Vitamin K Supplementation to Improve Vascular Stiffness in CKD: The K4Kidneys Randomized Controlled Trial.

BACKGROUND: Vascular calcification, a risk factor for cardiovascular disease, is common among patients with CKD and is an independent contributor to increased vascular stiffness and vascular risk in this patient group. Vitamin K is a cofactor for proteins involved in prevention of vascular calcification. Whether or not vitamin K supplementation could improve arterial stiffness in patients with CKD is unknown. METHODS: To determine if vitamin K supplementation might improve arterial stiffness in patients in CKD, we conducted a parallel-group, double-blind, randomized trial in participants aged 18 or older with CKD stage 3b or 4 (eGFR 15-45 ml/min per 1.73 m2). We randomly assigned participants to receive 400 µg oral vitamin K2 or matching placebo once daily for a year. The primary outcome was the adjusted between-group difference in carotid-femoral pulse wave velocity at 12 months. Secondary outcomes included augmentation index, abdominal aortic calcification, BP, physical function, and blood markers of mineral metabolism and vascular health. We also updated a recently published meta-analysis of trials to include the findings of this study. RESULTS: We included 159 randomized participants in the modified intention-to-treat analysis, with 80 allocated to receive vitamin K and 79 to receive placebo. Mean age was 66 years, 62 (39%) were female, and 87 (55%) had CKD stage 4. We found no differences in pulse wave velocity at 12 months, augmentation index at 12 months, BP, B-type natriuretic peptide, or physical function. The updated meta-analysis showed no effect of vitamin K supplementation on vascular stiffness or vascular calcification measures. CONCLUSIONS: Vitamin K2 supplementation did not improve vascular stiffness or other measures of vascular health in this trial involving individuals with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Vitamin K therapy to improve vascular health in patients with chronic kidney disease, ISRCTN21444964 (www.isrctn.com).

Data from the ERA-EDTA Registry were examined for trends in excess mortality in European adults on kidney replacement therapy.

The objective of this study was to investigate whether the improvement in survival seen in patients on kidney replacement therapy reflects the enhanced survival of the general population. Patient and general population statistics were obtained from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry and the World Health Organization databases, respectively. Relative survival models were composed to examine trends over time in all-cause and cause-specific excess mortality, stratified by age and modality of kidney replacement therapy, and adjusted for sex, primary kidney disease and country. In total, 280,075 adult patients started kidney replacement therapy between 2002 and 2015. The excess mortality risk in these patients decreased by 16% per five years (relative excess mortality risk (RER) 0.84; 95% confidence interval 0.83-0.84). This reflected a 14% risk reduction in dialysis patients (RER 0.86; 0.85-0.86), and a 16% increase in kidney transplant recipients (RER 1.16; 1.07-1.26). Patients on dialysis showed a decrease in excess mortality risk of 28% per five years for atheromatous cardiovascular disease as the cause of death (RER 0.72; 0.70-0.74), 10% for non-atheromatous cardiovascular disease (RER 0.90; 0.88-0.92) and 10% for infections (RER 0.90; 0.87-0.92). Kidney transplant recipients showed stable excess mortality risks for most causes of death, although it did worsen in some subgroups. Thus, the increase in survival in patients on kidney replacement therapy is not only due to enhanced survival in the general population, but also due to improved survival in the patient population, primarily in dialysis patients.

Sex Differences in Kidney Replacement Therapy Initiation and Maintenance.

BACKGROUND AND OBJECTIVES: More men than women undergo kidney replacement therapy (KRT) despite a larger number of women being affected by CKD. The aim of this multinational European study was to explore whether there might be historic and geographic trends in sex-specific incidence and prevalence of various KRT modalities. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We assessed sex-specific differences in KRT incidence and prevalence using data from nine countries reporting to the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry for at least 40 years, during the period 1965-2015. Sex distribution data were compared with the European general population (Eurostat). Statistical methodology included basic descriptive statistics, incidence and prevalence calculations per million population (pmp), as well as their male-to-female ratios. Analyses were stratified by age group and diabetic status. RESULTS: We analyzed data from 230,378 patients receiving KRT (38% women). For all KRT modalities, the incidence and prevalence rates were consistently higher in men than women. For example, the KRT incidence increased from 8 pmp in 1965-1974 to 98 pmp in 2005-2015 in women, whereas it rose from 12 to 173 pmp in men during the same period. Male-to-female ratios, calculated for incident and prevalent KRT patients, increased with age (range 1.2-2.4), showing consistency over decades and for individual countries, despite marked changes in primary kidney disease (diabetes more prevalent than glomerulonephritis in recent decades). The proportion of kidney transplants decreased less with age in incident and prevalent men compared with women on KRT. Stratified analysis of patients who were diabetic versus nondiabetic revealed that the male-to-female ratio was markedly higher for kidney transplantation in patients with diabetes. CONCLUSIONS: Since the beginning of KRT programs reporting to the ERA-EDTA Registry since the 1960s, fewer women than men have received KRT. The relative difference between men and women initiating and undergoing KRT has remained consistent over the last five decades and in all studied countries.

Characteristics and Outcomes of Patients With Systemic Sclerosis (Scleroderma) Requiring Renal Replacement Therapy in Europe: Results From the ERA-EDTA Registry.

RATIONALE & OBJECTIVE: Data for outcomes of patients with end-stage renal disease (ESRD) secondary to systemic sclerosis (scleroderma) requiring renal replacement therapy (RRT) are limited. We examined the incidence and prevalence of ESRD due to scleroderma in Europe and the outcomes among these patients following initiation of RRT. STUDY DESIGN: Registry study of incidence and prevalence and a matched cohort study of clinical outcomes. SETTING & PARTICIPANTS: Patients represented in any of 19 renal registries that provided data to the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry between 2002 and 2013. PREDICTOR: Scleroderma as the identified cause of ESRD. OUTCOMES: Incidence and prevalence of ESRD from scleroderma. Recovery from RRT dependence, patient survival after ESRD, and graft survival after kidney transplantation. ANALYTICAL APPROACH: Incidence and prevalence were calculated using population data from the European Union and standardized to population characteristics in 2005. Patient and graft survival were compared with 2 age- and sex-matched control groups without scleroderma: (1) diabetes mellitus as the cause of ESRD and (2) conditions other than diabetes mellitus as the cause of ESRD. Survival analyses were performed using Kaplan-Meier analysis and Cox regression. RESULTS: 342 patients with scleroderma (0.14% of all incident RRT patients) were included. Between 2002 and 2013, the range of adjusted annual incidence and prevalence rates of RRT for ESRD due to scleroderma were 0.11 to 0.26 and 0.73 to 0.95 per million population, respectively. Recovery of independent kidney function was greatest in the scleroderma group (7.6% vs 0.7% in diabetes mellitus and 2.0% in other primary kidney diseases control group patients, both P<0.001), though time required to achieve recovery was longer. The 5-year survival probability from day 91 of RRT among patients with scleroderma was 38.9% (95% CI, 32.0%-45.8%), whereas 5-year posttransplantation patient survival and 5-year allograft survival were 88.2% (95% CI, 75.3%-94.6%) and 72.4% (95% CI, 55.0%-84.0%), respectively. Adjusted mortality from day 91 on RRT was higher among patients with scleroderma than observed in both control groups (HRs of 1.25 [95% CI, 1.05-1.48] and 2.00 [95% CI, 1.69-2.39]). In contrast, patient and graft survival after kidney transplantation did not differ between patients with scleroderma and control groups. LIMITATIONS: No data for extrarenal manifestations, treatment, or recurrence. CONCLUSIONS: Survival of patients with scleroderma who receive dialysis for more than 90 days was worse than for those with other causes of ESRD. Patient survival after transplantation was similar to that observed among patients with ESRD due to other conditions. Patients with scleroderma had a higher rate of recovery from RRT dependence than controls.

Lifetime risk of renal replacement therapy in Europe: a population-based study using data from the ERA-EDTA Registry.

Background: Upcoming KDIGO guidelines for the evaluation of living kidney donors are expected to move towards a personal risk-based evaluation of potential donors. We present the age and sex-specific lifetime risk of renal replacement therapy (RRT) for end-stage renal disease in 10 European countries. Methods: We defined lifetime risk of RRT as the cumulative incidence of RRT up to age 90 years. We obtained RRT incidence rates per million population by 5-year age groups and sex using data from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry, and used these to estimate the cumulative incidence of RRT, adjusting for competing mortality risk. Results: Lifetime risk of RRT varied from 0.44% to 2.05% at age 20 years and from 0.17% to 1.59% at age 70 years across countries, and was twice as high in men as in women. Lifetime RRT risk decreased with age, ranging from an average of 0.77% to 0.44% in 20- to- 70-year-old women, and from 1.45% to 0.96% in 20- to- 70-year-old men. The lifetime risk of RRT increased slightly over the past decade, more so in men than in women. However, it appears to have stabilized or even decreased slightly in more recent years. Conclusions: The lifetime risk of RRT decreased with age, was lower in women as compared with men of equal age and varied considerably throughout Europe. Given the substantial differences in lifetime risk of RRT between the USA and Europe, country-specific estimates should be used in the evaluation and communication of the risk of RRT for potential living kidney donors.