Short- and Long-term Effects of Dialysate Calcium Concentrations on Mineral and Bone Metabolism in Hemodialysis Patients: The K4 Study.
ABSTRACT: Rationale & Objective:The short- and long-term impact of conversion of dialysate calcium concentration from either 2.5 or 3.0 mEq/L to 2.75 mEq/L on mineral and bone metabolism remains unknown in hemodialysis patients. Study Design:Nonrandomized intervention study. Setting & Population:12 hemodialysis patients treated at baseline with a 2.5-mEq/L dialysate calcium concentration and another 12 hemodialysis patients treated with a 3.0-mEq/L dialysate calcium concentration. Intervention:Use of 2.75-mEq/L dialysate calcium concentration. Outcomes:Changes in intradialytic calcium and phosphate clearance and changes in predialysis and intradialytic serum and ionized mineral and biochemical parameters over the 24 weeks following dialysate calcium conversion. Results:Conversion of dialysate calcium concentration from 2.5 to 2.75 mEq/L increased intradialytic calcium loading and serum total and ionized calcium levels, whereas conversion of dialysate calcium from 3.0 to 2.75 mEq/L decreased intradialytic calcium loading and serum total and ionized calcium levels. Dialysate calcium concentration conversion did not affect intradialytic serum parathyroid hormone level, intradialytic phosphate elimination, or predialysis serum calcium, phosphate, parathyroid hormone, and fibroblast growth factor 23 levels. Intradialytic calcium influx was determined by dialysate calcium concentration and predialysis serum calcium levels, whereas intradialytic phosphate elimination was determined by predialysis serum phosphate levels. Limitations:Small sample size and no control groups treated with 2.5- and 3.0-mEq/L dialysate calcium concentrations during the 24 weeks of the observation period. Conclusions:Conversion of dialysate calcium concentration from either 3.0 or 2.5 to 2.75 mEq/L results in expected changes in calcium loading based on predialysis calcium concentration. The dialysate calcium concentration should be personalized based on clinical factors. Funding:None. Trial Registration:University Hospital Medical Information Network, www.umin.ac.jp/english/, R000040105, UMIN000035184.
Project description:Purpose:Evocalcet is a novel oral calcimimetic drug that has demonstrated similar efficacy to cinacalcet in regulating serum parathyroid hormone (PTH), calcium, and phosphate levels, with fewer upper gastrointestinal tract-related adverse drug reactions (ADRs) in patients with secondary hyperparathyroidism undergoing hemodialysis in Japan. We investigated the efficacy and safety of once-daily oral evocalcet under different dialysate calcium concentrations. Patients and Methods:A post hoc analysis by dialysate calcium concentration (2.5, 2.75, and 3.0 mEq/L) was performed using data from a previous Phase 3 study that included cinacalcet as an active control. Efficacy endpoints were the proportion of patients who achieved the target intact PTH levels of ?60 and ?240 pg/mL between Week 28 and Week 30; time-course changes in serum intact PTH; calcium and phosphorus levels, bone turnover markers, and fibroblast growth factor 23 (FGF23) over the 30-week study period. Safety endpoints were overall ADRs and hypocalcemia- and upper gastrointestinal tract-related ADRs. Results:A total of 634 patients were included in the analysis. Levels of intact PTH, calcium, phosphate, bone turnover markers, and FGF23 showed improvement in all sub-groups, irrespective of dialysate calcium concentration. The incidence of upper gastrointestinal tract-related ADRs was significantly lower in the evocalcet group than the cinacalcet group with dialysate calcium concentrations of 2.75 and 3.0 mEq/L (p<0.05 for both concentrations). Conclusion:Evocalcet was effective and safe in regulating the levels of serum intact PTH, calcium, and phosphate in patients with secondary hyperparathyroidism undergoing hemodialysis, irrespective of dialysate calcium concentration.
Project description:<h4>Background</h4>Observational studies of hemodialysis patients treated thrice weekly have shown that serum and dialysate potassium and bicarbonate concentrations are associated with patient outcomes. The effect of more frequent hemodialysis on serum potassium and bicarbonate concentrations has rarely been studied, especially for treatments at low dialysate flow rate.<h4>Methods</h4>These post-hoc analyses evaluated data from patients who transferred from in-center hemodialysis (HD) to daily HD at low dialysate flow rates during the FREEDOM Study. The primary outcomes were the change in predialysis serum potassium and bicarbonate concentrations after transfer from in-center HD (mean during the last 3?months) to daily HD (mean during the first 3?months).<h4>Results</h4>After transfer from in-center HD to daily HD (data from 345 patients, 51?±?15?years of age, mean?±?standard deviation), predialysis serum potassium decreased (P?<?0.001) by approximately 0.4?mEq/L when dialysate potassium concentration during daily HD was 1?mEq/L; no change occurred when dialysate potassium concentration during daily HD was 2?mEq/L. After transfer from in-center HD to daily HD (data from 284 patients, 51?±?15?years of age), predialysis serum bicarbonate concentration decreased (P?=?0.0022) by 1.0?±?3.3?mEq/L when dialysate lactate concentration was 40?mEq/L but increased (P?<?0.001) by 2.5?±?3.5?mEq/L when dialysate lactate concentration was 45?mEq/L. These relationships were dependent on serum potassium and bicarbonate concentrations during in-center HD.<h4>Conclusions</h4>Control of serum potassium and bicarbonate concentrations during daily HD at low dialysate flow rates is readily achievable; the choice of dialysate potassium and lactate concentration can be informed when transfer is from in-center HD to daily HD.
Project description:AIM:Secondary hyperparathyroidism (SHPT), a complication of haemodialysis, is commonly treated with calcimimetics. The impact of dialysates containing different calcium (Ca) concentrations on clinical efficacy of calcimimetics are unclear. We examined whether dialysate Ca concentrations influence the efficacy and dosing of etelcalcetide with concomitant drugs. METHODS:We performed post hoc analyses of a 52-week, open-label, multicentre study of etelcalcetide in Japanese SHPT patients to determine whether dialysate Ca influences the therapeutic effects of etelcalcetide with concomitant drugs. We evaluated the differences in serum intact parathyroid hormone (iPTH), corrected Ca (cCa) and phosphate levels among three dialysate Ca concentration groups (2.5, 2.75 or 3.0 mEq/L Ca). Tartrate-resistant acid phosphatase 5b (TRACP-5b) and bone alkaline phosphatase (BAP) levels were also compared. Since the dialysate Ca concentration may influence dose adjustment, we assessed the etelcalcetide and concomitant drug doses. RESULTS:There were no clinically meaningful differences in iPTH, cCa and phosphate levels among the 2.5, 2.75 and 3.0 mEq/L groups (n = 34, 64 and 35, respectively) over 52?weeks. At Week 52, more than 82%, 71% and 67% of patients had iPTH, cCa and phosphate levels within target ranges (60-240?pg/mL, 8.4-10.0 mg/dL and 3.5-6.0 mg/dL, respectively) across the three groups. TRACP-5b and BAP levels decreased by Week 52 regardless of dialysate Ca. Changes in etelcalcetide and concomitant drug doses were generally similar in each group. CONCLUSION:The efficacy and dosing of etelcalcetide with concomitant drugs were essentially unaffected by the dialysate Ca concentration. Patients showed improvements in bone hypermetabolism during treatment.
Project description:BACKGROUND:Sudden death is a leading cause of death in patients on maintenance hemodialysis therapy. During hemodialysis sessions, the gradient between serum and dialysate levels results in rapid electrolyte shifts, which may contribute to arrhythmias and sudden death. Controversies exist about the optimal electrolyte concentration in the dialysate; specifically, it is unclear whether patient outcomes differ among those treated with a dialysate potassium concentration of 3 mEq/L compared to 2 mEq/L. STUDY DESIGN:Prospective cohort study. SETTING & PARTICIPANTS:55,183 patients from 20 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 1 to 5 (1996-2015). PREDICTOR:Dialysate potassium concentration at study entry. OUTCOMES:Cox regression was used to estimate the association between dialysate potassium concentration and both all-cause mortality and an arrhythmia composite outcome (arrhythmia-related hospitalization or sudden death), adjusting for potential confounders. RESULTS:During a median follow-up of 16.5 months, 24% of patients died and 7% had an arrhythmia composite outcome. No meaningful difference in clinical outcomes was observed for patients treated with a dialysate potassium concentration of 3 versus 2 mEq/L (adjusted HRs were 0.96 [95% CI, 0.91-1.01] for mortality and 0.98 [95% CI, 0.88-1.08] for arrhythmia composite). Results were similar across predialysis serum potassium levels. As in prior studies, higher serum potassium level was associated with adverse outcomes. However, dialysate potassium concentration had only minimal impact on serum potassium level measured predialysis (+0.09 [95% CI, 0.05-0.14] mEq/L serum potassium per 1 mEq/L greater dialysate potassium concentration). LIMITATIONS:Data were not available for delivered (vs prescribed) dialysate potassium concentration and postdialysis serum potassium level; possible unmeasured confounding. CONCLUSIONS:In combination, these results suggest that approaches other than altering dialysate potassium concentration (eg, education on dietary potassium sources and prescription of potassium-binding medications) may merit further attention to reduce risks associated with high serum potassium levels.
Project description:BACKGROUND:Hemodialysis patients have high rates of sudden death, but relationships between serum electrolytes, the dialysis prescription, and intra-dialytic shifts in fluid and electrolyte with arrhythmia are uncertain. METHODS:We analyzed sixty-six hemodialysis patients who underwent loop recorder implantation with continuous electrocardiographic monitoring, weekly to bi-weekly testing of pre- and post-dialysis electrolytes, and detailed capture of dialysis prescription and flow sheet data for 6?months. The incidence rate ratio (IRR) of reviewer confirmed arrhythmias (RCA) during dialysis through 8?h after dialysis and associations with serum chemistries and dialytic parameters were assessed using adjusted, negative-binomial regression. RESULTS:Among 66 individuals with a mean age of 56?years, 12,480 events were detected in 64 (97%) patients. RCA nadired 12-24?h after dialysis and increased during the final 12?h of the inter-dialytic interval through the first 8?h after dialysis. Higher pre-dialysis serum magnesium concentration was associated with lower incidence rate ratio for arrythmia (IRR per 1?mg/dL increase 0.49, 95% CI; 0.25, 0.94), as was dialysate calcium concentration?>?2.5?mEq/L vs. 2.5?mEq/L (IRR 0.52, 95% CI: 0.39, 0.70). Neither intradialytic serum potassium nor weight change were significantly associated with RCA rate. However, there was effect modification such that arrhythmia rate was maximal with concurrently high intradialytic volume and potassium removal (Pinteraction?=?0.01). CONCLUSIONS:Intra and post-dialytic arrhythmias are common in hemodialysis. Additional studies designed to further elucidate whether modification of the serum magnesium concentration, dialysate calcium concentration, and the extent of intradialytic potassium and fluid removal reduces the risk of per-dialytic arrhythmia are warranted. TRIAL REGISTRATION:Clinicaltrials.gov NCT01779856. Prospectively registered on January 22, 2013.
Project description:<h4>Background and objectives</h4>Almost half of patients on dialysis demonstrate a postdialysis serum potassium ?3.5 mEq/L. We aimed to examine the relationship between postdialysis potassium levels and all-cause mortality.<h4>Design, setting, patients, & measurements</h4>We conducted a cohort study of 3967 participants on maintenance hemodialysis from the Dialysis Outcomes and Practice Patterns Study in Japan (2009-2012 and 2012-2015). Postdialysis serum potassium was measured repeatedly at 4-month intervals and used as a time-varying variable. We estimated the hazard ratio of all-cause mortality rate using Cox hazard regression models, with and without adjusting for time-varying predialysis serum potassium. Models were adjusted for baseline characteristics and time-varying laboratory parameters. We also analyzed associations of combinations of pre- and postdialysis potassium with mortality.<h4>Results</h4>The age of participants at baseline was 65±12 years (mean±SD), 2552 (64%) were men, and 96% were treated with a dialysate potassium level of 2.0 to <2.5 mEq/L. The median follow-up period was 2.6 (interquartile range, 1.3-2.8) years. During the follow-up period, 562 (14%) of 3967 participants died, and the overall mortality rate was 6.7 per 100 person-years. Compared with postdialysis potassium of 3.0 to <3.5 mEq/L, the hazard ratios of postdialysis hypokalemia (<3.0 mEq/L) were 1.84 (95% confidence interval, 1.44 to 2.34) in the unadjusted model, 1.44 (95% confidence interval, 1.14 to 1.82) in the model without adjusting for predialysis serum potassium, and 1.10 (95% confidence interval, 0.84 to 1.44) in the model adjusted for predialysis serum potassium. The combination of pre- and postdialysis hypokalemia was associated with the highest mortality risk (hazard ratio, 1.72; 95% confidence interval, 1.35 to 2.19, reference; pre- and postdialysis nonhypokalemia).<h4>Conclusions</h4>Postdialysis hypokalemia was associated with mortality, but this association was not independent of predialysis potassium.
Project description:<h4>Introduction</h4>The concentration of dialysate calcium (dCa) has been suggested to affect vascular calcification, but evidence is scarce. Calcification propensity reflects the intrinsic capacity of serum to prevent calcium and phosphate to precipitate. The use of citric-acid dialysate may have a beneficial effect on the calcification propensity due to the chelating effect on calcium and magnesium. The aim of this study was to compare the intradialytic and short-term effects of haemodialysis with either standard acetic-acid dialysate with dCa1.50 (A1.5) or dCa1.25 (A1.25), as well as citric-acid dialysate with dCa1.50 (C1.5) in bicarbonate dialysis on the calcification propensity of serum.<h4>Methods</h4>Chronic stable hemodialysis patients were included. This multicenter randomized cross-over study consisted out of a baseline week (A1.5), followed by the randomized sequence of A1.25 or C1.5 for one week after which the alternate treatment was provided after a washout week with A1.5. Calcification propensity of serum was assessed by time-resolved nephelometry where the T50 reflects the transition time between formation of primary and secondary calciprotein particles.<h4>Results</h4>Eighteen patients (median age 70 years) completed the study. Intradialytic change in T50 was increased with C1.5 (121 [90-152]min) compared to A1.25 (83 [43-108]min, p<0.001) and A1.5 (66 [18-102]min, p<0.001). During the treatment week, predialysis T50 increased significantly from the first to the third session with C1.5 (271 [234-291] to 280 [262-339]min, p = 0.002) and with A1.25 (274 [213-308] to 307 [256-337]min, p<0.001), but not with A1.5 (284 [235-346] to 300 [247-335]min, p = 0.33).<h4>Conclusion</h4>Calcification propensity, as measured by the change in T50, improved significantly during treatment in C1.5 compared to A1.25 and A1.5. Long-term studies are needed to investigate the effects of different dialysate compositions concentrations on vascular calcification and bone mineral disorders.
Project description:<h4>Aim</h4>Hyperkalemia increases the risk of sudden cardiac death (SCD) in hemodialysis patients. Our objective was to determine the association between administering low potassium dialysate to hyperkalemic hemodialysis patients and SCD.<h4>Methods</h4>We conducted a retrospective cohort study with patients undergoing maintenance hemodialysis from May 1, 2006, through December 31, 2013. The dialysate composition was adjusted over time according to monthly laboratory results. A 1.0 mEq/L potassium dialysate was applied in patients with predialysis hyperkalemia (>5.5 mEq/L) and was included as a time-dependent confounding factor. The clinical characteristics of enrolled patients, the incidence and timing of SCD and risk factors for all-cause mortality and SCD were analyzed.<h4>Results</h4>There were 312 patients on maintenance hemodialysis during the study period. One hundred and fifty-seven patients had been dialyzed against a 1.0 mEq/L potassium dialysate at least once. The rates of all-cause mortality and SCD were 48.17 and 20.74 per 1000 patient-years, respectively. A 1.12-fold increase in the risk of SCD in the 24-hour period starting with the hemodialysis procedure and a 1.36-fold increase in the 24 hours preceding a weekly cycle were found (p = 0.017). Multivariate Cox proportional hazards models showed that age, diabetes mellitus and predialysis hyperkalemia (>5.0 mEq/L) were significant predictors of all-cause mortality and SCD. Exposure to 1.0 mEq/L potassium dialysate, Kt/V, and serum albumin were independent protective factors against all-cause mortality. Only exposure to 1.0 mEq/L potassium dialysate significantly prevented SCD (hazard ratio = 0.33, 95% CI = 0.13-0.85).<h4>Conclusions</h4>Using low potassium dialysate in hyperkalemic hemodialysis patients may prevent SCD.
Project description:BACKGROUND:Studies examining the association of dialysate potassium concentration and mortality in hemodialysis patients show conflicting findings. We hypothesized that low dialysate potassium concentrations are associated with higher mortality, particularly in patients with high pre-dialysis serum potassium concentrations. METHODS:We evaluated 624 hemodialysis patients from the prospective Malnutrition, Diet, and Racial Disparities in Kidney Disease study recruited from 16 outpatient dialysis facilities over 2011-2015 who underwent protocolized collection of dialysis treatment characteristics every 6 months. We examined the association of dialysate potassium concentration, categorized as 1, 2, and 3 mEq/L, with all-cause mortality risk in the -overall cohort, and stratified by pre-dialysis serum potassium (< 5 vs. ?5 mEq/L) using case-mix adjusted Cox models. RESULTS:In baseline analyses, dialysate potassium concentrations of 1 mEq/L were associated with higher mortality, whereas concentrations of 3 mEq/L were associated with similar mortality in the overall cohort (reference: 2 mEq/L): adjusted hazard ratios (aHRs; 95% CI) 1.70 (1.01-2.88) and 0.95 (0.64-1.39), respectively. In analyses stratified by serum potassium, baseline dialysate potassium concentrations of 1 mEq/L were associated with higher mortality in patients with serum potassium ?5 mEq/L but not in those with serum potassium < 5 mEq/L: aHRs (95% CI) 2.87 (1.51-5.46) and 0.74 (0.27-2.07), respectively (p interaction = 0.04). These findings were robust with incremental adjustment for serum potassium, potassium-binding resins, and potassium-modifying medications. CONCLUSION:Low (1 mEq/L) dialysate potassium -concentrations were associated with higher mortality, particularly in hemodialysis patients with high pre-dialysis serum potassium. Further studies are needed to identify therapeutic strategies that mitigate inter-dialytic serum potassium accumulation and subsequent high dialysate serum potassium gradients in this population.
Project description:Most hemodialysis patients worldwide are treated with bicarbonate dialysis using sodium bicarbonate as the base. Few studies have assessed outcomes of patients treated with different dialysate bicarbonate levels, and the optimal concentration remains uncertain.The Dialysis Outcomes and Practice Patterns Study (DOPPS) is an international prospective cohort study.This study included 17,031 patients receiving thrice-weekly in-center hemodialysis from 11 DOPPS countries (2002-2011).Dialysate bicarbonate concentration.All-cause and cause-specific mortality and first hospitalization, using Cox regression to estimate the effects of dialysate bicarbonate concentration, adjusting for potential confounders.Demographics, comorbid conditions, laboratory values, and prescriptions were abstracted from medical records.Mean dialysate bicarbonate concentration was 35.5 ± 2.7 (SD) mEq/L, ranging from 32.2 ± 2.3 mEq/L in Germany to 37.0 ± 2.6 mEq/L in the United States. Prescription of high dialysate bicarbonate concentration (?38 mEq/L) was most common in the United States (45% of patients). Approximately 50% of DOPPS facilities used a single dialysate bicarbonate concentration. 3,913 patients (23%) died during follow-up. Dialysate bicarbonate concentration was associated positively with mortality (adjusted HR, 1.08 per 4 mEq/L higher [95% CI, 1.01-1.15]; HR for dialysate bicarbonate ?38 vs 33-37 mEq/L, 1.07 [95% CI, 0.97-1.19]). Results were consistent across levels of pre-dialysis session serum bicarbonate and between facilities that used a single dialysate bicarbonate concentration and those that prescribed different concentrations to individual patients. The association of dialysis bicarbonate concentration with mortality was stronger in patients with longer dialysis vintage.Due to the observational nature of the present study, we cannot rule out that the reported associations may be biased by unmeasured confounders.High dialysate bicarbonate concentrations, especially prolonged exposure, may contribute to adverse outcomes, likely through the development of postdialysis metabolic alkalosis. Additional studies are warranted to identify the optimal dialysate bicarbonate concentration.