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Halimi J.-M.,Service de Nephrologie Immunologie Clinique

Nephrotic-range proteinuria has been known for years to be associated with poor renal outcome. Newer evidence indicates that early (1-3 months after transplantation) low-grade proteinuria and microalbuminuria (1) provide information on the graft in terms of donor characteristics and ischemia/reperfusion injury, (2) may occur before the development of donor-specific antibodies, (3) predict the development of diabetes and cardiovascular events, and (4) are associated with reduced long-term graft and patient survivals.Low-grade proteinuria and microalbuminuria are also predictive of diabetes, cardiovascular morbidity, and death in nontransplanted populations, which may help us to understand the pathophysiology of low-grade proteinuria or microalbuminuria in renal transplantation. The impact of immunosuppressive medications, including mammalian target of rapamycin inhibitors, on graft survival is still discussed, and the effect on proteinuria is crucial to the debate. The fact that chronic allograft rejection may exist as early as 3 months after renal transplantation indicates that optimal management of low-grade proteinuria or microalbuminuria should occur very early after transplantation to improve long-term renal function and the overall outcome of renal transplant recipients. The presence of low-grade proteinuria or microalbuminuria early after transplantation must be taken into account to choose adequate immunosuppressive and antihypertensive medications. Limited information exists regarding the benefit of therapeutic interventions to reduce low-grade proteinuria or microalbuminuria. Whether renin angiotensin blockade results in optimal nephroprotection in patients with low-grade proteinuria or microalbuminuria is not proven, especially in the absence of chronic allograft nephropathy. Observational studies and randomized clinical trials yield conflicting results. Finally, randomized clinical trials are urgently needed. Copyright © 2013 by Lippincott Williams & Wilkins. Source

Sodium-glucose cotransporter 2 (SGLT2) inhibitors constitute a new family of hypoglycemic agents. Their hypoglycemic action is due to the glycosuria they induce: they inhibit the reabsorption of glucose and sodium in the renal proximal tubule. The efficacy of SGLT2 inhibitors depends on initial glycemia (as all hypoglycemic agents) and glomerular filtration rate (GFR) (poor efficacy in patients with GFR <45ml/min/m2). They also reduce arterial pressure by-4 (systolic) and-2 (diastolic) mmHg, and body weight by 2-3kg. Short-term tolerance is a key issue since they can provoke acute kidney dysfunction and hypotension requiring surveillance and adequate management. There is presently no data suggesting that they can be nephrotoxic over the long term; in contrast, some studies suggests that they could be afford some degree of renal protection in some patients, especially those with glomerular hyperfiltration which can be corrected by SGLT2 inhibitors. © 2015 - Elsevier Masson SAS - Tous droits réservés. Source

Bigot A.,Service de Nephrologie Immunologie Clinique | Gusto G.,France Inter | Copin N.,France Inter | Lantieri O.,France Inter | And 2 more authors.
Annales de Cardiologie et d'Angeiologie

Introduction: Abnormal albuminuria (≥30mg/g) and low estimated glomerular filtration rate (eGFR<60mL/min/1.73m2) not only are renal risk factors, but also cardiovascular and coronarian risk factors. Though, the relation between coronary risk and renal risk, and its interaction with insufficiently controlled brachial pressure (BP) is poorly described in the literature. Subjects and methods: We realised a cross-sectional study on subjects 40 and older, having attended a medical exam in 11 IRSA centers between 2006 and 2010. Every subject filled a questionnaire, underwent biological analysis, and a clinical examination. eGFR and albuminuria were measured, and the 10-year risk of coronarian event was calculated (Laurier's equation). Results: We analysed 118314 subjects, amongst whom 96400 had no personal cardiovascular history. Amongst those, 9.1% had a 10-year coronary risk over 10%. There was a continuous relationship between coronary risk and renal risk: subjects with a risk above 15% had a significative risk of pathological albuminuria (OR: 6.87 [5.58-8.44]), and of low eGFR (2.26 [1.82-2.78]) compared to those with a risk under 5%. There was a continuous relationship between BP and renal risk, with a significative risk of pathological albuminuria (OR. = 7.75 [6.69-8.96]) and of low eGFR (OR: 1.33 [1.09-1.60]) in subjects with BP greater than or equal to 180/110. mmHg, compared to those with normal BP. Conclusion: In the French population, 9.1% of subjects have a 10-year coronary risk above 10%. This risk is associated to abnormalities of the renal function. The relation between coronary risk and renal risk is continuous and dose-dependent, as is the relation between BP and renal risk. © 2013 Elsevier Masson SAS. Source

Dieme B.,French Institute of Health and Medical Research | Halimi J.M.,Service de Nephrologie Immunologie Clinique | Halimi J.M.,University of Tours | Emond P.,French Institute of Health and Medical Research | And 9 more authors.

BACKGROUND: Biomarkers that can predict graft function and/or renal side effects of calcineurin inhibitors (CNI) at each stage of treatment in kidney transplantation are still lacking. We report the first untargeted GC-MS-based metabolomic study on urines of renal transplant patients. This approach would bring insight in biomarkers useable for graft function monitoring. METHODS: All consecutive patients receiving a kidney allograft in our transplantation department over a 6-month period were prospectively included and followed up for 12 months. We collected urine samples on the seventh day (D7) after transplantation, then at month 3 (M3) and month 12 (M12), and obtained mass-spectrometry-based urinary metabolic profiles. Multivariate analyses were conducted to compare metabolic profiles at the 3 different periods and to assess potential differences between cyclosporine and tacrolimus. Differences in metabolic signatures were also assessed according to graft function at D7 and renal function at M3 and M12. RESULTS: The urinary metabolic patterns varied over time in cyclosporine- and tacrolimus-treated patients and were somewhat different at D7, M3, and M12 between the 2 treatment groups. Principal metabolites that differed, regardless of the treatment used, were mainly sugars, inositol, and hippuric acid. Interestingly, among tacrolimus-treated patients, different metabolic signatures were found between patients with immediate or delayed graft function at D7. CONCLUSION: Urinary metabolomics represents a noninvasive way of monitoring immunosuppressive therapy in renal transplant patients. Although it is too early to consider it as a biomarker of CNI-induced injury or graft function, metabolomics appears a promising evaluation tool in this area. Copyright © 2014 by Lippincott Williams & Wilkins. Source

Shabir S.,Queen Elizabeth Hospital | Halimi J.-M.,Service de Nephrologie Immunologie Clinique | Cherukuri A.,University of Leeds | Ball S.,Queen Elizabeth Hospital | And 8 more authors.
American Journal of Kidney Diseases

Background Accurate prediction of kidney transplant failure remains imperfect. The objective of this study was to develop and validate risk scores predicting 5-year transplant failure, based on data available 12 months posttransplantation. Study Design Development and then independent multicenter validation of risk scores predicting death-censored and overall transplant failure. Setting & Participants Outcomes of kidney transplant recipients (n = 651) alive with transplant function 12 months posttransplantation in Birmingham, United Kingdom, were used to develop models predicting transplant failure risk 5 years posttransplantation. The resulting risk scores were evaluated for prognostic utility (discrimination, calibration, and risk reclassification) in independent cohorts from Tours, France (n = 736); Leeds, United Kingdom (n = 787); and Halifax, Canada (n = 475). Predictors Weighted regression coefficients for baseline and 12-month demographic and clinical predictor characteristics. Outcomes Death-censored and overall transplant failure 5 years posttransplantation. Measurements Baseline data and time to transplant failure. Results Following model development, variables included in separate scores for death-censored and overall transplant failure included recipient age, sex, and race; acute rejection; transplant function; serum albumin level; and proteinuria. In the validation cohorts, these scores showed good to excellent discrimination for death-censored transplant failure (C statistics, 0.78-0.90) and moderate to good discrimination for overall transplant failure (C statistics, 0.75-0.81). Both scores demonstrated good calibration (Hosmer-Lemeshow P > 0.05 in all cohorts). Compared with estimated glomerular filtration rate in isolation, application of the scores resulted in statistically significant and clinically relevant risk reclassification for death-censored transplant failure (net reclassification improvement [NRI], 36.1%-83.0%; all P < 0.001) and overall transplant failure (NRI, 38.7%-53.5%; all P < 0.001). Compared with the previously described US Renal Data System-based risk calculator, significant and relevant risk reclassification for overall transplant failure was seen (NRI, 30.0%; P < 0.001). Limitations Validation is required in further populations. Conclusions These validated risk scores may be of prognostic utility in kidney transplantation, accurately identifying at-risk transplants, and informing clinicians and patients. © 2014 by the National Kidney Foundation, Inc. Source

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