Navdeep Tangri

Multinational Assessment of Accuracy of Equations for Predicting Risk of Kidney Failure: A Meta-analysis

IMPORTANCE Identifying patients at risk of chronic kidney disease (CKD) progression may facilitate more optimal nephrology care. Kidney failure risk equations, including such factors as age, sex, estimated glomerular filtration rate, and calcium and phosphate concentrations, were previously developed and validated in 2 Canadian cohorts. Validation in other regions and in CKD populations not under the care of a nephrologist is needed. OBJECTIVE To evaluate the accuracy of the risk equations across different geographic regions and patient populations through individual participant data meta-analysis. DATA SOURCES Thirty-one cohorts, including 721,357 participants with CKD stages 3 to 5 in more than 30 countries spanning 4 continents, were studied. These cohorts collected data from 1982 through 2014. STUDY SELECTION Cohorts participating in the CKD Prognosis Consortium with data on end-stage renal disease. DATA EXTRACTION AND SYNTHESIS Data were obtained and statistical analyses were performed between July 2012 and June 2015. Using the risk factors from the original risk equations, cohort-specific hazard ratios were estimated and combined using random-effects meta-analysis to form new pooled kidney failure risk equations. Original and pooled kidney failure risk equation performance was compared, and the need for regional calibration factors was assessed. MAIN OUTCOMES AND MEASURES Kidney failure (treatment by dialysis or kidney transplant). RESULTS During a median follow-up of 4 years of 721,357 participants with CKD, 23,829 cases kidney failure were observed. The original risk equations achieved excellent discrimination (ability to differentiate those who developed kidney failure from those who did not) across all cohorts (overall C statistic, 0.90; 95% CI, 0.89-0.92 at 2 years; C statistic at 5 years, 0.88; 95% CI, 0.86-0.90); discrimination in subgroups by age, race, and diabetes status was similar. There was no improvement with the pooled equations. Calibration (the difference between observed and predicted risk) was adequate in North American cohorts, but the original risk equations overestimated risk in some non-North American cohorts. Addition of a calibration factor that lowered the baseline risk by 32.9% at 2 years and 16.5% at 5 years improved the calibration in 12 of 15 and 10 of 13 non-North American cohorts at 2 and 5 years, respectively (P = .04 and P = .02). CONCLUSIONS AND RELEVANCE Kidney failure risk equations developed in a Canadian population showed high discrimination and adequate calibration when validated in 31 multinational cohorts. However, in some regions the addition of a calibration factor may be necessary.

Risk prediction models for patients with chronic kidney disease: a systematic review.

BACKGROUND Patients with chronic kidney disease (CKD) are at increased risk for kidney failure, cardiovascular events, and all-cause mortality. Accurate models are needed to predict the individual risk for these outcomes. PURPOSE To systematically review risk prediction models for kidney failure, cardiovascular events, and death in patients with CKD. DATA SOURCES MEDLINE search of English-language articles published from 1966 to November 2012. STUDY SELECTION Cohort studies that examined adults with any stage of CKD who were not receiving dialysis and had not had a transplant; had at least 1 year of follow-up; and reported on a model that predicted the risk for kidney failure, cardiovascular events, or all-cause mortality. DATA EXTRACTION Reviewers extracted data on study design, population characteristics, modeling methods, metrics of model performance, risk of bias, and clinical usefulness. DATA SYNTHESIS Thirteen studies describing 23 models were found. Eight studies (11 models) involved kidney failure, 5 studies (6 models) involved all-cause mortality, and 3 studies (6 models) involved cardiovascular events. Measures of estimated glomerular filtration rate or serum creatinine level were included in 10 studies (17 models), and measures of proteinuria were included in 9 studies (15 models). Only 2 studies (4 models) met the criteria for clinical usefulness, of which 1 study (3 models) presented reclassification indices with clinically useful risk categories. LIMITATION A validated risk-of-bias tool and comparisons of the performance of different models in the same validation population were lacking. CONCLUSION Accurate, externally validated models for predicting risk for kidney failure in patients with CKD are available and ready for clinical testing. Further development of models for cardiovascular events and all-cause mortality is needed. PRIMARY FUNDING SOURCE None.

The impact of frailty on outcomes after cardiac surgery: A systematic review

OBJECTIVE Current preoperative assessments for cardiac surgery, such as the European System for Cardiac Operative Risk Evaluation II and the Society of Thoracic Surgeons risk score, are limited in their ability to predict postoperative outcomes. This is thought to be due to the reliance on chronological age as a predictor of health. In geriatrics, frailty assessments have been developed as a tool in determining physiologic functioning capacity. Whether or not frailty predicts postoperative outcomes independent of existing cardiac preoperative risk scores remains unknown. METHODS We performed a systematic review to determine the association of frailty with negative postoperative outcomes such as major adverse cardiac and cerebrovascular events (MACCE) in patients undergoing cardiac surgery. We searched PubMed, EMBASE, the Cochrane library, and Ageline from inception until July 2013 and screened 5913 abstracts for potential inclusion. Of these, 6 studies examined the relationship between objective frailty assessments and postoperative outcomes. Our included studies evaluated 4756 patients undergoing cardiac surgery. RESULTS Frailty, defined using multiple criteria, had a strong positive relationship with the risk of MACCE (odds ratio, 4.89; 95% confidence interval, 1.64-14.60). Relationships were stronger in older patients undergoing transcatheter aortic valve replacement (TAVR) than younger patients undergoing coronary artery bypass grafting and valvular surgery (hazard ratio for frailty in TAVR, 3.31-4.89 vs hazard ratio for non-TAVR, 1.10-3.16). CONCLUSIONS Patients deemed frail, determined using an objective assessment tool, have a higher likelihood of experiencing mortality, morbidity, functional decline, and MACCE following cardiac surgery, regardless of definition. Further study is needed to determine which components of frailty are most predictive of negative postoperative outcomes before integration in risk prediction scores.

Changes in dietary protein intake has no effect on serum cystatin C levels independent of the glomerular filtration rate

Cystatin C is being considered as a replacement for serum creatinine in the estimation of the glomerular filtration rate (GFR); however, its plasma levels might be affected by factors other than the GFR, such as protein intake. We performed a post hoc analysis of the data in the Modification of Diet in Renal Disease study, in which we compared serum creatinine and cystatin C levels in 741 patients with available estimates of protein intake at baseline prior to their randomization to diets containing various amounts of protein, and at 2 years of follow-up in 426 of these patients in whom a cystatin C measurement was available. The 503 patients in study A (GFR 25-55 ml/min per 1.73 m(2)) had been assigned a low (0.58 g/kg per day) or a usual (1.3 g/kg per day) protein intake, and the 238 participants in study B (GFR 13-24 ml/min per 1.73 m(2)) were assigned a very low (0.28 g/kg per day) or the low protein intake. In either study group, lowering the dietary protein intake reduced the change in creatinine, but did not have a significant change in cystatin C. Thus, in patients with moderate-to-severe chronic kidney disease, serum cystatin C unlike serum creatinine was not affected by dietary protein intake independent of changes in GFR. Hence, cystatin C may allow more accurate estimates of GFR than creatinine for patients with reduced protein intake. Further study of other non-GFR determinants of cystatin C is needed before the widespread adoption.

Predicting Mortality in Incident Dialysis Patients: An Analysis of the United Kingdom Renal Registry

BACKGROUND The risk of death in dialysis patients is high, but varies significantly among patients. No prediction tool is used widely in current clinical practice. We aimed to predict long-term mortality in incident dialysis patients using easily obtainable variables. STUDY DESIGN Prospective nationwide multicenter cohort study in the United Kingdom (UK Renal Registry); models were developed using Cox proportional hazards. SETTING & PARTICIPANTS Patients initiating hemodialysis or peritoneal dialysis therapy in 2002-2004 who survived at least 3 months on dialysis treatment were followed up for 3 years. Analyses were restricted to participants for whom information for comorbid conditions and laboratory measurements were available (n = 5,447). The data set was divided into data sets for model development (n = 3,631; training) and validation (n = 1,816) using random selection. PREDICTORS Basic patient characteristics, comorbid conditions, and laboratory variables. OUTCOMES All-cause mortality censored for kidney transplant, recovery of kidney function, and loss to follow-up. RESULTS In the training data set, 1,078 patients (29.7%) died within the observation period. The final model for the training data set included patient characteristics (age, race, primary kidney disease, and treatment modality), comorbid conditions (diabetes, history of cardiovascular disease, and smoking), and laboratory variables (hemoglobin, serum albumin, creatinine, and calcium levels); reached a C statistic of 0.75 (95% CI, 0.73-0.77); and could discriminate accurately among patients with low (6%), intermediate (19%), high (33%), and very high (59%) mortality risk. The model was applied further to the validation data set and achieved a C statistic of 0.73 (95% CI, 0.71-0.76). LIMITATIONS Number of missing comorbidity data and lack of an external validation data set. CONCLUSIONS Basic patient characteristics, comorbid conditions, and laboratory variables can predict 3-year mortality in incident dialysis patients with sufficient accuracy. Identification of subgroups of patients according to mortality risk can guide future research and subsequently target treatment decisions in individual patients.

Non-invasive endothelial function testing and the risk of adverse outcomes: a systematic review and meta-analysis

OBJECTIVES We performed a systematic review and meta-analysis to understand the role of flow-mediated dilatation (FMD) of the brachial artery (BA) and peripheral arterial tonometry (PAT) in predicting adverse events, including cardiovascular (CV) events and all-cause mortality. BACKGROUND FMD of the BA and PAT are non-invasive measures of endothelial function. Impairment of endothelial function is associated with increased CV events. While FMD is the more widely used and studied technique, PAT offers several advantages. The purpose of this systematic review and meta-analysis is to determine whether brachial FMD and PAT are independent risk factors for future CV events and mortality. METHODS Multiple electronic databases were searched for articles relating FMD or PAT to CV events. Data were extracted on study characteristics, study quality, and study outcomes. Relative risks (RRs) from individual studies were combined and a pooled multivariate RR was calculated. RESULTS Thirty-six studies for FMD were included in the systematic review, of which 32 studies consisting of 15, 191 individuals were meta-analysed. The pooled RR of CV events and all-cause mortality per 1% increase in brachial FMD, adjusting for potential confounders, was 0.90 (0.88-0.92). In contrast, only three studies evaluated the prognostic value of PAT for CV events, and the pooled RR per 0.1 increase in reactive hyperaemia index was 0.85 (0.78-0.93). CONCLUSION Brachial FMD and PAT are independent predictors of CV events and all-cause mortality. Further research to evaluate the prognostic utility of PAT is necessary to compare it with FMD as a non-invasive endothelial function test in clinical practice.

Vascular Access Choice in Incident Hemodialysis Patients: A Decision Analysis

Hemodialysis vascular access recommendations promote arteriovenous (AV) fistulas first; however, it may not be the best approach for all hemodialysis patients, because likelihood of successful fistula placement, procedure-related and subsequent costs, and patient survival modify the optimal access choice. We performed a decision analysis evaluating AV fistula, AV graft, and central venous catheter (CVC) strategies for patients initiating hemodialysis with a CVC, a scenario occurring in over 70% of United States dialysis patients. A decision tree model was constructed to reflect progression from hemodialysis initiation. Patients were classified into one of three vascular access choices: maintain CVC, attempt fistula, or attempt graft. We explicitly modeled probabilities of primary and secondary patency for each access type, with success modified by age, sex, and diabetes. Access-specific mortality was incorporated using preexisting cohort data, including terms for age, sex, and diabetes. Costs were ascertained from the 2010 USRDS report and Medicare for procedure costs. An AV fistula attempt strategy was found to be superior to AV grafts and CVCs in regard to mortality and cost for the majority of patient characteristic combinations, especially younger men without diabetes. Women with diabetes and elderly men with diabetes had similar outcomes, regardless of access type. Overall, the advantages of an AV fistula attempt strategy lessened considerably among older patients, particularly women with diabetes, reflecting the effect of lower AV fistula success rates and lower life expectancy. These results suggest that vascular access-related outcomes may be optimized by considering individual patient characteristics.

Filtration Markers May Have Prognostic Value Independent of Glomerular Filtration Rate

Serum levels of creatinine, cystatin C, or β trace protein allow estimation of GFR, but whether these markers contribute additional prognostic information beyond that reflected in GFR is unknown. Here, we analyzed data from the Modification of Diet in Renal Disease study, which provided baseline levels of these markers for 816 participants with a median follow-up of 16.6 years. We examined associations between the reciprocals of these filtration markers and (125)I iothalamate GFR, expressed per SD, with kidney failure and mortality. In univariate analysis, lower GFR and higher levels of each filtration marker associated with a higher risk for all outcomes. After adjustment for GFR in a Cox proportional hazards model, higher creatinine associated with a higher risk for kidney failure but a lower risk for all-cause mortality. Higher cystatin C and β trace protein associated with a higher risk for both kidney failure and all-cause mortality. In models including either cystatin C or β trace protein, the association of GFR with all-cause mortality was no longer significant after the addition of the filtration marker, suggesting the possibility of multicollinearity. In summary, after adjustment for GFR, levels of creatinine, cystatin C, and β trace protein, each remained directly associated with kidney failure but differed with respect to their associations with mortality. These differences may be a result of non-GFR-related associations of filtration markers, residual confounding by GFR, or collinearity between the filtration markers and GFR. β trace protein and cystatin C seem to provide more consistent prognostic information than creatinine.

Association of frailty and physical function in patients with non-dialysis CKD: a systematic review

BackgroundFrailty is a condition characterized by a decline in physical function and functional capacity. Common symptoms of frailty, such as weakness and exhaustion, are prevalent in patients with chronic kidney disease (CKD). The increased vulnerability of frail patients with coexisting CKD may place them at a heightened risk of encountering additional health complications. The purpose of this systematic review was to explore the link between frailty, CKD and clinical outcomes.MethodsWe searched for cross sectional and prospective studies in the general population and in the CKD population indexed in EMBASE, Pubmed, Web of Science, CINAHL, Cochrane and Ageline examining the association between frailty and CKD and those relating frailty in patients with CKD to clinical outcomes.ResultsWe screened 5,066 abstracts and retrieved 108 studies for full text review. We identified 7 studies associating frailty or physical function to CKD. From the 7 studies, we identified only two studies that related frailty in patients with CKD to a clinical outcome. CKD was consistently associated with increasing frailty or reduced physical function [odds ratios (OR) 1.30 to 3.12]. In patients with CKD, frailty was associated with a greater than two-fold higher risk of dialysis and/or death [OR from 2.0 to 5.88].ConclusionsCKD is associated with a higher risk of frailty or diminished physical function. Furthermore, the presence of frailty in patients with CKD may lead to a higher risk of mortality. Further research must be conducted to understand the mechanisms of frailty in CKD and to confirm its association with clinical outcomes.

Predictors of Sudden Cardiac Death: A Competing Risk Approach in the Hemodialysis Study

BACKGROUND AND OBJECTIVES There are few data on risk factors for sudden cardiac death (SCD) in patients undergoing hemodialysis (HD). The study objective was to identify predictors associated with various causes of death in the Hemodialysis (HEMO) Study and to develop a prediction model for SCD using a competing risk approach. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In this analysis of 1745 HEMO participants, all-cause mortality was classified as SCD, non-SCD, and noncardiac death. Predictors for each cause of death were evaluated using cause-specific Cox proportional hazards models, and a competing risk approach was used to calculate absolute risk predictions for SCD. RESULTS During a median follow-up of 2.5 years, 808 patients died. Rates of SCD, non-SCD, and noncardiac death were 22%, 17%, and 61%, respectively. Predictors of various causes of death differ somewhat in HD patients. Age, diabetes, peripheral vascular disease, ischemic heart disease, serum creatinine, and alkaline phosphatase were independent predictors of SCD. The 3-year C-statistic for SCD was 0.75 (95% confidence interval, 0.70-0.79), and calibration was good (χ(2)=1.1; P=0.89). At years 3 and 5 of follow-up, the standard Cox model overestimated the risk for SCD as compared with the competing risk approach on the relative scale by 25% and 46%, respectively, and on the absolute scale by 2% and 6%, respectively. CONCLUSIONS Predictors of various causes of death differ in HD patients. The proposed prediction model for SCD accounts for competing causes of death. External validation of this model is required.