the association of TT with clinical outcomes using both standard regression analyses and instrumental variable approaches. The study included 37,414 patients on in-center HD three times per week with prescribed TT from 120 to 420 min. RESULTS Facility mean TT ranged from 214 min in the USA to 256 min in Australia-New Zealand. Accounting for country effects, mortality risk was lower for patients with longer TT {hazard ratio for every 30 min: all-cause mortality: 0.94 [95% confidence interval (CI): 0.92-0.97], cardiovascular mortality: 0.95 (95% CI: 0.91-0.98) and sudden death: 0.93 (95% CI: 0.88-0.98)}. Patients with longer TT had lower pre- and post-dialysis systolic blood pressure, greater intradialytic weight loss, higher hemoglobin (for the same erythropoietin dose), serum albumin and potassium and lower serum phosphorus and white blood cell counts. Similar associations were found using the instrumental variable approach, although the positive associations of TT with weight loss and potassium were lost. CONCLUSIONS Favorable levels of a variety of clinical markers may contribute to the better survival of patients receiving longer TT. These findings support longer TT prescription in the setting of in-center, three times per week HD.

Serum Potassium and Outcomes in CKD: Insights from the RRI-CKD Cohort Study

BACKGROUND AND OBJECTIVES The relationship between serum potassium (S(K)) and mortality in chronic kidney disease (CKD) has not been systematically investigated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We examined the predictors and mortality association of S(K) in the Renal Research Institute CKD Study cohort, wherein 820 patients with CKD were prospectively followed at four US centers for an average of 2.6 years. Predictors of S(K) were investigated using linear and repeated measures regression models. Associations between S(K) and mortality, the outcomes of ESRD, and cardiovascular events in time-dependent Cox models were examined. RESULTS The mean age was 60.5 years, 80% were white, 90% had hypertension, 36% had diabetes, the average estimated GFR was 25.4 ml/min per 1.73 m(2), and mean baseline S(K) was 4.6 mmol/L. Higher S(K) was associated with male gender, lower estimated GFR and serum bicarbonate, absence of diuretic and calcium channel blocker use, diabetes, and use of angiotensin-converting enzyme inhibitors and/or statins. A U-shaped relationship between S(K) and mortality was observed, with mortality risk significantly greater at S(K) < or = 4.0 mmol/L compared with 4.0 to 5.5 mmol/L. Risk for ESRD was elevated at S(K) < or = 4 mmol/L in S(K) categorical models. Only the composite of cardiovascular events or death as an outcome was associated with higher S(K) (> or = 5.5). CONCLUSIONS Although clinical practice usually emphasizes greater attention to elevated S(K) in the setting of CKD, our results suggest that patients who have CKD and low or even low-normal S(K) are at higher risk for dying than those with mild to moderate hyperkalemia.

Predialysis serum sodium level, dialysate sodium, and mortality in maintenance hemodialysis patients: the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND Predialysis serum sodium concentrations recently have been linked to patient characteristics and outcomes in hemodialysis patients and may have implications for the dialysate sodium prescription. STUDY DESIGN Prospective cohort study. PARTICIPANTS 11,555 patients from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS), phases I (1996-2001) and III (2005-2008). PREDICTORS Demographics, comorbid conditions, laboratory measurements (model 1); mean serum sodium level, dialysate sodium concentration (model 2). OUTCOMES Serum sodium level, using adjusted linear mixed models (model 1); all-cause mortality, using Cox proportional hazards models (model 2). RESULTS Median follow-up was 12 months, with 1,727 deaths (15%) occurring during the study period (12,274 patient-years). Mean serum sodium level in the DOPPS countries was 138.5 ± 2.8 mEq/L. Japan had the highest (139.1 ± 2.6 mEq/L) and Australia/New Zealand had the lowest mean serum sodium level (137.4 ± 2.8 mEq/L). Serum sodium level was associated positively with male sex, black race, body mass index, serum albumin level, and creatinine level and negatively with neurologic and psychiatric disease, white blood cell count, and intradialytic weight loss (0.16 mEq/L lower per 1% loss). Higher serum sodium level was associated with lower adjusted all-cause mortality in a continuous model (HR, 0.95 per 1 mEq/L higher; 95% CI, 0.93-0.97). Dialysate sodium prescription was not associated with serum sodium level. Mortality analyses restricted to the serum sodium tertile with the highest mortality (serum sodium <137 mEq/L) showed lower mortality risk in patients with dialysate sodium prescriptions >140 mEq/L. LIMITATIONS Causality cannot be established in this observational study, which does not consider potential effects of dialysate sodium level on postdialysis thirst, dietary salt and water intake, interdialytic weight gain, and cardiovascular stability. CONCLUSIONS Lower serum sodium levels are associated with certain hemodialysis patient characteristics and higher adjusted risk of death. The lower mortality observed in our adjusted analyses in patients with serum sodium levels <137 mEq/L dialyzed against dialysate sodium prescriptions >140 mEq/L is intriguing, may be related to intradialytic cardiovascular stability, and deserves further study.

Enhanced training in vascular access creation predicts arteriovenous fistula placement and patency in hemodialysis patients: results from the Dialysis Outcomes and Practice Patterns Study.

Objective:To investigate whether intensity of surgical training influences type of vascular access placed and fistula survival. Summary Background Data:Wide variations in fistula placement and survival occur internationally. Underlying explanations are not well understood. Methods:Prospective data from 12 countries in the Dialysis Outcomes and Practice Patterns Study were analyzed; outcomes of interest were type of vascular access in use (fistula vs. graft) in hemodialysis patients at study entry and time from placement until primary and secondary access failures, as predicted by surgical training. Logistic and Cox regression models were adjusted for patient characteristics and time on hemodialysis. Results:During training, US surgeons created fewer fistulae (US mean = 16 vs. 39–426 in other countries) and noted less emphasis on vascular access placement compared with surgeons elsewhere. Significant predictors of fistula versus graft placement in hemodialysis patients included number of fistulae placed during training (adjusted odds ratio [AOR] = 2.2 for fistula placement, per 2 times greater number of fistulae placed during training, P < 0.0001) and degree of emphasis on vascular access creation during training (AOR = 2.4 for fistula placement, for much-to-extreme emphasis vs. no emphasis, P = 0.0008). Risk of primary fistula failure was 34% lower (relative risk = 0.66, P = 0.002) when placed by surgeons who created ≥25 (vs. <25) fistulae during training. Conclusions:Surgical training is key to both fistula placement and survival, yet US surgical programs seem to place less emphasis on fistula creation than those in other countries. Enhancing surgical training in fistula creation would help meet targets of the Fistula First Initiative.