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

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.

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

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).

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

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

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.

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

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.

[Pre-emptive renal transplantation from deceased donor]. / Il trapianto pre-emptive da donatore deceduto.

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.

[Kidney transplant in patients with HIV infection]. / IL trapianto di rene nel paziente con infezione da HIV.

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.

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

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.

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

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.

[Steroidi tra necessità e tossicità].

Steroid minimization has always been one of the most desired goals regarding immunosuppressive therapy after renal transplantation. Following the introduction of cyclosporine different steroid-free protocols became available, but their implementation was limited due to the high risk of acute rejection. In the last few years, the use of a very low dose of prednisone (5 mg/day) has been deemed to guarantee a good balance between steroid toxicity and efficacy. However, high interpatient variability in prednisolone exposure prevented the standard low dose to be as safe as expected in all patients. Therefore, steroid side effects can still be observed in a variable percentage of patients. In this setting, the personalization of steroid dosage might prevent an over exposure to the drug, but this strategy is not available yet. Thus, steroid withdrawal remains the only available strategy to limit side effects. In the last 40 years, we learned that steroid free protocols are associated with a higher risk of acute rejection, but they do not reduce graft survival. Hence, patients at higher risk for acute rejection or recurrence of their primary renal disease are usually excluded from these protocols. Early steroid withdrawal (within 7 days after transplantation) has been widely used and also suggested by American guidelines. However, steroid withdrawal 3-4 months after transplantation has been preferred by many Authors and deemed equally efficient. In addition, early but not late steroid withdrawal should always be associated to induction therapy. Lastly, Tacrolimus plus Mycophenolic Acid has become the most used association in steroid minimization protocols.

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.

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.

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

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.

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

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.

[Kidney transplantation and lymphomas]. / Linfomi nel trapianto renale.

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.

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

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.

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).

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.

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

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.

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

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.

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

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.

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

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/103 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/103 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.