Summary Background IgA nephropathy is thought to be associated with mucosal immune system dysfunction, which manifests as renal IgA deposition that leads to impairment and end-stage renal disease in ...20–40% of patients within 10–20 years. In this trial (NEFIGAN) we aimed to assess safety and efficacy of a novel targeted-release formulation of budesonide (TRF-budesonide), designed to deliver the drug to the distal ileum in patients with IgA nephropathy. Methods We did a randomised, double-blind, placebo-controlled phase 2b trial, comprised of 6-month run-in, 9-month treatment, and 3-month follow-up phases at 62 nephrology clinics across ten European countries. We recruited patients aged at least 18 years with biopsy-confirmed primary IgA nephropathy and persistent proteinuria despite optimised renin-angiotensin system (RAS) blockade. We randomly allocated patients with a computer algorithm, with a fixed block size of three, in a 1:1:1 ratio to 16 mg/day TRF-budesonide, 8 mg/day TRF-budesonide, or placebo, stratified by baseline urine protein creatinine ratio (UPCR). Patients self-administered masked capsules, once daily, 1 h before breakfast during the treatment phase. All patients continued optimised RAS blockade treatment throughout the trial. Our primary outcome was mean change from baseline in UPCR for the 9-month treatment phase, which was assessed in the full analysis set, defined as all randomised patients who took at least one dose of trial medication and had at least one post-dose efficacy measurement. Safety was assessed in all patients who received the intervention. This trial is registered with ClinicalTrials.gov , number NCT01738035. Findings Between Dec 11, 2012, and June 25, 2015, 150 randomised patients were treated (safety set) and 149 patients were eligible for the full analysis set. Overall, at 9 months TRF-budesonide (16 mg/day plus 8 mg/day) was associated with a 24·4% (SEM 7·7%) decrease from baseline in mean UPCR (change in UPCR vs placebo 0·74; 95% CI 0·59–0·94; p=0·0066). At 9 months, mean UPCR had decreased by 27·3% in 48 patients who received 16 mg/day (0·71; 0·53–0·94; p=0·0092) and 21·5% in the 51 patients who received 8 mg/day (0·76; 0·58–1·01; p=0·0290); 50 patients who received placebo had an increase in mean UPCR of 2·7%. The effect was sustained throughout followup. Incidence of adverse events was similar in all groups (43 88% of 49 in the TRF-budesonide 16 mg/day group, 48 94% of 51 in the TRF-budesonide 8 mg/day, and 42 84% of 50 controls). Two of 13 serious adverse events were possibly associated with TRF-budesonide—deep vein thrombosis (16 mg/day) and unexplained deterioration in renal function in follow-up (patients were tapered from 16 mg/day to 8 mg/day over 2 weeks and follow-up was assessed 4 weeks later). Interpretation TRF-budesonide 16 mg/day, added to optimised RAS blockade, reduced proteinuria in patients with IgA nephropathy. This effect is indicative of a reduced risk of future progression to end-stage renal disease. TRF-budesonide could become the first specific treatment for IgA nephropathy targeting intestinal mucosal immunity upstream of disease manifestation. Funding Pharmalink AB.
Summary
Kidney transplantation is the optimal treatment for patients with end stage renal disease (ESRD) who would otherwise require dialysis. Patients with ESRD are at dramatically increased ...cardiovascular (CV) risk compared with the general population. As well as improving quality of life, successful transplantation accords major benefits by reducing CV risk in these patients. Worldwide, cardiovascular disease remains the leading cause of death with a functioning graft and therefore is a leading cause of graft failure. This review focuses on the mechanisms underpinning excess CV morbidity and mortality and current evidence for improving CV risk in kidney transplant recipients. Conventional CV risk factors such as hypertension, diabetes mellitus, dyslipidaemia and pre‐existing ischaemic heart disease are all highly prevalent in this group. In addition, kidney transplant recipients exhibit a number of risk factors associated with pre‐existing renal disease. Furthermore, complications specific to transplantation may ensue including reduced graft function, side effects of immunosuppression and post‐transplantation diabetes mellitus. Strategies to improve CV outcomes post‐transplantation may include pharmacological intervention including lipid‐lowering or antihypertensive therapy, optimization of graft function, lifestyle intervention and personalizing immunosuppression to the individual patients risk profile.
Background Left ventricular hypertrophy (LVH) is common in patients with end-stage renal disease (ESRD) and an independent risk factor for premature cardiovascular death. Left atrial volume (LAV), ...measured using echocardiography, predicts death in patients with ESRD. Cardiovascular magnetic resonance (CMR) imaging is a volume-independent method of accurately assessing cardiac structure and function in patients with ESRD. Study Design Single-center prospective observational study to assess the determinants of all-cause mortality, particularly LAV, in a cohort of ESRD patients with LVH, defined using CMR imaging. Setting & Participants 201 consecutive ESRD patients with LVH (72.1% men; mean age, 51.6 ± 11.7 years) who had undergone pretransplant cardiovascular assessment were identified using CMR imaging between 2002-2008. LVH was defined as left ventricular mass index >84.1 g/m2 (men) or >74.6 g/m2 (women) based on published normal left ventricle dimensions for CMR imaging. Maximal LAV was calculated using the biplane area-length method at the end of left ventricle systole and corrected for body surface area. Predictors CMR abnormalities, including LAV. Outcome All-cause mortality. Results 54 patients died (11 after transplant) during a median follow-up of 3.62 years. Median LAV was 30.4 mL/m2 (interquartile range, 26.2-58.1). Patients were grouped into high (median or higher) or low (less than median) LAV. There were no significant differences in heart rate and mitral valve Doppler early to late atrial peak velocity ratio. Increased LAV was associated with higher mortality. Kaplan-Meier survival analysis showed poorer survival in patients with higher LAV (log rank P = 0.01). High LAV and left ventricular systolic dysfunction conferred similar risk and were independent predictors of death using multivariate analysis. Limitations Only patients undergoing pretransplant cardiac assessment are included. Limited assessment of left ventricular diastolic function. Conclusions Higher LAV and left ventricular systolic dysfunction are independent predictors of death in ESRD patients with LVH.
Short-term renal allograft survival has improved more quickly than long-term outcomes. Analysis of more than 100,000 deceased donor renal transplants in Europe from 1986 to 2015 identified a ...declining rate of improvement in 1-year, death-censored graft survival but a continued improvement in longer-term survival, with a year-on-year 3% reduction in the risk of graft failure. These reassuring observations likely reflect improved overall transplant management rather than specific advances.
Although advances in immunosuppression, tissue typing, surgery, and medical management have made transplantation a routine and preferred treatment for patients with irreversible renal failure, ...successful transplant recipients have a greatly increased risk of premature mortality because of cardiovascular disease and malignancy compared with the general population. Conventional cardiovascular risk factors such as hyperlipidaemia, hypertension, and diabetes are common in transplant recipients, partly because of the effects of immunosuppressive drugs, and are associated with adverse outcomes. However, the natural history of cardiovascular disease in such recipients differs from that in the general population, and only statin therapy has been studied in a large-scale interventional trial. Thus, the management of this disease and the balance between management of conventional risk factors and modification of immunosuppression is complex.
Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production.
In two phase 3, ...randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52.
A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval CI, 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter.
Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PRO
TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).
Vascular stiffness (VS) and vascular calcification (VC) are surrogate markers of vascular health associated with cardiovascular events. Vitamin K-dependent proteins (VKDP) are associated with VS and ...VC and require vitamin K for activity. We conducted a systematic review and meta-analysis of: (1) the effect of vitamin K supplementation on VS and VC and (2) association of inactive VKDP levels with incident cardiovascular disease and mortality.
Two authors searched MEDLINE and Embase databases and Cochrane and ISRCTN registries for studies of vitamin K clinical trials that measured effects on VC, VS or VKDP and longitudinal studies assessing effect of VKDP on incident CVD or mortality. Random effects meta-analyses were performed.
Thirteen controlled clinical trials (n=2162) and 14 longitudinal studies (n=10 726) met prespecified inclusion criteria. Vitamin K supplementation was associated with significant reduction in VC (-9.1% (95% CI -17.7 to -0.5); p=0.04) and VKDP (desphospho-uncarboxylated matrix Gla protein; -44.7% (95% CI -65.1 to -24.3), p<0.0001) and uncarboxylated osteocalcin; -12.0% (95% CI -16.7 to -7.2), p<0.0001) compared with control, with a non-significant improvement in VS. In longitudinal studies with median follow-up of 7.8 (IQR 4.9-11.3) years, VKDP levels were associated with a combined endpoint of CVD or mortality (HR 0.45 (95% CI 0.07 to 0.83), p=0.02).
Supplementation with vitamin K significantly reduced VC, but not VS, compared with control. The conclusions drawn are limited by small numbers of studies with substantial heterogeneity. VKDP was associated with combined endpoint of CVD or mortality. Larger clinical trials of effect of vitamin K supplementation to improve VC, VS and long-term cardiovascular health are warranted.
CRD42017060344.
Ambulatory blood pressure monitoring (ABPM) has become popular in the investigation and management of patients with essential hypertension. In patients receiving haemodialysis, ABPM identifies ...patients who may fare worse in the long term. However, the available studies are small, and when conventional risk factors are included, there is no added value to ABPM over conventional BP measurements. In haemodialysis, ABPM remains an experimental investigation, and in the absence of specific, evidence-based targets for blood pressure in this population, it would be better to invest in large-scale trials to provide specific blood pressure targets and strategies, rather than concentrating on an alternative technique for blood pressure measurement.
Although advances in immunosuppression, tissue typing, surgery, and medical management have made transplantation a routine and preferred treatment for patients with irreversible renal failure, ...successful transplant recipients have a greatly increased risk of premature mortality because of cardiovascular disease and malignancy compared with the general population. Conventional cardiovascular risk factors such as hyperlipidaemia, hypertension, and diabetes are common in transplant recipients, partly because of the effects of immunosuppressive drugs, and are associated with adverse outcomes. However, the natural history of cardiovascular disease in such recipients differs from that in the general population, and only statin therapy has been studied in a large-scale interventional trial. Thus, the management of this disease and the balance between management of conventional risk factors and modification of immunosuppression is complex. PUBLICATION ABSTRACT
Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival rates over 80%; however, improving longer-term outcomes remains a challenge. ...Improving the function of grafts and health of recipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient modifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes.COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across Europe. The group's remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant.The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year. In addition, the provision of a checklist increases the clinical utility and accessibility of these recommendations, by offering a systematic and efficient way to implement screening and monitoring of modifiable risks in the clinical setting.
PDF
