Time filter

Source Type

Cunningham J.,University College London | Locatelli F.,Dialysis and Renal Transplant | Rodriguez M.,Hospital Universitario Reina Sofia
Clinical Journal of the American Society of Nephrology | Year: 2011

Secondary hyperparathyroidism (SHPT) is a challenge frequently encountered in the management of patients with chronic kidney disease (CKD). Downregulation of the parathyroid vitamin D and calcium-sensing receptors represent critical steps that lead to abnormalities in mineral metabolism: high phosphate, low calcium, and vitamin D deficiency. These imbalances result in parathyroid hyperplasia and contribute to vascular calcification. New studies have established a central role for fibroblast growth factor 23 (FGF-23) in the regulation of phosphate-vitamin D homeostasis. FGF-23 concentration increases in CKD and contributes to SHPT. Achieving current targets for the key mineral parameters in the management of SHPT set by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines can be challenging. This review summarizes the current understanding and evidence supporting strategies for SHPT treatment in CKD patients. Treatment should include a combination of dietary phosphorus restriction, phosphate binders, vitamin D sterols, and calcimi-metics. Parathyroidectomy is effective in suitable candidates refractory to medical therapy and the standard against which new approaches should be measured. Future strategies may focus on the stimulation of apopto-tic activity of hyperplastic parathyroid cells. © 2011 by the American Society of Nephrology.


Frimat L.,Nancy University Hospital Center | Mariat C.,Dialysis and Renal Transplant | Landais P.,Hopital Necker | Kone S.,Hoffmann-La Roche | And 2 more authors.
BMJ Open | Year: 2013

Objective: The aim of this study was to describe the management of anaemia with a continuous erythropoietin receptor activator (C.E.R.A., methoxy polyethylene glycol epoetin-ß), in patients with chronic kidney disease (CKD) not on dialysis, naïve or nonnaïve to treatment with erythropoiesis-stimulating agents (ESAs) at inclusion. Design: National, multicentre, longitudinal, observational prospective study. Setting: 133 nephrologists practicing in France selected patients during their routine follow-up visits. The study was non-interventional. Participants: They were adult CKD patients not on dialysis or kidney transplant patients, naïve or not to ESA treatment: 524 patients not on dialysis (48% ESA-naïve) and 92 kidney transplant patients (24% ESA-naïve) were included and followed up every 3 months during 1 year. Outcome measures: The two main endpoints were the percentage of patients who achieved target haemoglobin (Hb) levels as per European Medicines Agency guidelines (10-12 g/dl) around 6 months of treatment and modalities of treatment. Results: Approximately one in two patients had an Hb level within 10-12 g/dl at baseline, and around 6 and 12 months of treatment. Ninety per cent of ESA-naïve patients achieved at least +1 g/dl increase over baseline Hb levels or had Hb within 10-12 g/dl around 6 and 12 months. The Hb level remained at approximately 11.5 g/dl during the 12 months of follow-up. Around 6 months: almost all patients were receiving a oncemonthly subcutaneous dose of C.E.R.A. (patients not on dialysis: 95±54 μg; kidney transplant patients: 121±70 μg); approximately half the patients did not require a change in C.E.R.A. dose. Adverse effects related to C.E.R.A. were observed in less than 5% of patients and led to modification or discontinuation of treatment in 2%. Conclusions: The efficacy and safety of C.E.R.A. in CKD patients not on dialysis, with or without kidney transplantation, were confirmed in routine clinical practice.


Zennaro C.,University of Trieste | Zennaro C.,Renal Research Laboratory | Mariotti M.,University of Milan | Carraro M.,University of Trieste | And 11 more authors.
PLoS ONE | Year: 2014

The zebrafish pronephros is gaining popularity in the nephrology community, because embryos are easy to cultivate in multiwell plates, allowing large number of experiments to be conducted in an in vivo model. In a few days, glomeruli reach complete development, with a structure that is similar to that of the mammalian counterpart, showing a fenestrated endothelium and a basement membrane covered by the multiple ramifications of mature podocytes. As a further advantage, zebrafish embryos are permeable to low molecular compounds, and this explains their extensive use in drug efficacy and toxicity experiments. Here we show that low concentrations of adriamycin (i.e. 10 and 20 μM), when dissolved in the medium of zebrafish embryos at 9 hours post-fertilization and removed after 48 hours (57 hpf), alter the development of podocytes with subsequent functional impairment, demonstrated by onset of pericardial edema and reduction of expression of the podocyte proteins nephrin and wt1. Podocyte damage is morphologically confirmed by electron microscopy and functionally supported by increased clearance of microinjected 70 kDa fluorescent dextran. Importantly, besides pericardial edema and glomerular damage, which persist and worsen after adriamycin removal from the medium, larvae exposed to adriamycin 10 and 20 μM do not show any myocardiocyte alterations nor vascular changes. The only extra-renal effect is a transient delay of cartilage formation that rapidly recovers once adriamycin is removed. In summary, this low dose adriamycin model can be applied to analyze podocyte developmental defects, such as those observed in congenital nephrotic syndrome, and can be taken in consideration for pharmacological studies of severe early podocyte injury. © 2014 Zennaro et al.


Mondini A.,Renal Research Laboratory | Messa P.,Dialysis and Renal Transplant | Rastaldi M.P.,Renal Research Laboratory
Current Opinion in Nephrology and Hypertension | Year: 2014

PURPOSE OF REVIEW: Segmental glomerulosclerosis is the end-point of a series of processes with have podocyte damage as a common denominator. This review summarizes the important advances that have been made in the past 2 years leading to the comprehension of several molecular mechanisms of regulation of podocyte physiology and pathology. RECENT FINDINGS: From recent studies it has become clear that the dynamic cytoskeleton of podocyte foot processes has to be highly regulated to maintain cell shape and function. The importance of intracellular calcium in this process has started to be revealed, together with the channels and the organelles appointed to calcium entry and buffering.Novel data highlight the centrality and the complexity of the mammalian target of rapamycin pathways, which are implicated in the regulation of autophagy. Similarities between podocytes and neuronal cells have been extended to the process of dynamin-regulated endocytosis, and further data in mice and humans provide support to the idea that podocytes can be directly targeted by old and new drugs. SUMMARY: Research is bringing numerous advances regarding the role of podocytes in the development of glomerulosclerosis, which can lead to novel and specific therapeutic approaches, as well as to a more rational use of drugs already in use. Consequently, renal biopsy becomes the indispensable instrument not only for diagnosis but also to precisely detect molecular therapeutic targets and guide personalized therapy. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Li M.,Renal Research Laboratory | Armelloni S.,Renal Research Laboratory | Zennaro C.,University of Trieste | Wei C.,Rush University Medical Center | And 13 more authors.
Journal of Pathology | Year: 2015

Idiopathic focal segmental glomerulosclerosis (FSGS) is a progressive and proteinuric kidney disease that starts with podocyte injury. Podocytes cover the external side of the glomerular capillary by a complex web of primary and secondary ramifications. Similar to dendritic spines of neuronal cells, podocyte processes rely on a dynamic actin-based cytoskeletal architecture to maintain shape and function. Brain-derived neurotrophic factor (BDNF) is a pleiotropic neurotrophin that binds to the tropomyosin-related kinase B receptor (TrkB) and has crucial roles in neuron maturation, survival, and activity. In neuronal cultures, exogenously added BDNF increases the number and size of dendritic spines. In animal models, BDNF administration is beneficial in both central and peripheral nervous system disorders. Here we show that BDNF has a TrkB-dependent trophic activity on podocyte cell processes; by affecting microRNA-134 and microRNA-132 signalling, BDNF up-regulates Limk1 translation and phosphorylation, and increases cofilin phosphorylation, which results in actin polymerization. Importantly, BDNF effectively repairs podocyte damage in vitro, and contrasts proteinuria and glomerular lesions in in vivo models of FSGS, opening a potential new perspective to the treatment of podocyte disorders. © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Regazzoni L.,University of Milan | Del Vecchio L.,Dialysis and Renal Transplant | Altomare A.,University of Milan | Yeum K.-J.,Tufts University | And 4 more authors.
Free Radical Research | Year: 2013

The aim of the present work was to monitor the covalent modifications of human serum albumin (HSA) in end stage renal diseases (ESRD) non-diabetic patients, before and after hemodialysis (HD), by direct infusion electrospray mass spectrometry (ESI-MS). Human serum samples were collected from healthy subjects (n = 10, 20-60 yr) and age-matched ESRD patients (n = 8) before and after HD, purified by affinity chromatography and analyzed by a triple-quadrupole mass spectrometer. The deconvoluted spectra from healthy subjects were all characterized by three peaks attributed to non-glycated mercaptoalbumin (HSA-SH) and to the corresponding adducts with cysteine (HSA-Cys) and glucose (HSA-Glc); relative contents: mercaptoalbumin in both glycated and non-glycated form, HSA-SHt (74 ± 6%), HSA-Cys (26 ± 5%) and HSA-Glc (24 ± 3%). HSA isolated from ESRD patients before HD was characterized by a significant reduction of HSA-SHt (42 ± 7%), and by a concomitant increase of the HSA-Cys adduct (58 ± 7%). Hemodialysis significantly reduced the cysteinylated form (37 ± 7%) and restored HSA-SHt (63 ± 8%) in all the ESRD patients. The mechanism of thiol oxidation and cysteinylation was then studied by mass spectrometry, using LQQCPF as a model peptide and H2O2 as an oxidizing agent. © 2013 Informa UK, Ltd.


Del Vecchio L.,Dialysis and Renal Transplant | Cavalli A.,Dialysis and Renal Transplant | Locatelli F.,Dialysis and Renal Transplant
Contributions to Nephrology | Year: 2012

Anemia is a common complication of patients receiving peritoneal dialysis (PD) but has been little studied compared to other chronic kidney disease (CKD) populations. A number of factors can affect its severity or response to erythropoiesis-stimulating agents (ESA). Some, such as iron deficiency, occult blood loss, infection, inflammation, oxidative stress, inadequate dialysis dose, and hyperparathyroidism are common to all dialysis patients but they may be more or less important depending on dialysis modality. The net balance of their contribution explains the fact that on average PD patients require less ESA doses compared to hemodialysis patients to correct anemia and maintain stable Hb levels. As in other CKD patients, low hemoglobin levels have been associated with increased mortality in PD patients. Unfortunately, no clinical trials have been carried out specifically in this population whether aiming at different Hb targets with ESAs may modify patient outcome. Given the lack of a vascular access, it is advisable to give PD patients ESA therapy subcutaneously. Long-acting molecules may be of advantage, especially when the drug is administered at the dialysis center. Copyright © 2012 S. Karger AG.


Locatelli F.,Dialysis and Renal Transplant | Cavalli A.,Dialysis and Renal Transplant | Manzoni C.,Dialysis and Renal Transplant | Pontoriero G.,Dialysis and Renal Transplant
Contributions to Nephrology | Year: 2011

Many observational studies have consistently shown that high-flux hemodialysis has positive effects on the survival and morbidity of uremic patients when compared with low-flux hemodialysis. However, the HEMO study, a randomized trial designed to evaluate the effect of membrane permeability on patient survival, showed only an 8% non-statistically significant reduction of mortality, albeit a secondary analysis suggested an advantage for high-flux membranes in certain patient subgroups. The prospective, randomized Membrane Permeability Outcome (MPO) study investigated the impact of membrane permeability on survival in incident hemodialysis patients who had low albumin (≤4 g/dl) and normal albumin (>4 g/dl) as separate randomization groups. Patients with serum albumin ≤4 g/dl had significantly better survival rates in the high-flux group compared with the low-flux group (p = 0.032). Moreover, a post-hoc secondary analysis showed that high-flux membranes may significantly improve survival in diabetic patients. No difference was found in patients with normal albumin levels. Considering the increasing number of dialysis patients with low serum albumin levels and with diabetes, the relevance of the MPO study led to the publication of a position statement by the European Renal Best Practice Advisory Board. This board strongly recommended that high-flux hemodialysis should be used for high-risk patients and, with a lower degree of evidence, even also for low-risk subjects due to the substantial reduction in β 2-microglobulin levels observed in the high-flux group. Copyright © 2011 S. Karger AG, Basel.


Locatelli F.,Dialysis and Renal Transplant
The oncologist | Year: 2011

The four currently available erythropoiesis-stimulating agents (ESAs), the main drugs for correcting anemia in patients with chronic kidney disease (CKD), are epoetin alfa, epoetin beta, darbepoetin alfa, and continuous erythropoietin receptor activator. The last two have much longer half-lives, which means they can be administered less frequently. The expiry of the patents for epoetin alfa and epoetin beta some years ago opened up the way for the production of a number of biosimilars that are now marketed in the European Union. Because biosimilars cannot be identical to their originator, a complex and still-evolving regulatory policy has been generated, but there are still a number of issues concerning international naming, automatic substitution, and safety. All ESAs are effective in correcting renal anemia and increasing hemoglobin levels, but the choice of which to use should also take into account their pharmacokinetics and pharmacodynamics, their administration route, and economic issues. Following the publication of a number of trials indicating no benefit (and even possible harm) when ESAs are used to aim at near-normal hemoglobin levels in CKD patients, the hemoglobin target has become a major subject of discussion. According to the position statement of the Anemia Group of the European Renal Best Practice, it should generally be about 11-12 g/dL; however, a risk-benefit evaluation is warranted in individual patients, and high ESA doses driven by hyporesponsiveness should be avoided.


Locatelli F.,Dialysis and Renal Transplant | Vecchio L.D.,Dialysis and Renal Transplant
Expert Opinion on Pharmacotherapy | Year: 2012

Introduction: Anemia, a frequent and early complication of chronic kidney disease (CKD), not only impairs quality of life but is also an independent risk factor for adverse cardiovascular outcomes. Erythropoiesis-stimulating agents (ESAs), together with iron, are the main therapeutic tool to correct anemia in CKD patients nowadays. Areas covered: Following a literature search on PubMed using 'anemia', 'hemoglobin', 'erythropoietin' and 'target' as keywords, we critically analyzed ESAs, looking in depth at their distinct characteristics and possible advantages in the clinical setting. The introduction of biosimilars into the European market is also discussed. Finally, we reviewed current evidence about the optimal hemoglobin (Hb) target to aim at in CKD patients receiving ESA and possible treatment indications by international guidelines or health institutions. Expert opinion: All ESAs are effective agents to correct anemia. Newer molecules have been developed with an improved pharmacokinetic and pharmacodynamic profile. This translates into longer administration intervals than can be a true advantage, mainly for CKD patients not receiving dialysis. Short-acting epoetins, including biosimilars, should be administered more often, but can be cheaper than last-generation molecules. Following publication of the TREAT study, there is considerable confusion about the optimal Hb target to aim for in CKD patients using ESA. While waiting for Kidney Disease Global Outcome (KDIGO) guidelines recommendations, we believe that the general approach to anemia management in CKD patients should still aim at Hb levels of 11 12 g/dl; however, it is wise to use caution in those patients who are hyporesponsive to ESA or have a previous history of stroke or malignancies. © 2012 Informa UK, Ltd.

Loading Dialysis and Renal Transplant collaborators
Loading Dialysis and Renal Transplant collaborators