Katherine E. Lynch

Association of Mortality Risk with Various Definitions of Intradialytic Hypotension

Intradialytic hypotension is a serious and frequent complication of hemodialysis; however, there is no evidence-based consensus definition of intradialytic hypotension. As a result, coherent evaluation of the effects of intradialytic hypotension is difficult. We analyzed data from 1409 patients in the HEMO Study and 10,392 patients from a single large dialysis organization to investigate the associations of commonly used intradialytic hypotension definitions and mortality. Intradialytic hypotension definitions were selected a priori on the basis of literature review. For each definition, patients were characterized as having intradialytic hypotension if they met the corresponding definition in at least 30% of baseline exposure period treatments or characterized as control otherwise. Overall and within subgroups of patients with predialysis systolic BP<120 or 120-159 mmHg, an absolute nadir systolic BP<90 mmHg was most potently associated with mortality. Within the subgroup of patients with predialysis BP≥160 mmHg, nadir BP<100 mmHg was most potently associated with mortality. Intradialytic hypotension definitions that considered symptoms, interventions, and decreases in BP during dialysis were not associated with outcome, and when added to nadir BP, symptom and intervention criteria did not accentuate associations with mortality. Our results suggest that nadir-based definitions best capture the association between intradialytic hypotension and mortality.

Prescribed dietary phosphate restriction and survival among hemodialysis patients.

BACKGROUND AND OBJECTIVES Hyperphosphatemia is common among hemodialysis patients. Although prescribed dietary phosphate restriction is a recommended therapy, little is known about the long-term effects on survival. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a post hoc analysis of data from the Hemodialysis Study (n = 1751). Prescribed dietary phosphate was recorded at baseline and annually thereafter. Marginal structural proportional hazard models were fit to estimate the adjusted association between dietary phosphate restriction and mortality in the setting of time-dependent confounding. RESULTS At baseline, prescribed daily phosphate was restricted to levels ≤ 870, 871 to 999, 1000, 1001 to 2000 mg, and not restricted in 300, 314, 307, 297, and 533 participants, respectively. More restrictive prescribed dietary phosphate was associated with poorer indices of nutritional status on baseline analyses and a persistently greater need for nutritional supplementation but not longitudinal changes in caloric or protein intake. On marginal structural analysis, there was a stepwise trend toward greater survival with more liberal phosphate prescription, which reached statistical significance among subjects prescribed 1001 to 2000 mg/d and those with no specified phosphate restriction: hazard ratios (95% CIs) 0.73 (0.54 to 0.97) and 0.71 (0.55 to 0.92), respectively. Subgroup analysis suggested a more pronounced survival benefit of liberal dietary phosphate prescription among nonblacks, participants without hyperphosphatemia, and those not receiving activated vitamin D. CONCLUSIONS Prescribed dietary phosphate restriction is not associated with improved survival among prevalent hemodialysis patients, and increased level of restriction may be associated with greater mortality particularly in some subgroups.

Updates on the Management of Diabetes in Dialysis Patients

Diabetes mellitus is the leading cause of end‐stage renal disease (ESRD) in the U.S. and many countries globally. The role of improved glycemic control in ameliorating the exceedingly high mortality risk of diabetic dialysis patients is unclear. The treatment of diabetes in ESRD patients is challenging, given changes in glucose homeostasis, the unclear accuracy of glycemic control metrics, and the altered pharmacokinetics of glucose‐lowering drugs by kidney dysfunction, the uremic milieu, and dialysis therapy. Up to one‐third of diabetic dialysis patients may experience spontaneous resolution of hyperglycemia with hemoglobin A1c (HbA1c) levels <6%, a phenomenon known as “Burnt‐Out Diabetes,” which remains with unclear biologic plausibility and undetermined clinical implications. Conventional methods of glycemic control assessment are confounded by the laboratory abnormalities and comorbidities associated with ESRD. Similar to more recent approaches in the general population, there is concern that glucose normalization may be harmful in ESRD patients. There is uncertainty surrounding the optimal glycemic target in this population, although recent epidemiologic data suggest that HbA1c ranges of 6% to 8%, as well as 7% to 9%, are associated with increased survival rates among diabetic dialysis patients. Lastly, many glucose‐lowering drugs and their active metabolites are renally metabolized and excreted, and hence, require dose adjustment or avoidance in dialysis patients.

Association Between Long-term Blood Pressure Variability and Mortality Among Incident Hemodialysis Patients

BACKGROUND Blood pressure variability (BPV) is one putative risk factor for cardiovascular disease and mortality in hemodialysis patients. The purposes of this study are to identify a suitable metric of long-term BPV in this population and determine whether an association between BPV and all-cause mortality exists. STUDY DESIGN Retrospective cohort study. SETTINGS & PARTICIPANTS Patients from the Accelerated Mortality on Renal Replacement (ArMORR) cohort who were adult, incident to hemodialysis at any Fresenius Medical Care unit between June 2004 and August 2005, and had suitable blood pressure data were studied (n = 6,961). PREDICTOR Predialysis blood pressures measured between dialysis days 91 and 180 were used to determine each patients absolute level of, trend in (slope over time), and variability in blood pressure. OUTCOME All-cause mortality beginning immediately after day 180 and continuing through day 365 or until censoring (median follow-up, 185 days). RESULTS Of the 4 candidate BPV metrics, only average residual-intercept ratio adequately distinguished BPV from absolute blood pressure level and temporal blood pressure trend. In the primary analysis, each SD increase in systolic and diastolic BPV was associated with adjusted hazard ratios for all-cause mortality of 1.13 (95% confidence interval, 1.03 to 1.23) and 1.15 (95% confidence interval, 1.06 to 1.26), respectively. Results were consistent across multiple sensitivity analyses in which inclusion and exclusion criteria and timing of blood pressure measurements were varied. LIMITATIONS Contingency of results on the validity of mathematic description of BPV; potential for misclassification bias and residual confounding. CONCLUSIONS Provided the mathematical descriptions of BPV are valid, the data suggest that systolic and diastolic BPV is associated with all-cause mortality in incident hemodialysis patients. Additional study is necessary to confirm and generalize findings, assess the interplay between systolic and diastolic BPV, and assess causality.

Association of Hemoglobin Variability and Mortality among Contemporary Incident Hemodialysis Patients

BACKGROUND AND OBJECTIVES Evidence exists that variability in hemoglobin may be an independent risk factor for mortality among hemodialysis patients. These observations were based on a 1996 cohort, a time when anemia management differed greatly from present. Design, settings, participants and measurements: A retrospective cohort study of patients incident to Fresenius Medical Care units between 2004 and 2005 (n = 6644). Hemoglobin variability (Hgb-Var) was defined for each subject as the residual SD of a linear regression model of time on hemoglobin. RESULTS The mean (SD) of Hgb-Var was 1.13 (0.55) g/dl. In the primary analysis, each g/dl increase of Hgb-Var was associated with an adjusted hazard ratio (95% confidence interval) for all-cause mortality of 1.11 (0.92 to 1.33). No significant interaction with Hgb-Var and mortality was found on the basis of age (P = 0.22), arterial disease (P = 0.45), Hgb slope (P = 0.68), or mean Hgb (P = 0.78). When Hgb-Var was defined by a regression model that included a quadratic term for time (enabling descriptions of curvilinear hemoglobin trajectories), model fit was greatly improved (P for difference <0.001). The corresponding adjusted hazard ratio (95% confidence interval) for all-cause mortality was 1.17 (0.93 to 1.49). CONCLUSIONS Hgb-Var was not found to be associated with all-cause mortality when examined in a contemporary incident hemodialysis population. More research is needed to determine whether differences in these findings compared with prior analyses relate to temporal trends in anemia management or from differences in the relationship between Hgb-Var and outcomes among incident versus prevalent hemodialysis patients.

Effects of L-carnitine on dialysis-related hypotension and muscle cramps: a meta-analysis.

BACKGROUND L-Carnitine is an endogenous compound thought to be helpful in treating patients with dialysis-related hypotension and muscle cramps; however, sufficient evidence for these indications is lacking. STUDY DESIGN Systematic review and meta-analysis. SETTING & POPULATION Adult patients with end-stage renal disease receiving long-term hemodialysis. SELECTION CRITERIA FOR STUDIES All published English-language reports of randomized placebo-controlled trials of L-carnitine supplementation in adult long-term hemodialysis patients. INTERVENTION Supplemental L-carnitine (or placebo) for at least 8 weeks. OUTCOME Random-effects pooled odds ratio for intradialytic cramping or hypotension in L-carnitine-treated participants. RESULTS Of 317 potentially relevant articles, 7 (total enrollment of 193 patients) met criteria for inclusion. Four articles reported results for both hypotension and cramps, 1 had results for only hypotension, and 2 reported results for only cramps. Using data from all 6 relevant trials, the pooled odds ratio for cramping after L-carnitine supplementation was 0.30 (95% confidence interval, 0.09 to 1.00; P = 0.05). Analysis of the 5 studies examining the response of intradialytic hypotension to l-carnitine supplementation yielded a pooled odds ratio of 0.28 (95% confidence interval, 0.04 to 2.23; P = 0.2). LIMITATIONS The small number of available studies yielded limited statistical power. In addition, there was considerable interstudy heterogeneity. CONCLUSIONS Although suggestive in the case of muscle cramping, the available evidence does not confirm a beneficial effect of L-carnitine supplementation on dialysis-related muscle cramping or intradialytic hypotension. Additional study in the form of large rigorous randomized trials is needed in both cases.

Sodium modelling to reduce intradialytic hypotension during haemodialysis for acute kidney injury in the intensive care unit.

Intradialytic hypotension often complicates haemodialysis for patients with acute kidney injury (AKI) and may impact renal recovery. Sodium modelling is sometimes used as prophylaxis against intradialytic hypotension in the chronic haemodialysis population, but there is little evidence for its use among critically ill patients with AKI.

Thiazolidinedione use is associated with improved all-cause mortality compared with sulfonylureas among diabetic hemodialysis patients.

Among diabetics on hemodialysis (HD), there are conflicting data as to whether thiazolidinedione (TZD) use improves or worsens survival. Ramirez et al. compared rosiglitazone and pioglitazone with non-TZD oral hypoglycemic agents and found 38% higher all-cause mortality and 59% higher cardiovascular mortality among rosiglitazone users, although no differences were seen for pioglitazone. In contrast, Brunelli et al. compared any TZD use with non-users and found 53% lower all-cause mortality among non-insulin users who used TZDs; no significant difference was seen among insulin users. Recent data in the general type 2 diabetic population have shown better survival among incident rosiglitazone versus glipizide users. However, data from the general population may not apply to dialysis patients because of unique physiological circumstances, greater burden of illness among dialysis patients, and competing risks. We conducted the present study to evaluate the comparative effectiveness of TZD versus sulfonylurea (SU) use with respect to mortality among HD patients. Data for the present retrospective study were obtained from a randomly selected cohort of 14 643 prevalent adult patients receiving thrice-weekly in-center HD in one of 1247 facilities operated by a large US dialysis organization between 1 January 2005 and 16 January 2009. We identified 608 patients with incident use of TZD or SU during the study period. Use of a TZD or SU was taken as evidence that these patients were diabetic. Incident use was defined as a new prescription, which started after a period of at least 90 days, during which the patient was dialyzed at the clinic and was not receiving either medication. Incident TZD users were matched (1:n) with replacement to incident SU users on the basis of insulin use and on a propensity score based on age, sex, race, dry weight, catheter use, heart failure, and serum albumin. Patients were considered at-risk for the outcome of all-cause mortality immediately after the start of the new TZD or SU prescription and remained at risk until death, transfer of care, transplant, or end of study (21 February 2009). Standardized differences were used to compare matched groups; standardized difference >10% (or <–10%) signifies substantive imbalance. Associations with mortality were estimated using Cox proportional hazard models. All analyses were performed using Stata 12 (StataCorp LP, College Station, TX, USA). This study was deemed exempt by the Partners Healthcare Institutional Review Board. In the unmatched cohort, unadjusted Kaplan–Meier survival curves showed an association between improved survival and TZD use compared with SU use (Fig. 1). Overall, 230 incident TZD users were matched to 434 incident SU users (94 TZD to 168 SU on insulin; 136 TZD to 266 SU not on insulin). Cumulative at-risk time was 966 patient-years; 207 deaths occurred. Baseline characteristics of TZD and matched SU users are presented in Table 1; the two groups were similar in terms of all variables studied, except that TZD users were more likely to have pre-existing liver disease and, on average, had a shorter dialysis vintage. Incident TZD users had a significantly lower risk of death (hazard ratio [HR] 0.70; 95% confidence interval [CI] 0.53–0.92). In contrast with the unadjusted analysis, there was suggestion of effect modification based on concurrent insulin status (Pinteraction = 0.06); the HR (95% CI) for TZD versus SU was 0.57 (0.40–0.82) among patients not on insulin, and 0.99 (0.63–1.55) among insulin users. For diabetics on HD, TZD use versus SU use was associated with 30% lower all-cause mortality. These findings are similar to the results obtained by Brunelli et al., who showed that TZD use versus non-use was Correspondence Katherine Lynch, 185 Pilgrim Road, Farr 8, Boston, MA 02215, USA. Tel.: +1 617 632 9880 Fax: +1 617 632 9890 Email: kelynch@bidmc.harvard.edu Received: 22 October 2013; revised 27 November 2013; accepted 8 December 2013. doi: 10.1111/1753-0407.12115 bs_bs_banner