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Ruggenenti P.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Debiec H.,French National Institute for Agricultural Research | Debiec H.,University of Paris Pantheon Sorbonne | Ruggiero B.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | And 12 more authors.
Journal of the American Society of Nephrology | Year: 2015

Rituximab induces nephrotic syndrome (NS) remission in two-thirds of patients with primary membranous nephropathy (MN), even after other treatments have failed. To assess the relationships among treatment effect, circulating nephritogenic anti-phospholipase A2 receptor (anti-PLA2R) autoantibodies and genetic polymorphisms predisposing to antibody production we serially monitored 24-hour proteinuria and antibody titer in patients with primary MN and long-lasting NS consenting to rituximab (375 mg/m2) therapy and genetic analyses. Over a median (range) follow-up of 30.8 (6.0-145.4) months, 84 of 132 rituximabtreated patients achieved complete or partial NS remission (primary end point), and 25 relapsed after remission. Outcomes of patients with or without detectable anti-PLA2R antibodies at baseline were similar. Among the 81 patients with antibodies, lower anti-PLA2R antibody titer at baseline (P=0.001) and full antibody depletion 6 months post-rituximab (hazard ratio [HR], 7.90; 95% confidence interval [95% CI], 2.54 to 24.60; P ≤ 0.001) strongly predicted remission. All 25 complete remissions were preceded by complete anti-PLA2R antibody depletion. On average, 50% anti-PLA2R titer reduction preceded equivalent proteinuria reduction by 10 months. Re-emergence of circulating antibodies predicted disease relapse (HR, 6.54; 95% CI, 1.57 to 27.40; P=0.01), whereas initial complete remission protected from the event (HR, 6.63; 95% CI, 2.37 to 18.53; P ≤ 0.001). Eighteen patients achieved persistent antibody depletion and complete remission and never relapsed. Outcome was independent of PLA2R1 and HLA-DQA1 polymorphisms and of previous immunosuppressive treatment. Therefore, assessing circulating anti- PLA2R autoantibodies and proteinuria may help in monitoring disease activity and guiding personalized rituximab therapy in nephrotic patients with primary MN. Copyright © 2015 by the American Society of Nephrology.


Schieppati A.,Unit of Nephrology | Schieppati A.,Irccs Instituto Of Ricerche Famacologiche Mario Negri | Perico N.,Irccs Instituto Of Ricerche Famacologiche Mario Negri | Remuzzi G.,Unit of Nephrology | Remuzzi G.,Irccs Instituto Of Ricerche Famacologiche Mario Negri
Seminars in Dialysis | Year: 2015

Acute kidney injury (AKI) is imposing a severe burden of morbidity and mortality both in developed and developing countries. Also AKI has a major economic impact on healthcare expenditure. This is particularly so in poor countries where AKI especially impacts young productive people, imposing severe penury upon their families. The mission is to lessen the high burden in terms of death consequent to this disorder in low-resource regions, which in many cases is preventable and treatable with simple measures. The International Society of Nephrology has launched a long-term program, called 0 by 25, which advocates that zero people should die of untreated AKI in the poorest part of Africa, Asia, and Latin America by 2025. This paper illustrates how the project will be developed. © 2014 Wiley Periodicals, Inc.


PubMed | Brotzu Hospital, University of Cagliari, Unit of Nephrology, Scientific Directorate and 2 more.
Type: Journal Article | Journal: Acta diabetologica | Year: 2016

Stable genetic background makes individuals from the Mediterranean island of Sardinia ideal to define the predictive power of islet-related autoantibodies (IRAs): glutamic acid decarboxylase antibodies (GADA), tyrosine phosphatase-like antibodies (IA-2A), islet cell antibodies (ICA) to identify T1DM progressors. The aims of the present study were: (1) determination of IRAs reference limits in healthy non-diabetic Sardinian schoolchildren (SSc). (2) Predictive power evaluation of IRAs as single or combined determination to identify islet to identify T1DM progressors.Between 1986 and 1994, 8448 SSc were tested for IRAs. All were followed up for 10years. The predictive power of single or combination of IRAs was determined as hazard ratio (HR), sensitivity, specificity, area under the ROC curve, negative and positive predictive value (NPV, PPV).All 43 progressors to T1DM, but three showed at least one autoantibody positivity. HR for any single-autoantibody positivity was 55.3 times greater when compared to SSc negative for all IRAs. Any single autoantibody performed at least 64.9% sensitivity with PPV always lower than 16%. The best performing combination was ICA, plus IA-2A (showing 52.6% sensitivity, 99.8% specificity, 0.76 area under the ROC curve, 51.3% PPV and 99.8% NPV.Determination of IRAs reference limits in healthy SSc by standard statistical methods is crucial to establish the power of IRAs as progression markers to T1DM. Our data offer a solid rationale for future testing of ICA and IA-2A as routine laboratory markers to identify individuals at high risk of T1DM in the general population.


Trillini M.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Cortinovis M.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Ruggenenti P.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Loaeza J.R.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | And 12 more authors.
Journal of the American Society of Nephrology | Year: 2015

Secondary hyperparathyroidism contributes to post-transplant CKD mineral and bone disorder. Paricalcitol, a selective vitamin D receptor activator, decreased serum parathyroid hormone levels and proteinuria in patients with secondary hyperparathyroidism. This single-center, prospective, randomized, crossover, open-label study compared the effect of 6-month treatment with paricalcitol (1 μg/d for 3 months and then uptitrated to 2 μg/d if tolerated) or nonparicalcitol therapy on serum parathyroid hormone levels (primary outcome), mineral metabolism, and proteinuria in 43 consenting recipients of renal transplants with secondary hyperparathyroidism. Participants were randomized 1:1 according to a computer-generated sequence. Compared with baseline, median (interquartile range) serum parathyroid hormone levels significantly declined on paricalcitol from 115.6 (94.8-152.0) to 63.3 (52.0-79.7) pg/ml (P<0.001) but not on nonparicalcitol therapy. At 6 months, levels significantly differed between treatments (P<0.001 by analysis of covariance). Serum bone-specific alkaline phosphatase and osteocalcin decreased on paricalcitol therapy only and significantly differed between treatments at 6 months (P<0.001 for all comparisons). At 6 months, urinary deoxypyridinoline-to-creatinine ratio and 24-hour proteinuria level decreased only on paricalcitol (P<0.05). L3 and L4 vertebral mineral bone density, assessed by dual-energy x-ray absorption, significantly improved with paricalcitol at 6 months (P<0.05 for both densities). Paricalcitol was well tolerated. Overall, 6-month paricalcitol supplementation reduced parathyroid hormone levels and proteinuria, attenuated bone remodeling and mineral loss, and reduced eGFR in renal transplant recipients with secondary hyperparathyroidism. Longterm studies are needed to monitor directly measured GFR, ensure that the bone remodeling and mineral effects are sustained, and determine if the reduction in proteinuria improves renal and cardiovascular outcomes. Copyright © 2015 by the American Society of Nephrology.


PubMed | Unit of Nephrology, Mount Sinai School of Medicine and Irccs Instituto Of Ricerche Farmacologiche Mario Negri
Type: Journal Article | Journal: Pediatric nephrology (Berlin, Germany) | Year: 2016

A multidrug treatment strategy that targets urinary proteins with an angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) up-titrated to the respective maximum tolerated dose combined with intensified blood pressure (BP) control has been found to prevent renal function loss in adults with proteinuric nephropathies. Herein, we investigated the effects of this treatment protocol in the pediatric patient population.From May 2002 to September 2014 we included in this observational, longitudinal, cohort study 20 consecutive children with chronic nephropathies and 24-h proteinuria of >200mg who had received ramipril and losartan up-titrated to the respective maximum approved and tolerated doses [mean (standard deviation) dose:2.48(1.37)mg/mMean ( standard deviation) patient age at inclusion was 13.82.8years, and the median [interquartile range (IQR)] serum creatinine level and proteinuria were 0.7(0.6-1.0) mg/dl and 690 (379-1270) mg/24h or 435 (252-711) mg/mCombination therapy with maximum approved doses of ACE inhibitors and ARBs is a safe strategy which may achieve proteinuria remission with kidney function stabilization or even improvement in a substantial proportion of children with proteinuric nephropathies.


Meneghini M.,Unit of Nephrology | Regalia A.,Unit of Nephrology | Regalia A.,Research Laboratory of Nephrology | Alfieri C.,Unit of Nephrology | And 8 more authors.
Transplantation | Year: 2013

BACKGROUND: Vascular calcifications (VCs) are a cardiovascular risk factor in patients affected by chronic kidney disease and after kidney transplantation (KTx). We evaluated the prevalence of VCs at the abdominal aortic site in KTx patients at the time of transplantation and 1 year after KTx, exploring the possibly associated factors. METHODS: In 107 transplanted patients, the following parameters were evaluated at the first and twelfth month after KTx: the aortic calcification index (ACI), fibroblast growth factor 23, osteoprotegerin (OPG), fetuin A, and clinical and biochemical parameters. Patients were followed up for 2 years after KTx. RESULTS: At the time of KTx, 60% of patients had some degree of VC (ACI>0), whereas 40% had no VC. One year after KTx, VCs worsened in 26% of patients, whereas in 74%, VCs remained stable or improved. The progression of VC was observed almost exclusively in patients with a positive ACI score at the first month. At the multivariate analysis, serum calcium, OPG, and estimated glomerular filtration rate were the only variables independently associated with the progression of VC. CONCLUSIONS: VCs at the aortic site are frequent in KTx patients, and in a significant percentage of them, they tend to progress even in the short time. High levels of serum calcium and OPG are significantly associated with the progression of VCs. Whether these associations are based on a cause-effect relationship and their correction might impact on the calcification process could be ascertained by prospective interventional studies. Copyright © 2013 by Lippincott Williams & Wilkins.


Cozzolino M.,University of Milan | Gentile G.,Unit of Nephrology | Gentile G.,Mario Negri Institute for Pharmacological Research | Mazzaferro S.,University of Rome La Sapienza | And 5 more authors.
American Journal of Kidney Diseases | Year: 2013

Chronic kidney disease (CKD) affects approximately 500 million people worldwide and is increasingly common in both industrialized and emerging countries. Although the mechanisms underlying the inexorable progression of CKD are incompletely defined, recent discoveries may pave the way to a more comprehensive understanding of the pathophysiology of CKD progression and the development of new therapeutic strategies. In particular, there is accumulating evidence indicating a key role for the complex and yet incompletely understood system of divalent cation regulation, which includes phosphate metabolism and the recently discovered fibroblast growth factor 23 (FGF-23)/klotho system, which seems inextricably associated with vitamin D deficiency. The aim of this review is to discuss the links between high blood pressure, proteinuria, phosphate levels, and CKD progression and explore new therapeutic strategies to win the fight against CKD. © 2013 National Kidney Foundation, Inc.


Cravedi P.,Mario Negri Institute for Pharmacological Research | Sghirlanzoni M.C.,Unit of Nephrology | Marasa M.,Unit of Nephrology | Salerno A.,Unit of Nephrology | And 2 more authors.
American Journal of Nephrology | Year: 2011

Background/Aims: First-line immunosuppression with the B-cell depleting antibody rituximab reduced proteinuria and induced remission of the disease in patients with nephrotic syndrome (NS) secondary to idiopathic membranous nephropathy (IMN). Here we evaluated whether rituximab is equally effective in patients who failed to respond to previous immunosuppressive treatment. Methods: This academic, matched-cohort study, compared 2-year outcomes of 11 consecutive IMN patients who received second-line rituximab therapy for NS persisting or relapsing after previous treatment with steroids alone or combined with alkylating agents, cyclosporine, or immunoglobulin G, with those of 11 age- (±5 years), gender- and proteinuria- (±1 g/24h) matched reference patients given first-line rituximab therapy. Results: Patients' and reference patients' baseline characteristics were similar. Compared to baseline, 24-hour proteinuria similarly declined at 1 and 2 years post-rituximab (by 50.5 ± 25.1% and 60.9 ± 17.4% in patients and by 52.7 ± 31.5% and 69.4 ± 40.4% in reference patients, respectively; p < 0.01 for all comparisons vs. baseline). 8 patients and 7 reference patients achieved full (3 vs. 2) or partial (5 per cohort) proteinuria remission. Hypoalbuminemia and hyperlipidemia normalized in both groups. Self-limited infusion-related reactions occurred in 1 subject per cohort. Conclusion: Rituximab reduced proteinuria in IMN patients with no or only transientresponse to unselective immunosuppression as effectively and safely as in patients without previous immunosuppression. Copyright © 2011 S. Karger AG, Basel.


Chiarelli L.R.,University of Pavia | Molinaro M.,Pharmacokinetics Unit | Libetta C.,Unit of Nephrology | Tinelli C.,Clinical Epidemiology and Biometric Unit | And 4 more authors.
British Journal of Clinical Pharmacology | Year: 2010

Aims Long-term mycophenolate mofetil (MMF) therapy may induce inosine 5′-monophosphate dehydrogenase (IMPDH) activity in peripheral blood mononuclear cells (PBMCs), thus decreasing MMF immunosuppressive properties. Pharmacodynamic monitoring was used to investigate whether biological activity is altered after long-term therapy. Methods IMPDH activity was measured in PBMC samples from 54 stable kidney transplant patients, already on MMF (for at least 3 months), before (t0) and 2 h after (t2) MMF morning dose administration; levels were monitored for up to 15 months, together with total mycophenolic acid (MPA) and free MPA concentrations. RESULTS During the 15 months' monitoring, t0 IMPDH activity in transplant recipients increased from 5.9 ± 3.7 nmol h-1 mg-1 [95% confidence interval (CI) 4.9, 6.9] to 9.0 ± 3.9 nmol h-1 mg-1 (95% CI 7.2, 10.8), with an intra- and interpatient variability of 28% and 42%. Five patients experienced acute rejection during the follow-up: t0 IMPDH activity was increased during rejection vs. nonrejection, and the trend was significantly higher in rejecting than in nonrejecting subjects for the whole monitoring period. Conclusions Even though a correlation has been found between IMPDH activity and rejection, its efficacy as a predictive tool in long-term transplant outcomes may be affected by high interpatient variability; on the other hand, continuous monitoring of the IMPDH trend could make an effective prognostic parameter of rejection. Other trials also including pre-transplant data on both IMPDH expression and activity are warranted to better assess their role as biomarkers for MPA effect in clinical practice. © 2010 The British Pharmacological Society.


PubMed | Unit of Nephrology and University of Pavia
Type: Editorial | Journal: Seminars in dialysis | Year: 2016

Progressive hemodialysis is based on the simple idea of adjusting its dose according to residual renal function (RRF). The progressive, infrequent paradigm is slowly gaining a foothold among nephrologists, despite a lot of skepticism in the scientific world. Given the importance of RRF preservation in conservative therapy, it seems a contradiction to ignore the contribution of RRF when patients initiate hemodialysis (HD), especially when it is routinely considered with peritoneal dialysis. While a three-times-weekly HD regimen is broadly considered the standard starting regimen for new patients, twice-weekly HD has been used in selected patients and is currently a common practice in South-East Asia. Small studies indicate that a once-weekly HD regimen may be a viable starting option as well. Progressive hemodialysis still requires validation, yet it is promising. We share the belief that a randomized clinical trial to investigate progressive hemodialysis is much needed, but we also strongly recommend including a once-weekly HD starting dose as part of any such investigation.

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