Twice-Weekly Hemodialysis With Adjuvant Pharmacotherapy and Transition to Thrice-Weekly Hemodialysis: A Pilot Study.

RATIONALE & OBJECTIVE: Thrice-weekly hemodialysis (HD) is the most common treatment modality for kidney failure in the United States. We conducted a pilot study to assess the feasibility and safety of incremental-start HD in patients beginning maintenance HD. STUDY DESIGN: Pilot study. SETTING & PARTICIPANTS: Adults with estimated glomerular filtration rate (eGFR) ≥5 mL/min/1.73 m2 and urine volume ≥500 mL/d beginning maintenance HD at 14 outpatient dialysis units. EXPOSURE: Randomized allocation (1:1 ratio) to twice-weekly HD and adjuvant pharmacologic therapy for 6 weeks followed by thrice-weekly HD (incremental HD group) or thrice-weekly HD (conventional HD group). OUTCOME: The primary outcome was feasibility. Secondary outcomes included changes in urine volume and solute clearance. RESULTS: Of 77 patients invited to participate, 51 consented to do so, representing 66% of eligible patients. We randomized 23 patients to the incremental HD group and 25 patients to the conventional HD group. Protocol-based loop diuretics, sodium bicarbonate, and patiromer were prescribed to 100%, 39%, and 17% of patients on twice-weekly HD, respectively. At a mean follow-up of 281.9 days, participant adherence was 96% to the HD schedule (22 of 23 and 24 of 25 in the incremental and conventional groups, respectively) and 100% in both groups to serial timed urine collection. The incidence rate ratio for all-cause hospitalization was 0.31 (95% CI, 0.08-1.17); and 7 deaths were recorded (1 in the incremental and 6 in the conventional group). At week 24, the incremental HD group had lower declines in urine volume (a difference of 51.0 [95% CI, -0.7 to 102.8] percentage points) and in the averaged urea and creatinine clearances (a difference of 57.9 [95% CI, -22.6 to 138.4] percentage points). LIMITATIONS: Small sample size, time-limited twice-weekly HD. CONCLUSIONS: It is feasible to enroll patients beginning maintenance HD into a randomized study of incremental-start HD with adjuvant pharmacotherapy who adhere to the study protocol during follow-up. Larger multicenter clinical trials are indicated to determine the efficacy and safety of incremental HD with longer twice-weekly HD periods. FUNDING: Funding was provided by Vifor Inc. TRIAL REGISTRATION: Registered at ClinicalTrials.gov, identifier NCT03740048.

Association of serum potassium with decline in residual kidney function in incident hemodialysis patients.

BACKGROUND: Hyperkalemia is associated with kidney function decline in patients with non-dialysis dependent chronic kidney disease, but this relationship is unclear for residual kidney function (RKF) among hemodialysis (HD) patients. METHODS: We conducted a retrospective cohort study of 6655 patients, who started HD January 2007 and December 2011 and who had data on renal urea clearance (KRU). Serum potassium levels were stratified into four groups (i.e. ≤4.0, >4.0 to ≤4.5, >4.5 to ≤5.0 and >5.0 mEq/L) and 1-year KRU slope for each group was estimated by a linear mixed-effects model. RESULTS: Higher serum potassium was associated with a greater decline in KRU, and the greatest decrease in KRU (-0.20, 95% confidence interval -0.50 to -0.06) was observed for baseline potassium >5.0 mEq/L in the fully adjusted model. Mediation analysis showed that KRU slope mediated 1.78% of the association between serum potassium and mortality. CONCLUSIONS: Hyperkalemia is associated with a decline in RKF amongst incident HD patients. These findings may have important clinical implications in the management of hyperkalemia in advanced CKD if confirmed in additional clinical trials.

The variable target model: a paradigm shift in the incremental haemodialysis prescription.

Background: The recent interest in incremental haemodialysis (HD) is hindered by the current prescription based on a fixed target model (FTM) for the total (dialytic + renal) equivalent continuous clearance (ECC). The latter is expressed either as standard Kt/V (stdKt/V), i.e. the pre-dialysis averaged concentration of urea-based ECC, or EKRc, i.e. the time averaged concentration-based ECC, corrected for volume (V) = 40 L. Accordingly, there are two different targets: stdKt/V = 2.3 volumes per week (v/wk) and EKRc = 13 mL/min/40 L. However, fixing the total ECC necessarily implies perfect equivalence of its components-the residual renal urea clearance (Kru) and dialysis clearance (Kd). This assumption is wrong because Kru has much greater clinical weight than Kd. Here we propose that the ECC target varies as an inverse function of Kru, from a maximum value in anuria to a minimum value at Kru levels not yet requiring dialysis. The aim of the present study was to compare the current FTM with the proposed variable target model (VTM). Methods: The double pool urea kinetic model was used to model dialysis sessions for 360 virtual patients and establish equations predicting the ECC as a function of Kd, Kru and the number of sessions per week. An end-dialysis urea distribution V of 35 L (corresponding to a body surface area of 1.73 m 2 ) was used, so that the current EKRc target of 13 mL/min/40 L could be recalculated at an EKRc 35 value of 12 mL/min/35 L equal to 12 mL/min/1.73 m 2 . The latter also coincides with the maximum value of the EKRc 35 variable target in anuria. The minimum target value of EKRc 35 was assumed to coincide with Kru corrected for V = 35 L (i.e. Krc 35 = 6 mL/min/1.73 m 2 ). The corresponding target for stdKt/V was assumed to vary from 2.3 v/wk at Krc 35 = 0 to 1.7 v/wk at Krc 35 = 6 mL/min/1.73 m 2 . On this basis, the variable target values can be obtained from the following linear equations: target EKRc 35 = 12 - Krc 35 ; target stdKt/V = 2.3 - 0.1 × Krc 35 . Two versions of stdKt/V were considered: the classic version (stdKt/V Gotch ) with Kru at 70%, and the current version (stdKt/V Daug ) with Kru at 100%. Results: The VTM with stdKt/V Gotch produces results very close to those using the FTM with stdKt/V Daug . Once-weekly HD is virtually not allowed by the FTM. In contrast, the VTM allows dialysis to start at Krc 35 ∼5 mL/min/1.73 m 2 on a once-weekly HD schedule, at least in relatively healthy patients; this schedule can be maintained until Krc 35 falls below 4 mL/min/1.73 m 2 , at which point the schedule should be changed to a twice-weekly HD schedule, that, in turn, could be maintained until Krc 35 falls below 2 mL/min/1.73 m 2 . Conclusions: A paradigm shift from the FTM to the VTM in the prescription of incremental HD is proposed, whereby the VTM would allow less frequent treatments at lower Kru, with important clinical and economic implications. This approach is likely to be safe but needs to be confirmed by randomized controlled trials.

Incremental Hemodialysis, Residual Kidney Function, and Mortality Risk in Incident Dialysis Patients: A Cohort Study.

BACKGROUND: Maintenance hemodialysis is typically prescribed thrice weekly irrespective of a patient's residual kidney function (RKF). We hypothesized that a less frequent schedule at hemodialysis therapy initiation is associated with greater preservation of RKF without compromising survival among patients with substantial RKF. STUDY DESIGN: A longitudinal cohort. SETTING & PARTICIPANTS: 23,645 patients who initiated maintenance hemodialysis therapy in a large dialysis organization in the United States (January 2007 to December 2010), had available RKF data during the first 91 days (or quarter) of dialysis, and survived the first year. PREDICTOR: Incremental (routine twice weekly for >6 continuous weeks during the first 91 days upon transition to dialysis) versus conventional (thrice weekly) hemodialysis regimens during the same time. OUTCOMES: Changes in renal urea clearance and urine volume during 1 year after the first quarter and survival after the first year. RESULTS: Among 23,645 included patients, 51% had substantial renal urea clearance (≥3.0mL/min/1.73m(2)) at baseline. Compared with 8,068 patients with conventional hemodialysis regimens matched based on baseline renal urea clearance, urine volume, age, sex, diabetes, and central venous catheter use, 351 patients with incremental regimens exhibited 16% (95% CI, 5%-28%) and 15% (95% CI, 2%-30%) more preserved renal urea clearance and urine volume at the second quarter, respectively, which persisted across the following quarters. Incremental regimens showed higher mortality risk in patients with inadequate baseline renal urea clearance (≤3.0mL/min/1.73m(2); HR, 1.61; 95% CI, 1.07-2.44), but not in those with higher baseline renal urea clearance (HR, 0.99; 95% CI, 0.76-1.28). Results were similar in a subgroup defined by baseline urine volume of 600mL/d. LIMITATIONS: Potential selection bias and wide CIs. CONCLUSIONS: Among incident hemodialysis patients with substantial RKF, incremental hemodialysis may be a safe treatment regimen and is associated with greater preservation of RKF, whereas higher mortality is observed after the first year of dialysis in those with the lowest RKF. Clinical trials are needed to examine the safety and effectiveness of twice-weekly hemodialysis.

Incremental dialysis: two complementary views.

Franco Casino and Mariana Murea discuss today's knowledge about the 'incremental dialysis' concept. Franco Casino frames the problem by saying that, in the presence of substantial residual kidney function, kidney replacement therapy can begin with low doses and/or frequencies, to be gradually increased to compensate for any subsequent losses of residual kidney function, keeping the total clearance above the minimum levels of adequacy. He remarks that studies so far have documented that this approach is safe. He recognizes that adequate randomized controlled trials (RCTs) are necessary to confirm the safety and simplify and standardize the practical aspects of this approach. Mariana Murea objects that most of the evidence gathered so far primarily derives from retrospective and observational studies, which can be influenced by socioeconomic constraints. She argues for the need for RCTs to provide compelling empirical evidence on the efficacy of incremental dialysis. Nephrologists are still reluctant to adopt this approach for various reasons, including unfamiliarity with the method, lack of practical guidance and financial disincentives. Several countries have ongoing or planned RCTs comparing incremental dialysis with conventional dialysis. These trials can shift the haemodialysis paradigm if they validate the safety and effectiveness of this approach. The moderators believe that the results of ongoing trials must be carefully interpreted, and further validation may be needed across different patient populations or healthcare settings. The ultimate goal is to gather robust evidence that could lead to widespread adoption of incremental haemodialysis, optimizing treatment, reducing overtreatment, preserving resources and improving patients' quality of life.

Residual Kidney Function and Cause-Specific Mortality Among Incident Hemodialysis Patients.

Introduction: The survival benefit of residual kidney function (RKF) in patients on hemodialysis is presumably due to enhanced fluid management and solute clearance. However, data are lacking on the association of renal urea clearance (CLurea) with specific causes of death. Methods: We conducted a longitudinal cohort study of 39,623 adults initiating thrice-weekly in-center hemodialysis from 2007 to 2011 and had data on renal CLurea and urine volume. Multivariable cause-specific proportional hazards model was used to examine the associations between baseline RKF and cause-specific mortality, including sudden cardiac death (SCD), non-SCD cardiovascular death (CVD), and non-CVD. Restricted cubic splines were fitted for change in RKF over 6 months after initiating hemodialysis. Results: Among 39,623 patients with data on baseline renal CLurea and urine volume, there was a significant trend toward a higher mortality risk across lower RKF levels, irrespective of cause of death in a case-mix adjustment model (Ptrend < 0.05). Adjustment for ultrafiltration rate (UFR) slightly attenuated the association between low renal CLurea and high cause-specific mortality, whereas adjustment for highest potassium did not have substantial effect. Among 12,169 patients with data on change in RKF, a 6-month decline in renal CLurea showed graded associations with SCD, non-SCD CVD, and non-CVD risk, whereas the graded associations between faster 6-month decline in urine output and higher death risk were clear only for SCD and non-CVD. Conclusion: Lower RKF and loss of RKF were associated with higher cause-specific mortality among patients initiating thrice-weekly in-center hemodialysis.

The lacking equation that estimates the protein catabolic rate in patients on once-weekly haemodialysis.

BACKGROUND: The normalized protein catabolic rate (PCRn) is one of the key indices derived from the urea kinetic model (UKM) in haemodialysis (HD) patients. Ideally, it should be assessed using the double pool UKM (KDOQI clinical practice guidelines, AIKD, 2015), as the web-based software Solute-Solver (SS) does (Daugirdas et al., AJKD, 2009). Simple formulae exist to compute PCRn for patients on thrice- or twice-weekly HD schedule, but not for patients on once-weekly HD schedule (1HD/wk). Aim of the present technical note was to introduce the lacking equation that estimates PCRn in the 1HD/wk regimen. METHODS: Data of a single HD session associated to monthly UKM studies were retrieved from the electronic database of our dialysis unit for 80 historical patients on 1HD/wk regimen. The UKM parameters, as calculated with SS, were used in a subgroup of 40 randomly selected patients (group 1) to build-up a multiple regression model of PCRn. The latter was used to predict PCRn (PCRnPred) values in the cohort of the remaining 40 patients (group 2). The Bland-Altman plot was used to analyse the agreement between PCRnPred and the paired "observed" (PCRnObs) values, as measured with SS. RESULTS: The following equation was established by means of the multiple regression analysis: PCRn = - 0.46 + 0.01 × C0 + 0.09 × eKt/V + 3.94 × Kru/V, where C0 is pre-dialysis blood urea nitrogen concentration, eKt/V is the equilibrated Kt/V, Kru is the residual renal urea clearance and V is the post-dialysis urea distribution volume. The PCRnPred values were 0.99 ± 0.24 g/kg/day; the PCRnObs values were 0.96 ± 0.23 g/kg/day (mean difference 0.03 ± 0.05 g/kg/day). Their difference at the Bland-Altman analysis ranged from - 0.08 to + 0.13 g/kg/day. Finally, a nomogram was drawn: it can be used to estimate not only PCRn from Kru/V and C0, but also C0 as a function of Kru/V and PCRn. CONCLUSIONS: The equation here introduced allows a simple and accurate estimate of PCRn in patients on once-weekly HD regimen. The availability of the nomogram relating C0 to PCRn and Kru/V could be a further step to make safer and safer the once-weekly HD regimen. The following equation was established by means of the multiple regression analysis [Formula: see text] where PCRn is the normalized protein catabolic rate (PCRn), C0 is pre-dialysis blood urea nitrogen concentration (BUN), eKt/V is the equilibrated Kt/V, Kru is the residual renal urea clearance and V is the post-dialysis urea distribution volume. A nomogram relating pre-dialysis BUN to PCRn and Kru/V could be drawn: it can be used to estimate not only PCRn from Kru/V and pre-dialysis BUN, but also pre-dialysis BUN as a function of Kru/V and PCRn.

Daily Hemodialysis versus Standard Hemodialysis: TAC, TAD, Weekly eKt/V, std(Kt/V), and PCRn.

Seven patients, mean age 42.57 ± 15.69 years (range 21 - 67 years), on standard hemodialysis (SHD), 4 - 5 hours, three times per week for 11.0 ± 6.63 years (range 1 - 18 years), were switched to daily hemodialysis (DHD), 2 - 2.5 hours, six times per week. For each type of treatment similar parameters were applied, and the total weekly time was the same. Mean duration of DHD was 15.4 ± 4.98 months (range 7 - 20 months). We report here our results of quantification in each method, including time-averaged concentration (TAC), normalized protein catabolic rate (PCRn), equilibrated Kt/V (eKt/V), equivalent normalized continuous standard clearance [std(Kt/V)], equivalent renal urea clearance (eKRn), and time-averaged deviation (TAD). With DHD, urea TAC was reduced from 19.09 ± 3.47 to 15.16 ± 3.21 mmol/L (p = 0.026), urea TAD diminished from 4.76 ± 1.04 to 2.52 ± 0.57 mmol/L (p = 0.000 53), PCRn increased from 1.11 ± 0.23 to 1.42 ± 0.24 g/kg/day (p = 0.001), weekly eKt/V increased from 4.11 ± 0.31 to 4.74 ± 0.43 (p = 0.000 25), std(Kt/V) rose from 2.17 ± 0.06 to 4.02 ± 0.25 (p = 0.0001), and eKRn increased from 12.96 ± 0.60 to 21.7 ± 3.09 mL/min (p = 0.000 45). On DHD the most important quantitative variation is the decrease of urea TAD (closer to that of a healthy kidney), due to the increased frequency of dialysis; std(Kt/V) practically doubled and represents 30% of that of normal renal function. These changes are probably the main explanation for the clinical improvements, but it is difficult to dissociate the effects of increased dialysis dose from the effects of decreased TAD.