Seroresponse to Inactivated and Recombinant Influenza Vaccines Among Maintenance Hemodialysis Patients.

RATIONALE & OBJECTIVE: High-dose influenza vaccine provides better protection against influenza infection in older adults than standard-dose vaccine. We compared vaccine seroresponse among hemodialysis patients over a period of 4 months after administration of high-dose trivalent inactivated (HD-IIV3), standard-dose quadrivalent inactivated (SD-IIV4), or quadrivalent recombinant quadrivalent (RIV4) influenza vaccine. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: Patients at 4 hemodialysis clinics who received influenza vaccine. EXPOSURE: Type of influenza vaccine. OUTCOME: Hemagglutination inhibition (HI) titers were measured at baseline and at 1, 2, 3, and 4 months after vaccination. The primary outcome was seroprotection rates at HI titers of at least 1:40 and at least 1:160 (antibody levels providing protection from infection in approximately 50% and 95% of immunocompetent individuals, respectively) at 1, 2, 3, and 4 months after vaccination. ANALYTICAL APPROACH: We calculated geometric mean titer as well as seroprotection and seroconversion rates. Adjusted generalized linear models with additional trend analyses were performed to evaluate the association between vaccine type and outcomes. RESULTS: 254 hemodialysis patients were vaccinated against influenza with HD-IIV3 (n = 141), SD-IIV4 (n = 36), or RIV4 (n = 77). A robust initial seroresponse to influenza A strains was observed after all 3 vaccines. Geometric mean titer and seroprotection (HI titer ≥1:160) rates against influenza A strains were higher and more sustained with HD-IIV3 than SD-IIV4 or RIV4. More than 80% of patients vaccinated with HD-IIV3 were seroprotected (HI titer ≥1:160) at month 4 (P < 0.001), whereas, among patients vaccinated with SD-IIV4 or RIV4, seroprotection rates were similar to those at baseline. Seroprotection rates were lower against B strains for all vaccines. LIMITATIONS: Because of the use of observational data, bias from unmeasured confounders may exist. Some age subgroups were small in number. Clinical outcome data were not available. CONCLUSIONS: Hemodialysis patients exhibited high seroprotection rates after all 3 influenza vaccines. The seroresponse waned more slowly with HD-IIV3 compared with SD-IIV4 and RIV4 vaccines.

Primary results of the randomized trial of metformin administration in polycystic kidney disease (TAME PKD).

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by growth of kidney cysts and glomerular filtration rate (GFR) decline. Metformin was found to impact cystogenesis in preclinical models of polycystic disease, is generally considered safe and may be a promising candidate for clinical investigation in ADPKD. In this phase 2 two-year trial, we randomly assigned 97 patients, 18-60 years of age, with ADPKD and estimated GFR over 50 ml/min/1.73 m2, in a 1:1 ratio to receive metformin or placebo twice daily. Primary outcomes were medication safety and tolerability. Secondary outcomes included estimated GFR decline, and total kidney volume growth. Thirty-eight metformin and 39 placebo participants still received study product at 24-months. Twenty-one participants in the metformin arm reduced drug dose due to inability to tolerate, compared with 14 in the placebo arm (not significant). Proportions of participants experiencing serious adverse events was similar between the groups. The Gastrointestinal Symptoms Rating Scale score was low at baseline and did not significantly change over time. The annual change for estimated GFR was -1.71 with metformin and -3.07 ml/min/1.73m2 per year with placebo (mean difference 1.37 {-0.70, 3.44} ml/min/1.73m2), while mean annual percent change in height-adjusted total kidney volume was 3.87% in metformin and 2.16% per year in placebo, (mean difference 1.68% {-2.11, 5.62}). Thus, metformin in adults with ADPKD was found to be safe and tolerable while slightly reducing estimated GFR decline but not to a significant degree. Hence, evaluation of efficacy requires a larger trial, with sufficient power to detect differences in endpoints.

COVID-19 Among US Dialysis Patients: Risk Factors and Outcomes From a National Dialysis Provider.

RATIONALE & OBJECTIVE: During the coronavirus disease 2019 (COVID-19) pandemic, patients receiving maintenance dialysis are a highly vulnerable population due to their comorbidities and circumstances that limit physical distancing during treatment. This study sought to characterize the risk factors for and outcomes following COVID-19 in this population. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Maintenance dialysis patients in clinics of a midsize national dialysis provider that had at least 1 patient who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from February to June 2020. PREDICTORS: Demographics, dialysis characteristics, residence in a congregated setting, comorbid conditions, measurements of frailty, and use of selected medications. OUTCOMES: COVID-19, defined as having a positive SARS-CoV-2 test result, and all-cause mortality among those with COVID-19. ANALYTICAL APPROACH: Logistic regression analyses conducted to identify clinical characteristics associated with COVID-19 and risk factors associated with mortality among patients following COVID-19. RESULTS: 438 of 7948 (5.5%) maintenance dialysis patients developed COVID-19. Male sex, Black race, in-center dialysis (vs home dialysis), treatment at an urban clinic, residence in a congregate setting, and greater comorbidity were associated with contracting COVID-19. Odds of COVID-19 were 17-fold higher for those residing in a congregated setting (odds ratio [OR], 17.10 [95% CI, 13.51-21.54]). Of the 438 maintenance dialysis patients with COVID-19, 109 (24.9%) died. Older age, heart disease, and markers of frailty were associated with mortality. LIMITATIONS: No distinction was detected between symptomatic and asymptomatic SARS-CoV-2 positivity, with asymptomatic screening limited by testing capacity during this initial COVID-19 surge period. CONCLUSIONS: COVID-19 is common among patients receiving maintenance dialysis, particularly those residing in congregate settings. Among maintenance dialysis patients with COVID-19, mortality is high, exceeding 20%.

Comparison of Dialysis Unit and Home Blood Pressures: An Observational Cohort Study.

RATIONALE & OBJECTIVE: Prior studies of patients receiving maintenance hemodialysis have shown that, on average, blood pressure (BP) measured predialysis is higher than BP measured at home. We hypothesized that a subset of hemodialysis patients has BP that is higher when measured at home than when measured predialysis and this subgroup of patients has a higher prevalence of left ventricular hypertrophy. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: 97 hypertensive hemodialysis patients enrolled in the Blood Pressure in Dialysis Study (BID), a randomized trial of comparing target predialysis BP ≤140/90 to 155-165/90 mm Hg. EXPOSURE: Differences between predialysis and next-day home systolic BP measured ≥6 times over 1 year. OUTCOME: Left ventricular mass index (LVMI) by cardiac magnetic resonance imaging. ANALYTICAL APPROACH: A hierarchical clustering analysis divided patients into 3 clusters based on the average and variability of differences in systolic predialysis and home BP. Clusters were compared with respect to clinical factors and LVMI. RESULTS: Mean differences between predialysis and home systolic BP were 19.1 (95% CI, 17.0 to 21.1) mm Hg for cluster 1 ("home lower"), 3.7 (95% CI, 1.6 to 5.8) mm Hg for cluster 2 ("home and predialysis similar"), and -9.7 (95% CI, -12.0 to -7.4) mm Hg for cluster 3 ("home higher"). Systolic BP declined during dialysis in clusters 1 and 2 but increased in cluster 3. Interdialytic weight gains did not differ. After adjusting for sex and treatment arm, LVMI was higher in cluster 3 than in clusters 1 and 2: differences in means of 10.6 ± 4.96 (SE) g/m2 (P = 0.04) and 12.0 ± 5.08 g/m2 (P = 0.02), respectively. LIMITATIONS: Limited statistical power. CONCLUSIONS: Nearly one-third of participants had home BPs higher than predialysis BPs. These patients had LVMI higher than those with similar or lower BPs at home, indicating that their BP may have been undertreated.

Multidisciplinary Medication Therapy Management and Hospital Readmission in Patients Undergoing Maintenance Dialysis: A Retrospective Cohort Study.

RATIONALE & OBJECTIVES: Dialysis patients frequently experience medication-related problems. We studied the association of a multidisciplinary medication therapy management (MTM) with 30-day readmission rates. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Maintenance dialysis patients discharged home from acute-care hospitals between May 2016 and April 2017 who returned to End-Stage Renal Disease Seamless Care Organization dialysis clinics after discharge were eligible. Patients who were readmitted within 3 days, died, or entered hospice within 30 days were excluded. EXPOSURE: MTM consisting of nurse medication reconciliation, pharmacist medication review, and nephrologist oversight was categorized into 3 levels of intensity: no MTM, partial MTM (defined as an incomplete MTM process), or full MTM (defined as a complete MTM process). OUTCOME: The primary outcome was 30-day readmission. ANALYTICAL APPROACH: Time-varying Prentice, Williams, and Peterson total time hazards models explored associations between MTM and time to readmission after adjusting for age, race, sex, diabetes comorbidity, albumin level, vascular access type, kidney failure cause, dialysis vintage and modality, marital status, home medications, frequent prior hospitalizations, length of stay, discharge diagnoses, hierarchical condition category, and facility standardized hospitalization rates. Propensity score matching was performed to examine the robustness of the associations in a comparison between the full- and no-MTM exposure groups on time to readmission. RESULTS: Among 1,452 discharges, 586 received no MTM, 704 received partial MTM, and 162 received full MTM; 30-day readmission rates were 29%, 19%, and 11%, respectively (P < 0.001). Compared with no MTM, discharges with full MTM had the lowest time-varying risk for readmission within 30 days (HR, 0.26; 95% CI, 0.15-0.45); discharges with partial MTM also had lower readmission risk (HR, 0.50; 95% CI, 0.37-0.68). In propensity score-matched sensitivity analysis, full MTM was associated with lower 30-day readmission risk (HR, 0.20; 95% CI, 0.06-0.69). LIMITATIONS: Reliance on observational data. Residual bias and confounding. CONCLUSIONS: MTM services following hospital discharge were associated with fewer 30-day readmissions in dialysis patients. Randomized controlled studies evaluating different MTM delivery models and cost-effectiveness in dialysis populations are warranted.

Chronic disease burdens of incident U.S. dialysis patients, 1996 - 2015
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INTRODUCTION: The United States Renal Data System has collected data on incident hemodialysis (HD) and peritoneal dialysis (PD) patients since 1995, allowing prevalence of chronic diseases over the past 20 years to be measured. MATERIALS AND METHODS: All first-time HD/PD patients 1996 - 2015 were analyzed. Diabetes and cardiovascular diseases were grouped into single variables. Prevalence of each condition was evaluated with logistic regression. Odds ratios (OR) for a 5-year difference in year of dialysis initiation were calculated. Models were adjusted for age, sex, and race, with interactions between modality and year. One- and 5-year mortality were calculated. RESULTS: Age increased among 1,847,212 HD and 156,965 PD patients; PD patients were younger. First-year mortality fell from 24.4 to 21.1% in HD patients and from 17.1 to 8.5% in PD. 5-year mortality fell from 65.9 to 58.6% in HD patients and from 56.3 to 40.4% in PD. Hypertension increased (OR = 1.34 for HD, 1.35 for PD), as did diabetes (OR = 1.16 for HD, 1.06 for PD) and cancer (OR = 1.09 for HD, 1.10 for PD). Cardiovascular disease decreased in PD (OR = 0.87) only. Stroke decreased (OR = 0.98 for HD, 0.90 for PD), as did peripheral vascular disease (OR = 0.91 for HD, 0.82 for PD). Lung disease increased in HD (OR = 1.10) but decreased in PD (OR = 0.97). DISCUSSION: Mortality and cardiovascular disease burden have declined for dialysis patients in the United States despite an aging population that is increasingly hypertensive and diabetic. Comorbid disease burdens among HD and PD patients have diverged over time, with PD patients having fewer comorbid conditions.

The TiME Trial: A Fully Embedded, Cluster-Randomized, Pragmatic Trial of Hemodialysis Session Duration.

BACKGROUND: Data from clinical trials to inform practice in maintenance hemodialysis are limited. Incorporating randomized trials into dialysis clinical care delivery should help generate practice-guiding evidence, but the feasibility of this approach has not been established. METHODS: To develop approaches for embedding trials into routine delivery of maintenance hemodialysis, we performed a cluster-randomized, pragmatic trial demonstration project, the Time to Reduce Mortality in ESRD (TiME) trial, evaluating effects of session duration on mortality (primary outcome) and hospitalization rate. Dialysis facilities randomized to the intervention adopted a default session duration ≥4.25 hours (255 minutes) for incident patients; those randomized to usual care had no trial-driven approach to session duration. Implementation was highly centralized, with no on-site research personnel and complete reliance on clinically acquired data. We used multiple strategies to engage facility personnel and participating patients. RESULTS: The trial enrolled 7035 incident patients from 266 dialysis units. We discontinued the trial at a median follow-up of 1.1 years because of an inadequate between-group difference in session duration. For the primary analysis population (participants with estimated body water ≤42.5 L), mean session duration was 216 minutes for the intervention group and 207 minutes for the usual care group. We found no reduction in mortality or hospitalization rate for the intervention versus usual care. CONCLUSIONS: Although a highly pragmatic design allowed efficient enrollment, data acquisition, and monitoring, intervention uptake was insufficient to determine whether longer hemodialysis sessions improve outcomes. More effective strategies for engaging clinical personnel and patients are likely required to evaluate clinical trial interventions that are fully embedded in care delivery.

Influenza in dialysis patients: an opportunity to decrease mortality?

PURPOSE OF REVIEW: Influenza is a major cause of morbidity in dialysis patients. RECENT FINDINGS: A recent meta-analysis finds reduced influenza infections, hospitalizations and deaths with use of high dose as compared with standard-dose vaccine in the elderly. There remain no randomized clinical trials of vaccine efficacy in dialysis patients. One observational study finds reduced all-cause hospitalization with high-dose as compared with standard-dose vaccine but another study finds no difference in influenza related events. A simulation study, in which the timing of vaccination and antibody waning rates are varied, finds vaccine efficacy among populations prone to premature waning, to be greater if the vaccine is administered later, as long as the opportunity to vaccinate does not decline. In a phase 3 trial involving low-risk patients with uncomplicated influenza, baloxavir (which is of a novel class of antiinfluenza treatment), was associated with a faster decline in virus titers and no difference in resolution of symptoms as compared with oseltamivir. SUMMARY: By extension of high-quality evidence in the elderly, we recommend using the high dose vaccine in all dialysis patients. Vaccine efficacy may be enhanced in dialysis patients if vaccination is delayed until late October to mid-November. It is premature to use baloxavir over oseltamivir or the combination to treat influenza in dialysis patients though trials are forthcoming.

Transfers to Hemodialysis Among US Patients Initiating Renal Replacement Therapy With Peritoneal Dialysis.

RATIONALE & OBJECTIVE: Identifying patients who are likely to transfer from peritoneal dialysis (PD) to hemodialysis (HD) before transition could improve their subsequent care. This study developed a prediction tool for transition from PD to HD. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adults initiating PD between January 2008 and December 2011, followed up through June 2015, for whom data were available in the US Renal Data System (USRDS). PREDICTORS: Clinical characteristics at PD initiation and peritonitis claims. OUTCOMES: Transfer to HD, with the competing outcomes of death and kidney transplantation. ANALYTICAL APPROACH: Outcomes were ascertained from USRDS treatment history files. Subdistribution hazards (competing-risk) models were fit using clinical characteristics at PD initiation. A nomogram was developed to classify patient risk at 1, 2, 3, and 4 years. These data were used to generate quartiles of HD transfer risk; this quartile score was incorporated into a cause-specific hazards model that additionally included a time-dependent variable for peritonitis. RESULTS: 29,573 incident PD patients were followed up for a median of 21.6 (interquartile range, 9.0-42.3) months, during which 41.2% transferred to HD, 25.9% died, 17.1% underwent kidney transplantation, and the rest were followed up to the study end in June 2015. Claims for peritonitis were present in 11,733 (40.2%) patients. The proportion of patients still receiving PD decreased to <50% at 22.6 months and 14.2% at 5 years. Peritonitis was associated with a higher rate of HD transfer (HR, 1.82; 95% CI, 1.76-1.89; P < 0.001), as were higher quartile scores of HD transfer risk (HRs of 1.31 [95% CI, 1.25-1.37), 1.51 [95% CI, 1.45-1.58], and 1.78 [95% CI, 1.71-1.86] for quartiles 2, 3, and 4 compared to quartile 1 [P < 0.001 for all]). LIMITATIONS: Observational data, reliant on the Medical Evidence Report and Medicare claims. CONCLUSIONS: A large majority of the patients who initiated renal replacement therapy with PD discontinued this modality within 5 years. Transfer to HD was the most common outcome. Patient characteristics and comorbid diseases influenced the probability of HD transfer, death, and transplantation, as did episodes of peritonitis.

BP in Dialysis: Results of a Pilot Study.

The optimal BP target for patients receiving hemodialysis is unknown. We randomized 126 hypertensive patients on hemodialysis to a standardized predialysis systolic BP of 110-140 mmHg (intensive arm) or 155-165 mmHg (standard arm). The primary objectives were to assess feasibility and safety and inform the design of a full-scale trial. A secondary objective was to assess changes in left ventricular mass. Median follow-up was 365 days. In the standard arm, the 2-week moving average systolic BP did not change significantly during the intervention period, but in the intensive arm, systolic BP decreased from 160 mmHg at baseline to 143 mmHg at 4.5 months. From months 4-12, the mean separation in systolic BP between arms was 12.9 mmHg. Four deaths occurred in the intensive arm and one death occurred in the standard arm. The incidence rate ratios for the intensive compared with the standard arm (95% confidence intervals) were 1.18 (0.40 to 3.33), 1.61 (0.87 to 2.97), and 3.09 (0.96 to 8.78) for major adverse cardiovascular events, hospitalizations, and vascular access thrombosis, respectively. The intensive and standard arms had similar median changes (95% confidence intervals) in left ventricular mass of -0.84 (-17.1 to 10.0) g and 1.4 (-11.6 to 10.4) g, respectively. Although we identified a possible safety signal, the small size and short duration of the trial prevent definitive conclusions. Considering the high risk for major adverse cardiovascular events in patients receiving hemodialysis, a full-scale trial is needed to assess potential benefits of intensive hypertension control in this population.

Patterns of Kidney Function Decline in Autosomal Dominant Polycystic Kidney Disease: A Post Hoc Analysis From the HALT-PKD Trials.

BACKGROUND: Previous clinical studies of autosomal dominant polycystic kidney disease (ADPKD) reported that loss of kidney function usually follows a steep and relentless course. A detailed examination of individual patterns of decline in estimated glomerular filtration rate (eGFR) has not been performed. STUDY DESIGN: Longitudinal post hoc analysis of data collected during the Halt Progression of Polycystic Kidney Disease (HALT-PKD) trials. SETTING & PARTICIPANTS: 494 HALT-PKD Study A participants (younger; preserved eGFR) and 435 Study B participants (older; reduced eGFR) who had more than 3 years of follow-up and 7 or more eGFR assessments. MEASUREMENTS: Longitudinal eGFR assessments using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation. PREDICTORS: Demographic, clinical, laboratory, and imaging features of participants. OUTCOMES: Probability of linear and nonlinear decline patterns or of stable eGFR calculated for each participant from a Bayesian model of individual eGFR trajectories. RESULTS: Most (62.5% in Study A and 81% in Study B) participants had a linear decline in eGFR during up to 8 years of follow-up. A proportion (22% in Study A and 13% in Study B) of progressors had a nonlinear pattern. 15.5% of participants in Study A and 6% in Study B had a prolonged (≥4.5 years) period of stable eGFRs. These individuals (Study A) had significantly smaller total kidney volumes, higher renal blood flows, lower urinary albumin excretion, and lower body mass index at baseline and study end. In Study B, participants with reduced but stable eGFRs were older than the progressors. Two-thirds of nonprogressors in both studies had PKD1 mutations, with enrichment for weak nontruncating mutations. LIMITATIONS: Relatively short follow-up of a clinical trial population. CONCLUSIONS: Although many individuals with ADPKD have a linear decline in eGFR, prolonged intervals of stable GFRs occur in a substantial fraction. Lower body mass index was associated with more stable kidney function in early ADPKD.

A Randomized Clinical Trial of Metformin to Treat Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Metformin inhibits cyclic AMP generation and activates AMP-activated protein kinase (AMPK), which inhibits the cystic fibrosis transmembrane conductance regulator and Mammalian Target of Rapamycin pathways. Together these effects may reduce cyst growth in autosomal dominant polycystic kidney disease (ADPKD). METHODS: A phase II, double-blinded randomized placebo-controlled trial of 26 months duration. Participants will include nondiabetic adults (n = 96) aged 18-60 years, with an estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73 m2 and ADPKD, recruited from university-based practices in Baltimore and Boston. Participants will be randomized in 1: 1 ratio to metformin or placebo at 500 mg once daily, increased every 2 weeks to a maximum of 1,000 mg twice daily as tolerated. Dose is decreased if eGFR falls to 30-45 mL/min/1.73 m2 and discontinued at eGFR < 30 mL/min/1.73 m2. RESULTS: The primary outcomes are safety, assessed by the rates of hypoglycemia, elevated lactic acid levels, adverse events, and tolerability assessed by the Gastrointestinal Severity Rating Scale and maximum tolerated dose of study medication. Secondary outcomes include changes in total kidney and liver volumes, pain, and health-related quality of life, and changes in urinary metabolomic biomarkers. CONCLUSIONS: Results of this trial will provide important information on the feasibility, safety, and tolerability of long-term use of metformin in patients with -ADPKD and provide preliminary information regarding its efficacy in slowing disease progression. Furthermore, results may support or refute the hypothesis that metformin effects on disease progression are mediated through the activation of the AMPK pathway. These results will be essential for the justification and design of a full-scale efficacy trial.

Evaluation of non-response to the In-Center Hemodialysis Consumer Assessment of Healthcare Providers and Systems (ICH CAHPS) survey.

BACKGROUND: The In-Center Hemodialysis Consumer Assessment of Healthcare Providers and Systems (ICH CAHPS) Survey is the first patient reported outcome measure included in the U.S. Medicare End Stage Renal Disease Quality Incentive Program. Administered twice yearly, it assesses in-center dialysis experience and survey responses are tied to dialysis facility payments. Low response rates, currently approximately 35%, raise concern for possible underrepresentation of patient groups. METHODS: Cross-sectional analysis of survey administration in 2012 to all in-center hemodialysis patients in Dialysis Clinic, Inc. (DCI) facilities nationally over 18 years old who received hemodialysis at their facility for at least 3 months. Patient-level covariates included demographic, clinical, laboratory, and functional characteristics. Random effects multivariable logistic regression was used to assess survey non-response. RESULTS: Among 11,055 eligible patients 6541 (59%) were non-responders. Of the remaining 4514 responders, 549 (14%) surveys were not usable due to presence of proxy help or incomplete responses. Non-responders were more likely to be men, non-white, younger, single, dual Medicare/Medicaid eligible, less educated, non-English speaking, and not active on the transplant list; non-responders had longer ESRD vintage, lower body mass index, lower serum albumin, worse functional status, and more hospitalizations, missed treatments, and shortened treatments. Similar associations were found using more parsimonious multivariable analyses and after imputing missing data. CONCLUSIONS: Non-responders to the ICH CAHPS significantly differed from responders, broadly spanning individuals with fewer socioeconomic advantages and greater illness burden, raising limitations in interpreting facility survey results. Future research should assess reasons for non-response to improve ICH CAHPS generalizability and utility.

Angiotensin blockade in late autosomal dominant polycystic kidney disease.

BACKGROUND: Hypertension develops early in patients with autosomal dominant polycystic kidney disease (ADPKD) and is associated with disease progression. The renin-angiotensin-aldosterone system (RAAS) is implicated in the pathogenesis of hypertension in patients with ADPKD. Dual blockade of the RAAS may circumvent compensatory mechanisms that limit the efficacy of monotherapy with an angiotensin-converting-enzyme (ACE) inhibitor or angiotensin II-receptor blocker (ARB). METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 486 patients, 18 to 64 years of age, with ADPKD (estimated glomerular filtration rate [GFR], 25 to 60 ml per minute per 1.73 m(2) of body-surface area) to receive an ACE inhibitor (lisinopril) and placebo or lisinopril and an ARB (telmisartan), with the doses adjusted to achieve a blood pressure of 110/70 to 130/80 mm Hg. The composite primary outcome was the time to death, end-stage renal disease, or a 50% reduction from the baseline estimated GFR. Secondary outcomes included the rates of change in urinary aldosterone and albumin excretion, frequency of hospitalizations for any cause and for cardiovascular causes, incidence of pain, frequency of ADPKD-related symptoms, quality of life, and adverse study-medication effects. Patients were followed for 5 to 8 years. RESULTS: There was no significant difference between the study groups in the incidence of the composite primary outcome (hazard ratio with lisinopril-telmisartan, 1.08; 95% confidence interval, 0.82 to 1.42). The two treatments controlled blood pressure and lowered urinary aldosterone excretion similarly. The rates of decline in the estimated GFR, urinary albumin excretion, and other secondary outcomes and adverse events, including hyperkalemia and acute kidney injury, were also similar in the two groups. CONCLUSIONS: Monotherapy with an ACE inhibitor was associated with blood-pressure control in most patients with ADPKD and stage 3 chronic kidney disease. The addition of an ARB did not alter the decline in the estimated GFR. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study B] ClinicalTrials.gov number, NCT01885559.).

Blood pressure in early autosomal dominant polycystic kidney disease.

BACKGROUND: Hypertension is common in autosomal dominant polycystic kidney disease (ADPKD) and is associated with increased total kidney volume, activation of the renin-angiotensin-aldosterone system, and progression of kidney disease. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 558 hypertensive participants with ADPKD (15 to 49 years of age, with an estimated glomerular filtration rate [GFR] >60 ml per minute per 1.73 m(2) of body-surface area) to either a standard blood-pressure target (120/70 to 130/80 mm Hg) or a low blood-pressure target (95/60 to 110/75 mm Hg) and to either an angiotensin-converting-enzyme inhibitor (lisinopril) plus an angiotensin-receptor blocker (telmisartan) or lisinopril plus placebo. The primary outcome was the annual percentage change in the total kidney volume. RESULTS: The annual percentage increase in total kidney volume was significantly lower in the low-blood-pressure group than in the standard-blood-pressure group (5.6% vs. 6.6%, P=0.006), without significant differences between the lisinopril-telmisartan group and the lisinopril-placebo group. The rate of change in estimated GFR was similar in the two medication groups, with a negative slope difference in the short term in the low-blood-pressure group as compared with the standard-blood-pressure group (P<0.001) and a marginally positive slope difference in the long term (P=0.05). The left-ventricular-mass index decreased more in the low-blood-pressure group than in the standard-blood-pressure group (-1.17 vs. -0.57 g per square meter per year, P<0.001); urinary albumin excretion was reduced by 3.77% with the low-pressure target and increased by 2.43% with the standard target (P<0.001). Dizziness and light-headedness were more common in the low-blood-pressure group than in the standard-blood-pressure group (80.7% vs. 69.4%, P=0.002). CONCLUSIONS: In early ADPKD, the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume. As compared with standard blood-pressure control, rigorous blood-pressure control was associated with a slower increase in total kidney volume, no overall change in the estimated GFR, a greater decline in the left-ventricular-mass index, and greater reduction in urinary albumin excretion. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study A] ClinicalTrials.gov number, NCT00283686.).

Intravenous iron administration strategies and anemia management in hemodialysis patients.

Background: The effect of maintenance intravenous (IV) iron administration on subsequent achievement of anemia management goals and mortality among patients recently initiating hemodialysis is unclear. Methods: We performed an observational cohort study, in adult incident dialysis patients starting on hemodialysis. We defined IV administration strategies over a 12-week period following a patient's initiation of hemodialysis; all those receiving IV iron at regular intervals were considered maintenance, and all others were considered non-maintenance. We used multivariable models adjusting for demographics, clinical and treatment parameters, iron dose, measures of iron stores and pro-infectious and pro-inflammatory parameters to compare these strategies. The outcomes under study were patients' (i) achievement of hemoglobin (Hb) of 10-12 g/dL, (ii) more than 25% reduction in mean weekly erythropoietin stimulating agent (ESA) dose and (iii) mortality, ascertained over a period of 4 weeks following the iron administration period. Results: Maintenance IV iron was administered to 4511 patients and non-maintenance iron to 8458 patients. Maintenance IV iron administration was not associated with a higher likelihood of achieving an Hb between 10 and 12 g/dL {adjusted odds ratio (OR) 1.01 [95% confidence interval (CI) 0.93-1.09]} compared with non-maintenance, but was associated with a higher odds of achieving a reduced ESA dose of 25% or more [OR 1.33 (95% CI 1.18-1.49)] and lower mortality [hazard ratio (HR) 0.73 (95% CI 0.62-0.86)]. Conclusions: Maintenance IV iron strategies were associated with reduced ESA utilization and improved early survival but not with the achievement of Hb targets.

Blood Pressure Management in Hemodialysis Patients: What We Know And What Questions Remain.

Despite having thousands of blood pressure (BP) readings on individual dialysis patients over the course of a year, our knowledge about the optimal assessment of BP, the mechanisms underlying hypertension and its management remain incomplete. Observational studies reveal that BP is lower at home than when measured in the dialysis unit. However, we do not know if using home vs. in-center measurements to guide treatment decisions improves BP control and/or clinical outcomes. Moreover, a recent US study suggests that typical hemodialysis patients are unlikely to adhere to home monitoring over the long term. Volume excess is one of probably many factors mediating hypertension in this population. A randomized clinical trial of aggressively challenging dry weight in patients without overt signs of fluid overload was shown to reduce BP, but there was an increase in vascular access thrombosis and intradialytic hypotension episodes. Long-term studies have not been done; thus, we do not know whether "squeezing dry weight" as a means to control BP is of more benefit than harm. Daily or prolonged nocturnal dialysis consistently has been shown to lower BP. To what extent this is a result of enhanced solute clearance vs. removal of excess volume is not clear. Use of bioimpedance or relative blood volume monitoring to guide fluid management has been tested in small studies, but more data are needed to determine whether their use impacts clinical outcomes. Well-designed clinical trials to determine whether a specific antihypertensive drug class is of benefit, independent of BP lowering, are lacking. The BP target that optimizes outcomes HD patients is also unknown. Observational studies consistently show poorer survival with predialysis BP <140/90 mmHg, although such studies likely are confounded by low BP due to cardiovascular disease and other comorbidities. In this review, we discuss what is known and the questions that remain regarding the epidemiology, diagnosis, etiology, and management of hypertension in hemodialysis patients.

Ergocalciferol Supplementation in Hemodialysis Patients With Vitamin D Deficiency: A Randomized Clinical Trial.

Locally produced 1,25-dihydroxyvitamin D3 may have pleiotropic effects outside of bone. Experimental and observational studies suggest that nutritional vitamin D may enhance erythropoiesis in settings of 25-hydroxy vitamin D (25(OH)D) deficiency. We conducted a double-blind, placebo-controlled, randomized clinical trial to assess the effects of supplementation with ergocalciferol on epoetin utilization and other secondary outcomes in patients on hemodialysis with serum 25(OH)D <30 ng/ml. In all, 276 patients were randomized to 6 months of ergocalciferol or placebo. Mean±SD serum 25(OH)D increased from 16.0±5.9 ng/ml at baseline to 39.2±14.9 ng/ml in the ergocalciferol arm and did not change (16.9±6.4 ng/ml and 17.5±7.4 ng/ml, respectively) in the placebo arm. There was no significant change in epoetin dose over 6 months in the ergocalciferol or placebo arms (geometric mean rate 0.98 [95% confidence interval (95% CI), 0.94 to 1.02] versus 0.99 [95% CI, 0.95 to 1.03], respectively) and no difference across arms (P=0.78). No change occurred in serum calcium, phosphorus, intact parathyroid hormone, or C-reactive protein levels, cinacalcet use, or phosphate binder or calcitriol dose in either study arm. Rates of all-cause, cardiovascular, and infection-related hospitalizations did not differ by study arm, although statistical power was limited for these outcomes. In conclusion, 6 months of supplementation with ergocalciferol increased serum 25(OH)D levels in patients on hemodialysis with vitamin D insufficiency or deficiency, but had no effect on epoetin utilization or secondary biochemical and clinical outcomes.

Comparison of Prescribed and Measured Dialysate Sodium: A Quality Improvement Project.

BACKGROUND: There is controversy regarding the optimal dialysate sodium concentration for hemodialysis patients. Dialysate sodium concentrations of 134 to 138 mEq/L may decrease interdialytic weight gain and improve hypertension control, whereas a higher dialysate sodium concentration may offer protection to patients with low serum sodium concentrations and hypotension. We conducted a quality improvement project to explore the hypothesis that prescribed and delivered dialysate sodium concentrations may differ significantly. STUDY DESIGN: Cross-sectional quality improvement project. SETTING & PARTICIPANTS: 333 hemodialysis treatments in 4 facilities operated by Dialysis Clinic, Inc. QUALITY IMPROVEMENT PLAN: Measure dialysate sodium to assess the relationships of prescribed and measured dialysate sodium concentrations. OUTCOMES: Magnitude of differences between prescribed and measured dialysate sodium concentrations. MEASUREMENTS: Dialysate sodium measured pre- and late dialysis. RESULTS: The least square mean of the difference between prescribed minus measured dialysate sodium concentration was -2.48 (95% CI, -2.87 to -2.10) mEq/L. Clinics with a greater number of different dialysate sodium prescriptions (clinic 1, n=8; clinic 2, n=7) and that mixed dialysate concentrates on site had greater differences between prescribed and measured dialysate sodium concentrations. Overall, 57% of measured dialysate sodium concentrations were within ±2 mEq/L of the prescribed dialysate sodium concentration. Differences were greater at higher prescribed dialysate sodium concentrations. LIMITATIONS: We only studied 4 facilities and dialysate delivery machines from 2 manufacturers. Because clinics using premixed dialysate used the same type of machine, we were unable to independently assess the impact of these factors. Pressures in dialysate delivery loops were not measured. CONCLUSIONS: There were significant differences between prescribed and measured dialysate sodium concentrations. This may have beneficial or deleterious effects on clinical outcomes, as well as confound results from studies assessing the relationships of dialysate sodium concentrations to outcomes. Additional studies are needed to identify factors that contribute to differences between prescribed and measured dialysate sodium concentrations. Quality assurance and performance improvement (QAPI) programs should include measurements of dialysate sodium.

Liver involvement in early autosomal-dominant polycystic kidney disease.

BACKGROUND & AIMS: Polycystic liver disease (PLD), the most common extrarenal manifestation of autosomal-dominant polycystic kidney disease (ADPKD), has become more prevalent as a result of increased life expectancy, improved renal survival, reduced cardiovascular mortality, and renal replacement therapy. No studies have fully characterized PLD in large cohorts. We investigated whether liver and cyst volumes are associated with volume of the hepatic parenchyma, results from liver laboratory tests, and patient-reported outcomes. METHODS: We performed a cross-sectional analysis of baseline liver volumes, measured by magnetic resonance imaging, and their association with demographics, results from liver laboratory and other tests, and quality of life. The data were collected from a randomized, placebo-controlled trial underway at 7 tertiary-care medical centers to determine whether the combination of an angiotensin I-converting enzyme inhibitor and angiotensin II-receptor blocker was superior to the inhibitor alone, and whether low blood pressure (<110/75 mm Hg) was superior to standard blood pressure (120-130/70-80 mm Hg), in delaying renal cystic progression in 558 patients with ADPKD, stages 1 and 2 chronic kidney disease, and hypertension (age, 15-49 y). RESULTS: We found hepatomegaly to be common among patients with ADPKD. Cysts and parenchyma contributed to hepatomegaly. Cysts were more common and liver and cyst volumes were greater in women, increasing with age. Patients with advanced disease had a relative loss of liver parenchyma. We observed small abnormalities in results from liver laboratory tests, and that splenomegaly and hypersplenism were associated with PLD severity. Higher liver volumes were associated with a lower quality of life. CONCLUSIONS: Hepatomegaly is common even in early stage ADPKD and is not accounted for by cysts alone. Parenchymal volumes were larger, compared with liver volumes of patients without ADPKD or with those predicted by standardized equations, even among patients without cysts. The severity of PLD was associated with altered biochemical and hematologic features, as well as quality of life. ClinicalTrials.gov identifier: NCT00283686.