Genetic testing for misclassified monogenic diabetes in Maori and Pacific peoples in Aotearoa New Zealand with early-onset type 2 diabetes.

Aims: Monogenic diabetes accounts for 1-2% of diabetes cases yet is often misdiagnosed as type 2 diabetes. The aim of this study was to examine in Maori and Pacific adults clinically diagnosed with type 2 diabetes within 40 years of age, (a) the prevalence of monogenic diabetes in this population (b) the prevalence of beta-cell autoantibodies and (c) the pre-test probability of monogenic diabetes. Methods: Targeted sequencing data of 38 known monogenic diabetes genes was analyzed in 199 Maori and Pacific peoples with BMI of 37.9 ± 8.6 kg/m2 who had been diagnosed with type 2 diabetes between 3 and 40 years of age. A triple-screen combined autoantibody assay was used to test for GAD, IA-2, and ZnT8. MODY probability calculator score was generated in those with sufficient clinical information (55/199). Results: No genetic variants curated as likely pathogenic or pathogenic were found. One individual (1/199) tested positive for GAD/IA-2/ZnT8 antibodies. The pre-test probability of monogenic diabetes was calculated in 55 individuals with 17/55 (31%) scoring above the 20% threshold considered for diagnostic testing referral. Discussion: Our findings suggest that monogenic diabetes is rare in Maori and Pacific people with clinical age, and the MODY probability calculator likely overestimates the likelihood of a monogenic cause for diabetes in this population.

A Polynesian-specific missense CETP variant alters the lipid profile.

Identifying population-specific genetic variants associated with disease and disease-predisposing traits is important to provide insights into the genetic determinants of health and disease between populations, as well as furthering genomic justice. Various common pan-population polymorphisms at CETP associate with serum lipid profiles and cardiovascular disease. Here, sequencing of CETP identified a missense variant rs1597000001 (p.Pro177Leu) specific to Maori and Pacific people that associates with higher HDL-C and lower LDL-C levels. Each copy of the minor allele associated with higher HDL-C by 0.236 mmol/L and lower LDL-C by 0.133 mmol/L. The rs1597000001 effect on HDL-C is comparable with CETP Mendelian loss-of-function mutations that result in CETP deficiency, consistent with our data, which shows that rs1597000001 lowers CETP activity by 27.9%. This study highlights the potential of population-specific genetic analyses for improving equity in genomics and health outcomes for population groups underrepresented in genomic studies.

Association of Gout Polygenic Risk Score With Age at Disease Onset and Tophaceous Disease in European and Polynesian Men With Gout.

OBJECTIVE: To determine whether a gout polygenic risk score (PRS) is associated with age at gout onset and tophaceous disease in European, East Polynesian, and West Polynesian men and women with gout. METHODS: A 19-variant gout PRS was produced in 7 European gout cohorts (N = 4,016), 2 East Polynesian gout cohorts (N = 682), and 1 West Polynesian gout cohort (N = 490). Sex-stratified regression models were used to estimate the relationship between the PRS and age at gout onset and tophaceous disease. RESULTS: The PRS was associated with earlier age at gout onset in men (ß = -3.61 in years per unit PRS [95% confidence interval (95% CI) -4.32, -2.90] in European men; ß = -6.35 [95% CI -8.91, -3.80] in East Polynesian men; ß = -3.51 [95% CI -5.46, -1.57] in West Polynesian men) but not in women (ß = 0.07 [95% CI -2.32, 2.45] in European women; ß = 0.20 [95% CI -7.21, 7.62] in East Polynesian women; ß -3.33 [95% CI -9.28, 2.62] in West Polynesian women). The PRS showed a positive association with tophaceous disease in men (odds ratio [OR] for the association 1.15 [95% CI 1.00, 1.31] in European men; OR 2.60 [95% CI 1.66, 4.06] in East Polynesian men; OR 1.53 [95% CI 1.07, 2.19] in West Polynesian men) but not in women (OR for the association 0.68 [95% CI 0.42, 1.10] in European women; OR 1.45 [95% CI 0.39, 5.36] in East Polynesian women). The PRS association with age at gout onset was robust to the removal of ABCG2 variants from the PRS in European and East Polynesian men (ß = -2.42 [95% CI -3.37, -1.46] and ß = -6.80 [95% CI -10.06, -3.55], respectively) but not in West Polynesian men (ß = -1.79 [95% CI -4.74, 1.16]). CONCLUSION: Genetic risk variants for gout also harbor risk for earlier age at gout onset and tophaceous disease in European and Polynesian men. Our findings suggest that earlier gout onset involves the accumulation of gout risk alleles in men but perhaps not in women, and that this genetic risk is shared across multiple ancestral groups.

A stop-gain variant in BTNL9 is associated with atherogenic lipid profiles.

Current understanding of lipid genetics has come mainly from studies in European-ancestry populations; limited effort has focused on Polynesian populations, whose unique population history and high prevalence of dyslipidemia may provide insight into the biological foundations of variation in lipid levels. Here, we performed an association study to fine map a suggestive association on 5q35 with high-density lipoprotein cholesterol (HDL-C) seen in Micronesian and Polynesian populations. Fine-mapping analyses in a cohort of 2,851 Samoan adults highlighted an association between a stop-gain variant (rs200884524; c.652C>T, p.R218∗; posterior probability = 0.9987) in BTNL9 and both lower HDL-C and greater triglycerides (TGs). Meta-analysis across this and several other cohorts of Polynesian ancestry from Samoa, American Samoa, and Aotearoa New Zealand confirmed the presence of this association (ßHDL-C = -1.60 mg/dL, p HDL-C = 7.63 × 10-10; ßTG = 12.00 mg/dL, p TG = 3.82 × 10-7). While this variant appears to be Polynesian specific, there is also evidence of association from other multiancestry analyses in this region. This work provides evidence of a previously unexplored contributor to the genetic architecture of lipid levels and underscores the importance of genetic analyses in understudied populations.

Plasma exchange and glucocorticoids to delay death or end-stage renal disease in anti-neutrophil cytoplasm antibody-associated vasculitis: PEXIVAS non-inferiority factorial RCT.

BACKGROUND: Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortality. The lack of a robust evidence base to guide the use of plasma exchange and glucocorticoid dosing contributes to variation in practice and suboptimal outcomes. OBJECTIVES: We aimed to determine the clinical efficacy of plasma exchange in addition to immunosuppressive therapy and glucocorticoids with respect to death and end-stage renal disease in patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis. We also aimed to determine whether or not a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death and end-stage renal disease. DESIGN: This was an international, multicentre, open-label, randomised controlled trial. Patients were randomised in a two-by-two factorial design to receive either adjunctive plasma exchange or no plasma exchange, and either a reduced or a standard glucocorticoid dosing regimen. All patients received immunosuppressive induction therapy with cyclophosphamide or rituximab. SETTING: Ninety-five hospitals in Europe, North America, Australia/New Zealand and Japan participated. PARTICIPANTS: Participants were aged ≥ 16 years with a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and either proteinase 3 anti-neutrophil cytoplasm antibody or myeloperoxidase anti-neutrophil cytoplasm antibody positivity, and a glomerular filtration rate of < 50 ml/minute/1.73 m2 or diffuse alveolar haemorrhage attributable to active anti-neutrophil cytoplasm antibody-associated vasculitis. INTERVENTIONS: Participants received seven sessions of plasma exchange within 14 days or no plasma exchange. Oral glucocorticoids commenced with prednisolone 1 mg/kg/day and were reduced over different lengths of time to 5 mg/kg/day, such that cumulative oral glucocorticoid exposure in the first 6 months was 50% lower in patients allocated to the reduced-dose regimen than in those allocated to the standard-dose regimen. All patients received the same glucocorticoid dosing from 6 to 12 months. Subsequent dosing was at the discretion of the treating physician. PRIMARY OUTCOME: The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial. RESULTS: The study recruited 704 patients from June 2010 to September 2016. Ninety-nine patients died and 138 developed end-stage renal disease, with the primary end point occurring in 209 out of 704 (29.7%) patients: 100 out of 352 (28%) in the plasma exchange group and 109 out of 352 (31%) in the no plasma exchange group (adjusted hazard ratio 0.86, 95% confidence interval 0.65 to 1.13; p = 0.3). In the per-protocol analysis for the non-inferiority glucocorticoid comparison, the primary end point occurred in 92 out of 330 (28%) patients in the reduced-dose group and 83 out of 325 (26%) patients in the standard-dose group (partial-adjusted risk difference 0.023, 95% confidence interval 0.034 to 0.08; p = 0.5), thus meeting our non-inferiority hypothesis. Serious infections in the first year occurred in 96 out of 353 (27%) patients in the reduced-dose group and in 116 out of 351 (33%) patients in the standard-dose group. The rate of serious infections at 1 year was lower in the reduced-dose group than in the standard-dose group (incidence rate ratio 0.69, 95% confidence interval 0.52 to 0.93; p = 0.016). CONCLUSIONS: Plasma exchange did not prolong the time to death and/or end-stage renal disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis with severe renal or pulmonary involvement. A reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen and was associated with fewer serious infections. FUTURE WORK: A meta-analysis examining the effects of plasma exchange on kidney outcomes in anti-neutrophil cytoplasm antibody-associated vasculitis is planned. A health-economic analysis of data collected in this study to examine the impact of both plasma exchange and reduced glucocorticoid dosing is planned to address the utility of plasma exchange for reducing early end-stage renal disease rates. Blood and tissue samples collected in the study will be examined to identify predictors of response to plasma exchange in anti-neutrophil cytoplasm in antibody-associated vasculitis. The benefits associated with reduced glucocorticoid dosing will inform future studies of newer therapies to permit further reduction in glucocorticoid exposure. Data from this study will contribute to updated management recommendations for anti-neutrophil cytoplasm antibody-associated vasculitis. LIMITATIONS: This study had an open-label design which may have permitted observer bias; however, the nature of the end points, end-stage renal disease and death, would have minimised this risk. Despite being, to our knowledge, the largest ever trial in anti-neutrophil cytoplasm antibody-associated vasculitis, there was an insufficient sample size to assess clinically useful benefits on the separate components of the primary end-point: end-stage renal disease and death. Use of a fixed-dose plasma exchange regimen determined by consensus rather than data-driven dose ranging meant that some patients may have been underdosed, thus reducing the therapeutic impact. In particular, no biomarkers have been identified to help determine dosing in a particular patient, although this is one of the goals of the biomarker plan of this study. TRIAL REGISTRATION: This trial is registered as ISRCTN07757494, EudraCT 2009-013220-24 and Clinicaltrials.gov NCT00987389. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 38. See the NIHR Journals Library website for further project information.

Anti-neutrophil cytoplasm antibody vasculitis is a rare and severe disease in which the patient makes antibodies that damage their blood vessels. It can cause lung damage, kidney failure and early death. Treatment aims to suppress the harmful effects of the antibodies and associated inflammation. In particular: Plasma exchange aims to remove the antibodies from the bloodstream.Steroids aim to reduce the harmful activity of the antibodies. Unfortunately, plasma exchange is expensive and time-consuming, and we do not know if it really works long term to reduce kidney damage or the risk of death. We know steroids work, but they have many severe side effects that are related to higher doses. Again, we do not know if lower doses are equally effective. We conducted a randomised trial, PEXIVAS (Plasma Exchange In VASculitis), to measure the clinical effectiveness of plasma exchange and of reduced steroid doses. Anti-neutrophil cytoplasm antibody vasculitis patients with severe kidney or lung disease were allocated randomly to either plasma exchange or no plasma exchange. The same patients were then randomly allocated to a 'reduced' or 'standard' steroid dose. All patients received an immunosuppressive drug: cyclophosphamide or rituximab. The primary end point for both trials was the occurrence of either kidney failure or death. A total of 704 patients were recruited between 2010 and 2016, and they were followed up until the end of the trial in July 2017. Ninety-nine patients died and 138 developed kidney failure. Plasma exchange did not reduce the chances of death or kidney failure. There was also no difference between the two steroid dose groups in the number of deaths or patients developing kidney failure. However, there were fewer serious infections in the reduced steroid dose group. These results do not support the routine use of plasma exchange for all patients with severe vasculitis. They do show that the reduced-dose steroid regimen is just as effective as, and safer than, a 'standard'-dose steroid regimen. These results have the potential to save money and make the treatment of vasculitis patients safer in the future.

Delay in funding of tolvaptan for polycystic kidney disease in Aotearoa New Zealand.

Autosomal dominant polycystic kidney disease (ADPKD) is the fifth most common cause of end stage kidney disease (ESKD) in Aotearoa New Zealand. Identification of two genes, PCKD1 and PCKD2, which cause the majority of this disease, has played a key role in the development of DNA-sequence molecular diagnostics. ADPKD is characterised by the formation and growth of multiple cysts within the kidney, with some but not all patients progressing to ESKD. The diagnosis of ADPKD is based on the presence of family history, and radiological imaging although increasingly genetic testing is being used for screening and diagnosis. Once diagnosed, standard management of ADPKD includes laboratory monitoring of chronic kidney disease (CKD) parameters, lowering of blood pressure, and a high fluid intake. Over the last decade much research has been undertaken for targeted therapies for ADPKD; however, despite funding of these medications overseas since May 2015, and applications to Te Pataka Whaioranga, The Pharmaceutical Management Agency (PHARMAC), these therapies remain unavailable to New Zealanders resulting in an increased burden of disease to individuals and the whanau and financial cost to the health system.

A Polynesian-specific copy number variant encompassing the MICA gene associates with gout.

Gout is of particularly high prevalence in the Maori and Pacific (Polynesian) populations of Aotearoa New Zealand (NZ). Here, we investigated the contribution of common population-specific copy number variation (CNV) to gout in the Aotearoa NZ Polynesian population. Microarray-generated genome-wide genotype data from Aotearoa NZ Polynesian individuals with (n = 1196) and without (n = 1249) gout were analyzed. Comparator population groups were 552 individuals of European ancestry and 1962 of Han Chinese ancestry. Levels of circulating major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA) were measured by enzyme-linked immunosorbent assay. Fifty-four CNV regions (CNVRs) appearing in at least 10 individuals were detected, of which seven common (>2%) CNVRs were specific to or amplified in Polynesian people. A burden test of these seven revealed associations of insertion/deletion with gout (odds ratio (OR) 95% confidence interval [CI] = 1.80 [1.01; 3.22], P = 0.046). Individually testing of the seven CNVRs for association with gout revealed nominal association of CNVR1 with gout in Western Polynesian (Chr6: 31.36-31.45 Mb, OR = 1.72 [1.03; 2.92], P = 0.04), CNVR6 in the meta-analyzed Polynesian sample sets (Chr1: 196.75-196.92 Mb, OR = 1.86 [1.16; 3.00], P = 0.01) and CNVR9 in Western Polynesian (Chr1: 189.35-189.54 Mb, OR = 2.75 [1.15; 7.13], P = 0.03). Analysis of European gout genetic association data demonstrated a signal of association at the CNVR1 locus that was an expression quantitative trait locus for MICA. The most common CNVR (CNVR1) includes deletion of the MICA gene, encoding an immunomodulatory protein. Expression of MICA was reduced in the serum of individuals with the deletion. In summary, we provide evidence for the association of CNVR1 containing MICA with gout in Polynesian people, implicating class I MHC-mediated antigen presentation in gout.

Frailty prevalence in Aotearoa New Zealand haemodialysis patients and its association with hospitalisations.

AIMS: To use two frailty tools to assess frailty prevalence in a cohort of Aotearoa New Zealand haemodialysis (HD) patients and determine factors associated with frailty and frailty's association with adverse health outcomes. METHODS: Frailty was measured using the Fried score and Edmonton Frail Scale (EFS) in HD patients dialysing at dependent or satellite clinic sites in Waitemata District Health Board, Auckland. Linear regression models were used to explore factors associated with frailty measurements. Logistic regression models were used to assess associations between frailty and mortality and hospitalisations. RESULTS: 138 participants. Mean (SD) age: 61.5 (13.5) years. 70 females (51%). 51 (37%) were frail by Fried score. 51 (37%) were frail by EFS (overlap of 32 participants). Age, marital status, smoking status and albumin were independently associated with both measures of frailty. Medication number was additionally associated with Fried score. Pacific ethnicity and Charlson Comorbidity Index were associated with EFS score. After adjusting for covariables, only Fried frailty was associated with hospitalisations at six months. CONCLUSIONS: Pacific ethnicity was independently associated with increased risk of EFS frailty. Fried frailty was associated with hospitalisations at six months. Given the paucity of literature on the New Zealand population, further work within these ethnic groups is warranted.

Mid-pass whole genome sequencing enables biomedical genetic studies of diverse populations.

BACKGROUND: Historically, geneticists have relied on genotyping arrays and imputation to study human genetic variation. However, an underrepresentation of diverse populations has resulted in arrays that poorly capture global genetic variation, and a lack of reference panels. This has contributed to deepening global health disparities. Whole genome sequencing (WGS) better captures genetic variation but remains prohibitively expensive. Thus, we explored WGS at "mid-pass" 1-7x coverage. RESULTS: Here, we developed and benchmarked methods for mid-pass sequencing. When applied to a population without an existing genomic reference panel, 4x mid-pass performed consistently well across ethnicities, with high recall (98%) and precision (97.5%). CONCLUSION: Compared to array data imputed into 1000 Genomes, mid-pass performed better across all metrics and identified novel population-specific variants with potential disease relevance. We hope our work will reduce financial barriers for geneticists from underrepresented populations to characterize their genomes prior to biomedical genetic applications.

Intracellular activation of 4-hydroxycyclophosphamide into a DNA-alkylating agent in human leucocytes.

1.The conversion of the cyclophosphamide intermediate metabolite 4-hydroxycyclophosphamide (4-OHCP) to the final cytotoxic metabolite phosphoramide mustard (PAM) is classically assumed to occur via chemical hydrolysis of the phospho-ester bond. Whilst it has been suggested previously that this reaction could be enzyme-catalysed, there was only indirect evidence for this (i.e. formation of the by-product acrolein).2. Using an assay to detect formation of DNA-alkylating adducts which block PCR amplification (QPCR-block assay), we have demonstrated that 4-OHCP can be activated by peripheral blood mononuclear cells (PBMC). The DNA-alkylating potency of 4-OHCP in PBMC increased >18-fold compared to the intrinsic reactivity of 4-OHCP for purified gDNA.3. We also found that immortalised T-cells (Jurkat) had a similar ability to activate 4-OHCP into a DNA alkylating agent, whereas there was no appreciable activation in epithelial derived (Caco-2) cells. This suggests the possibility of tissue-specific enzyme expression.4. Of the candidate enzymes tested only recombinant human cAMP-phosphodiesterase-PDE4B and snake-venom phosphodiesterase (PDE-I) could catalyse this activation into a DNA-alkylating agent.5. This enzymatic catalysis of the phospho-ester bond (P-O-C) is a hitherto unrecognised feature of this important immunomodulatory drug and should be investigated further.

Three week compared to seven week run-in period length and the assessment of pre-randomization adherence: A study within a trial.

BACKGROUND/AIMS: To examine how measuring adherence at 3 weeks by self-report and pill counts compares to measurements at 7 weeks in a pre-randomization run-in period. METHODS: Study within a trial of an international parallel group randomized controlled trial (RCT) that compares spironolactone to placebo. Adults receiving dialysis enter an 8-week active run-in period with spironolactone. Adherence was assessed by both self-report and pill counts in a subgroup of participants at both 3 weeks and 7 weeks. RESULTS: 332 participants entered the run-in period of which 166 had complete data. By self-report, 146/166 (94.0%) and 153/166 (92.2%) had at least 80% adherence at 3 and 7 weeks respectively (kappa = 0.27 (95% C.I. 0.16 to 0.38). By pill counts, the mean (SD) adherence was 96.5% (16.1%) and 92.4% (18.2%) at 3 and 7 weeks respectively (r = 0.32) with a mean (SD) difference of 3.1% (17.8%) and a 95% limit of agreement from -31.7% to +37.9%. The proportion of adherent participants by self-report and pill counts at 3 weeks agreed in 87.4% of participants (McNemar's p-value 0.58, kappa 0.11, p = 0.02) and at 7 weeks agreed in 92.2% (McNemar's p-value 0.82, kappa 0.47, p < 0.001). CONCLUSIONS: Three and seven-week run-in periods and both self-reported and pill count assessments performed similarly. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03020303.

Quality of Life in Caregivers of Patients Randomized to Standard- Versus Extended-Hours Hemodialysis.

INTRODUCTION: Caregivers are essential for the health, safety, and independence of many patients and incur financial and personal cost in this role, including increased burden and lower quality of life (QOL) compared to the general population. Extended-hours hemodialysis may be the preference of some patients, but little is known about its effects on caregivers. METHODS: Forty caregivers of participants of the ACTIVE Dialysis trial, who were randomized to 12 months extended (median 24 hours/wk) or standard (12 hours/wk) hemodialysis, were included. Utility-based QOL was measured by EuroQOL-5 Dimension-3 Level (EQ-5D-3L) and Short Form-6 Dimensions (SF-6D) and health-related QOL (HRQOL) was measured by the 36-Item Short Form Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS) and the Personal Wellbeing Index (PWI) at enrolment and then every 3 months until the end of the study. RESULTS: At baseline, utility-based QOL and HRQOL were similar in both groups. At follow-up, caregivers of people randomized to extended-hours dialysis experienced a greater decrease in utility-based QOL measured by EQ-5D-3L compared with caregivers of people randomized to standard hours (-0.18±0.30 vs. -0.02±0.16, P = 0.04). There were no differences between extended- and standard-hours groups in mean change in SF-6D (0.03±0.12 vs. -0.04±0.1, P = 0.8), PCS (-1.2±9.8 vs. -5.6±9.8, P = 0.2), MCS (-4.1±11.2 vs. -0.5±7.1, P = 0.4), and PWI (2.3±17.6 vs. 0.00±20.4, P = 0.9). CONCLUSION: Poorer utility-based QOL, as measured by the EQ-5D-3L, was observed in caregivers of patients receiving extended-hours hemodialysis in this small study. Though the findings are exploratory, the possibility that mode of dialysis delivery negatively impacts on caregivers supports the prioritization of research on burden and impact of service delivery in this population.

Effects of Allopurinol on the Progression of Chronic Kidney Disease.

BACKGROUND: Elevated serum urate levels are associated with progression of chronic kidney disease. Whether urate-lowering treatment with allopurinol can attenuate the decline of the estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease who are at risk for progression is not known. METHODS: In this randomized, controlled trial, we randomly assigned adults with stage 3 or 4 chronic kidney disease and no history of gout who had a urinary albumin:creatinine ratio of 265 or higher (with albumin measured in milligrams and creatinine in grams) or an eGFR decrease of at least 3.0 ml per minute per 1.73 m2 of body-surface area in the preceding year to receive allopurinol (100 to 300 mg daily) or placebo. The primary outcome was the change in eGFR from randomization to week 104, calculated with the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. RESULTS: Enrollment was stopped because of slow recruitment after 369 of 620 intended patients were randomly assigned to receive allopurinol (185 patients) or placebo (184 patients). Three patients per group withdrew immediately after randomization. The remaining 363 patients (mean eGFR, 31.7 ml per minute per 1.73 m2; median urine albumin:creatinine ratio, 716.9; mean serum urate level, 8.2 mg per deciliter) were included in the assessment of the primary outcome. The change in eGFR did not differ significantly between the allopurinol group and the placebo group (-3.33 ml per minute per 1.73 m2 per year [95% confidence interval {CI}, -4.11 to -2.55] and -3.23 ml per minute per 1.73 m2 per year [95% CI, -3.98 to -2.47], respectively; mean difference, -0.10 ml per minute per 1.73 m2 per year [95% CI, -1.18 to 0.97]; P = 0.85). Serious adverse events were reported in 84 of 182 patients (46%) in the allopurinol group and in 79 of 181 patients (44%) in the placebo group. CONCLUSIONS: In patients with chronic kidney disease and a high risk of progression, urate-lowering treatment with allopurinol did not slow the decline in eGFR as compared with placebo. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; CKD-FIX Australian New Zealand Clinical Trials Registry number, ACTRN12611000791932.).

No evidence of a legacy effect on survival following randomization to extended hours dialysis in the ACTIVE Dialysis trial.

AIM: Extended hours haemodialysis is associated with superior survival to standard hours. However, residual confounding limits the interpretation of this observation. We aimed to determine the effect of a period of extended hours dialysis on long-term survival among participants in the ACTIVE Dialysis trial. METHODS: Two-hundred maintenance haemodialysis recipients were randomized to extended hours dialysis (median 24 h/wk) or standard hours dialysis (median 12 h/wk) for 12 months. Further pre-specified observational follow up occurred at 24, 36 and 60 months. Vital status and modality of renal replacement therapy were ascertained. RESULTS: Over the 5 years, 38 participants died, 30 received a renal transplant, and 6 were lost to follow up. Total weekly dialysis hours did not differ between standard and extended groups during the follow-up period (14.1 hours [95%CI 13.4-14.8] vs 14.8 hours [95%CI 14.1-15.6]; P = .16). There was no difference in all-cause mortality (hazard ratio for extended hours 0.91 [95%CI 0.48-1.72]; P = .77). Similar results were obtained after censoring participants at transplantation, and after adjusting for potential confounding variables. Subgroup analysis did not reveal differences in treatment effect by region, dialysis setting or vintage (P-interaction .51, .54, .12, respectively). CONCLUSION: Twelve months of extended hours dialysis did not improve long-term survival nor affect dialysis hours after the intervention period. An urgent need remains to further define the optimal dialysis intensity across the broad range of dialysis recipients.

Predictors of Change in Left-Ventricular Structure and Function in a Trial of Extended Hours Hemodialysis.

BACKGROUND: Myocardial pathology is common in patients undergoing hemodialysis. To explore the effects of differing aspects of dialysis treatment on its evolution, we examined the impact of change in markers of volume status, hemodynamics and solute clearance on left ventricular (LV) parameters in a randomized trial of extended hours dialysis. METHODS AND RESULTS: A Clinical Trial of IntensiVE (ACTIVE) Dialysis randomized 200 patients undergoing hemodialysis to extended dialysis hours (≥ 24 hours/week) or standard hours (12-18 hours/week) for 12 months. In a prespecified substudy, 95 participants underwent cardiac magnetic resonance imaging (CMR) at baseline and at the study's end. Generalized linear regression was used to model the relationship between changes in LV parameters and markers of volume status (normalized ultrafiltration rate and total weekly interdialytic weight gain), hemodynamic changes (systolic and diastolic blood pressure) and solute control (urea clearance, dialysis hours and phosphate). Randomization to extended hours dialysis was not associated with change in any CMR parameter. Reduction in ultrafiltration rate was associated with reduction in LV mass index (P = 0.049) and improved ejection fraction (P = 0.024); reduction in systolic blood pressure was also associated with improvement in ejection fraction (P = 0.045); reduction in interdialytic weight gain was associated with reduced stroke volume (P = 0.038). There were no associations between change in urea clearance, phosphate or total hours per week and CMR parameters. CONCLUSIONS: Reduction in ultrafiltration rate and blood pressure are associated with improved myocardial parameters in hemodialysis recipients independently of solute clearance or dialysis time. These findings underscore the importance of fluid status and related parameters as potential treatment targets in this population.

Effect of Low-Sodium versus Conventional Sodium Dialysate on Left Ventricular Mass in Home and Self-Care Satellite Facility Hemodialysis Patients: A Randomized Clinical Trial.

BACKGROUND: Fluid overload in patients undergoing hemodialysis contributes to cardiovascular morbidity and mortality. There is a global trend to lower dialysate sodium with the goal of reducing fluid overload. METHODS: To investigate whether lower dialysate sodium during hemodialysis reduces left ventricular mass, we conducted a randomized trial in which patients received either low-sodium dialysate (135 mM) or conventional dialysate (140 mM) for 12 months. We included participants who were aged >18 years old, had a predialysis serum sodium ≥135 mM, and were receiving hemodialysis at home or a self-care satellite facility. Exclusion criteria included hemodialysis frequency >3.5 times per week and use of sodium profiling or hemodiafiltration. The main outcome was left ventricular mass index by cardiac magnetic resonance imaging. RESULTS: The 99 participants had a median age of 51 years old; 67 were men, 31 had diabetes mellitus, and 59 had left ventricular hypertrophy. Over 12 months of follow-up, relative to control, a dialysate sodium concentration of 135 mmol/L did not change the left ventricular mass index, despite significant reductions at 6 and 12 months in interdialytic weight gain, in extracellular fluid volume, and in plasma B-type natriuretic peptide concentration (ratio of intervention to control). The intervention increased intradialytic hypotension (odds ratio [OR], 7.5; 95% confidence interval [95% CI], 1.1 to 49.8 at 6 months and OR, 3.6; 95% CI, 0.5 to 28.8 at 12 months). Five participants in the intervention arm could not complete the trial because of hypotension. We found no effect on health-related quality of life measures, perceived thirst or xerostomia, or dietary sodium intake. CONCLUSIONS: Dialysate sodium of 135 mmol/L did not reduce left ventricular mass relative to control, despite improving fluid status. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: The Australian New Zealand Clinical Trials Registry, ACTRN12611000975998.

Successful treatment of carbapenemase producing Enterobacteriaceae peritonitis: 'Old therapy for a new bug'.

Multidrug-resistant organisms cause significant morbidity and mortality. Infections due to resistant gram-negative bacilli are increasingly being reported. For years, carbapenem antibiotics have been successfully used to treat infections due to resistant Enterobacteriaceae, such as Escherichia coli and Klebsiella pneumoniae, including those producing extended spectrum ß-lactamases, a subset of ß-lactamase enzymes that confer broad resistance to penicillins and cephalosporins. More recently, carbapenem-resistant Enterobacteriaceae have emerged as pathogenic organisms, which confer broad resistance to most ß-lactam antibiotics including 'last-line' carbapenems. However, different types of carbapenemases confer diverse spectra of antibiotic resistance. Here, we describe the case of an 84-year-old lady on peritoneal dialysis (PD) for 3 years who, on developing carbapenem-resistant Klebsiella pneumoniae PD peritonitis, was successfully treated with colistin, an antimicrobial agent first used in the 1950s.