Background. An increase in C-reactive protein (CRP) levels during a single haemodialysis (HD) session has been associated with mortality. These associations, however, are difficult to understand... Show moreBackground. An increase in C-reactive protein (CRP) levels during a single haemodialysis (HD) session has been associated with mortality. These associations, however, are difficult to understand from the current understanding of CRP metabolism. Methods. In 190 Swedish haemodialysis (HD) patients from the Mapping of Inflammatory Markers in Chronic Kidney Disease (MIMICK) cohort, CRP was measured before and after a HD session. During follow-up, events of death and censoring were recorded, and hazard ratios were calculated and analysed as a function of CRP variation. Results were replicated in 94 Dutch HD patients from the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD). In this cohort, also correlation and kappa statistics were calculated to assess concordance in CRP changes amid multiple dialysis sessions from the same individuals. Results. In both cohorts, mean CRP values did not increase during a single HD session. In the MIMICK, median (interquartile range) dialysis vintage was 29.0 (14.8-57.0) months. In both crude [hazard ratio (95% confidence interval): 1.008 (0.971-1.047)] and multivariate Cox models [0.996 (0.949-1.046)], no association was observed with mortality. In the NECOSAD, individuals endured 6.0 (6.012.0) months on dialysis. No association was found with mortality neither in a crude [0.961 (0.908-1.018)] nor in an adjusted analysis [0.978 (0.923-1.037)]. Finally, the concordance between changes in different sessions was poor. Conclusions. CRP changes during a single HD session do not associate with mortality, thereby adding to the biological uncertainty concerning the ability of CRP to rise in such a short period. Show less
Chavele et al. studied the role of the mannose receptor (MR) in crescentic nephritis [1]. The accelerated nephrotoxic model of glomerulonephritis was induced on both wild-type (WT) and MR-deficient... Show moreChavele et al. studied the role of the mannose receptor (MR) in crescentic nephritis [1]. The accelerated nephrotoxic model of glomerulonephritis was induced on both wild-type (WT) and MR-deficient mice. The mice lacking the MR showed a markedly altered phenotype. They were largely protected against the development of glomerulonephritis with less affected glomeruli, less proteinuria and much better renal function when compared to the WT mice. Whilst more infiltrating macrophages were present in the WT animals, there was no difference in the deposition of sheep and mouse immunoglobulins. To elucidate the mechanism of MR-mediated damage, the authors additionally performed a series of in vitro experiments. They show that the Fab portion of sheep immunoglobulins binds to MR binding domains. Interestingly, the MR seems to interact with FcR-mediated cellular reactions. When MR-deficient macrophages and mesangial cells were treated with immune complexes, the macrophages showed a significantly poorer oxygen burst when compared with WT cells. In line with this possible interaction between Fc-receptors and MR, co-localization of Fca-receptors and MR was demonstrated on macrophages. Additionally, the authors observed that MR-deficient mesangial cells in culture proliferated more abundantly and showed a markedly increased rate of spontaneous apoptosis compared with WT cells. These findings led the authors to test whether this increased apoptosis could play a role in the suppression of glomerular inflammation. Indeed, TNF-a production by LPS-stimulated macrophages was markedly reduced in the presence or apoptotic cells. The anti-inflammatory effect of apoptotic mesangial cells was increased when MR-deficient macrophages were used instead of WT cells (Figure 1). Show less
Heikkila, E.; Juhila, J.; Lassila, M.; Messing, M.; Perala, N.; Lehtonen, E.; ... ; Holthofer, H. 2010
Background. Glomerular slit diaphragm (SD) represents a modified adherens junction composed of molecules belonging to both immunoglobulin and cadherin superfamilies. Cadherins associate with the... Show moreBackground. Glomerular slit diaphragm (SD) represents a modified adherens junction composed of molecules belonging to both immunoglobulin and cadherin superfamilies. Cadherins associate with the cytosolic scaffolding protein beta-catenin, but the precise role of beta-catenin in mature or injured podocytes is not known. Methods. The conditional podocyte-specific beta-catenin-deficient mouse line was generated using the doxycycline-inducible Cre-loxP system. Expression of the beta-catenin-deficient gene was turned off at the age of 8 weeks by doxycycline treatment and the kidney phenotype was analysed. In addition, beta-catenin-deficient and control mice were treated with adriamycin (ADR) and analysed for albuminuria and morphological alterations. Results. Deletion of beta-catenin in mature podocytes did not change the morphology of podocytes nor did it lead to albuminuria. However, lack of beta-catenin attenuated albuminuria after ADR treatment. Electron microscopic examination showed increased podocyte foot process effacement associated with SD abnormalities in ADR-treated control mice compared to beta-catenin-deficient mice. Conclusions. These results show that beta-catenin in podocytes is dispensable for adult mice, but appears to be important in modulating the SD during ADR-induced perturbation of the filtration barrier. Show less
Yang, R.; Otten, M.A.; Hellmark, T.; Collin, M.; Bjorck, L.; Zhao, M.H.; ... ; Segelmark, M. 2010
Background. Anti-glomerular basement membrane (anti-GBM) disease often results in end-stage renal failure despite therapy with plasma exchange and immunosuppressive drugs. The newly discovered... Show moreBackground. Anti-glomerular basement membrane (anti-GBM) disease often results in end-stage renal failure despite therapy with plasma exchange and immunosuppressive drugs. The newly discovered streptococcal enzymes IgG-degrading enzyme of S.pyogenes (IdeS) and endoglycosidase S (EndoS) act with remarkable specificity on circulating IgG. In this study, we investigate their ability in vivo to prevent damage mediated by kidney-bound antibodies in a mouse model of anti-GBM disease. Methods. Anti-GBM disease was induced in mice by injection of subnephritogenic doses of rabbit anti-mouse GBM, followed a week later by injection of monoclonal mouse anti-rabbit IgG antibodies. By administrating IdeS or EndoS as fusion partners with GST between these antibody injections, we tested their ability to prevent damage by acting on kidney-bound rabbit anti-GBM. Control animals received placebo injections. Results. All animals in the positive control groups developed severe albuminuria immediately after the second antibody injection (mean, 2.51 mg/24 h; range, 0.13-8.20). This was significantly diminished by EndoS (1.3 +/- 1.3 mg/24 h) and completely prevented by IdeS (0.017 +/- 0.014 mg/24 h). Immunofluorescence studies showed that IdeS treatment effectively removed the Fc fragments of the rabbit IgG. This was accompanied by a significant reduction of the deposition of the complement components C3 and C1q, and this diminished the recruitment of leukocytes to the glomeruli. Conclusion. IdeS degrades IgG bound to the GBM in vivo, thereby preventing renal damage in this animal model. Most likely, IdeS would degrade both circulating and kidney-bound anti-GBM in patients with Goodpasture's disease. Whether this would lead to a halt in disease progression and a better prognosis remains to be determined. Show less
Kuijk, J.P. van; Flu, W.J.; Chonchol, M.; Welten, G.M.J.M.; Verhagen, H.J.M.; Bax, J.J.; Poldermans, D. 2010
Background. Atherosclerotic disease is often extended to multiple affected vascular beds (AVB). Polyvascular disease (PVD) and chronic kidney disease (CKD) have both separately been associated with... Show moreBackground. Atherosclerotic disease is often extended to multiple affected vascular beds (AVB). Polyvascular disease (PVD) and chronic kidney disease (CKD) have both separately been associated with an adverse cardiovascular outcome. We assessed the prevalence of PVD in vascular surgery patients with preoperative CKD and studied the influence on long-term cardiovascular survival. Methods. Consecutive patients (2933) were preoperatively screened for PVD, defined as 1-, 2- or 3-AVB. Preoperative glomerular filtration rate (GFR in ml/min/1.73 m(2) body-surface area) was estimated by the Modification of Diet in Renal Disease (MDRD) prediction equation, and patients were categorized according their estimated GFR. Primary end point was (cardiovascular) mortality during a median follow-up of 6.0 years (IQR 2-9). Results. Preoperative MDRD-GFR was classified as normal kidney function (GFR >= 90) or mild (GFR 60-89), moderate (GFR 30-59) and severe (GFR < 30) kidney disease in 779 (27%), 1423 (48%), 605 (21%) and 124 (4%) patients, respectively. One-vessel disease was present in 54% of the patients with normal kidney function, while 62% of the patients with CKD (GFR < 60) had PVD. In patients with moderate or severe kidney disease, the presence of PVD was independently associated with even higher cardiovascular mortality rates (2-AVB: HR 1.65 95%CI 1.09-2.48; 3-AVB: 2.07 95%CI 1.08-3.99), compared to 1-AVB. Conclusion. Patients with CKD had a high prevalence of PVD, which was independently associated with increased all-cause and cardiovascular mortality. Show less
Tripepi, G.; Jager, K.J.; Dekker, F.W.; Zoccali, C. 2010
Although most statistical textbooks describe techniques for sample size calculation, it is often difficult for investigators to decide which method to use. There are many formulas available which... Show moreAlthough most statistical textbooks describe techniques for sample size calculation, it is often difficult for investigators to decide which method to use. There are many formulas available which can be applied for different types of data and study designs. However, all of these formulas should be used with caution since they are sensitive to errors, and small differences in selected parameters can lead to large differences in the sample size. In this paper, we discuss the basic principles of sample size calculations, the most common pitfalls and the reporting of these calculations. Show less
The aim of aetiologic studies in epidemiology is to investigate whether factors are causally related to diseases and therefore become a potential target for therapeutic interventions. Mendelian... Show moreThe aim of aetiologic studies in epidemiology is to investigate whether factors are causally related to diseases and therefore become a potential target for therapeutic interventions. Mendelian randomization enables estimation of causal relationships in observational studies using genetic variants as instrumental variables. An instrumental variable is a variable that can be considered to mimic the coin toss in a randomized study. Given the random assignment of alleles in gamete formation, the use of genetic variants is an alternative method to control for confounding. This educational article describes the approach of Mendelian randomization, its underlying rationale and its necessary assumptions. Show less
Tripepi, G.; Jager, K.J.; Dekker, F.W.; Zoccali, C. 2010
Calibration is the ability of a prognostic model to correctly estimate the probability of a given event across the whole range of prognostic estimates (for example, 30% probability of death, 40%... Show moreCalibration is the ability of a prognostic model to correctly estimate the probability of a given event across the whole range of prognostic estimates (for example, 30% probability of death, 40% probability of myocardial infarction, etc.). The key difference between calibration and discrimination is that the latter reflects the ability of a given prognostic biomarker to distinguish a status (died/survived, event/non-event), while calibration measures how much the prognostic estimation of a predictive model matches the real outcome probability (that is, the observed proportion of the event). Re-classification is another measure of prognostic accuracy and it reflects how much a new prognostic biomarker increases the proportion of individuals correctly re-classified as having or not having a given event compared to a previous classification based on an existing prognostic biomarker or predictive model. Show less
Background. Proteinuria predicts progressive renal failure. Next to being a progression marker, non-selective proteinuria itself is thought to be toxic to the tubulointerstitium. In proteinuric... Show moreBackground. Proteinuria predicts progressive renal failure. Next to being a progression marker, non-selective proteinuria itself is thought to be toxic to the tubulointerstitium. In proteinuric states, activation of filtered or locally produced complement is toxic for renal tubular cells and likely contributes to the progression of renal failure. Recent experimental evidence suggests an important role for properdin in promoting intrarenal complement activation. We measured properdin in proteinuric urine and assessed its relation with urinary SC5b-9 levels, the soluble form of the effector phase of complement activation. Methods. Seventy patients with renal disease of different origin but all with a protein excretion of at least 1 g/day were studied. Urinary properdin and SC5b-9 levels were measured using an ELISA technique. Results. Properdin was detectable in the urine of 37 patients (53%). These subjects had higher urinary SC5b-9 levels {median 0.50 U/ml [interquartile range (IQR) 0.13-1.81] versus 0.049 U/ml (IQR 0.024-0.089), P < 0.001}. When adjusted for proteinuria and renal function, properdin excretion was strongly associated with increased urinary SC5b-9 levels (odds ratio 16.2, 95% confidence interval 3.6-74.4). Properdin excretion was associated with worse renal function. Conclusion. Our results suggest that urinary properdin excretion enhances intrarenal complement activation and thus may contribute to the progression of renal damage in proteinuric states. Show less
Background. Information on demographics and survival of patients starting renal replacement therapy (RRT) for end-stage renal disease (ESRD) due to multiple myeloma (MM) or light-chain deposit... Show moreBackground. Information on demographics and survival of patients starting renal replacement therapy (RRT) for end-stage renal disease (ESRD) due to multiple myeloma (MM) or light-chain deposit disease (LCDD) is scarce. The aim of this study was to describe the incidence, characteristics, causes of death and survival rates of RRT for ESRD due to MM or LCDD in the ERA-EDTA Registry. Methods. Thirteen national registries providing data on patients who started RRT from 1986-2005 to the ERA-EDTA Registry participated. Incidence per million population (pmp) of RRT for ESRD due to MM or LCDD and other causes (non-MM) was observed overtime. Patient survival on RRT was examined, unadjusted and adjusted for age and gender. Results. Of the 159 637 patients on RRT, 2453 (1.54%) had MM or LCDD. The incidence of RRT for ESRD due to MM or LCDD, adjusted for age and gender, increased from 0.70 pmp in 1986-1990 to 2.52 pmp in 2001-2005. MM and LCDD patients compared to non-MM patients were older and a higher percentage was on haemodialysis at day 91 after the start of RRT. The most common causes of death in MM and LCDD patients were malignancy (36.1%), cardiovascular causes (17.2%) and infection (14.7%). MM and LCDD patients had a 2.77 (95% CI, 2.65-2.90) higher risk of death compared to non-MM patients. The unadjusted median survival on RRT was 0.91 years in MM and LCDD patients and 4.46 years in nonMM patients. During follow-up, 35 patients were transplanted and their mean survival was 9.6 years. Conclusion. The incidence of RRT for ESR.D due to MM or LCDD has increased over the past 20 years in Europe. The median patient survival on RRT for MM and LCDD patients Show less
Methods. In a prospective fashion, symptoms of depression were evaluated in ESRD patients on RRT using the depression subscore of the Hospital Anxiety and Depression Scale (HADS). Fatal and non... Show moreMethods. In a prospective fashion, symptoms of depression were evaluated in ESRD patients on RRT using the depression subscore of the Hospital Anxiety and Depression Scale (HADS). Fatal and non-fatal clinical events were determined during a 1-year follow-up. Results. Of 101 patients with ESRD, 42% showed manifest depressive symptoms, defined as a HADS-D score >= 7. No association was found between depressive symptoms and severity of somatic disease. During follow-up, all-cause mortality was significantly higher in patients with depressive symptoms above threshold (n = 42, mortality: 26%) compared to patients with depressive symptoms below threshold (n = 59, mortality 8%), (crude HR 3.3, CI 1.2-9.6, P = 0.02). The excess in mortality was mainly caused by a higher incidence of septicaemia (0 versus 12%, P = 0.01). After adjustment for clinical parameters, this association between depressive symptoms and mortality became even stronger. There was no significant difference observed in the incidence of cardiovascular events. Conclusions. Patients with ESRD treated with dialysis show a high level of depressive symptoms that is independently associated with poor survival. Future research should address appropriate therapeutic regimens. Show less
Reinders, M.E.J.; Fibbe, W.E.; Rabelink, T.J. 2010
Cell therapies aim at differentiation of stem cells into the specific cell type required to repair damaged or destroyed cells or tissues. Over recent years, cell therapy has been introduced in a... Show moreCell therapies aim at differentiation of stem cells into the specific cell type required to repair damaged or destroyed cells or tissues. Over recent years, cell therapy has been introduced in a variety of application areas, including cardiovascular repair, diabetes, musculoskeletal disorders and renal repair. Multipotent mesenchymal stromal cells (MSCs), often referred to as mesenchymal stem cells, are of particular interest as a cell therapy model, as this is one of the few cell types that are on the brink of entering the clinical arena in different areas of application. MSCs can be differentiated in vitro and in vivo into various cell types of mesenchymal origin such as bone, fat and cartilage. They have important effects on the innate and adaptive immune system and possess striking anti-inflammatory properties that make them attractive for potential use in diseases characterized by autoimmunity and inflammation. In addition, MSCs have been shown to migrate to sites of tissue injury and to enhance repair by secreting anti-fibrotic and pro-angiogenic factors. In this review, evidence for the renoprotective mechanisms of MSCs as well as their therapeutic possibilities and potential hazards in acute and chronic renal disease and allograft rejection is summarized. Show less
