More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use ...of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m
of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD).
Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval CI, 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups.
Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).
Vasculitis in New Zealand de Zoysa, Janak Rashme
Clinical and experimental nephrology,
10/2013, Letnik:
17, Številka:
5
Journal Article
Recenzirano
Background
The Asia Pacific Meeting for Vasculitis and ANCA Workshop was held in Tokyo in May 2012. This review of vasculitis in New Zealand (NZ) was prepared for the meeting.
Methods
A review of ...significant NZ demographic and health data is presented with information from relevant studies on vasculitis originating from NZ.
Results
Giant cell arteritis occurs in older adults, and has an annual incidence of 12.7/100,000 adults over the age of 50 years in NZ. Kawasaki disease, a rare cause of acquired cardiac disease primarily affecting young children, has an annual incidence of 8.0/100,000 children aged less than 5 years. The prevalence of granulomatosis with polyangiitis varies within NZ, with a 5-year prevalence varying from 29 to 75 cases per million people. Dual anti-glomerular basement membrane disease and ANCA-associated systemic vasculitis is rare, with an annual incidence estimated at 0.47 cases per million people.
Conclusions
Vasculitis is an uncommon but a significant cause of morbidity and mortality in NZ.
Introduction
AL amyloidosis is a systemic disease where the immunoglobin light chains produced by clonal plasma cells accumulate as insoluble fibrils causing end organ damage. In patients with AL ...amyloidosis, renal involvement is common, and proteinuria is frequently detected. Current treatment for AL amyloidosis aims at reducing production of these pathological immunoglobulin light chains by eliminating the clonal plasma cell population. Following treatment and normalisation of serum free light chains (SFLCs), improvement in end organ function, as demonstrated by reduction of proteinuria in patients with renal AL amyloidosis, occurs at a much slower rate. Although reduction in proteinuria has been linked to improved outcomes, the rate of this reduction has not been documented in detail in the literature. The purpose of this study is to analyse the tempo of proteinuria resolution in patients with renal AL amyloidosis following bortezomib based chemotherapy.
Methods
Cases were selected by retrospectively reviewing the hospital electronic database. All patients with biopsy confirmed renal AL amyloidosis were included. Induction chemotherapy was a combination of weekly bortezomib (1.6mg/m2), cyclophosphamide (300mg/m2) and dexamethasone (40mg) given in 4-weekly cycles. During the follow-up period, proteinuria was measured by urinary protein / creatinine ratio (PCR) from random urine samples. The results of the PCR over time were plotted on a scatter plot, and a best fit curve was fitted using IBM SPSS Statistics 20 software to determine the trend of PCR over time. Patients who did not complete bortezomib chemotherapy, or did not have follow-up urinary PCR were excluded.
Results
After applying the exclusion criteria, seven patients were analysed, and the baseline characteristics are listed in table 1. The median follow-up was 30.9 months (range: 13.2 – 44.1 months). The median age was 68.8 years (range: 52.5 – 80.5 years). Patients received a median of 6 cycles of chemotherapy (range: 2 – 9 cycles), and all patients received full doses of bortezomib based on their body surface area (average dose of 1.6mg/m2, range: 1.53 – 1.64mg/m2). Five of the 7 patients normalised their SFLCs after one cycle of chemotherapy, and the median time to normalisation was 26 days (range: 13 – 185 days).
PCR was used to monitor the level of proteinuria following chemotherapy. One patient was excluded in this part of the analysis due to progressive diabetic and hypertensive nephropathy following an initial improvement in PCR after normalisation of SFLCs. Although there was marked fluctuation of PCR (figure 1), the PCRs followed an exponential decay pattern over time (R2 between 0.223 – 0.976). The median half-life of reduction was 6.2 months (range: 3.4 – 18.2 months).
Conclusions
PCR from random urine samples is a useful and convenient way of assessing proteinuria in everyday outpatient setting. Although PCR fluctuates over time in patients with renal AL amyloidosis, there is a general downward trend following bortezomib based chemotherapy and normalisation of SFLCs. This downward trend appears to follow an exponential decay pattern, and most patients have a protracted delay between normalisation of SFLCs and improvement in proteinuria. In view of such delay, normalisation of SFLCs should be the goal of initial therapy, rather than reduction in proteinuria when treating patients with renal AL amyloidosis.
Table 1Baseline patient characteristicsValue(range)Age (median)68.8 years(52.5 – 80.5 years)Male (%)55.6%Plasma cell burden (median)12.5%(6 – 25%)Kappa/Lambda light chain ratio (median)0.164(0.011 – 37.333)eGFR > 30ml/min (%)88.9%Protein / creatinine ratio at diagnosis (mean)698mg/L(243 – 1636mg/L)
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Simpson:Onyx: Honoraria, Research Funding; Celgene: Honoraria; Janssen Cilag: Honoraria.
The current literature recognises that left ventricular hypertrophy makes a key contribution to the high rate of premature cardiovascular mortality in dialysis patients. Determining how we might ...intervene to ameliorate left ventricular hypertrophy in dialysis populations has become a research priority. Reducing sodium exposure through lower dialysate sodium may be a promising intervention in this regard. However there is clinical equipoise around this intervention because the benefit has not yet been demonstrated in a robust prospective clinical trial, and several observational studies have suggested sodium lowering interventions may be deleterious in some dialysis patients.
The Sodium Lowering in Dialysate (SoLID) study is funded by the Health Research Council of New Zealand. It is a multi-centre, prospective, randomised, single-blind (outcomes assessor), controlled parallel assignment 3-year clinical trial. The SoLID study is designed to study what impact low dialysate sodium has upon cardiovascular risk in dialysis patients. The study intends to enrol 118 home hemodialysis patients from 6 sites in New Zealand over 24 months and follow up each participant over 12 months. Key exclusion criteria are: patients who dialyse more frequently than 3.5 times per week, pre-dialysis serum sodium of <135 mM, and maintenance hemodiafiltration. In addition, some medical conditions, treatments or participation in other dialysis trials, which contraindicate the SoLID study intervention or confound its effects, will be exclusion criteria. The intervention and control groups will be dialysed using dialysate sodium 135 mM and 140 mM respectively, for 12 months. The primary outcome measure is left ventricular mass index, as measured by cardiac magnetic resonance imaging, after 12 months of intervention. Eleven or more secondary outcomes will be studied in an attempt to better understand the physiologic and clinical mechanisms by which lower dialysate sodium alters the primary end point.
The SoLID study is designed to clarify the effect of low dialysate sodium upon the cardiovascular outcomes of dialysis patients. The study results will provide much needed information about the efficacy of a cost effective, economically sustainable solution to a condition which is curtailing the lives of so many dialysis patients.
Australian and New Zealand Clinical Trials Registry number: ACTRN12611000975998.
After the publication of our paper Dunlop et al. "Rationale and design of the Sodium Lowering In Dialysate (SoLID) trial: a randomised controlled trial of low versus standard dialysate sodium ...concentration during hemodialysis for regression of left ventricular mass", we became aware of further data correlating left ventricular (LV) mass index at baseline and their corresponding mass at 12 months, using cardiac magnetic resonance imaging (MRI) in patients on hemodialysis. The original published sample size for the SoLID trial of 118 was a conservative estimate, calculated using analysis of covariance and a within person Pearson's correlation for LV mass index of 0.75. New data communicated to the SoLID trial group has resulted in re-calcuation of the sample size, based upon a within person Pearson's correlation of 0.8 but otherwise unchanged assumptions. As a result, the SoLID trial will now recruit 96 participants.
The Sodium Lowering in Dialysate (SoLID) trial is an ongoing a multi-center, prospective, randomised, single-blind (assessor), controlled, parallel assignment clinical trial, enrolling 96 home and ...self-care hemodialysis (HD) patients from 7 centers in New Zealand. The trial will evaluate the hypothesis that lower dialysate Na+ during HD results in lower left ventricular (LV) mass. Since it's inception, observational evidence has suggested increased mortality risk with lower dialysate Na+, possibly due to exacerbation of intra-dialytic hypotension and subsequent myocardial micro-injury. The Myocardial Micro-injury and Cardiac Remodeling Extension Study in the Sodium Lowering In Dialysate Trial (Mac-SoLID study) aims to determine whether lower dialysate Na+ results in (i) increased levels of high-sensitivity Troponin T (hsTnT), a well-established marker of intra-dialytic myocardial micro-injury in HD populations, and (ii) increased fixed LV segmental wall motion abnormalities, a marker of recurrent myocardial stunning and micro-injury, and (iii) detrimental changes in LV geometry due to maladaptive homeostatic mechanisms.
The SoLID trial and the Mac-SoLID study are funded by the Health Research Council of New Zealand. Key exclusion criteria: patients who dialyse > 3.5 times per week, pre-dialysis serum sodium <135 mM, and maintenance haemodiafiltration. In addition, some medical conditions, treatments or participation in other dialysis trials that contraindicate the study intervention or confound its effects, will be exclusion criteria. The intervention and control groups will receive dialysate sodium 135 mM and 140 mM respectively, for 12 months. The primary outcome measure for the Mac-SOLID study is repeated measures of hsTnT at 0, 3, 6, 9, and 12 months. The secondary outcomes will be assessed using cardiac magnetic resonance imaging (MRI), and comprise LV segmental wall motion abnormality scores, LV mass to volume ratio and patterns of LV remodeling at 0 and 12 months.
The Mac-SoLID study enhances and complements the SoLID trial. It tests whether potential gains in cardiovascular health (reduced LV mass) which low dialysate Na+ is expected to deliver, are counteracted by deterioration in cardiovascular health through alternative mechanisms, namely repeated LV stunning and micro-injury.
Australian and New Zealand Clinical Trials Registry number: ACTRN12611000975998.
Podocyte biology in human disease DE ZOYSA, JANAK RASHME; TOPHAM, PETER STEWART
Nephrology (Carlton, Vic.),
08/2005, Letnik:
10, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The podocyte is a highly specialized cell that plays a key role in regulating the glomerular filtration barrier. A number of advances have been made in recent years, linked to the discovery of ...single‐gene defects in hereditary glomerular disease, which highlight the role of this cell in preventing proteinuria. This article reviews the molecular biology of the podocyte, focusing on known genetic abnormalities.
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