Publications by authors named "Enrico Minetti"

31 Publications

Mycophenolate mofetil versus azathioprine in kidney transplant recipients on steroid-free, low-dose cyclosporine immunosuppression (ATHENA): A pragmatic randomized trial.

PLoS Med 2021 06 24;18(6):e1003668. Epub 2021 Jun 24.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.

Background: We compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression.

Methods And Findings: ATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat. Participants were included between June 2007 and July 2012 and followed up to August 2016. Between-group donor and recipient characteristics, donor/recipient mismatches, and follow-up CsA blood levels were similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m2, p = 0.50], and adverse events (AEs) were not significantly different between groups. Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design.

Conclusions: In this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression.

Trial Registration: ClinicalTrials.gov NCT00494741; EUDRACT 2006-005604-14.
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http://dx.doi.org/10.1371/journal.pmed.1003668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224852PMC
June 2021

An enigmatic case of IgG4-related nephropathy and an updated review of the literature.

Clin Exp Med 2021 Aug 8;21(3):493-500. Epub 2021 Mar 8.

Division of Nephrology, Dialysis and Renal Transplantation, ASST Grande Ospedale Metropolitano Niguarda, 20162, Milan, Italy.

IgG4-related disease (IgG4-RD) is still an underestimated disorder which affects multiple organs, and its recognition as a distinct clinical disease has been only proved in the recent decades. The renal involvement has been documented in approximately 15% of patients with IgG4-RD, and the typical manifestation is a tubulo-interstitial nephritis. The main histological findings in IgG4-RD are typically a dense tissue infiltration of IgG4-positive plasma cells, storiform fibrosis, obliterative phlebitis, and frequently elevated IgG4 serum levels. Herein we report our atypical and peculiar clinical presentation of an IgG4-related nephropathy (IgG4-RN) and the remarkable response to rituximab (RTX) treatment at the renal imaging with computerized tomography assessment. The current nephrological evidences support the renal function recovery after steroids or steroids plus RTX therapy, even if the renal imaging data are not always shown. In a complex and enigmatic clinical scenario such as the IgG4-RN, both the renal biopsy and the renal imaging before and after the immunosuppressive therapy become mandatory tools to thoroughly define the diagnosis, the management and the response to the immunological therapy.
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http://dx.doi.org/10.1007/s10238-021-00696-xDOI Listing
August 2021

Mortality from cancer is not increased in elderly kidney transplant recipients compared to the general population: a competing risk analysis.

J Nephrol 2020 Dec 3;33(6):1309-1319. Epub 2020 Sep 3.

Section of Dermatology, Dermatology Unit, Department of Medicine, University of Verona, Ospedale Civile Maggiore, Piazzale Stefani 1, 37126, Verona, VR, Italy.

Background: The impact of cancer on death of elderly kidney transplant recipients has been extensively investigated, but with conflicting results. Unlike their younger counterparts, in elderly kidney transplant recipients cardiovascular and infectious disease may outweigh cancer in causing the patient's death.

Methods: Using competing risk analysis on a large retrospective cohort of kidney transplant recipients, we estimated the cause-specific cumulative incidence and hazard of death in different age categories and calculated standardized mortality ratios (SMRs) to compare mortality rates with the general population.

Results: Six thousand seven hundred eighty-nine kidney transplant recipients were followed-up for a median of 9 years. Ten years after transplantation, in transplant recipients aged 20-39, 40-59, and 60+, the cumulative incidence of cancer-related death was 0.6 (95% confidence interval [CI]: 0.3-1.0), 2.9 (2.3-3.6) and 5.3% (3.5-7.5), whereas the SMR was 9.1 (5.5-15.0), 2.0 (1.6-2.5), and 0.8 (0.6-1.0), respectively. At variance with young recipients, the hazard and the cumulative incidence of cardiovascular-related death in elderly recipients was well above that of cancer-related death.

Conclusions: Relative to the general population, cancer-related death is increased in young but not in elderly kidney transplant recipients because of the more marked increased incidence of competing cause of death in the latter category.
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http://dx.doi.org/10.1007/s40620-020-00847-5DOI Listing
December 2020

A simple method for the calculation of dialysis Kt factor as a quantitative measure of removal efficiency of uremic retention solutes: Applicability to high-dialysate vs low-dialysate volume technologies.

PLoS One 2020 29;15(5):e0233331. Epub 2020 May 29.

Division of Nephrology, Dialysis and Renal Transplantation, ASST GOM Niguarda, Milan, Italy.

Dialysis urea removal metrics may not translate into proportional removal efficiency of non-urea solutes. We show that the Kt factor (plasma volume totally cleared of any solutes) differentiates removal efficiency of non-urea solutes in different technologies, and can easily be calculated by instant blood-dialysate collections. We performed mass balances of urea, creatinine, phosphorus and beta2-microglobulin by whole dialysate collection in 4 low-flux and 3 high-flux hemodialysis, 2 high-volume post-hemodiafiltration and 7 short-daily dialysis with the NxStage-One system. Instant dialysate/blood determinations were also performed at different times, and Kt was calculated as the product of the D/P ratio by volume of delivered dialysate plus UF. There were significant differences in single session and weekly Kt (whole dialysate and instant calculations) between methodologies, most notably for creatinine, phosphorus and beta2-microglobulin. Urea Kt messured in balance studies was almost equal to that derived from the usual plasma kinetic model-based Daugirdas' equation (eKt/V) and independent V calculation, indicating full correspondence. Non-urea solute Kt as a fraction of urea Kt (i.e. fractional removal relative to urea) showed significant differences between technologies, indicating non-proportional removal of non-urea solutes and urea. Instant Kt was higher than that in full balances, accounting for concentration disequilibrium between arterial and systemic blood, but measured and calculated quantitative solute removal were equal, as were qualitative Kt comparisons between technologies. Thus, we show that urea metrics may not reliably express removal efficiency of non-urea solutes, as indicated by Kt. Kt can easily be measured without whole dialysate collection, allowing to expand the metrics of dialytic efficiency to almost any non-urea solute removed by dialysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233331PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259768PMC
August 2020

A 3-month, Multicenter, Randomized, Open-label Study to Evaluate the Impact on Wound Healing of the Early (vs Delayed) Introduction of Everolimus in De Novo Kidney Transplant Recipients, With a Follow-up Evaluation at 12 Months After Transplant (NEVERWOUND Study).

Transplantation 2020 02;104(2):374-386

Fondazione Policlinico Tor Vergata, Dipartimento Scienze Chirurgiche, Università degli Studi di Roma Tor Vergata, Roma, Italy.

Background: The risk of wound healing complications (WHCs) and the early use of mammalian target of rapamycin inhibitors after kidney transplantation (KT) have not been fully addressed.

Methods: The NEVERWOUND study is a 3-month, multicenter, randomized, open-label study designed to evaluate whether a delayed (ie, 28 ± 4 d posttransplant) immunosuppression regimen based on everolimus (EVR) reduces the risk of WHC versus EVR started immediately after KT. Secondary endpoints were treatment failure (biopsy-proven acute rejection, graft loss, or death), delayed graft function, patient and graft survival rates, and renal function.

Results: Overall, 394 KT recipients were randomized to receive immediate (N = 197) or delayed (N = 197) EVR after KT. At 3 months, WHC-free rates in the immediate EVR versus delayed EVR arm, considering the worst- and best-case scenario approach, were 0.68 (95% confidence interval [CI], 0.62-0.75) versus 0.62 (95% CI, 0.55-0.68) (log-rank P = 0.56) and 0.70 (95% CI, 0.64-0.77) versus 0.72 (95% CI, 0.65-0.78) (log-rank P = 0.77), respectively. The 3- and 12-month treatment failure rates, delayed graft function and renal function, and patient and graft survival were not different between the arms.

Conclusions: The early introduction of EVR after KT did not increase the risk of WHC, showing good efficacy and safety profile.
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http://dx.doi.org/10.1097/TP.0000000000002851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004468PMC
February 2020

Eculizumab prevents thrombotic microangiopathy in patients with atypical haemolytic uraemic syndrome in a long-term observational study.

Clin Kidney J 2019 Apr 16;12(2):196-205. Epub 2018 May 16.

Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.

Background: Eculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).

Methods: In five parent studies, eculizumab effectively prevented TMA and improved renal and haematologic outcomes in patients with aHUS; therefore, these patients could enrol in this long-term, prospective, observational and multicentre study. The primary endpoint was the TMA manifestation rate off and on eculizumab post-parent study. analyses evaluated rates during labelled versus non-labelled dosing regimens, and in those with versus without identified complement abnormalities. Serious targeted treatment-emergent adverse events (TEAEs) were evaluated.

Results: Of 87 patients in the current study, 39 and 76 had off- and on-treatment periods, respectively; 17 (44%) with off periods reinitiated eculizumab. TMA manifestation rate per 100 patient-years was 19.9 off and 7.3 on treatment [hazard ratio (HR), 4.7; P = 0.0008]; rates were highest off treatment and lowest during labelled regimens. TMA manifestations with hospitalizations/serious AEs occurred more frequently off versus on treatment. TMA rates were higher among patients with identified complement abnormalities (HR, 4.5; P = 0.0082). Serious targeted TEAEs occurred at similar rates off and on treatment.

Conclusions: As expected, patients with aHUS have increased risk of TMA manifestations after discontinuation of eculizumab or in the setting of non-labelled eculizumab dosing. Collectively, results show that maintaining eculizumab treatment minimizes risk of TMA, particularly in patients with identified complement abnormalities. Future studies are needed to further characterize TMA and longer term outcomes on labelled or non-labelled eculizumab regimens and after discontinuation of treatment.
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http://dx.doi.org/10.1093/ckj/sfy035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452204PMC
April 2019

Outcomes in patients with atypical hemolytic uremic syndrome treated with eculizumab in a long-term observational study.

BMC Nephrol 2019 04 10;20(1):125. Epub 2019 Apr 10.

Division of Pediatric Nephrology, Emory University School of Medicine and Children's Healthcare of Atlanta, 2015 Uppergate Drive NE, Atlanta, GA, 30322, USA.

Background: There are limited long-term outcome data in eculizumab-treated patients with atypical hemolytic uremic syndrome (aHUS). We report final results from the largest prospective, observational, multicenter study of patients with aHUS treated with eculizumab.

Methods: Patients with aHUS who participated in any of five parent eculizumab trials and received at least one eculizumab infusion were eligible for enrollment in a long-term follow-up study. Rates of thrombotic microangiopathy (TMA) manifestations off versus on eculizumab were evaluated. Additional endpoints included change from baseline estimated glomerular filtration rate (eGFR), long-term renal outcomes, and serious targeted treatment-emergent adverse events.

Results: Among 93 patients (0-80 years of age), 51 (55%) remained on eculizumab and 42 (45%) discontinued; for those who discontinued, 21 (50%) reinitiated therapy. Patients who reinitiated eculizumab had similar baseline clinical characteristics to patients who remained on eculizumab, with higher likelihood of genetic/autoimmune complement abnormalities, more prior TMAs, and longer disease course versus those who did not reinitiate. Mean eGFR improved rapidly and remained stable for up to 6 years on eculizumab. In patients who discontinued, there was a trend toward decreasing renal function over time from discontinuation. Additionally, off-treatment TMA manifestation rates were higher in those aged < 18 years at diagnosis, with identified genetic/autoimmune complement abnormalities, or history of multiple TMAs prior to eculizumab initiation. The safety profile was consistent with previous studies. Three definite and one possible meningococcal infections related to eculizumab were reported and resolved with treatment. Three deaths unrelated to eculizumab were reported.

Conclusions: The current study confirms the efficacy and safety of eculizumab in aHUS, particularly with regard to long-term renal function and TMA events. Pediatric age at disease onset and presence of genetic or autoimmune complement abnormalities are risk factors for TMA events off treatment. Overall, patients who discontinue eculizumab may be at risk for additional TMA manifestations and renal function decreases. Discontinuation of eculizumab, with careful monitoring, is an option in select patients with consideration of patient preference, organ function normalization, and risk factors for relapse, including mutational analysis, age of onset, and history of multiple TMA episodes.

Trial Registration: ClinicalTrials.gov NCT01522170 , January 31, 2012.
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http://dx.doi.org/10.1186/s12882-019-1314-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456946PMC
April 2019

Correction to: Changes in global longitudinal strain in renal transplant recipients following 12 months of exercise.

Intern Emerg Med 2018 12;13(8):1347

Sports Medicine Center, Clinical and Experimental Department, University of Florence, Florence, Italy.

In the original publication, the given name and family name of the first author Dr. Enrico Minetti were incorrectly published.
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http://dx.doi.org/10.1007/s11739-018-1906-yDOI Listing
December 2018

Changes in global longitudinal strain in renal transplant recipients following 12 months of exercise.

Intern Emerg Med 2018 08 20;13(5):805-809. Epub 2018 Jun 20.

Sports Medicine Center, Clinical and Experimental Department, University of Florence, Florence, Italy.

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http://dx.doi.org/10.1007/s11739-018-1893-zDOI Listing
August 2018

Standardized Duplex Ultrasound-Based Protocol for Early Diagnosis of Transplant Renal Artery Stenosis: Results of a Single-Institution Retrospective Cohort Study.

Biomed Res Int 2018 11;2018:2580181. Epub 2018 Apr 11.

Department of Urological Robotic Surgery and Renal Transplantation, University of Florence, Careggi Hospital, Florence, Italy.

Transplant renal artery stenosis (TRAS) is the most frequent vascular complication after kidney transplantation (KT) and has been associated with potentially reversible refractory hypertension, graft dysfunction, and reduced patient survival. The aim of the study is to describe the outcomes of a standardized Duplex Ultrasound- (DU-) based screening protocol for early diagnosis of TRAS and for selection of patients potentially requiring endovascular intervention. We retrospectively reviewed our prospectively collected database of KT from January 1998 to select patients diagnosed with TRAS. The follow-up protocol was based on a risk-adapted, dynamic subdivision of eligible KT patients in different risk categories (RC) with different protocol strategies (PS). Of 598 patients included in the study, 52 (9%) patients had hemodynamically significant TRAS and underwent percutaneous angioplasty (PTA) and stent placement. Technical and clinical success rates were 97% and 90%, respectively. 7 cases of restenosis were recorded at follow-up and treated with re-PTA plus stenting. Both DU imaging and clinical parameters improved after stent placement. Prospective high-quality studies are needed to test the efficacy and safety of our protocol in larger series. Accurate trial design and standardized reporting of patient outcomes will be key to address the current clinical needs.
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http://dx.doi.org/10.1155/2018/2580181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5925009PMC
October 2018

Thrombotic microangiopathy induced by interferon beta in patients with multiple sclerosis: three cases treated with eculizumab.

Clin Kidney J 2017 Oct 16;10(5):625-631. Epub 2017 Feb 16.

Nephrology Unit, Careggi University Hospital, Florence, Italy.

Background: Interferon-beta (IFN-beta) is one of the most widely prescribed medications for relapsing-remitting multiple sclerosis (RRMS). IFN-related thrombotic microangiopathy (TMA) is a rare but severe complication, with a fulminant clinical onset and a possibly life-threatening outcome that may occur years after a well-tolerated treatment with IFN. Most patients evolve rapidly to advanced chronic kidney disease and eventually to renal failure.

Methods: We performed a retrospective analysis of TMA cases diagnosed and managed in our Nephrology Department from 2010 to 2015, and performed a literature review of IFN-beta-induced TMA.

Results: Three cases of TMA among patients treated with IFN-beta were identified who did not show any renal improvement following conventional therapy: IFN withdrawal and plasma exchange (PE, range 8-18) sessions. All of them responded favourably to eculizumab, with progressive clinical and renal improvement, allowing dialysis discontinuation, without recurrence of TMA during a long-term follow-up (range 1-5 years).

Conclusions: TMA is a recognized severe complication in RRMS patients treated with IFN-beta. Withdrawal of IFN and treatment with PE, steroids or rituximab did not improve the poor renal prognosis in our three patients and in all the previously described cases in the literature. In our experience, eculizumab had a strikingly favourable effect on renal recovery, suggesting a role of IFN-beta as a trigger in complement-mediated TMA. Neurologists and nephrologists should be vigilant to this complication to prevent possibly irreversible renal damage.
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http://dx.doi.org/10.1093/ckj/sfw143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622889PMC
October 2017

1,25 Dihydroxyvitamin D circulating levels, calcitriol administration, and incidence of acute rejection, CMV infection, and polyoma virus infection in renal transplant recipients.

Clin Transplant 2016 10 23;30(10):1347-1359. Epub 2016 Sep 23.

Renal Unit, Careggi University Hospital, Florence, Italy.

Observation that 1,25-Dihydroxyvitamin-D3 has an immunomodulatory effect on innate and adaptive immunity raises the possible effect on clinical graft outcome. Aim of this study was to evaluate the correlation of biopsy-proven acute rejection, CMV infection, BKV infection, with 1,25-Dihydroxyvitamin-D3 deficiency and the benefit of calcitriol supplementation before and during the transplantation. Risk factors and kidney graft function were also evaluated. All RTRs received induction therapy with basiliximab, cyclosporine, mycophenolic acid, and steroids. During the first year, the incidence of BPAR (4% vs 11%, P=.04), CMV infection (3% vs 9%, P=.04), and BKV infection (6% vs 19%, P=.04) was significantly lower in users compared to controls. By multivariate Cox regression analysis, 1,25-Dihydroxyvitamin-D3 deficiency and no calcitriol exposure were independent risk factors for BPAR (HR=4.30, P<.005 and HR=3.25, P<.05), for CMV infection (HR=2.33, P<.05 and HR=2.31, P=.001), and for BKV infection (HR=2.41, P<.05 and HR=2.45, P=.001). After one year, users had a better renal function: eGFR was 62.5±6.7 mL/min vs 51.4±7.6 mL/min (P<.05). Only one user developed polyomavirus-associated nephropathy vs 15 controls. Two users lost their graft vs 11 controls. 1,25(OH)2-D3 deficiency circulating levels increased the risk of BPAR, CMV infection, BKV infection after kidney transplantation. Administration of calcitriol is a way to obtain adequate 1,25(OH)2-D3 circulating levels.
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http://dx.doi.org/10.1111/ctr.12829DOI Listing
October 2016

Terminal Complement Inhibitor Eculizumab in Adult Patients With Atypical Hemolytic Uremic Syndrome: A Single-Arm, Open-Label Trial.

Am J Kidney Dis 2016 Jul 21;68(1):84-93. Epub 2016 Mar 21.

Adult Kidney Transplant Unit, Université Paris Descartes and Hôpital Necker, Paris, France.

Background: Atypical hemolytic uremic syndrome (aHUS) is a rare genetic life-threatening disease of chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA) and severe end-organ damage. Eculizumab, a terminal complement inhibitor approved for aHUS treatment, was reported to improve hematologic and renal parameters in 2 prior prospective phase 2 studies. This is the largest prospective study of eculizumab in aHUS to date, conducted in an adult population.

Study Design: Open-label single-arm phase 2 trial.

Setting & Participants: Patients 18 years or older with aHUS (platelet count <150 × 10(3)/μL, hemoglobin ≤ lower limit of normal, lactate dehydrogenase ≥1.5 × upper limit of normal [ULN], and serum creatinine ≥ ULN) were included in this multicenter multinational study.

Intervention: Intravenous eculizumab (900mg/wk for 4 weeks, 1,200mg at week 5 and then every 2 weeks) for 26 weeks.

Outcomes & Measurements: Primary end point was complete TMA response within 26 weeks, defined as hematologic normalization (platelet count ≥150 × 10(3)/μL, LDH ≤ ULN), and preservation of kidney function (<25% serum creatinine increase from baseline), confirmed by 2 or more consecutive measurements obtained 4 or more weeks apart.

Results: 41 patients were treated; 38 (93%) completed 26 weeks of treatment. 30 (73%) were included during their first TMA manifestation. 30 (73%) had complete TMA response. Platelet counts and estimated glomerular filtration rates increased from baseline (P<0.001). All 35 patients on baseline plasma exchange/plasma infusion discontinued by week 26. Of 24 patients requiring baseline dialysis, 5 recovered kidney function before eculizumab initiation and 15 of the remaining 19 (79%) discontinued dialysis during eculizumab treatment. No patients lost existing transplants. Quality-of-life measures were significantly improved. Two patients developed meningococcal infections; both recovered, and 1 remained on eculizumab treatment.

Limitations: Single-arm open-label design.

Conclusions: Results highlight the benefits of eculizumab in adult patients with aHUS: improvement in hematologic, renal, and quality-of-life parameters; dialysis discontinuation; and transplant protection.
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http://dx.doi.org/10.1053/j.ajkd.2015.12.034DOI Listing
July 2016

Short-term prospective study of prescribed physical activity in kidney transplant recipients.

Intern Emerg Med 2016 Feb 4;11(1):61-7. Epub 2015 Sep 4.

Region of Tuscany, Directorate-General for the Rights of Citizenship and Social Cohesion, Florence, Italy.

Regular physical exercise plays a role in improving cardiovascular and muscular fitness in many metabolic diseases. This study aims to verify any possible benefits, including the eventual influence on any associated risk factors, in a group of kidney transplant recipients after a short period of personalized training programs with mixed exercises. In January 2013, at the Sports Medicine Center of the University of Florence, Italy, we began studying a group of 20 kidney transplant recipients. After 6 months of exercise, they underwent Cardiopulmonary Test (CPET), ECG, skin fold, bioimpedance analysis and stress test for the lower and upper limbs. EF increased significantly from 63.38 ± 4 to 67.30 ± 5.9 with p < 0.05; the anaerobic threshold improved from 14.48 ± 6.3 to 20.24 ± 3.7 (p < 0.05) with good stress tolerance, estimated by CR10 scale; weight decreased significantly (70.06-65.03 kg) as did skin folds at pectoral level (p < 0.002). Upper limb muscular strength increased significantly (p < 0.005). Regular mixed exercise is a proposed program in post-transplant syndrome with the expectation of improving cardiovascular performance and enhancing exercise tolerance. Muscle strength improves with physical fitness with consequent reduction of risk factors linked to visceral fat. Proof of an eventual positive impact on other complex aspects associated with post-transplant metabolic syndrome will require a longer follow-up.
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http://dx.doi.org/10.1007/s11739-015-1294-5DOI Listing
February 2016

Posttransplant outcome of atypical haemolytic uraemic syndrome in a patient with thrombomodulin mutation: a case without recurrence.

Clin Kidney J 2015 Jun 27;8(3):329-31. Epub 2015 Apr 27.

Nephrology Unit , Careggi University Hospital , Florence , Italy.

Atypical haemolytic uraemic syndrome (aHUS) is a rare disease characterized by thrombocytopenia, microangiopathic haemolytic anaemia and renal impairment. Mutations in genes encoding inhibitors of the alternative pathway of the complement system are involved in ∼50% of the cases. Thrombomodulin (THBD) gene mutations occur in ∼3-5% of the cases. The risk of aHUS recurrence after kidney transplantation depends on the complement abnormality involved. In all three cases of THBD mutation reported to date, aHUS recurred after kidney transplantation (KT) with early graft loss. No data exist about therapeutic approaches before kidney transplantation to reduce the risk of recurrence in patients carrying this mutation. Favourable data on the use of eculizumab have been reported, in terms of plasmatherapy withdrawal and renal function recovery in aHUS recurrence after KT. To our knowledge, this case report presents the first case of successful kidney transplantation in a patient with aHUS due to THBD mutation who was treated with a single plasma-exchange immediately before surgery without recurrence of the disease 12 months after transplantation.
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http://dx.doi.org/10.1093/ckj/sfv025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440472PMC
June 2015

Anti-human leukocyte antigen DQ antibodies in renal transplantation: Are we underestimating the most frequent donor specific alloantibodies?

Transplant Rev (Orlando) 2015 Jul 1;29(3):135-8. Epub 2015 May 1.

Nephrology Unit, Careggi University Hospital, Florence, Italy.

The role of anti-human leukocyte antigens DQ region (HLA-DQ) in transplantation is historically less studied than HLA-DR and HLA class I regions, but several studies are demonstrating that anti HLA-DQ antibodies are among the most frequent anti HLA antibodies that develop after transplantation and can have great influence on the developing of humoral rejection and graft loss. In this article we review the gene structure and nomenclature of the HLA-DQ region, the role of anti HLA-DQ antibodies after and before transplantation and briefly the associations of particular HLA-DQ alleles and other diseases.
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http://dx.doi.org/10.1016/j.trre.2015.04.003DOI Listing
July 2015

[Free light chains reduction on acute kidney injury in multiple myeloma: critical role of high cut-off membranes].

G Ital Nefrol 2014 Nov-Dec;31(6)

We report our experience with five patients, with dialysis dependent AKI and multiple myeloma (MM). Two of them were already suffering from a mild degree of renal insufficiency, one was on follow-up for smouldering MM and two had a relapse of symptomatic MM. Median concentration of the involved FLC (iFLC) was 15104 mg/L (range 1196-24384). All patients underwent three times per week HCO-HD for 6 hour sessions using Theralite 2100 (median 10, range 6-13 sessions) with one having further twelve sessions of 4 hours using SUPRA device (Bellco). In addition, they followed a bortezomib and dexamethasone regimen according to a bi-weekly schedule (3-5 cycles) plus Thalidomide. iFLC concentrations were measured by immunonephelometry in blood at the beginning of each dialysis session. All patients but one, showed a very good partial hematological response. The only exception demonstrated a partial response. iFLCs decreased between 72,8% and 99,7% in a median period of three weeks. After 6 months three patients underwent autologous stem-cell transplantation (ASCT), one of whom repeated the procedure 6 months later. In conclusion, three patients became dialysis independent at the end of the HCO-HD period, one patient became dialysis independent three months later and one remained dialysis dependent. Recovery of renal function in 4 out of 5 patients with a very good hematological response is a consequence of an early and fast removal of the iFLC joined to an efficient therapeutic regimen.
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November 2016

Unplanned pregnancies in kidney transplanted patients treated with everolimus: three case reports.

Transpl Int 2015 Mar;28(3):370-2

Nephrology unit, Careggi University Hospital, Florence, Italy.

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http://dx.doi.org/10.1111/tri.12479DOI Listing
March 2015

Predictive model for delayed graft function based on easily available pre-renal transplant variables.

Intern Emerg Med 2015 Mar 28;10(2):135-41. Epub 2014 Aug 28.

Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, 37126, Verona, Italy,

Identification of pre-transplant factors influencing delayed graft function (DGF) could have an important clinical impact. This could allow clinicians to early identify dialyzed chronic kidney disease (CKD) patients eligible for special transplant programs, preventive therapeutic strategies and specific post-transplant immunosuppressive treatments. To achieve these objectives, we retrospectively analyzed main demographic and clinical features, follow-up events and outcomes registered in a large dedicated dataset including 2,755 patients compiled collaboratively by four Italian renal/transplant units. The years of transplant ranged from 1984 to 2012. Statistical analysis clearly demonstrated that some recipients' characteristics at the time of transplantation (age and body weight) and dialysis-related variables (modality and duration) were significantly associated with DGF development (p ≤ 0.001). The area under the receiver-operating characteristic (ROC) curve of the final model based on the four identified variables predicting DGF was 0.63 (95 % CI 0.61, 0.65). Additionally, deciles of the score were significantly associated with the incidence of DGF (p value for trend <0.001). Therefore, in conclusion, in our study we identified a pre-operative predictive model for DGF, based on inexpensive and easily available variables, potentially useful in routine clinical practice in most of the Italian and European dialysis units.
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http://dx.doi.org/10.1007/s11739-014-1119-yDOI Listing
March 2015

Impact of the pre-transplant histological score on 3-year graft outcomes of kidneys from marginal donors: a single-centre study.

Nephrol Dial Transplant 2013 Oct 30;28(10):2637-44. Epub 2013 Jul 30.

Nephrology Unit, Careggi University Hospital, Florence, Italy.

Background: The reliability of kidney biopsy as the sole means for assessing kidneys from extended-criteria donors (ECDs) to be allocated to single or dual transplantation is still a matter of debate.

Methods: We compared retrospectively 3 years graft survival and renal function in 44 recipients of a single kidney graft from a marginal donor with good renal function and a Karpinski histological score of ≤ 3 and 56 recipients of a single transplant with a Karpinski score of 4 or 5. The donors' and recipients' characteristics were compared by means of Wilcoxon's rank-sum test and Fisher's exact test, and survival was analysed using the log-rank test and Cox regression survival analysis.

Results: The donors with the worse histological scores were slightly younger (68.0 ± 4.74 versus 71.3 ± 4.6 years, P < 0.01) and had a higher glomerular filtration rate (85.8 ± 28.2 versus 76.3 ± 26.53 mL/min, P = 0.013), but there was no difference in serum creatinine levels (0.83 ± 0.24 versus 0.85 ± 0.30 mg/dL, P = 0.381). Three years after transplantation, there was no difference between the two groups in terms of recipient serum creatinine levels (1.94 ± 0.69 versus 1.74 ± 0.49 mg/dL, P = 0.134), estimated glomerular filtration rate (eGFR, 45.6 ± 21.1 versus 51.7 ± 22.0 mL/min, P = 0.331) or the rates of graft loss (27.3 versus 35.7%, P = 0.47), delayed graft function or acute rejection.

Conclusions: In our experience, provided the donor has a normal renal function, a difference in the pre-transplant histological score of kidneys from marginal cadaveric donors do not have a significant influence on the outcome 3 years after transplantation. Our findings might represent a basis for designing a randomized controlled trial of using a higher histological score threshold for the DKT allocation of grafts from ECDs with a normal renal function.
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http://dx.doi.org/10.1093/ndt/gft292DOI Listing
October 2013

Optimizing utilization of kidneys from deceased donors over 60 years: five-year outcomes after implementation of a combined clinical and histological allocation algorithm.

Transpl Int 2013 Aug 19;26(8):833-41. Epub 2013 Jun 19.

Kidney - Pancreas Transplant Unit, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy.

This 5 year observational multicentre study conducted in the Nord Italian Transplant programme area evaluated outcomes in patients receiving kidneys from donors over 60 years allocated according to a combined clinical and histological algorithm. Low-risk donors 60-69 years without risk factors were allocated to single kidney transplant (LR-SKT) based on clinical criteria. Biopsy was performed in donors over 70 years or 60-69 years with risk factors, allocated to Single (HR-SKT) or Dual kidney transplant (HR-DKT) according to the severity of histological damage. Forty HR-DKTs, 41 HR-SKTs and 234 LR-SKTs were evaluated. Baseline differences generally reflected stratification and allocation criteria. Patient and graft (death censored) survival were 90% and 92% for HR-DKT, 85% and 89% for HR-SKT, 88% and 87% for LR-SKT. The algorithm appeared user-friendly in daily practice and was safe and efficient, as demonstrated by satisfactory outcomes in all groups at 5 years. Clinical criteria performed well in low-risk donors. The excellent outcomes observed in DKTs call for fine-tuning of cut-off scores for allocation to DKT or SKT in high-risk patients.
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http://dx.doi.org/10.1111/tri.12135DOI Listing
August 2013

Everolimus leads to a lower risk of BKV viremia than mycophenolic acid in de novo renal transplantation patients: a single-center experience.

Clin Transplant 2013 Jul-Aug;27(4):546-54. Epub 2013 Jun 13.

Renal Unit, Careggi University Hospital, Florence, Italy.

Background: There are limited published data concerning the effects of different immunosuppressive regimens on the development of polyomavirus (BKV) viremia. We examined the risk of developing BKV viremia in kidney transplant recipients receiving everolimus (EVR) or mycophenolic acid (MPA) as maintenance therapy.

Methods: We observationally analyzed 296 patients who underwent renal transplantation at our center between 2005 and 2010: 58 were treated with EVR and low-dose cyclosporine (LD-CyA) (group 1) and 238 with MPA and standard-dose CyA (group 2). All of the patients received induction therapy with basiliximab and maintenance steroids. BKV viremia (a whole-blood viral load of >850 copies/mL) was measured by means of real-time polymerase chain reaction at least once a month during a 12-month follow-up period.

Results: BKV viremia was detected in 57 patients (19%), five (9%) in group 1 and 52 (22%) in group 2. Kaplan-Meier analyses showed that freedom from BKV viremia was significantly more frequent in group 1. The mean time of onset of BKV viremia was about four months after transplantation in both groups. The median viral load was greater in group 2 (12.5 ± 6.1 vs. 2.5 ± 1.8 × 10(4) copies/mL; p = 0.01). After the onset of BKV viremia, graft function significantly declined in group 2: 11 patients developed polyomavirus-associated nephropathy (PVAN) and four presumptive PVAN; nine experienced an acute rejection after the discontinuation of MPA, and 11 (21%) lost their graft. There was no graft loss in group 1.

Conclusion: These findings suggest that in comparison with MPA and Cya, an EVR and LD-CyA regimen lowers the risk of BKV viremia after kidney transplantation and favorably alters outcomes.
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http://dx.doi.org/10.1111/ctr.12151DOI Listing
March 2014

Lymphocele after renal transplantation, a medical complication.

Authors:
Enrico E Minetti

J Nephrol 2011 Nov-Dec;24(6):707-16

Division of Nephrology, Niguarda Ca' Granda Hospital, Milan, Italy.

After 50 years, the incidence of lymphocele and lymphorrhea associated with renal transplantation remains substantially high in spite of more accurate surgical technique, reduction of other complications and improvement of general outcomes. The data from the literature point to the allograft as the source of increased lymph production, which in spite of an accurate hilar lymphatics ligature, can find a transcapsular outlet. Subclinical and clinical graft rejection and inflammation greatly enhance lymph production and leakage. This mechanism may partially mediate the effects of some immunosuppressive drugs on the incidence of lymphocele.
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http://dx.doi.org/10.5301/jn.5000004DOI Listing
April 2012

[Renal outcome after pancreas transplant in patients with unstable diabetes mellitus].

G Ital Nefrol 2010 Nov-Dec;27 Suppl 52:S78-81

S.C. Nefrologia, A.O. Ospedale Niguarda Ca' Granda, Milano, Italy.

Combined kidney-pancreas transplant is currently the best treatment option for patients with type 1 diabetes associated with chronic renal failure. The favorable results of simultaneous pancreas-kidney transplants (SPK), introduced in the early 1990s, led to the introduction of the pancreas after kidney transplant (PAK) and the pancreas transplant alone (PTA), a good option for patients with uncontrolled diabetes. The superior results of SPK over PAK are partly related to better donor selection and partly to immunological factors. In conclusion, PAK transplant is a good preemptive choice for patients for whom a living kidney donor is available, so that long-term uremia while the patient is waiting for a cadaver pancreas graft can be avoided. Despite a high surgical complication rate in all types of pancreas transplant (SPK, PAK, PTA), patient survival is good and graft survival is improving year by year.
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March 2011

Kidney transplantation from anti-HBc+ donors: results from a retrospective Italian study.

Transplantation 2006 Jan;81(1):76-80

Department Trasfusionale e di Riferimento per il Trapianto di Organi e Tessuti, IRCCS Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy.

Background: The risk of transmitting a hepatitis B virus (HBV) infection from donor kidneys with a past HBV serological profile may be negligible. Data on HBV transmission to kidney transplant recipients from donor organs that were anti-HBc/HBsAg in Italy has not been previously reported. Anti-HBc testing in cadaver organ donors has been mandatory in Italy since 2002, when anti-HBc determinations were included in the National Guidelines for donor evaluation. Therefore, prior to that date kidney recipients from anti-HBc/HBsAg donors can be identified retrospectively where stored serum is available for testing.

Methods: The prevalence of anti-HBc Italian organ donors, the incidence of HBV transmission according to the recipients' HBV status (vaccinated, recovered, or naive), and the clinical impact (5-year graft and patient survival rates) in the North Italy Transplant program was evaluated by retrospectively screening for anti-HBc antibodies in the sera of cadaver kidney donors used in transplants from 1997 to 1999.

Results: Two hundred and ten donors were found to have been anti-HBc. At the time of the study, no active infection was observed in any of the 344 HBsAg recipients, but 4/140 (2.86%) of the vaccinated recipients were found to have been anti-HBc/HBsAg. None of these patients, however, had any biochemical or clinical history of HBV infection. Patient and graft survival rates of anti-HBc or anti-HBc kidney recipients did not differ statistically.

Conclusion: Kidney grafts from anti-HBc donors should be considered in all recipients because the benefit obtained from the transplantation out weighs the negligible risk of HBV transmission.
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http://dx.doi.org/10.1097/01.tp.0000189930.89031.1bDOI Listing
January 2006

Renal transplantation. Strategies to prevent organ rejection--the role of an inter-regional reference center.

Contrib Nephrol 2005 ;146:1-10

Dipartimento Trasfusionale e di Riferimento per il Trapianto di Organi e Tessuti, RCCS Ospedale Maggiore Policlinico, Milano; Italy.

This paper summarizes the role of the Inter-Regional Reference Center (RC) of the North Italy Transplant program (NITp), in coordinating a donor procurement and organ transplantation network, with a special focus on the strategies to minimize immunological risk and complications after transplantation. In the NITp, patients enrolled on the renal transplantation (RT) waiting list are typed for HLA-A,B,DRB1 antigens with a genomic method. They are periodically screened for the presence of lymphocytotoxic antibodies in their serum by the RC and their suitability to receive the transplant is checked periodically. Cadaver kidney allocation is ruled by a computerized algorithm, named NITK3, established in 1997, which aims at ensuring quality, equity, transparency and traceability during all the phases of the allocation decision-making process. NITK3 has been set up by the NITp Working Group on the basis of biological, medical and administrative criteria and it is periodically reviewed after the analysis of transplant results. In this paper, we show the results of a preliminary analysis of RTs performed from 1998 to 2002 in nine out of sixteen centers of the NITp area, which demonstrates the general quality of the NITp program in terms of patients and graft survival and the special attention to the patients at higher immunological risk.
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http://dx.doi.org/10.1159/000082056DOI Listing
December 2004

Images in clinical medicine. Bilateral renal arteriovenous malformation.

N Engl J Med 2004 Sep;351(10):e9

Ospedale Niguarda Ca'Granda, 20162 Milan, Italy.

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http://dx.doi.org/10.1056/ENEJMicm030333DOI Listing
September 2004

Multiple organ failure in a kidney transplant patient receiving both colchicine and cyclosporine.

J Nephrol 2003 May-Jun;16(3):421-5

Nephrology, Dialysis and Medical Therapy of Renal Transplant Section, Niguarda Cà Granda Hospital, Milan, Italy.

Colchicine is a relatively safe and effective medication when given at appropriate doses to patients with normal kidney and liver function. A clinical picture of multiple organ failure has been described in cases of colchicine poisoning and in kidney graft recipients treated with usual doses of colchicine during cyclosporine therapy. We report a case of multiple organ failure in a renal transplant patient who received appropriate doses of colchicine in combination with cyclosporine therapy. Interaction between colchicine and cyclosporine is postulated but boosting of CSA toxicity was excluded because of the low CSA blood through levels before and throughout the episode, in the presence of relatively stable renal function and for the prompt CSA withdrawal. Mechanism of toxicity and modulation of the P-glycoprotein by cyclosporine are reviewed. Although the proscription of the drug in cyclosporine-treated patients is not justified, caution is recommended in prescribing colchicine to patients receiving cyclosporine therapy, particularly in the presence of suboptimal kidney graft function.
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July 2003
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