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Institute
- Medizinische Klinik und Poliklinik I (54) (remove)
Sonstige beteiligte Institutionen
EU-Project number / Contract (GA) number
- 602133 (1)
Background: Dose requirements of erythropoietin-stimulating agents (ESAs) can vary considerably over time and may be associated with cardiovascular outcomes. We aimed to longitudinally assess ESA responsiveness over time and to investigate its association with specific clinical end points in a time-dependent approach. Methods: The German Diabetes and Dialysis study (4D study) included 1,255 diabetic dialysis patients, of whom 1,161 were receiving ESA treatment. In those patients, the erythropoietin resistance index (ERI) was assessed every 6 months during a median follow-up of 4 years. The association between the ERI and cardiovascular end points was analyzed by time-dependent Cox regression analyses with repeated ERI measures. Results: Patients had a mean age of 66 ± 8.2 years; 53% were male. During follow-up, a total of 495 patients died, of whom 136 died of sudden death and 102 of infectious death. The adjusted and time-dependent risk for sudden death was increased by 19% per 5-unit increase in the ERI (hazard ratio, HR = 1.19, 95% confidence interval, CI = 1.07-1.33). Similarly, mortality increased by 25% (HR = 1.25, 95% CI = 1.18-1.32) and infectious death increased by 27% (HR = 1.27, 95% CI = 1.13-1.42). Further analysis revealed that lower 25-hydroxyvitamin D levels were associated with lower ESA responsiveness (p = 0.046). Conclusions: In diabetic dialysis patients, we observed that time-varying erythropoietin resistance is associated with sudden death, infectious complications and all-cause mortality. Low 25-hydroxyvitamin D levels may contribute to a lower ESA responsiveness.
Background: Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD. Methods: Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality. Results: The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events. Conclusion: BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD.
Long-term treatment effect studies in large female Fabry patient groups are challenging to design because of phenotype heterogeneity and lack of appropriate comparison groups, and have not been reported. We compared long-term cardiomyopathy and kidney function outcomes after agalsidase beta treatment with preceding treatment-naive outcomes.
Methods and results Self-controlled pretreatment and post-treatment comparison (piecewise mixed linear modelling) included Fabry female patients ≥18 years at treatment initiation who received agalsidase beta (0.9–1.1 mg/kg every other week) for ≥2 years, with ≥2 pretreatment and ≥2 post-treatment outcome measurements during 10-year follow-up. Left ventricular posterior wall thickness (LVPWT)/interventricular septal thickness (IVST) and estimated glomerular filtration rate (eGFR, Chronic Kidney Disease Epidemiology Collaboration creatinine equation) analyses included 42 and 86 patients, respectively, aged 50.0 and 46.3 years at treatment initiation, respectively. LVPWT and IVST increased pretreatment (follow-up 3.5 years) but stabilized during 3.6 years of treatment (LVPWT: n = 38, slope difference [95% confidence interval (CI)] = - 0.41 [ - 0.68, - 0.15] mm/year, P\(_{pre–post difference}\)<0.01; IVST: n = 38, slope difference =-0.32 [-0.67, 0.02] mm/year, P\(_{pre–post difference}\) = 0.07). These findings were not modified by renal involvement or antiproteinuric agent use. Compared with the treatment-naive period (follow-up 3.6 years), eGFR decline remained modest and stabilized within normal ranges during 4.1 years of treatment (slope difference, 95% CI: -0.13 [-1.15, 0.89] mL/min/1.73m\(^2\)/year, P\(_{pre–post difference}\) = 0.80).
Conclusions Cardiac hypertrophy, progressing during pretreatment follow-up, appeared to stabilize during sustained agalsidase beta treatment. eGFR decline remained within normal ranges. This suggests that treatment may prevent further Fabry-related progression of cardiomyopathy in female patients and maintain normal kidney function.
Background: Left ventricular hypertrophy (LVH), defined by the left ventricular mass index (LVMI), is highly prevalent in hemodialysis patients and a strong independent predictor of cardiovascular events. Compared to cardiac magnetic resonance imaging (CMR), echocardiography tends to overestimate the LVMI. Here, we evaluate the diagnostic performance of transthoracic echocardiography (TTE) compared to CMR regarding the assessment of LVMI in hemodialysis patients.
Methods: TTR and CMR data for 95 hemodialysis patients who participated in the MiREnDa trial were analyzed. The LVMI was calculated by two-dimensional (2D) TTE-guided M-mode measurements employing the American Society of Echocardiography (ASE) and Teichholz (Th) formulas, which were compared to the reference method, CMR.
Results: LVH was present in 44% of patients based on LVMI measured by CMR. LVMI measured by echocardiography correlated moderately with CMR, ASE: r = 0.44 (0.34-0.62); Th: r = 0.44 (0.32-0.62). Compared to CMR, both echocardiographic formulas overestimated LVMI (mean increment LVMI (ASE-CMR): 19.5 +/- 19.48 g/m(2),p < 0.001; mean increment LVMI (Th-CMR): 15.9 +/- 15.89 g/m(2),p < 0.001). We found greater LVMI overestimation in patients with LVH using the ASE formula compared to the Th formula. Stratification of patients into CMR LVMI quartiles showed a continuous decrease in increment LVMI with increasing CMR LVMI quartiles for the Th formula (p < 0.001) but not for the ASE formula (p = 0.772). Bland-Altman analysis showed that the Th formula had a constant bias independent of LVMI. Both methods had good discrimination ability for the detection of LVH (ROC-AUC: 0.819 (0.737-0.901) and 0.808 (0.723-0.892) for Th and ASE, respectively).
Conclusions: The ASE and Th formulas overestimate LVMI in hemodialysis patients. However, the overestimation is less with the Th formula, particularly with increasing LVMI. The results suggest that the Th formula should be preferred for measurement of LVMI in chronic hemodialysis patients.
Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects.
Introduction: Calciphylaxis/calcific uremic arteriolopathy affects mainly end-stage kidney disease patients but is also associated with malignant disorders such as myeloma, melanoma and breast cancer. Genetic risk factors of calciphylaxis have never been studied before.
Methods: We investigated 10 target genes using a tagging SNP approach: the genes encoding CD73/ ecto-5'-nucleotidase (purinergic pathway), Matrix Gla protein, Fetuin A, Bone Gla protein, VKORC1 (all related to intrinsic calcification inhibition), calcium-sensing receptor, FGF23, Klotho, vitamin D receptor, stanniocalcin 1 (all related to CKD-MBD). 144 dialysis patients from the German calciphylaxis registry were compared with 370 dialysis patients without history of CUA. Genotyping was performed using iPLEX Gold MassARRAY(Sequenom, San Diego, USA), KASP genotyping chemistry (LGC, Teddington, Middlesex, UK) or sequencing. Statistical analysis comprised logistic regression analysis with adjustment for age and sex.
Results: 165 SNPs were finally analyzed and 6 SNPs were associated with higher probability for calciphylaxis (OR>1) in our cohort. Nine SNPs of three genes (CD73, FGF23 and Vitamin D receptor) reached nominal significance (p< 0.05), but did not reach statistical significance after correction for multiple testing. Of the CD73 gene, rs4431401 (OR = 1.71, 95%CI 1.08-2.17, p = 0.023) and rs9444348 (OR = 1.48, 95% CI 1.11-1.97, p = 0.008) were associated with a higher probability for CUA. Of the FGF23 and VDR genes, rs7310492, rs11063118, rs13312747 and rs17882106 were associated with a higher probability for CUA.
Conclusion: Polymorphisms in the genes encoding CD73, vitamin D receptor and FGF23 may play a role in calciphylaxis development. Although our study is the largest genetic study on calciphylaxis, it is limited by the low sample sizes. It therefore requires replication in other cohorts if available.
Background
The X-chromosomally linked life-limiting Fabry disease (FD) is associated with deposits of the sphingolipid globotriaosylceramide 3 (Gb3) in various tissues. Skin is easily accessible and may be used as an additional diagnostic and follow-up medium. Our aims were to visualize skin Gb3 deposits in FD patients applying immunofluorescence and to determine if cutaneous Gb3 load correlates with disease severity.
Methods
At our Fabry Center for Interdisciplinary Therapy we enrolled 84 patients with FD and 27 healthy controls. All subjects underwent 5-mm skin punch biopsy at the lateral lower leg and the back. Skin samples were processed for immunohistochemistry using antibodies against CD77 (i.e. Gb3). Cutaneous Gb3 deposition was quantified in a blinded manner and correlated to clinical data.
Results
We found that Gb3 load was higher in distal skin of male FD patients compared to healthy controls (p<0.05). Men (p<0.01) and women (p<0.05) with a classic FD phenotype had higher distal skin Gb3 load than healthy controls. Men with advanced disease as reflected by impaired renal function, and men and women with small fiber neuropathy had more Gb3 deposits in distal skin samples than males with normal renal function (p<0.05) and without small fiber neuropathy. Gb3 deposits were not different between patients with and without enzyme replacement therapy.
Conclusions
Immunofluorescence on minimally invasive skin punch biopsies may be useful as a tool for assessment and follow-up in FD patients.
Background
Agalsidase beta is a form of enzyme replacement therapy for Fabry disease, a genetic disorder characterised by low alpha-galactosidase A activity, accumulation of glycosphingolipids and life-threatening cardiovascular, renal and cerebrovascular events. In clinical trials, agalsidase beta cleared glycolipid deposits from endothelial cells within 6 months; clearance from other cell types required sustained treatment. We hypothesised that there might be a 'lag time' to clinical benefit after initiating agalsidase beta treatment, and analysed the incidence of severe clinical events over time in patients receiving agalsidase beta.
Methods
The incidence of severe clinical events (renal failure, cardiac events, stroke, death) was studied in 1044 adult patients (641 men, 403 women) enrolled in the Fabry Registry who received agalsidase beta (average dose 1 mg/kg every 2 weeks) for up to 5 years.
Results
The incidence of all severe clinical events was 111 per 1000 person-years (95% CI 84 to 145) during the first 6 months. After 6 months, the incidence decreased and remained stable within the range of 40-58 events per 1000 patient-years. The largest decrease in incidence rates was among male patients and those aged >= 40 years when agalsidase beta was initiated.
Conclusions
Contrary to the expected increased incidence of severe clinical events with time, adult patients with Fabry disease had decreased incidence of severe clinical events after 6 months treatment with agalsidase beta 1 mg/kg every 2 weeks.
High-Sensitivity Troponin: A Clinical Blood Biomarker for Staging Cardiomyopathy in Fabry Disease
(2016)
Background
High‐sensitivity troponin (hs‐TNT), a biomarker of myocardial damage, might be useful for assessing fibrosis in Fabry cardiomyopathy. We performed a prospective analysis of hs‐TNT as a biomarker for myocardial changes in Fabry patients and a retrospective longitudinal follow‐up study to assess longitudinal hs‐TNT changes relative to fibrosis and cardiomyopathy progression.
Methods and Results
For the prospective analysis, hs‐TNT from 75 consecutive patients with genetically confirmed Fabry disease was analyzed relative to typical Fabry‐associated echocardiographic findings and total myocardial fibrosis as measured by late gadolinium enhancement (LE) on magnetic resonance imaging. Longitudinal data (3.9±2.0 years), including hs‐TNT, LE, and echocardiographic findings from 58 Fabry patients, were retrospectively collected. Hs‐TNT level positively correlated with LE (linear correlation coefficient, 0.72; odds ratio, 32.81 [95% CI, 3.56–302.59]; P=0.002); patients with elevated baseline hs‐TNT (>14 ng/L) showed significantly increased LE (median: baseline, 1.9 [1.1–3.3] %; follow‐up, 3.2 [2.3–4.9] %; P<0.001) and slightly elevated hs‐TNT (baseline, 44.7 [30.1–65.3] ng/L; follow‐up, 49.1 [27.6–69.5] ng/L; P=0.116) during follow‐up. Left ventricular wall thickness and EF of patients with elevated hs‐TNT were decreased during follow‐up, indicating potential cardiomyopathy progression.
Conclusions
hs‐TNT is an accurate, easily accessible clinical blood biomarker for detecting replacement fibrosis in patients with Fabry disease and a qualified predictor of cardiomyopathy progression. Thus, hs‐TNT could be helpful for staging and follow‐up of Fabry patients.
The prevalence of diabetes around the world has reached epidemic proportions and is projected to increase to 642 million people by 2040. Diabetes is already the leading cause of end-stage kidney disease (ESKD) in most developed countries, and the growth in the number of people with ESKD around the world parallels the increase in diabetes. The presence of kidney disease is associated with a markedly elevated risk of cardiovascular disease and death in people with diabetes. Several new therapies and novel investigational agents targeting chronic kidney disease patients with diabetes are now under development. This conference was convened to assess our current state of knowledge regarding optimal glycemic control, current antidiabetic agents and their safety, and new therapies being developed to improve kidney function and cardiovascular outcomes for this vulnerable population.
The protein-bound uremic toxins para-cresyl sulfate (pCS) and indoxyl sulfate (IS) are associated with cardiovascular disease in chronic renal failure, but the effect of different dialysis procedures on their plasma levels over time is poorly studied. The present prospective, randomized, cross-over trial tested dialysis efficacy and monitored pre-treatment pCS and IS concentrations in 15 patients on low-flux and high-flux hemodialysis and high-convective volume postdilution hemodiafiltration over six weeks each. Although hemodiafiltration achieved by far the highest toxin removal, only the mean total IS level was decreased at week three (16.6 ± 12.1 mg/L) compared to baseline (18.9 ± 13.0 mg/L, p = 0.027) and to low-flux dialysis (20.0 ± 12.7 mg/L, p = 0.021). At week six, the total IS concentration in hemodiafiltration reached the initial values again. Concentrations of free IS and free and total pCS remained unaltered. Highest beta2-microglobulin elimination in hemodiafiltration (p < 0.001) led to a persistent decrease of the plasma levels at week three and six (each p < 0.001). In contrast, absent removal in low-flux dialysis resulted in rising beta2-microglobulin concentrations (p < 0.001). In conclusion, this trial demonstrated that even large differences in instantaneous protein-bound toxin removal by current extracorporeal dialysis techniques may have only limited impact on IS and pCS plasma levels in the longer term.
Background
Diabetes mellitus (DM) is the leading cause of end-stage renal disease. Little is known about practice patterns of anti-diabetic therapy in the presence of chronic kidney disease (CKD) and correlates with glycaemic control. We therefore aimed to analyze current antidiabetic treatment and correlates of metabolic control in a large contemporary prospective cohort of patients with diabetes and CKD.
Methods
The German Chronic Kidney Disease (GCKD) study enrolled 5217 patients aged 18–74 years with an estimated glomerular filtration rate (eGFR) between 30–60 mL/min/1.73 m2 or proteinuria >0.5 g/d. The use of diet prescription, oral anti-diabetic medication, and insulin was assessed at baseline. HbA1c, measured centrally, was the main outcome measure.
Results
At baseline, DM was present in 1842 patients (35 %) and the median HbA1C was 7.0 % (25th–75th percentile: 6.8–7.9 %), equalling 53 mmol/mol (51, 63); 24.2 % of patients received dietary treatment only, 25.5 % oral antidiabetic drugs but not insulin, 8.4 % oral antidiabetic drugs with insulin, and 41.8 % insulin alone. Metformin was used by 18.8 %. Factors associated with an HbA1C level >7.0 % (53 mmol/mol) were higher BMI (OR = 1.04 per increase of 1 kg/m2, 95 % CI 1.02–1.06), hemoglobin (OR = 1.11 per increase of 1 g/dL, 95 % CI 1.04–1.18), treatment with insulin alone (OR = 5.63, 95 % CI 4.26–7.45) or in combination with oral antidiabetic agents (OR = 4.23, 95 % CI 2.77–6.46) but not monotherapy with metformin, DPP-4 inhibitors, or glinides.
Conclusions
Within the GCKD cohort of patients with CKD stage 3 or overt proteinuria, antidiabetic treatment patterns were highly variable with a remarkably high proportion of more than 50 % receiving insulin-based therapies. Metabolic control was overall satisfactory, but insulin use was associated with higher HbA1C levels.
Background
Chronic kidney disease (CKD) is a global health burden, yet it is still underrepresented within public health agendas in many countries. Studies focusing on the natural history of CKD are challenging to design and conduct, because of the long time-course of disease progression, a wide variation in etiologies, and a large amount of clinical variability among individuals with CKD. With the difference in health-related behaviors, healthcare delivery, genetics, and environmental exposures, this variability is greater across countries than within one locale and may not be captured effectively in a single study.
Methods
Studies were invited to join the network. Prerequisites for membership included: 1) observational designs with a priori hypotheses and defined study objectives, patient-level information, prospective data acquisition and collection of bio-samples, all focused on predialysis CKD patients; 2) target sample sizes of 1,000 patients for adult cohorts and 300 for pediatric cohorts; and 3) minimum follow-up of three years. Participating studies were surveyed regarding design, data, and biosample resources.
Results
Twelve prospective cohort studies and two registries covering 21 countries were included. Participants age ranges from >2 to >70 years at inclusion, CKD severity ranges from stage 2 to stage 5. Patient data and biosamples (not available in the registry studies) are measured yearly or biennially. Many studies included multiple ethnicities; cohort size ranges from 400 to more than 13,000 participants. Studies’ areas of emphasis all include but are not limited to renal outcomes, such as progression to ESRD and death.
Conclusions
iNET-CKD (International Network of CKD cohort studies) was established, to promote collaborative research, foster exchange of expertise, and create opportunities for research training. Participating studies have many commonalities that will facilitate comparative research; however, we also observed substantial differences. The diversity we observed across studies within this network will be able to be leveraged to identify genetic, behavioral, and health services factors associated with the course of CKD. With an emerging infrastructure to facilitate interactions among the investigators of iNET-CKD and a broadly defined research agenda, we are confident that there will be great opportunity for productive collaborative investigations involving cohorts of individuals with CKD.
Background
Fabry disease (FD) is an X-linked recessive hereditary lysosomal storage disorder which results in the accumulation of globotriaosylceramid (Gb3) in tissues of kidney and heart as well as central and peripheral nervous system.
Besides prominent renal and cardiac organ involvement, cochlear symptoms like high-frequency hearing loss and tinnitus are frequently found with yet no comprehensive data available in the literature.
Objective
To examine hearing loss in patients with FD depending on cardiac and renal function.
Material and methods
Single-center study with 68 FD patients enrolled between 2012 and 2016 at the Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery of the University of Würzburg. Every subject underwent an oto-rhino-laryngological examination as well as behavioral, electrophysiological and electroacoustical audiological testing. High-frequency thresholds were evaluated by using a modified PTA\(_{6}\) (0.5, 1, 2, 4, 6, 8) and HF-PTA (6, 8 kHz). Renal function was measured by eGFR, cardiac impairment was graduated by NYHA class.
Results
Sensorineural hearing loss was detected in 58.8% of the cohort, which occurred typically in sudden episodes and affected especially high frequencies. Hearing loss is asymmetric, beginning unilaterally and affecting the contralateral ear later. Tinnitus was reported by 41.2%. Renal and cardiac impairment influenced the severity of hearing loss (p < 0.05).
Conclusions
High frequency hearing loss is a common problem in patients with FD. Although not life-threatening, it can seriously reduce quality of life and should be taken into account in diagnosis and therapy. Optimized extensive hearing assessment including higher frequency thresholds should be used.
Aims
Sudden cardiac death (SCD) is a major contributor to the excess mortality of patients on maintenance dialysis. Homoarginine deficiency may lead to decreased nitric oxide availability and endothelial dysfunction. Based on this rationale we assessed whether homoarginine deficiency is a risk factor for SCD in dialysis patients.
Methods and results
This study examined the association of homoarginine with cardiovascular outcomes in 1255 diabetic haemodialysis patients from the German diabetes and dialysis study. During a median of 4 years of follow-up, hazard ratios (HR) (95% CI) for reaching the following pre-specified, adjudicated endpoints were determined: SCD, myocardial infarction, stroke, death due to heart failure, and combined cardiovascular events. There was a strong association of low homoarginine concentrations with the presence of congestive heart failure and left ventricular hypertrophy as well as increased levels of brain natriuretic peptide. Per unit decrease in homoarginine, the risk of SCD increased three-fold (HR 3.1, 95% CI 2.0–4.9), attenuating slightly in multivariate models (HR 2.4; 95% CI 1.5–3.9). Patients in the lowest homoarginine quintile experienced a more than two-fold increased risk of SCD, and more than three-fold increased risk of heart failure death than patients in the highest quintile, which accounted for the high incidence of combined cardiovascular events. Low homoarginine showed a trend towards increased risk of stroke, however, myocardial infarction was not meaningfully affected.
Conclusion
Low homoarginine is a strong risk factor for SCD and death due to heart failure in haemodialysis patients. Further studies are needed to elucidate the underlying mechanisms, offering the potential to develop new interventional strategies.
Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10\(^{−9}\)). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10\(^{−8}\)), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.
Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR < 60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.
Female patients affected by Fabry disease, an X-linked lysosomal storage disorder, exhibit a wide spectrum of symptoms, which renders diagnosis, and treatment decisions challenging. No diagnostic test, other than sequencing of the alpha-galactosidase A gene, is available and no biomarker has been proven useful to screen for the disease, predict disease course and monitor response to enzyme replacement therapy. Here, we used urine proteomic analysis based on capillary electrophoresis coupled to mass spectrometry and identified a biomarker profile in adult female Fabry patients. Urine samples were taken from 35 treatment-naive female Fabry patients and were compared to 89 age-matched healthy controls. We found a diagnostic biomarker pattern that exhibited 88.2% sensitivity and 97.8% specificity when tested in an independent validation cohort consisting of 17 treatment-naive Fabry patients and 45 controls. The model remained highly specific when applied to additional control patients with a variety of other renal, metabolic and cardiovascular diseases. Several of the 64 identified diagnostic biomarkers showed correlations with measures of disease severity. Notably, most biomarkers responded to enzyme replacement therapy, and 8 of 11 treated patients scored negative for Fabry disease in the diagnostic model. In conclusion, we defined a urinary biomarker model that seems to be of diagnostic use for Fabry disease in female patients and may be used to monitor response to enzyme replacement therapy.
Background:
Competing risks methodology allows for an event-specific analysis of the single components of composite time-to-event endpoints. A key feature of competing risks is that there are as many hazards as there are competing risks. This is not always well accounted for in the applied literature.
Methods:
We advocate a simulation point of view for understanding competing risks. The hazards are envisaged as momentary event forces. They jointly determine the event time. Their relative magnitude determines the event type. 'Empirical simulations' using data from a recent study on cardiovascular events in diabetes patients illustrate subsequent interpretation. The method avoids concerns on identifiability and plausibility known from the latent failure time approach.
Results:
The 'empirical simulations' served as a proof of concept. Additionally manipulating baseline hazards and treatment effects illustrated both scenarios that require greater care for interpretation and how the simulation point of view aids the interpretation. The simulation algorithm applied to real data also provides for a general tool for study planning.
Conclusions:
There are as many hazards as there are competing risks. All of them should be analysed. This includes estimation of baseline hazards. Study planning must equally account for these aspects.
Background
This article summarizes the 2012 European Renal Association—European Dialysis and Transplant Association Registry Annual Report (available at www.era-edta-reg.org) with a specific focus on older patients (defined as ≥65 years).
Methods
Data provided by 45 national or regional renal registries in 30 countries in Europe and bordering the Mediterranean Sea were used. Individual patient level data were received from 31 renal registries, whereas 14 renal registries contributed data in an aggregated form. The incidence, prevalence and survival probabilities of patients with end-stage renal disease (ESRD) receiving renal replacement therapy (RRT) and renal transplantation rates for 2012 are presented.
Results
In 2012, the overall unadjusted incidence rate of patients with ESRD receiving RRT was 109.6 per million population (pmp) (n = 69 035), ranging from 219.9 pmp in Portugal to 24.2 pmp in Montenegro. The proportion of incident patients ≥75 years varied from 15 to 44% between countries. The overall unadjusted prevalence on 31 December 2012 was 716.7 pmp (n = 451 270), ranging from 1670.2 pmp in Portugal to 146.7 pmp in the Ukraine. The proportion of prevalent patients ≥75 years varied from 11 to 32% between countries. The overall renal transplantation rate in 2012 was 28.3 pmp (n = 15 673), with the highest rate seen in the Spanish region of Catalonia. The proportion of patients ≥65 years receiving a transplant ranged from 0 to 35%. Five-year adjusted survival for all RRT patients was 59.7% (95% confidence interval, CI: 59.3–60.0) which fell to 39.3% (95% CI: 38.7–39.9) in patients 65–74 years and 21.3% (95% CI: 20.8–21.9) in patients ≥75 years.