Randomized Trial Comparing Proactive, High-Dose versus Reactive, Low-Dose Intravenous Iron Supplementation in Hemodialysis (PIVOTAL): Study Design and Baseline Data

BACKGROUND: Intravenous (IV) iron supplementation is a standard maintenance treatment for hemodialysis (HD) patients, but the optimum dosing regimen is unknown. METHODS: PIVOTAL (Proactive IV irOn Therapy in hemodiALysis patients) is a multicenter, open-label, blinded endpoint, randomized controlled (PROBE) trial. Incident HD adults with a serum ferritin 700 µg/L and/or TSAT ≥40%) or a reactive, low-dose IV iron arm (iron sucrose administered if ferritin <200 µg/L or TSAT < 20%). We hypothesized that proactive, high-dose IV iron would be noninferior to reactive, low-dose IV iron for the primary outcome of first occurrence of nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure or death from any cause. If noninferiority is confirmed with a noninferiority limit of 1.25 for the hazard ratio of the proactive strategy relative to the reactive strategy, a test for superiority will be carried out. Secondary outcomes include infection-related endpoints, ESA dose requirements, and quality-of-life measures. As an event-driven trial, the study will continue until at least 631 primary outcome events have accrued, but the expected duration of follow-up is 2–4 years. RESULTS: Of the 2,589 patients screened across 50 UK sites, 2,141 (83%) were randomized. At baseline, 65.3% were male, the median age was 65 years, and 79% were white. According to eligibility criteria, all patients were on ESA at screening. Prior stroke and MI were present in 8 and 9% of the cohort, respectively, and 44% of patients had diabetes at baseline. Baseline data for the randomized cohort were generally concordant with recent data from the UK Renal Registry. CONCLUSION: PIVOTAL will provide important information about the optimum dosing of IV iron in HD patients representative of usual clinical practice. TRIAL REGISTRATION: EudraCT number: 2013-002267-25

Differences in Immunoglobulin Light Chain Species Found in Urinary Exosomes in Light Chain Amyloidosis (AL)

Renal involvement is a frequent consequence of plasma cell dyscrasias. The most common entities are light chain amyloidosis, monoclonal immunoglobulin deposition disease and myeloma cast nephropathy. Despite a common origin, each condition has its own unique histologic and pathophysiologic characteristic which requires a renal biopsy to distinguish. Recent studies have shown urinary exosomes containing kidney-derived membrane and cytosolic proteins that can be used to probe the proteomics of the entire urinary system from the glomerulus to the bladder. In this study, we analyzed urine exosomes to determine the differences between exosomes from patients with light chain amyloidosis, multiple myeloma, monoclonal gammopathy of undetermined significance, and non-paraproteinemia related kidney disease controls. In patients with light chain amyloidosis, multiple myeloma and monoclonal gammopathy of undetermined significance, immunoreactive proteins corresponding to monomeric light chains were found in exosomes by western blot. In all of the amyloidosis samples with active disease, high molecular weight immunoreactive species corresponding to a decamer were found which were not found in exosomes from the other diseases or in amyloidosis exosomes from patients in remission. Few or no light chains monomeric bands were found in non-paraproteinemia related kidney disease controls. Our results showed that urinary exosomes may have tremendous potential in furthering our understanding of the pathophysiology and diagnosis of plasma cell dyscrasia related kidney diseases

Endotoxaemia in Haemodialysis: A Novel Factor in Erythropoetin Resistance?

Background/Objectives Translocated endotoxin derived from intestinal bacteria is a driver of systemic inflammation and oxidative stress. Severe endotoxaemia is an underappreciated, but characteristic finding in haemodialysis (HD) patients, and appears to be driven by acute repetitive dialysis induced circulatory stress. Resistance to erythropoietin (EPO) has been identified as a predictor of mortality risk, and associated with inflammation and malnutrition. This study aims to explore the potential link between previously unrecognised endotoxaemia and EPO Resistance Index (ERI) in HD patients. Methodology/Principal Findings 50 established HD patients were studied at a routine dialysis session. Data collection included weight, BMI, ultrafiltration volume, weekly EPO dose, and blood sampling pre and post HD. ERI was calculated as ratio of total weekly EPO dose to body weight (U/kg) to haemoglobin level (g/dL). Mean haemoglobin (Hb) was 11.3±1.3 g/dL with a median EPO dose of 10,000 [IQR 7,500–20,000] u/wk and ERI of 13.7 [IQR 6.9–23.3] ((U/Kg)/(g/dL)). Mean pre-HD serum ET levels were significantly elevated at 0.69±0.30 EU/ml. Natural logarithm (Ln) of ERI correlated to predialysis ET levels (r = 0.324, p = 0.03) with a trend towards association with hsCRP (r = 0.280, p = 0.07). Ln ERI correlated with ultrafiltration volume, a driver of circulatory stress (r = 0.295, p = 0.046), previously identified to be associated with increased intradialytic endotoxin translocation. Both serum ET and ultrafiltration volume corrected for body weight were independently associated with Ln ERI in multivariable analysis. Conclusions This study suggests that endotoxaemia is a significant factor in setting levels of EPO requirement. It raises the possibility that elevated EPO doses may in part merely be identifying patients subjected to significant circulatory stress and suffering the myriad of negative biological consequences arising from sustained systemic exposure to endotoxin

An Analysis of Vascular Access Thrombosis Events From the Proactive IV irOn Therapy in hemodiALysis Patients Trial

INTRODUCTION: Treatment of anemia in dialysis patients has been associated with increased risk of vascular access thrombosis (VAT). Proactive IV irOn Therapy in hemodiALysis Patients (PIVOTAL) was a clinical trial of proactive compared with reactive i.v. iron therapy in patients requiring hemodialysis. We analyzed the trial data to determine whether randomized treatment arm, alongside other clinical and laboratory variables, independently associated with VAT. METHODS: In PIVOTAL, 2141 adult patients were randomized. The type of vascular access (arteriovenous fistula [AVF], arteriovenous graft [AVG], or central venous catheter [CVC]) was recorded at baseline and every month after randomization. The associations between clinical and laboratory data and first VAT were evaluated in a multivariate analysis. RESULTS: A total of 480 (22.4%) participants experienced VAT in a median of 2.1 years of follow-up. In multivariable analyses, treatment arm (proactive vs. reactive) was not an independent predictor of VAT (hazard ratio [HR] 1.13, P = 0.18). Diabetic kidney disease (HR 1.45, P < 0.001), AVG use (HR 2.29, P < 0.001), digoxin use (HR 2.48, P < 0.001), diuretic use (HR 1.25, P = 0.02), female sex (HR 1.33, P = 0.002), and previous/current smoker (HR 1.47, P = 0.004) were independently associated with a higher risk of VAT. Angiotensin receptor blocker (ARB) use (HR 0.66, P = 0.01) was independently associated with a lower risk of VAT. CONCLUSION: In PIVOTAL, VAT occurred in nearly 1 quarter of participants in a median of just >2 years. In this post hoc analysis, randomization to proactive i.v. iron treatment arms did not increase the risk of VAT

Calculating Stage Duration Statistics in Multistage Diseases

Many human diseases are characterized by multiple stages of progression. While the typical sequence of disease progression can be identified, there may be large individual variations among patients. Identifying mean stage durations and their variations is critical for statistical hypothesis testing needed to determine if treatment is having a significant effect on the progression, or if a new therapy is showing a delay of progression through a multistage disease. In this paper we focus on two methods for extracting stage duration statistics from longitudinal datasets: an extension of the linear regression technique, and a counting algorithm. Both are non-iterative, non-parametric and computationally cheap methods, which makes them invaluable tools for studying the epidemiology of diseases, with a goal of identifying different patterns of progression by using bioinformatics methodologies. Here we show that the regression method performs well for calculating the mean stage durations under a wide variety of assumptions, however, its generalization to variance calculations fails under realistic assumptions about the data collection procedure. On the other hand, the counting method yields reliable estimations for both means and variances of stage durations. Applications to Alzheimer disease progression are discussed

Survival after starting renal replacement treatment in patients with autosomal dominant polycystic kidney disease: a single-centre 40-year study.

BACKGROUND/AIMS: Adult polycystic kidney disease (ADPKD) has a predictable natural history and the relative lack of co-morbidity allows a relatively unconfounded assessment of survival. We examined whether survival on renal replacement treatment (RRT) has improved over the last four decades compared to that in the general population. METHODS: We conducted a retrospective cohort study of all patients with ADPKD who received RRT between 1971 and 2000 at the Oxford Kidney Unit. The main exposure was period of start of treatment (1971-1985 vs. 1986-2000) and the key outcome was overall survival. Standard Cox regression techniques were used to assess the association between these baseline variables and survival. RESULTS: Age at start of RRT (HR per 1 year 1.08; 95% CI 1.06-1.10) and presence of a functioning transplant (HR 0.22; 95% CI 0.16-0.31) were associated with improved survival in unadjusted analyses. After adjustment for age the period of treatment also became a significant predictor of overall survival (HR 0.67; 95% CI 0.47-0.97). CONCLUSIONS: Survival on RRT appears to have improved and exceeds that observed in the general population, such that RRT now provides almost two-thirds of the life expectancy of the general population, compared to about half in earlier decades

Cardiovascular abnormalities in osteogenesis imperfecta.

To investigate the prevalence of cardiac abnormalities in osteogenesis imperfecta we performed a clinical and echocardiographic study on 20 patients. One patient had aortic regurgitation, 13 had soft late apical systolic murmurs (without significant mitral regurgitation), and seven had systemic hypertension. In only one patient was there echocardiographic evidence of mitral valve prolapse. The aortic root diameter exceeded the normal range in six patients, two of whom were hypertensive. The overall mean value (+/- 1 S.D.) in the 16 patients without marked skeletal deformity was 2.02 +/- 0.33 cm/m2. The echocardiographic appearances suggested that the left-sided valve cusps were thin, and in 13 patients the aortic valve leaflets showed a coarse systolic flutter

Late presentation of patients with end-stage renal disease for renal replacement therapy--is it always avoidable?

BACKGROUND: Twenty-five to 30% of new renal replacement therapy (RRT) patients present late to renal services. The proportion in whom this is avoidable, and whether awareness of chronic kidney disease (CKD) has reduced its incidence is not known. METHODS: Adult patients starting RRT (2003-2008) in a single unit were grouped according to the time interval between first presentation to the unit and start of RRT: &lt;90 days (late presenters); 90-364 days; ≥ 365 days. 'Late presenters' were classified as follows: acute kidney injury--patients who had acute but irreversible renal failure; 'avoidable' late referrals, if they had known pre-existing CKD and 'unavoidable' late referrals, if they had unpredictable rapid progression of their CKD or had no prior contact with health care. Mortality risk associated with late presentation was explored using multivariable Cox regression. RESULTS: Late presentation was common (24.3%) but late referrals accounted for only 7.4% and 3.9% were avoidable. The incidence of late referrals decreased from 9.2% in 2003-2005 to 5.5% in 2006-2008 (trend P = 0.07). Late presentation was associated with increased mortality after adjusting for comorbidity, transplantation and permanent vascular access, and the majority of late presenters died due to malignancy or withdrawal of RRT. CONCLUSIONS: The lower incidence of late referrals and the falling trend could be due to implementation of automated estimated glomerular filtration rate reporting and the increased awareness of CKD in primary care. Future prospective studies are needed to examine the extent to which frailty contributes to this mortality risk