Publications by authors named "Silvio Sandrini"

48 Publications

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

PLoS Med 2021 Jun 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

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 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

Everolimus in kidney transplant recipients at high cardiovascular risk: a narrative review.

J Nephrol 2020 Feb 27;33(1):69-82. Epub 2019 Apr 27.

Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.

Kidney transplant recipients (KTRs) are at increased risk of cardiovascular (CV) morbidity and mortality, and side effects induced by immunosuppressive therapy may be a major contributor to this risk, together with traditional CV risk factors. Many strategies have been considered in order to reduce CV risk in KTRs, such as steroid and/or calcineurin inhibitor (CNI) minimization, but current data are inconclusive. The introduction of mammalian target of rapamycin (mTOR) inhibitors, the cornerstone of CNI minimization, in the immunosuppressive protocol may reduce both the incidence and severity of CNI-associated side effects; however, whether this strategy has an impact on CV risk after kidney transplantation needs to be evaluated. To this end, a panel of Italian experts in the field of transplantation was convened in a series of meetings to assess the current literature on the potential of the mTOR inhibitor everolimus as a cardioprotective agent. This narrative review summarizes the panel's round-table discussions and provides recommendations for CV risk management in KTRs.
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http://dx.doi.org/10.1007/s40620-019-00609-yDOI Listing
February 2020

Safety and efficacy of eculizumab for the prevention of antibody-mediated rejection after deceased-donor kidney transplantation in patients with preformed donor-specific antibodies.

Am J Transplant 2019 10 24;19(10):2865-2875. Epub 2019 May 24.

Formerly Alexion Pharmaceuticals, Boston, Massachusetts.

The presence of preformed donor-specific antibodies in transplant recipients increases the risk of acute antibody-mediated rejection (AMR). Results of an open-label single-arm trial to evaluate the safety and efficacy of eculizumab in preventing acute AMR in recipients of deceased-donor kidney transplants with preformed donor-specific antibodies are reported. Participants received eculizumab as follows: 1200 mg immediately before reperfusion; 900 mg on posttransplant days 1, 7, 14, 21, and 28; and 1200 mg at weeks 5, 7, and 9. All patients received thymoglobulin induction therapy and standard maintenance immunosuppression including steroids. The primary end point was treatment failure rate, a composite of biopsy-proved grade II/III AMR (Banff 2007 criteria), graft loss, death, or loss to follow-up, within 9 weeks posttransplant. Eighty patients received transplants (48 women); the median age was 52 years (range 24-70 years). Observed treatment failure rate (8.8%) was significantly lower than expected for standard care (40%; P < .001). By 9 weeks, 3 of 80 patients had experienced AMR, and 4 of 80 had experienced graft loss. At 36 months, graft and patient survival rates were 83.4% and 91.5%, respectively. Eculizumab was well tolerated and no new safety concerns were identified. Eculizumab has the potential to provide prophylaxis against injury caused by acute AMR in such patients (EudraCT 2010-019631-35).
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http://dx.doi.org/10.1111/ajt.15397DOI Listing
October 2019

Effectiveness of kidney transplantation in HIV-infected recipients under combination antiretroviral therapy: a single-cohort experience (Brescia, Northern Italy).

Infection 2018 Feb 4;46(1):77-82. Epub 2017 Nov 4.

University Department of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, P. le Spedali Civili 1, 25123, Brescia, Italy.

Purpose: Kidney transplantation was recently introduced for the treatment of end stage renal disease (ESRD) in HIV-infected patients. We report the results of the first 28 procedures at our centre.

Methods: A retrospective study was conducted on HIV-infected patients evaluated for kidney transplantation between January 2005 and October 2016. Patients were selected and monitored by the kidney transplantation and infectious diseases teams, according to the national protocol.

Results: 60 patients were evaluated; 32 entered the list and 28 were transplanted. Median CD4+ count was 337 cell/μL at transplantation and 399 cell/μL 12 months thereafter. HIV RNA was undetectable at transplantation in 27/28 patients and became undetectable within 24 weeks in the only patient starting antiretroviral combination therapy (cART) after surgery. Four patients experienced virological failure, but reached again undetectability after cART regimen change. At last available point of follow-up (median 126.1 weeks), HIV RNA was undetectable in all patients. Three patients experienced AIDS-defining events. We observed a cumulative number of 19 acute rejections in 16 patients (median time from transplantation to first rejection 5.2 weeks). Survival rate was 82.1%. To avoid pharmacokinetics (PK) interactions, cART regimen was changed from a protease inhibitor (PI)/non-nucleoside reverse transcriptase inhibitor (NNRTI)-based to an integrase inhibitor (InSTI)-based regimen in 11/20 alive patients with functioning graft.

Conclusions: Kidney transplantation appears to be safe in HIV-infected patients carefully selected. As previously reported, we observed a high incidence of acute rejection. We expect that the recent implementation of the immunosuppressive protocols will allow a better immunologic control. Moreover, the introduction of InSTI permits a better strategy of cART, with lower incidence of PK interactions with immunosuppressive drugs.
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http://dx.doi.org/10.1007/s15010-017-1092-2DOI Listing
February 2018

De novo cancer in patients on dialysis and after renal transplantation: north-western Italy, 1997-2012.

J Nephrol 2017 Dec 19;30(6):851-857. Epub 2017 Mar 19.

Operative Unit of Nephrology, ASST Spedali Civili, Brescia, Italy.

Background: Kidney transplant recipients (KTR) are known to have a higher risk of cancer than the general population, especially of malignancies related to oncogenic viral infections. This study assessed the incidence of de novo malignancies (DNMs) in patients receiving kidney transplantation and in dialysis patients (DP) on the waiting list for transplantation at the same centre. The aim was to quantify the contribution of post-transplant immunosuppression to the underlying risk of developing a DNM in dialysis patients on the waiting list for kidney transplant.

Methods: Cancer incidence rates were computed using the Kaplan-Meier product-limit method. The number of DNMs observed in both groups was compared to the expected incidence in the general Italian population through calculation of the standardized incidence ratios (SIR) and their 95% confidence intervals (CI). To identify risk factors, incidence rate ratios (IRR) and 95% CIs were computed using Poisson regression analysis. The comparison of incidence rates between the two cohorts was also performed using age standardized incidence rates (ASR) and their ratio (age standardized rate ratio, ASRR).

Results: In 4858 person-years (PYs) of observation, 75 out of 735 KTR were diagnosed with DNM: 57 solid neoplasms, 13 post-transplant lymphoproliferative disorders (PTLD), and 12 Kaposi sarcomas (KS). The overall incidence was 17.5 cases/10 PYs, resulting in a 2.1-fold increased risk. Twenty-four out of 912 DP, over a follow-up of 2400 PYs, were diagnosed with a solid neoplasm, but none had PTLD or KS. The use of induction therapy after transplant was associated with a significant increased risk of KS (IRR: 3.52; 95% CI 1.04-11.98, p < 0.05). ASRR for all cancers and for solid cancers only was 1.84- and 1.19-fold higher in KTR, respectively, than in the general population. The overall incidence in DP was 10.0 cases/10 PYs, with a 1.6 significantly increased cancer risk compared to the general population.

Conclusion: Our study confirms the increased risk of cancer after transplantation and during dialysis, but showed that virus-related cancers only occur after post-transplant immunosuppression.
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http://dx.doi.org/10.1007/s40620-017-0385-yDOI Listing
December 2017

[Diabetes after Kidney Transplantation].

G Ital Nefrol 2016 Malattie Metaboliche e Rene;33(S68)

Abnormal glucose metabolism is one of the most important complication encountered after renal transplantation. Besides the well-known type 2 diabetes mellitus, there are other two abnormal conditions that must be mentioned, high fasting plasma glucose and impaired glucose tolerance. The last one is often misdiagnosed because it needs an oral glucose tolerance (OGT), rarely used in clinical practice. The 15-30% of patients on waiting list of renal transplantation have impaired glucose tolerance. Therefore OGT should be performed in non-diabetic patients and when glycosylated hemoglobin is > 5.8 %. At 1 year after renal transplantation, about 15% of patients develops de novo diabetes, 28% after 3 years. Besides traditional risk factors, a primary role is played by immunosuppressive drugs because they reduce both the synthesis and peripheral activity of insulin. Hence the therapy of diabetes after renal transplantation must look at the cautious management of immunosuppressive therapy, in particular of the drugs like corticosteroids and tacrolimus. In most cases, either reducing or weaning these drugs can help us to achieve an improving of glucose metabolism.
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October 2017

Transplantation of kidneys with tumors.

J Nephrol 2016 Apr 20;29(2):163-168. Epub 2015 Nov 20.

Nephrology, Dialysis and Renal Transplantation Unit, Ospedali Riuniti, V. Conca 71, 60020, Ancona, Italy.

The shortage of donors in the face of the increasing number of patients wait-listed for renal transplantation has prompted several strategies including the use of kidneys with a tumor, whether found by chance on harvesting from a deceased donor or intentionally removed from a living donor and transplanted after excision of the lesion. Current evidence suggests that a solitary well-differentiated renal cell carcinoma, Fuhrman nuclear grade I-II, less than 1 cm in diameter and resected before grafting may be considered at minimal risk of recurrence in the recipient who, however, should be informed of the possible risk and consent to receive such a graft.
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http://dx.doi.org/10.1007/s40620-015-0249-2DOI Listing
April 2016

Renal cancer in kidney transplanted patients.

J Nephrol 2015 Dec 23;28(6):659-68. Epub 2015 Jul 23.

Nephrology and Dialysis Unit, San Carlo Borromeo Hospital, Milan, Italy.

Renal cancer occurs more frequently in renal transplanted patients than in the general population, affecting native kidneys in 90% of cases and the graft in 10 %. In addition to general risk factors, malignancy susceptibility may be influenced by immunosuppressive therapy, the use of calcineurin inhibitors (CNI) as compared with mammalian target of rapamycin inhibitors, and the length of dialysis treatment. Acquired cystic kidney disease may increase the risk for renal cancer after transplantation, while autosomal dominant polycystic kidney disease does not seem to predispose to cancer development. Annual ultrasound evaluation seems appropriate in patients with congenital or acquired cystic disease or even a single cyst in native kidneys, and every 2 years in patients older than 60 years if they were on dialysis for more than 5 years before transplantation. Immunosuppression should be lowered in patients who develop renal cancer, by reduction or withdrawal of CNI. Although more evidence is still needed, it seems reasonable to shift patients from CNI to everolimus or sirolimus if not already treated with one of these drugs, with due caution in subjects with chronic allograft nephropathy.
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http://dx.doi.org/10.1007/s40620-015-0219-8DOI Listing
December 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

Kidney transplantation in HIV-positive patients treated with a steroid-free immunosuppressive regimen.

Transpl Int 2014 Oct 20;27(10):1050-9. Epub 2014 Aug 20.

Operative Unit of Nephrology, A.O. Spedali Civili and University of Brescia, Brescia, Italy.

One of the main concerns associated with renal transplantation in HIV-infected patients is the high risk of acute rejection, which makes physicians reluctant to use steroid-free immunosuppressive therapy in this subset of patients. However, steroid therapy increases cardiovascular morbidity and mortality. The aim of this study was to define the efficacy of a steroid-sparing regimen in HIV-infected renal transplant recipients. Thirteen HIV-infected patients were consecutively transplanted. The induction therapy consisted of basiliximab and methylprednisolone for 5 days followed by a calcineurin inhibitor plus mycophenolate acid. The mean follow-up was 50 ± 22 months. Eight patients (61.5%) experienced acute rejection, and 75% of the first episodes occurred within 2 months after transplantation. The probability of first acute rejection was 58% after 1 year and 69% after 4 years. Seven of eight patients recovered or maintained their kidney function after antirejection therapy and steroid resumption. At the last follow-up, seven of 13 patients (54%) had resumed steroid therapy. The 4-year patient and graft survivals were 100% and 88.9%, respectively. The benefits of this steroid-free regimen in HIV-infected renal recipients must be reconsidered because of the high rate of acute rejection. New immunosuppressive steroid-free strategies should be identi-fied in this set of patients.
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http://dx.doi.org/10.1111/tri.12377DOI Listing
October 2014

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

[Pre-emptive renal transplantation from deceased donor].

G Ital Nefrol 2012 Sep-Oct;29(5):525-34

U.O.S. Trapianti Rene-Pancreas, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.

Preemptive transplantation from deceased donors is an important issue due to its ethical and clinical implications. In this paper, two nephrologists discuss the problem from different angles, expressing their opinion on specific points and highlighting the limitations and advantages. The first point discussed relates to the advantages of preemptive renal transplant from a deceased donor versus dialysis. The second point considers the possibility that the former could reduce the already limited resources for patients on the transplant waiting list. The third point discusses whether preemptive transplant should be reserved for patients with particular background diseases. The last discussion point relates to the possibility that a preemptive program from deceased donors could hamper an already limited living donor program. The ethical aspects are examined separately by a bioethicist who critically evaluates all discussion points and lists some principles that should guide clinicians, before or after starting dialysis, in the proper use of renal transplant, an efficacious but scarce resource.
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December 2012

[Living donor kidney transplant: the role of the nephrologist].

G Ital Nefrol 2012 Nov-Dec;29 Suppl 58:S99-103

Cattedra e Divisione di Nefrologia, A.O. Spedali Civili e Universita' degli Studi di Brescia, Brescia - Italy.

Living donor kidney transplant is the best available treatment for chronic kidney disease. The nephrologist plays a key role in activating and promoting this program. The ''historical'' mistrust surrounding it is easily overcome by the current knowledge of the benefits and safety of this type of transplant. The complexity of its organization could from now on be the only constraint on its more widespread use. Only a well-trained nephrologist and the activation of an efficient predialysis program will be able to overcome this obstacle and to make this transplant modality available to an ever increasing number of patients.
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August 2015

Risk of de novo cancers after transplantation: results from a cohort of 7217 kidney transplant recipients, Italy 1997-2009.

Eur J Cancer 2013 Jan 10;49(2):336-44. Epub 2012 Oct 10.

Department of Epidemiology, INMI L. Spallanzani, Rome, Italy.

To assess incidence and risk factors for de novo cancers (DNCs) after kidney transplant (KT), we carried out a cohort investigation in 15 Italian KT centres. Seven thousand two-hundred seventeen KT recipients (64.2% men), transplanted between 1997 and 2007 and followed-up until 2009, represented the study group. Person years (PY) were computed from 30 days after transplant to cancer diagnosis, death, return to dialysis or to study closure. The number of observed DNCs was compared to that expected in the general population of Italy through standardised incidence ratios (SIR) and 95% confidence intervals (CI). To identify risk factors, incidence rate ratios (IRR) were computed. Three-hundred ninety five DNCs were diagnosed during 39.598PYs, with Kaposi's sarcoma (KS), post-transplant lymphoproliferative disorders (PTLD), particularly non-Hodgkin' lymphoma (NHL), lung, kidney and prostate as the most common types. The overall IR was 9.98/1.000PY, with a 1.7-fold augmented SIR (95% CI: 1.6-1.9). SIRs were particularly elevated for KS (135), lip (9.4), kidney carcinoma (4.9), NHL (4.5) and mesothelioma (4.2). KT recipients born in Southern Italy were at reduced risk of kidney cancer and solid tumors, though at a higher KS risk, than those born in Northern Italy. Use of mTOR inhibitors (mTORi) exerted, for all cancers combined, a 46% significantly reduced risk (95% CI: 0.4-0.7). Our study findings confirmed, in Italy, the increased risks for cancer following KT, and they also suggested a possible protective effect of mTORi in reducing the frequency of post transplant cancers.
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http://dx.doi.org/10.1016/j.ejca.2012.09.013DOI Listing
January 2013

Monitoring of inosine monophosphate dehydrogenase activity and expression during the early period of mycophenolate mofetil therapy in de novo renal transplant patients.

Drug Metab Pharmacokinet 2013 14;28(2):109-17. Epub 2012 Aug 14.

Clinical Pharmacokinetics in Transplantation and Autoimmune Diseases, Foundation IRCCS Policlinico S. Matteo, Pavia, Italy.

Measurement of inosine-monophosphate dehydrogenase (IMPDH) activity or gene expression was used as a further approach in pharmacokinetics (PK)/pharmacodynamic (PD)-guided mycophenolate mofetil (MMF) therapy. Forty-four de novo kidney transplant patients were enrolled; 35 of these completed the study, and were followed for 24 weeks for clinical status, PK parameters, IMPDH activity and IMPDH1/2 gene expression. IMPDH activity and expression were measured in peripheral blood mononuclear cells before transplant and at week 2,4,12 and 24, drawn before (t0) and 2 h (t2 h) after MMF administration. No significant correlation was found between IMPDH activity/expression and PK parameters. For both genes, significant enhancement in t2 h expression was observed, then decreases towards week 24 with a trend following steroid dosages. Seven patients experienced acute rejection (AR) and exhibited significantly higher pre-transplant expression of both IMPDH1 (median 3.42 vs. 0.84; p=0.0025), and IMPDH2 genes (135 vs. 104; p=0.0218) with respect to non-rejecting patients. A significant association was also found between pre-transplant IMPDH1 mRNA and haematological complications (p=0.032). This study suggests that high steroid dosages may influence IMPDH1/2 expression, hampering their use as a PD biomarker, particularly during the early post-transplant period. The measurement of pre-transplant levels of IMPDH1/2 may contribute to prediction of individual drug responsiveness to improve the clinical management of patients in MMF therapy.
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http://dx.doi.org/10.2133/dmpk.dmpk-12-rg-048DOI Listing
July 2014

[Kidney transplant in patients with HIV infection].

G Ital Nefrol 2012 Jul-Aug;29(4):404-17

Divisione e Cattedra di Nefrologia, Spedali Civili e Universita' di Brescia, Italy.

Until recently, human immunodeficiency virus (HIV) infection was an absolute contraindication to solid organ transplantation because it was feared that the anti-rejection therapy could result in accelerated HIV disease. At the end of the 1990s it became clear that HIV infection, once deemed a fatal disease, could be effectively turned into a chronic condition by the use of highly active antiretroviral therapy. Since then, the mortality rate from opportunistic infections has decreased dramatically, while liver and renal insufficiency have become the major causes of morbidity and mortality in these patients in the long term. A growing number of HIV patients develop end-stage renal disease secondary to immune-mediated glomerulonephritis, HIV-associated nephropathy, nephrotoxic effects induced by antiretroviral medication, or diabetic and vascular nephropathy, and therefore need maintenance dialysis. For this reason we have to reconsider kidney transplant as a possible treatment option. During the last decade, the results of many studies have shown that transplantation can be safe and effective as long as the HIV infection is effectively controlled by antiretroviral therapy. The short- and medium-term patient and graft survival rates in HIV-positive transplant recipients are comparable with those of the overall transplant population, but the incidence of acute rejection episodes is higher. The main clinical problem in the management of HIV-positive transplant recipients originates from the interference between immunosuppressive regimens and antiretroviral drugs. Thus, a close collaboration between infectious disease specialists and nephrologists is mandatory in order to optimize transplantation programs in these patients.
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October 2012

Perioperative Minimal Induction Therapy: A Further Step toward More Effective Immunosuppression in Transplantation.

J Transplant 2012 20;2012:426042. Epub 2012 May 20.

Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano, 87, 24126 Bergamo, Italy.

Dual induction with low doses of rabbit anti-human thymoglobulin (RATG) and basiliximab effectively and safely prevented allograft rejection in high-risk renal transplant recipients. To assess whether treatment timing affects efficacy and tolerability, in this single-center, matched-cohort study, we compared posttransplant outcomes in 25 patients and 50 gender-, age-, and treatment-matched reference patients induced with the same course of 7 daily RATG infusions (0.5 mg/kg/day) started before or after engraftment, respectively. All subjects received basiliximab (20 mg) before and 4 days after transplantation, withdrew steroids within 6 days after surgery, and were maintained on steroid-free immunosuppression with cyclosporine and mycophenolate mofetil or azathioprine. Over 12 months after transplant, 1 patient (4%) and 13 reference patients (26%) had acute rejection episodes. One patient and 5 reference-patients required dialysis therapy because of delayed graft function. In all patients circulating CD4+ and CD8+ T lymphocytes were fully depleted before engraftment. Both treatments were well tolerated. In kidney transplantation, perioperative RATG infusion enhances the protective effect of low-dose RATG and basiliximab induction against graft rejection and delayed function, possibly because of more effective inhibition of early interactions between circulating T cells and graft antigens.
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http://dx.doi.org/10.1155/2012/426042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364007PMC
August 2012

Tacrolimus versus cyclosporine for early steroid withdrawal after renal transplantation.

J Nephrol 2012 Jan-Feb;25(1):43-9

Division and Chair of Nephrology, University Hospital Spedali Civili, Brescia, Italy.

Introduction: This study compares cyclosporine (CsA) with tacrolimus (Tac) in preventing acute rejection (AR) after steroid withdrawal (SW) 5 days after renal transplantation (Tx).

Methods: The data were collected from 2 prospective sequential studies carried out from February 2002 to May 2006. Forty-nine patients received CsA, 56 patients Tac. Rapamycin (Rapa) was added to both calcineurin inhibitors (CNIs). The studies were homogeneous regarding both clinical procedures and patient demographics.

Results: Three years after SW, Tac was more effective than CsA in reducing the risk both of AR (35% vs. 53%; p<0.06) and mainly of relapses (9% vs. 33%; p<0.007). In addition, Tac enabled more patients to go onto a steroid-free regime (88% vs. 65%; p<0.01). No difference arose concerning the timing of AR, graft function, CNI withdrawal, incidence of side effects or patient and graft survival rates. In both groups, rejection after SW was associated with a worse graft function.

Conclusions: Tac was more effective than CsA in preventing AR after early SW, and increased significantly patient probability of maintaining a steroid-free regime. In this setting, Tac and CsA had the same safety profile. However, a follow-up longer than 3 years might be needed to estimate the consequences of the higher rate of AR encountered under CsA therapy.
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http://dx.doi.org/10.5301/jn.5000070DOI Listing
June 2012

Analysis of the 3'UTR of the prostaglandin synthetase-2 (PTGS-2/COX-2) gene in non-melanoma skin cancer after organ transplantation.

Exp Dermatol 2011 Dec 13;20(12):1025-7. Epub 2011 Oct 13.

To define the potential involvement of polymorphisms in the 3'untranslated region (3'UTR) of the prostaglandin synthetase-2 (PTGS-2) gene to non-melanoma skin cancer (NMSC) predisposition after transplantation, we screened for genetic variant, relevant parts of this region. It contains binding sites for trans-acting factors, an alternative polyadenylation site and putative target sequences for miRNAs. Variant +8473T>C did not appear to play a functional role in the regulation of gene expression in human keratinocyte-transfected cells. In addition to the well-known +8473T>C, we identified four polymorphisms: +8293G>C, +10259T>G, +10267G>A and +10335G>A. No allele frequency differences were observed between cases and controls neither for +8473T>C nor for any of the identified polymorphisms, suggesting that polymorphisms in the 3'UTR of the PTGS2 gene are rare and unlikely to represent risk factor for NMSC after transplantation.
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http://dx.doi.org/10.1111/j.1600-0625.2011.01381.xDOI Listing
December 2011

Quantitative viral load measurement for BKV infection in renal transplant recipients as a predictive tool for BKVAN.

New Microbiol 2011 Apr 30;34(2):165-71. Epub 2011 Apr 30.

Institute of Microbiology, University of Brescia, A.O. Spedali Civili, Brescia, Italy. [email protected]

Infection by polyomavirus BK (BKV) is an emerging problem in the clinical management of renal transplant patients because it is responsible for nephropathy and consequently can cause loss of the transplanted organ (BKV associated nephropathy, BKVAN). Aim of this study was to evaluate the use of blood viral load measurement as a screening tool for diagnosis of BKV infection and to identify a threshold value for the management of patients. A total of 75 kidney transplant patients, corresponding to 338 consecutive plasma samples, were analyzed by an automatic system for nucleic acid extraction and quantitative real-time polymerase chain reaction (PCR) for detection of BKV. BKV was detected in 170 samples (26 patients) with a median viral load of 4.1 log10 copies/mL; among these 26 patients, seven (34.7%) were found to have BKVAN on allograft biopsy together with a median viral load of 5 log10 copies/mL. The ROC curve analysis identified a viral load equal to 4.1 log10 copies/mL as the best discriminant cut-off value to predict the disease and to identify patients at risk of developing BKVAN.
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April 2011

[Kidney transplantation and lymphomas].

G Ital Nefrol 2010 Sep-Oct;27 Suppl 50:S46-50

Cattedra e Divisione di Nefrologia, A.O. Spedali Civili ed Universita', Brescia, Italy.

Post-transplant lymphoproliferative disease (PTLD) accounts for 30% of nonskin cancers after kidney transplants. Diffuse large B-cell lymphoma is the most frequent form of PTLD. The incidence of PTLD increases over time: from 1.2% at 5 years to 6.8% at 20 years. Its late occurrence is therefore not unusual. Moreover, not only is it more frequent but also more serious than the early type because of the lower responsiveness to therapy. Epstein-Barr virus (EVB) infection is one of the most important risk factors for this disease, along with the use of antilymphocyte agents, which should be avoided in EVB-negative patients. During the first year after transplant, EBV-PCR monitoring can be helpful for the early diagnosis of EBV-associated PTLD, especially in children. No effective strategy has yet been reported for the prevention of late PTLD. Interruption of immunosuppression is the first step of therapy, but it is rarely effective by itself. Rituximab (4-8 doses) is widely used and is successful in about 50% of cases. Chemotherapy becomes essential in relapsed or refractory disease, but it significantly increases the risk of life-threatening infections. The mortality rate is around 50% 12 months after diagnosis, often due to the side effects of chemotherapy.
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January 2011

The number of circulating recent thymic emigrants is severely reduced 1 year after a single dose of alemtuzumab in renal transplant recipients.

Transpl Int 2010 Aug 3;23(8):786-95. Epub 2010 Feb 3.

Rheumatology and Clinical Immunology, and Nephrology, Spedali Civili, Brescia, Italy.

To better understand the kinetics of the delayed reconstitution of peripheral CD4+ T-cells after depletion with a single administration of alemtuzumab (AL) for renal transplantation, we evaluated in these patients the percentage and absolute number of recent thymic emigrants (RTEs) CD4+ T cells, together with naive and memory subsets, defined by the analysis of CD31, CD45RA and CCR7 expression, and compared with patients treated with a nondepleting protocol based on basiliximab, and with healthy controls. In AL-treated patients, the number of circulating CD4+ T cells was greatly reduced 1 year after the infusion (P < 0.01), but the proportions of central memory, effector memory and terminally differentiated effector memory subsets among CD4+ cells were significantly increased. On the contrary, the proportion and the absolute number of naïve CD4+ T cells, although progressively increasing with time, were severely reduced. In particular, the absolute number of RTEs had only very slight increase with time (P = 0.049) and was dramatically low 1 year after the therapy (P < 0.01 vs. healthy controls; P < 0.05 vs. basiliximab-treated transplant recipients). These data suggest that a prolonged defective thymic output after AL therapy in renal transplant recipients is one of the main causes of the persistent CD4+ T-cell lymphopenia observed in these patients.
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http://dx.doi.org/10.1111/j.1432-2277.2010.01052.xDOI Listing
August 2010

Early (fifth day) vs. late (sixth month) steroid withdrawal in renal transplant recipients treated with Neoral(®) plus Rapamune(®): four-yr results of a randomized monocenter study.

Clin Transplant 2010 Sep-Oct;24(5):669-77

Division of Nephrology, A.O. Spedali Civili and University, Brescia, Italy.

The most advisable timing for steroid withdrawal (CSWD) after renal transplantation (Tx) is still an open issue. This randomized study has compared early CSWD (at day 5) with late (at month 6) in patients under Neoral + Sirolimus. The primary end point was the percentage of success in CSWD at month 48. Ninety-six transplants from deceased donors were randomized to withdraw steroids either early (n = 49) or late (n = 47). At four yr, the two strategies were comparable for: success in CSWD (65% in both), graft survival (95% and 98%), patient survival (92% and 96%) creatininemia (1.7 ± 0.3 and 1.6 ± 0.4 mg/dL), side effects, being still on Sirolimus + Neoral (69% and 74%), reversibility of rejection (AR) (all cases), severity of AR (grade 1A/1B: 81% and 63%). The major differences were incidence of AR: at month twelve (48% vs. 30%, p < 0.04), at 48 (53% and 33%, p < 0.03); timing of AR (72 ± 86 d vs. 202 ± 119 d, p < 0.0001). The timing of CSWD influences neither the rate of successful CSWD nor the long-term results. However, early suspension causes a higher AR rate, mostly arising within month one, but always responsive to steroids. Yet, the early appearance of AR can make patient management easier and safer.
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http://dx.doi.org/10.1111/j.1399-0012.2009.01171.xDOI Listing
February 2011

[Presentation of the issue dedicated to living donor kidney transplant].

Authors:
Silvio Sandrini

G Ital Nefrol 2009 Jul-Aug;26(4):413-4

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December 2009

ABCB1 genotypes predict cyclosporine-related adverse events and kidney allograft outcome.

J Am Soc Nephrol 2009 Jun 21;20(6):1404-15. Epub 2009 May 21.

Department of Medicine and Transplantation, Ospedali Riuniti-Mario Negri Institute for Pharmacological Research, Bergamo, Italy.

Cyclosporine A (CsA) is a substrate of P-glycoprotein, an efflux transporter encoded by the ABCB1 gene. Compared with carriers of the wild-type gene, carriers of T allelic variants in exons 21 or 26 have reduced P-glycoprotein activity and, secondarily, increased intracellular concentration of CsA; therefore, carriers of T variants might be at increased risk for CsA-related adverse events. We evaluated the associations between ABCB1 genotypes (in exons 12, 21, and 26) and CsA-related outcomes in 147 renal transplant recipients who were receiving CsA-based immunosuppression and were included in the Mycophenolate Steroids Sparing study. During a median of 65.5 mo follow-up, carriers of T allelic variants in exons 21 or 26 had a three-fold risk for delayed graft function (DGF), a trend to slower recovery of renal function and lower GFR at study end, and significantly higher incidences of new-onset diabetes and cytomegalovirus reactivation compared with carriers of the wild-type genotype. T variants in both exons 21 and 26 were independently associated with 3.8- and 3.5-fold higher risk for DGF, respectively (P = 0.022 and P = 0.034). The incidence of acute rejection and the mean CsA dose and blood levels were comparable in genotype groups. In conclusion, renal transplant recipients with T allelic variants in ABCB1 exons 21 or 26 are at increased risk for CsA-related adverse events. Genetic evaluation may help to identify patients at risk and to modulate CsA therapy to optimize graft and patient outcomes.
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http://dx.doi.org/10.1681/ASN.2008080819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689900PMC
June 2009

Steroid withdrawal five days after renal transplantation allows for the prevention of wound-healing complications associated with sirolimus therapy.

Clin Transplant 2009 Jan-Feb;23(1):16-22. Epub 2008 Aug 22.

Division of Nephrology, Department of Surgery, University and Spedali Civili, Brescia, Italy.

Background: Sirolimus (SRL) can increase the risk of wound complications. In this study, we investigated the impact of steroids when added to SRL, in this side effect.

Methods: One hundred and forty-eight patients entered prospective studies comparing early (fifth day) with late (sixth month) steroid withdrawal. All patients were on SRL, added either to Tacrolimus (n = 56) or to cyclosporine (n = 97). At 15th day after transplantation, 68 patients were on steroids (On-St group) and 80 were not (Off-St group). Wound complications considered were as follows: dehiscence, lymphocele, wound leakage, hematoma and seromas. Risk factors under analysis were as follows: body mass index, diabetes, rejection, creatininemia, length of dialysis before transplantation, recipient age, being on steroids at 15th day, SRL levels.

Results: The overall incidence of wound complications was significantly lower in Off-St group than in On-St group: 18.8% vs. 45.6%, respectively (p < 0.0004). In detail, lymphocele: 5.0% vs. 32.3% (p < 0.0001); dehiscence 0% vs. 10.3% (p < 0.009), leakage 6.2% vs. 8.8% (p = NS), seromas 1.4% vs. 7.5% (NS). At multivariate analysis, the addition of steroids to SRL increases 4.2-fold the risk for wound complications.

Conclusions: Early steroid withdrawal is effective in preventing both the incidence and the severity of wound-healing complications because of SRL regime, even when started with a loading dose.
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http://dx.doi.org/10.1111/j.1399-0012.2008.00890.xDOI Listing
April 2009

A randomized exploratory trial of steroid avoidance in renal transplant patients treated with everolimus and low-dose cyclosporine.

Nephrol Dial Transplant 2008 Feb 21;23(2):707-14. Epub 2007 Sep 21.

Nephrology Unit, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, IRCCS, Milan, 20122, Italy.

Background: Everolimus and cyclosporine exhibit synergistic immunosuppressive activity when given in combination. In this randomized trial, we explored whether the use of everolimus associated with low-dose cyclosporine could allow an early avoidance of steroids in de novo renal transplant recipients.

Methods: In this exploratory multicenter trial, 65 out of 133 patients treated with basiliximab (days 0 and 4), everolimus 3 mg/day and cyclosporine were randomized to stop steroids on the seventh post-transplant day (group A), whereas the remaining 68 continued low-dose steroid treatment (group B).

Results: During the follow-up, 30 patients of group A (46%) resumed steroids. According to the intention-to-treat analysis, the 3-year graft survival rate was 95% in group A and 87% in group B (P = ns). There were more biopsy-proven rejections in group A, the difference being of borderline significance (32% vs 18%; P = 0.059). After 3 years, mean creatinine clearance was 52.3 +/- 17.1 ml/min in group A and 52.2 +/- 21.5 ml/min in group B. It was similar in the group A patients who experienced rejection (49.8 +/- 14.7 ml/min) and those who did not (53.6 +/- 18.3 ml/min; P = 0.319). Mean serum cholesterol and triglyceride levels were, respectively, less than 250 mg/dl and less than 200 mg/dl in both groups, without any significant difference. Vascular thrombosis (0 vs 11.7%; P = 0.0043) was more frequent in group B.

Conclusions: Treatment based on everolimus and low-dose cyclosporine allowed excellent renal graft survival and stable graft function at 3 years. An early discontinuation of steroids increased the risk of acute rejection, but was associated with a better graft survival in the long-term. However, it was well tolerated only by 54% of patients.
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http://dx.doi.org/10.1093/ndt/gfm621DOI Listing
February 2008
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