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Background. The incidence of renal replacement therapy (RRT) in the general population >= 75 years of age varies considerably between countries and regions in Europe. Our aim was to study characteristics and survival of elderly RRT patients and to find explanations for differences in RRT incidence. Methods. Patients >= 75 years of age at the onset of RRT in 2010-2013 from 29 national or regional registries providing data to the European Renal Association-European Dialysis and Transplant Association Registry were included. Chi-square and Mann-Whitney U tests were used to assess variation in patient characteristics and linear regression was used to study the association between RRT incidence and various factors. Kaplan-Meier curves and Cox regression were employed for survival analyses. Results. The mean annual incidence of RRT in the age group >= 75 years of age ranged from 157 to 924 per million age-related population. The median age at the start of RRT was higher and comorbidities were less common in areas with higher RRT incidence, but overall the association between patient characteristics and RRT incidence was weak. The unadjusted survival was lower in high-incidence areas due to an older age at onset of RRT, but the adjusted survival was similar [relative risk 1.00 (95% confidence interval, 0.97-1.03)] in patients from low- and high-incidence areas. Conclusions. Variation in the incidence of RRT among the elderly across European countries and regions is remarkable and could not be explained by the available data. However, the survival of patients in low-and high-incidence areas was remarkably similar.

Background. Patients with end-stage renal disease (ESRD) have a decreased quality of life (QoL), which is attributable in part to ESRD-related hyperparathyroidism (HPT). Both cinacalcet and parathyroidectomy (PTx) are treatments for advanced HPT, but their effects on QoL are unclear. We performed a systematic review to evaluate the impact of cinacalcet and PTx on QoL.Methods. A systematic literature search was performed using PubMed and EMBASE databases to identify relevant articles. The search was based on the following keywords: 'parathyroidectomy' or 'cinacalcet', 'secondary hyperparathyroidism' or 'renal hyperparathyroidism' combined with 'quality of life' or 'SF-36' or 'symptomatology'. Only studies reporting on QoL at baseline and during follow-up were included. QoL scores were extracted from the selected manuscripts and weighted means were calculated. Due to a lack of available data on QoL improvement in patients using cinacalcet, a meta-analysis could not be performed.Results. In all, eight articles reached our inclusion criteria. Of this, five articles reported the effect of PTx on QoL. All PTx studies were observational and non-controlled. The physical component scores of the 36-item Medical Outcomes Study Short-Form Health Survey increased significantly with a weighted mean of 35.5% (P Conclusions. PTx improved QoL in patients treated for ESRD-related HPT, whereas cinacalcet did not. The difference in impact between PTx and cinacalcet on QoL has not been compared directly.

BACKGROUND: Chronic kidney disease (CKD) progression is currently assessed by a decline in estimated glomerular filtration rate (eGFR) and/or an increase in urinary albumin excretion (UAE). However, these markers are considered either to be late-stage markers or to have low sensitivity or specificity. In this study, we investigated the performance of the urinary proteome-based classifier CKD273, compared with UAE, in a number of different narrow ranges of CKD severity, with each range separated by an eGFR of 10 mL/min/1.73 m 2 . METHODS: A total of 2672 patients with different CKD stages were included in the study. Of these, 394 individuals displayed a decline in eGFR of >5 mL/min/1.73 m 2 /year (progressors) and the remaining individuals were considered non-progressors. For all samples, UAE values and CKD273 classification scores were obtained. To assess UAE values and CKD273 scores at different disease stages, the cohort was divided according to baseline eGFRs of ≥80, 70-79, 60-69, 50-59, 40-49, 30-39 and

Background: Among chronic dialysis patients, associations have been found between inflammatory markers and depressive symptoms. In this population, no studies have examined the mechanism linking the association between inflammatory markers and depressive symptoms. We examined whether the association between inflammatory markers and depressive symptoms is mediated by tryptophan (TRP) degradation along the kynurenine (KYN) pathway.Methods: The data are part of an observational, prospective cohort study in five urban dialysis centres in The Netherlands. Depressive symptoms were determined with the Beck Depression Inventory. Peripheral blood was collected before dialysis to measure inflammatory markers [high sensitivity C-reactive protein (HsCRP), interleukin (IL)-1 beta, IL-6, IL-10 and tumour necrosis factor-alpha (TNF-alpha)], TRP, KYN and 3-hydroxykynurenine. The KYN/TRP ratio was used as a measure of TRP degradation. The association between inflammatory markers and depressive symptoms was determined using linear regression analysis and adjusted for the KYN/TRP ratio.Results: In total, 490 chronic dialysis patients were included. HsCRP [beta= 3.8; confidence interval (CI): 1.0-6.6], IL-6 (beta= 9.1; CI: 4.0-14.1) and TNF-alpha (beta= 1.3; CI: 0.9-1.7) were associated with the KYN/TRP ratio. We found significant associations between HsCRP (beta= 0.8; CI: 0.3-1.3) and IL-6 (beta= 1.2; CI: 0.3-2.2) levels and depressive symptoms. However, this association was not attenuated after adjustment for the KYN/TRP ratio. Also, no significant associations were found between the KYN/TRP ratio and depressive symptoms.Conclusion: The association between inflammatory markers and depressive symptoms in chronic dialysis patients was not mediated by TRP degradation along the KYN pathway.

Contains fulltext : 173022.pdf (Publisher’s version ) (Closed access) Background.: Blockade of the renin-angiotensin-aldosterone system (RAAS) retards progression of chronic kidney disease. Yet, in many patients, the renoprotective effect is incomplete. A high circulating level of the phosphaturic hormone fibroblast growth factor 23 is associated with an impaired response to RAAS blockade-based therapy in clinical studies. Therefore, we addressed whether administration of recombinant fibroblast growth factor 23 (FGF23) interferes with the efficacy of angiotensin receptor blocker (ARB) treatment in a mouse model of renal fibrosis [unilateral ureteral obstruction (UUO)]. Methods.: UUO mice were treated with losartan (100 mg/L in drinking water), recombinant FGF23 (160 ng/kg i.p. twice daily), their combination or vehicle ( n = 10 per group). Seven days after the UUO procedure, kidney tissue was analyzed for markers of RAAS activity, inflammation and fibrosis using real-time PCR and immunohistochemistry. Results.: In the contralateral (non-affected) kidneys of ARB-treated UUO mice, administration of FGF23 reversed the induction of renin, ACE, ACE2 and AT1 receptor mRNA expression, suggesting interference with the physiological response to RAAS blockade by FGF23. Furthermore, recombinant FGF23 infusion prevented ARB-induced klotho upregulation in contralateral kidneys. In the UUO kidneys, klotho was majorly reduced in all groups. Pro-inflammatory gene expression (MCP-1, TNF-alpha) induced in UUO kidneys was reduced by ARB treatment; this anti-inflammatory effect was reversed by FGF23. In contrast, ARB-induced reduction of (pre-)fibrotic gene expression was not reversed by FGF23. Conclusions.: Our findings show pharmacological interaction between exogenous FGF23 and losartan, thus serving as a proof of principle for crosstalk between the FGF23-klotho axis and RAAS.

Residual proteinuria, the amount of proteinuria that remains during optimally dosed renin-angiotensin-aldosterone system (RAAS) blockade, is an independent risk factor for progressive renal function loss and cardiovascular complications in chronic kidney disease (CKD) patients. Dual RAAS blockade may reduce residual proteinuria but without translating into improved cardiorenal outcomes at least in diabetic nephropathy; rather, dual RAAS blockade may increase the risk of adverse events. These findings have challenged the concept of residual proteinuria as an absolute treatment target. Therefore, new strategies must be explored to address whether by further reduction of residual proteinuria using interventions not primarily targeting the RAAS benefit in terms of cardiorenal risk reduction would accrue. Both clinical and experimental intervention studies have demonstrated that vitamin D can reduce residual proteinuria through both RAAS-dependent and RAAS-independent pathways. Future research should prospectively explore vitamin D treatment as an adjunct to RAAS blockade in an interventional trial exploring clinically relevant cardiorenal end points.

Diabetic kidney disease occurs in similar to 25-40% of patients with type 2 diabetes. Given the high risk of progressive renal function loss and end-stage renal disease, early identification of patients with a renal risk is important. Novel biomarkers may aid in improving renal risk stratification. In this review, we first focus on the classical panel of albuminuria and estimated glomerular filtration rate as the primary clinical predictors of renal disease and then move our attention to novel biomarkers, primarily concentrating on assay-based multiple/panel biomarkers, proteomics biomarkers and metabolomics biomarkers. We focus on multiple biomarker panels since the molecular processes of renal disease progression in type 2 diabetes are heterogeneous, rendering it unlikely that a single biomarker significantly adds to clinical risk prediction. A limited number of prospective studies of multiple biomarkers address the predictive performance of novel biomarker panels in addition to the classical panel in type 2 diabetes. However, the prospective studies conducted so far have small sample sizes, are insufficiently powered and lack external validation. Adequately sized validation studies of multiple biomarker panels are thus required. There is also a paucity of studies that assess the effect of treatments on novel biomarker panels and determine whether initial treatment-induced changes in novel biomarkers predict changes in long-term renal outcomes. Such studies can not only improve our healthcare but also our understanding of the mechanisms of actions of existing and novel drugs and may yield biomarkers that can be used to monitor drug response. We conclude that this will be an area to focus research on in the future.

Background. alpha-Klotho is a protein mainly produced in the kidney. Its circulating form has been suggested to link renal damage and distant tissue pathology. As three assays to measure alpha-Klotho became commercially available, we performed an evaluation of these commercially available Klotho assays.Methods. We studied within-run variation, between-run variation, matrix effects, linearity, and recovery of added recombinant human Klotho in the alpha-Klotho assays of IBL (IBL International GmbH, Hamburg, Germany), Cusabio (Cusabio Biotech, Wuhan, China) and USCN (USCN life Science, Inc., Wuhan, China) using both serum and ethylenediaminetetraacetic acid plasma.Results. Within run variation was 4, 13 and 32% for the IBL, Cusabio and USCN assay, respectively. Agreement between serum and EDTA plasma was good in the IBL assay, but poor in the USCN and Cusabio assays however improved after modifications in the Cusabio assay. Standardization and agreement between assays was poor.Conclusions. The commercially available methods for the measurement of alpha-Klotho differ in quality. Some of the manufacturers should improve their assays in order to produce accurate results so that reliable conclusions can be drawn from studies in which these assays are used.

Background. As many subjects with a cardiovascular (CV) risk factor are undiagnosed, guidelines to prevent cardiovascular disease argue for case finding on those risk factors. Such an approach is, however, labour and cost intensive. An elevated urinary albumin loss is an early marker of vascular damage and is associated with an increased CV risk. As albuminuria is easy to measure, we tested whether a screening approach in which detailed risk factor measurement is done only after selection of subjects with an elevated albuminuria results in a higher yield of subjects at risk.Methods. A random sample of the general population as investigated in the Prevention of Renal and Vascular End-Stage Disease study was used. Plasma glucose, blood pressure, serum cholesterol and renal function were measured in an overall random sample of the population, in subgroups according to their urinary albumin concentration (UAC) of one first morning urine void and in subgroups in whom the elevated albuminuria level was confirmed with two 24 h urine collections for measurement of urinary albumin excretion (UAE).Results. In the overall population, the number of subjects with any newly found CV risk factor was higher than the number of subjects already known with any CV risk factor (n = 1331 versus 370; 39.2 versus 10.9%). The prevalence of subjects with any newly diagnosed CV risk factor was higher in the group of 267 subjects with a first morning UAC of >= 20 mg/L (61.0%; P = 20 mg/L to detect a subject with at least one CV risk factor was relatively low (12%), the specificity was very high (96%). The positive predictive value was 70%. When the elevated UAC could be confirmed in two subsequent 24-h urine collections, the diagnostic yield still further improved.Conclusion. The prevalence of undiagnosed CV risk factors in the general population is much higher than the prevalence of known risk factors. After a selection of subjects with an elevated albuminuria, the relative prevalence of subjects with newly diagnosed CV risk factors increases while the number of subjects to test for presence of CV risk factors is smaller. Such an approach facilitates a more effective and simple strategy for risk factor screening.

Testing urinary albumin concentration by immune detection methods has recently turned out to be a highly rewarding procedure, as low level albumin excretion has turned out to be a powerful predictor of cardiovascular and renal risk in diabetic and nondiabetic patients. In the following we discuss a text dating back to the 19th century in order to make today's nephrologists aware of the remarkable and prescient, but meanwhile completely forgotten investigations on urinary albumin excretion in individuals without primary kidney disease. The treatise of Hermann Senator convincingly disproved the then held dogma that albuminuria was always a sign of primary renal disease. These observations are all the more remarkable since he was forced to use relatively simple and not absolutely specific methods. He further provided an explanation of the renal handling of albumin which to a large extent is still valid today.

Background. Hyperphosphataemia is associated with increased mortality in patients with chronic kidney disease (CKD) stage IV or on dialysis. Furthermore, in animal studies, elevated plasma phosphate has been shown to be associated with an accelerated decline in renal function. The aim of this study was to determine the association of plasma phosphate with renal function loss and mortality in CKD stage IV - V pre-dialysis patients with GFR Methods. Incident pre-dialysis patients were included between 1999 and 2001 in the multi-centre PREPARE study, and followed until 2003 or death. Rate of decline in renal function for each patient was calculated by linear regression using the Modification of Diet in Renal Disease (MDRD) formula to estimate GFR (eGFR).Results. A total of 448 patients were included [mean (SD) age 60 (15) years, eGFR 13 (5.4) ml/min/1.73 m(2), decline in renal function 0.38 (0.95) ml/min/ month]. Phosphate concentration at baseline was 4.71 (1.16) mg/dl, calcium 9.25 (0.77) mg/dl and calcium - phosphate product 43.5 (10.9) mg(2)/dl(2). For each mg/dl higher phosphate concentration, the mean (95% CI) decline in renal function increased with 0.154 (0.071 - 0.237) ml/min/ month. After adjustment, this association remained [beta 0.178 ( 0.082 - 0.275)]. Seven percent of the patients died. Crude mortality risk was 1.25 (0.85 - 1.84) per mg/dl increase in phosphate, which increased to 1.62 (1.02 - 2.59) after adjustment.Conclusions. High plasma phosphate is an independent risk factor for a more rapid decline in renal function and a higher mortality during the pre-dialysis phase. Plasma phosphate within the normal range is likely of vital importance in pre-dialysis patients.