Cadmium-Induced Renal Cell Toxicity Is Associated With MicroRNA Deregulation.

Cadmium is an environmental pollutant well known for its nephrotoxic effects. Nevertheless, mechanisms underlying nephrotoxicity continue to be elucidated. MicroRNAs (miRNAs) have emerged in recent years as modulators of xenobiotic-induced toxicity. In this context, our study aimed at elucidating whether miRNAs are involved in renal proximal tubular toxicity induced by cadmium exposure. We showed that cadmium exposure, in 2 distinct renal proximal tubular cell models (renal proximal tubular epithelial cell [RPTEC]/human telomerase reverse transcriptase [hTERT] and human kidney-2), resulted in cytotoxicity associated with morphological changes, overexpression of renal injury markers, and induction of apoptosis and inflammation processes. Cadmium exposure also resulted in miRNA modulation, including the significant upregulation of 38 miRNAs in RPTEC/hTERT cells. Most of these miRNAs are known to target genes whose coding proteins are involved in oxidative stress, inflammation, and apoptosis, leading to tissue remodeling. In conclusion, this study provides a list of dysregulated miRNAs which may play a role in the pathophysiology of cadmium-induced kidney damages and highlights promising cadmium molecular biomarkers that warrants to be further evaluated.

Genome-Wide Association Study of Acute Renal Graft Rejection.

Acute renal rejection is a major risk factor for chronic allograft dysfunction and long-term graft loss. We performed a genome-wide association study to detect loci associated with biopsy-proven acute T cell-mediated rejection occurring in the first year after renal transplantation. In a discovery cohort of 4127 European renal allograft recipients transplanted in eight European centers, we used a DNA pooling approach to compare 275 cases and 503 controls. In an independent replication cohort of 2765 patients transplanted in two European countries, we identified 313 cases and 531 controls, in whom we genotyped individually the most significant single nucleotide polymorphisms (SNPs) from the discovery cohort. In the discovery cohort, we found five candidate loci tagged by a number of contiguous SNPs (more than five) that was never reached in iterative in silico permutations of our experimental data. In the replication cohort, two loci remained significantly associated with acute rejection in both univariate and multivariate analysis. One locus encompasses PTPRO, coding for a receptor-type tyrosine kinase essential for B cell receptor signaling. The other locus involves ciliary gene CCDC67, in line with the emerging concept of a shared building design between the immune synapse and the primary cilium.

Treating diabetes with islet transplantation: lessons from the past decade in Lille.

Type 1 diabetes (T1D) is due to the loss of both beta-cell insulin secretion and glucose sensing, leading to glucose variability and a lack of predictability, a daily issue for patients. Guidelines for the treatment of T1D have become stricter as results from the Diabetes Control and Complications Trial (DCCT) demonstrated the close relationship between microangiopathy and HbA1c levels. In this regard, glucometers, ambulatory continuous glucose monitoring, and subcutaneous and intraperitoneal pumps have been major developments in the management of glucose imbalance. Besides this technological approach, islet transplantation (IT) has emerged as an acceptable safe procedure with results that continue to improve. Research in the last decade of the 20th century focused on the feasibility of islet isolation and transplantation and, since 2000, the success and reproducibility of the Edmonton protocol have been proven, and the mid-term (5-year) benefit-risk ratio evaluated. Currently, a 5-year 50% rate of insulin independence can be expected, with stabilization of microangiopathy and macroangiopathy, but the possible side-effects of immunosuppressants, limited availability of islets and still limited duration of insulin independence restrict the procedure to cases of brittle diabetes in patients who are not overweight or have no associated insulin resistance. However, various prognostic factors have been identified that may extend islet graft survival and reduce the number of islet injections required; these include graft quality, autoimmunity, immunosuppressant regimen and non-specific inflammatory reactions. Finally, alternative injection sites and unlimited sources of islets are likely to make IT a routine procedure in the future.

Anti-viral therapy in haemodialysed HCV patients: efficacy, tolerance and treatment strategy.

BACKGROUND: In end-stage renal disease (ESRD) patients, hepatitis C virus (HCV) eradication improves patient and graft survival. AIM: To determine optimal use of erythropoietin (EPO) and ribavirin, to compare ribavirin concentrations with those of HCV patients having normal renal function and to evaluate sustained virological response (SVR) in a prospective observatory of ESRD candidates for renal transplantation. METHODS: Thirty-two naïve patients were treated with Peg-IFN-α2a and ribavirin. Two different schedules of ribavirin and EPO administration were used: starting ribavirin at 600mg per week and adapting EPO when haemoglobin (Hb) fell below 10g/dL (adaptive strategy) or starting ribavirin at 1000mg per week while increasing EPO from the start of treatment (preventive strategy). RESULTS: Patients treated with the adaptive strategy had lower median Hb levels (9.6 vs. 10.9g/dL, P=0.02) and more frequent median Hb levels below 10g/dL (58 vs. 5%, P=0.0007) despite lower median ribavirin doses (105 vs. 142mg/day, P<0.0001) than patients treated with the preventive strategy. There was a trend for more frequent transfusion in patients treated with the adaptive strategy than in patients treated with preventive strategy (50 vs. 20%, P=0.08). Compared to patients with normal renal function, ESRD patients had lower ribavirin concentrations during the first month (0.81 vs. 1.7mg/L, P=0.007) and similar concentrations thereafter. SVR was reached in 50%. CONCLUSIONS: Pegylated interferon (Peg-IFN) and an adapted schedule of ribavirin are effective in ESRD patients. Increasing EPO from the start of treatment provides better haematological tolerance. The optimal dosage of ribavirin remains unresolved, in light of frequent side effects.

[Minimize kidney failure in transplantation patients with proliferation signal inhibitors]. / Minimiser l'insuffisance rénale avec les inhibiteurs du signal de prolifération chez les malades transplantés.

Chronic renal dysfunction is a multifactorial and frequent event after organ transplantation. The measurement or the estimation of glomerular filtration rate is essential to detect early progressive renal dysfunction. Proliferation signal inhibitors are nonnephrotoxic immunosuppressive drugs which may be useful to minimize calcineurin inhibitors-related side effects through a conversion strategy. Most studies in the setting of kidney transplantation showed improvement in glomerular filtration rate as high than conversion was early. Proliferation signal inhibitors may be included quickly in new immunosuppressive regimen for liver transplanted patients with chronic renal dysfunction.

Long-term kinetics of a T-lymphocytes subset in kidney transplant recipients: relationship with posttransplant malignancies.

UNLABELLED: Immunosuppression is associated with a high incidence of malignancies among renal transplant patients. In this study, we investigated the relationship between CD4 lymphopenia and the development of posttransplant malignancy (PTM) after induction therapies in renal transplant recipients (RTR). PATIENTS AND METHODS: This retrospective study included 966 RTR who were transplanted between 1993 and 2005 and had a mean follow-up of 83 +/- 46 months. Induction with antithymocyte globulin (ATG) was employed in 747 patients, while remaining 219 recipients received anti-CD25 antibodies. CD4 T-cell counts determined yearly were correlated with the occurrence of PTM. RESULTS: Eighty-five (8.8%) patients developed a PTM: cutaneous neoplasia (n = 33), lymphoma (n = 14), noncutaneous solid cancer (n = 36). Only age was observed to be significantly different among patients with versus without PTM (48 +/- 10 vs 41 +/- 12 years; P < .001). An early CD4 lymphopenia (<300/mm(3)) was frequent after ATG as compared with anti-CD25 induction (69.8% vs 12.1% at 3 months; P < .0001). The proportion of T CD4 lymphopenic patients progressively decreased over time remaining stable at 5- and 10-year follow-ups (12% and 10.8%, respectively). However, CD4 lymphopenia was not associated with a greater incidence of PTM. CONCLUSION: ATG induced CD4 lymphopenia, which persisted in a small proportion of patients in the long term, but did not seem to be correlated with the occurrence of PTM.

[Weaning from corticosteroid therapy after kidney transplantation]. / Sevrage de la corticothérapie après transplantation rénale.

For years, the numerous side effects of long term steroid administration have motivated their elimination from the immunosuppressive regimen in renal transplantation. However until the 90's, steroid withdrawal induced an increase in the incidence of acute rejection episodes, and some studies described a significant risk of graft loss. New immunosuppressive drugs (tacrolimus, mycophenolate and mTOR inhibitors) have led to reevaluate steroid discontinuation. Recent trials with these drugs have shown that late steroid withdrawal (3 months post-transplant) was no more associated with a higher risk of acute rejection or graft loss. Some studies have demonstrated an improvement in the cardiovascular risk factors and a decreased incidence of infections and osteoporosis. Its positive impact on patient survival remains to be confirmed in long term follow-up studies.

[Immunosuppressive strategies and chronic graft dysfunction in kidney transplantation]. / Stratégies immunosuppressives et dysfonction chronique du greffon en transplantation rénale.

Chronic graft dysfunction is a major cause of return to dialysis. In the majority of cases, it is correlated with histological signs of cellular and/or humoral rejection, the nephrotoxicity of anticalcineurins, or nonspecific lesions of interstitial fibrosis and tubular atrophy. Although the incidence of acute rejection has considerably decreased, renal toxicity of the calcineurin inhibitors remains problematic. In cases of established nephrotoxicity, the use of non-nephrotoxic immunosuppressors such as mycophenolic acid or the proliferation signal inhibitors makes it possible to reduce or even stop the anticalcineurins. In prevention of anticalcineurin nephrotoxicity, many attempts to minimize or wean patients from them have shown that improvement in renal function is only obtained at the cost of an increase in the incidence of acute rejection. This makes it necessary to select patients who may benefit from anticalcineurin-sparing treatment, based on clinical, histological, and biological markers. Finally, long-term follow-up is also fundamental in order to validate the positive impact on renal function of this strategy in terms of graft survival.

[Ataxic neuropathy associated with disialosylated antibodies: description of new clinical and biochemical forms]. / Neuropathie ataxiante associée à des anticorps anti-gangliosides disialylés: description de nouvelles formes cliniques et biologiques.

INTRODUCTION: Polyneuropathies associated with IgM monoclonal gammopathy were recently recognized. Antibodies can react with glycoproteins such as myelin associated glycoprotein (MAG), or gangliosides containing one sialosyl epitope such as GM1 or several sialosyl epitopes (polysialyted gangliosides) including GD2, GD3, GT1b, GT1a, GQ1b. METHODS: We report on three patients presenting oculomotor dysfunction, chronic sensitive ataxic polyneuropathy, high sedimentation rate, IgM monoclonal paraprotein of unknown signification and antidisialosyl IgM antibodies and for two of them cold agglutinins. Such features have been previously described under the acronym "CANOMAD" (chronic ataxic neuropathy with ophthalmoplegia, M protein, agglutination and disialosyl antibodies). RESULTS: One of the patients presents extramembranous glomerulopathy and severe motor disability associated with this syndrome. The pathophysiology of the glomerulopathy seems to be linked with the polyneuropathy. Patients were treated either by intravenous immunoglobulin, corticosteroids or cyclophosphamid. Response to treatment differs in the three cases and there is currently no consensus. CONCLUSION: Our study demonstrates that spectrum of polyneuropathy associated with monoclonal polyneuropathy may be larger than originally described.

[Campylobacter fetus subsp fetus bacteremia in a female patient infected by the hepatitis C virus]. / Bactériémie à Campylobacter fetus subsp fetus chez une patiente infectée par le virus de l'hépatite C.

Campylobacter fetus subsp fetus was identified as an unusual etiologic agent of septicemia in an immuno-compromized patient VHC positive by utilizing a 16S rRNA molecular kit in our hospital's clinical laboratory. This method would appear as a performing approach to identify pathogens when discrepancies exist between phenotypical tests.

Evolution pattern of auto-antibodies against oxidized low-density lipoproteins in renal transplant recipients.

An increased degree of oxidative stress in renal transplant recipients and a possible role of ciclosporin A (Cs-A) immunosuppressive therapy in this process have already been described. However, prospective data using in vivo markers and the influence of Cs-A in the oxidizability of low-density lipoprotein (LDL) are scarce. We aimed at investigating in this prospective study the evolution pattern of auto-antibodies directed against malondialdehyde-modified LDL (MDA-LDL) and Cu2+-oxidized LDL in 28 stable renal transplant recipients on Cs-A immunosuppressive therapy before and after 3 successive years of renal transplantation. Also, the effect of enrichment of LDL with Cs-A on the susceptibility of LDL to in vitro oxidation was tested. The results showed a significant increase of both auto-antibody titres (MDA-LDL and Cu2+-oxidized LDL) after 1 year, and the values remained high during the 2nd and the 3rd year following transplantation. The yearly mean relative variations of auto-antibodies against MDA-LDL and Cu2+-oxidized LDL during the follow-up period were 133, 149, and 137%, and 111, 115, and 117%, respectively. A significant correlation was observed during the 1st year between Cs-A trough blood level and Cu2+-oxidized LDL auto-antibody: r = 0.04 (p = 0.046). Incorporation of Cs-A into LDL from healthy volunteers showed no changes during the lag phase in comparison with Cs-A-free LDL, indicating that Cs-A had no effect on in vitro LDL oxidizability. Our results suggest that Cs-A may be involved earlier in the LDL oxidation, but the mechanism by which it acts is still unclear.

The loss of desmosomes after retinoic acid treatment results in an apparent inhibition of HaCaT keratinocyte differentiation.

Epithelial tissue cohesion is based on various types of intercellular adhering junctions of which the desmosomes are particularly abundant in stratified epithelia. The desmogleins (dsg) and desmocollins are their transmembrane components. One or more of the three isoforms of these desmosomal cadherins are co-expressed and specific subtypes prevail at different stages of epidermal differentiation. In HaCaT keratinocytes, desmosomal cadherin expression increased with ongoing differentiation, apart from dsg2. Continuous treatment with retinoic acid (RA) inhibits the differentiation of HaCaT keratinocyte cultures. RA strongly increased the shedding of cells into the culture medium where they quickly underwent cellular death. Electron microscopy showed a marked reduction of desmosomes with nearly complete absence of their structural components, suggesting that RA inhibits their synthesis. RA indeed downregulated the transcript levels of all HaCaT desmosomal cadherins, except dsg2. Immunostaining revealed that desmosomal protein contents corresponded to alterations in transcription rates. Our findings indicate that the RA-induced inhibition of differentiation of keratinocyte cultures results from removal of cells committed to differentiation. In vivo, less adhering but still differentiating cells cannot be removed as easily as they can be in a culture system. The consequence is a sticky and fragile skin.