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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.

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., Piero Ruggenenti and co-workers study maintenance immunosuppression in deceased-donor kidney transplantation., Author summary Why was this study done? Based on the results of registration trials showing that mycophenolate mofetil (MMF) prevented acute cellular rejection (ACR) more effectively than azathioprine (AZA) in the setting of a regimen including the oil-based cyclosporine (CsA) formulation, MMF progressively replaced AZA as part of standard maintenance immunosuppressive treatment in most kidney transplant centers worldwide. However, subsequent academic studies with standard doses of a more stable CsA microemulsion formulation found that MMF offered no benefit over AZA on the incidence of ACR or chronic allograft nephropathy (CAN). Whether MMF and AZA are associated with similar long-term graft and patient outcomes also in kidney transplant recipients given antibody induction therapy and maintenance immunosuppression with low-dose CsA without steroids is unknown. What did the researchers do and find? Based on immune studies supporting the concept that combined induction with low-dose thymoglobulin and basiliximab is protolerogenic, in this prospective, randomized trial, we compared the effects of MMF and AZA in 233 recipients of a kidney transplant from a deceased donor who received dual induction and steroid-free maintenance immunosuppression with lower than standard doses of CsA microemulsion. We found that during a median follow-up of nearly 4 years, the cumulative incidence of biopsy-proven CAN (primary endpoint) was similar in patients assigned to MMF and in those allocated to AZA therapy. Biopsy-proven clinical and subclinical acute rejection, patient and graft survival, delayed graft function (DGF), and renal function recovery were also similar between groups, as was the rate of adverse events (AEs), in particular of those that were treatment related. What do these findings mean? In deceased donor kidney transplant recipients, MMF and AZA share a similar long-term risk/benefit profile, even in the context of minimized maintenance immunosuppressive therapy. Considering that MMF is an expensive medication, the preferential use of AZA instead of MMF for maintenance immunosuppression would provide substantial cost saving, without affecting graft outcomes. Considering also the reduced costs for low-dose CsA chronic therapy, dual induction combined with steroid-free minimized maintenance immunosuppression, in addition to reduce treatment-related long-term side effects, might facilitate the access to a kidney transplant in particular in resource-limited settings.

Background and Aims In renal transplant field, the progressive increase both of donor and recipient age has led further challenges in patient management. In this setting, the personalization of immunosuppressive therapies (IT) has been strongly suggested. We have investigated renal histology at 12 months after transplantation to assess whether surveillance biopsies (SB) could be considered an additional tool to further improve management of immunosuppression. Method Monocentric retrospective analysis of SB performed 12 months post-transplant (Tx) between 2009-2018. For each SB were collected recipient and donor demographic data, HLA mismatch, induction and maintenance IT, DGF, cold ischemia time, PRA, DSA and nDSA, previous episodes of acute rejection (AR), serum creatinine (Cr) at the time of SB and 1, 3 and 5 years later, histological score according to Banff classification in force at the time of SB. Statistics included comparison between groups and Cox regression. Results We analyzed 209 SB in as many pts, most of them at low immunological risk (first Tx in 94.3%, PRA SB showed normal histology in only 26.3% of cases. There were no differences in renal function between normal and pathological biopsies (Cr 1.40 vs 1.46 mg/dl, p=NS). Major histologic findings, isolated or associated with each other [Fig. 1], were vascular lesions (VL, 40%), IFTA (33%) and inflammatory lesions (IL, 32%). VL correlated with donor age (OR 1.07, p All types of lesions were found to be related with previous AR (VL with OR 3.08, p= 0.003, IFTA with OR 2.15, p=0.04, IL with OR 4.71, p2: 50.5% vs 32%, p=0.045). Indipendent histological variables that predicted a worsening of renal function were glomerulitis/capillaritis (HR 6.996, P Conclusion Our data confirm that stable renal function does not exclude the presence of subclinical histological lesions, even in patients at low immunological risk. Abnormal findings are present in 73.7% of our SB. Glomerulitis/capillaritis and VL can affected renal function, so their recognition should be considered for immunosuppression optimization. Patients with previous AR are at higher risk for all types of histologic lesions and may require a closer monitoring.

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. 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. 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. 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.

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. 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). 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

Background: Although optimization of immunosuppressive schemes in renal transplantation have minimized acute posttransplant complications, long-term outcomes are still not optimal and most of the chronic graft damage is drug-related. Therefore, to define the best long-term maintenance immunosuppressive regimen is of major importance in renal transplantation. To assess this objective, we undertook a large, multicenter cohort study in Italy. Methods: We retrospectively analyzed data of 5635 patients (enrolled from 1983 to 2012) and we assessed the impact of 3 major immunosuppressive regimens (calcineurin inhibitors+antimetabolites+corticosteroids [CNI+ANT+CS] vs CNI+mammalian target-of-rapamycin (mTOR) inhibitors+CS [CNI+mTOR-I+CS] vs CNI+CS) on long-term clinical outcomes by employing several statistical algorithms. Results: The overall difference in the incidence of outcome over time was not statistically different within the first 5 years of follow-up (P =.13); however, it became significant at 10 years and 20 years (P

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.

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. 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. 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. 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.

This multicenter, randomized, prospective, controlled trial (EVIDENCE study) aimed to determine short-term effects of early steroid withdrawal in renal transplant patients initially treated with everolimus, low-dose cyclosporine (CsA), and steroids. Patients were randomized to standard triple therapy with CsA, everolimus twice daily and steroids (group A), steroid-free immunosuppression (group B), or triple therapy once daily (group C). However, since patient enrollment was slower than expected, group C randomization was prematurely discontinued. The primary end point was treatment failure rate (composite end point of death, graft loss, biopsy-proven acute rejection, and loss to follow-up) between randomization and month 12. Patients evaluable for the primary end point included 139 randomized patients. According to intention-to-treat analysis, 2.8% of patients in group A and 14.7% in group B experienced treatment failure (95% upper confidence limit 19.7%). As this was higher than the predefined noninferiority limit of 10%, noninferiority could not be proved. No conclusive statements can be made on noninferiority of the steroid withdrawal regimen vs the standard regimen in these patients. Additional studies with longer follow-up are required to determine the efficacy of steroid-free immunosuppression in renal transplant recipients receiving everolimus.

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 is5.8 %. 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.

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.

Summary 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

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.

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

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.

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

The aim of this retrospective study was to assess the impact of steroid therapy on cardiovascular disease (CVD) and patient mortality, in 486 on-CsA renal transplant recipients, with a follow-up of 9.5 +/- 4.3 yr. Two hundred and one patients had their steroids permanently withdrawn at sixth month after transplantation (G1); 285 patients did not (G2) as they were unable (acute rejection after suspension) or unsuitable (because of clinical criteria or immunosuppressive protocols). The CVD considered were coronary artery disease diagnosed by angiography and myocardial infarction. G1 and G2 patients were well-matched regarding CVD risk factors, except for age (G1: 44 +/- 14 yr; G2: 40 +/- 12 yr; p < 0.003), incidence of male (G1: 62%; G2: 72%, p < 0.02) incidence of acute rejection (G1: 39%; G2: 83%, p < 0.0001). Both CVD and deaths occurring during the first year of transplantation were excluded from the analysis. At 20 yr, the cumulative probability of developing a CVD, was 3.8% in G1; 23.8% in G2 (p < 0.0005). Patient survival rate was 95% in G1; 62% in G2 (p < 0.003). Mortality caused by CVD was higher in G2 (4.2% vs. 0.5%; p < 0.03). The Cox analysis identified in steroid therapy the main independent risk factors for both CVD (hazard ratio 9.56 p < 0.0001) and patient mortality (hazard ratio 5.99, p < 0.0001). At 10th and 15th year after transplantation, the mean-daily dose of steroids was 4.2 mg. In the long-term, steroid therapy, even in low-doses, increases significantly both the rate of CVD and patient mortality. This retrospective study suggests that steroid-free regime should always be recommended for the prevention of post-transplant CVD. This relevant statement should be followed by a long-term prospective study.

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Background.Solidorgantransplantedpatientshaveathree-tofourfoldhigherlifetimeriskofdevelopingacancerthan the general population. However, the incidence of a second primary cancer in transplanted patients has never been studied, despite the fact that the presence of regular follow-ups and the increased survival of these patients make them a very attractive model. Methods. We investigated the incidence of a second primary cancer (SPC) in 7,636 patients who underwent a kidney, liver, lung or heart transplant between 1970 and 2004, and were followed-up for 51,819 person-years. Results. During the follow-up, 499 subjects developed a first cancer (annual incidence: 98.610,000 PY), and 22 of them developed a SPC (annual incidence: 3.910,000 PY). The annual incidence of a SPC in the transplanted patients who developed a first cancer was 107.810,000 PY, giving a standardized incidence ratio of 1.1 (95% CI: 0.83–1.41). Conclusions. This result shows that the incidence of the SPC was the same as the incidence of a first cancer. Our study does not indicate an increased risk of SPC in transplanted subjects who already suffered a first malignancy.

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.

Delayed graft function (DGF) occurs in approximately 30% of renal transplant patients, and significantly increases risk of long-term graft loss. This article reviews the potential for use of interleukin-2 receptor (IL-2R) antagonists to reduce the burden of DGF. IL-2R antagonists decrease incidence of acute rejection without increasing risk of cytomegalovirus infection or malignancy, and show equivalent efficacy to lymphocyte-depleting antibody agents in standard risk patients with immediate graft function. The nephrotoxicity associated with calcineurin inhibitors (CNIs) has led to use of delayed or low-dose CNI regimens with induction therapy in patients with DGF. In this setting, use of an IL-2R antagonist with mycophenolate mofetil and steroids with delayed cyclosporine appears to be associated with a low incidence of biopsy-proven rejection and comparable renal function to patients with immediate function. Additionally, there is intriguing evidence to suggests that IL-2R antagonists may reduce risk of DGF occurring. A number of large-scale and smaller studies have reported a trend to reduced incidence of DGF or improved early renal function using IL-2R antagonists compared with placebo, although data are not entirely consistent. In conclusion, the ability of IL-2R antagonists to reduce acute rejection with no additional safety concerns makes them an attractive option for patients with DGF.

BACKGROUND Viaspan (University of Wisconsin [UW]) solution is the gold standard for abdominal organ preservation. Celsior (CEL) is an extracellular-type, low-potassium, low-viscosity solution, initially used for heart and lung preservation. We have performed a prospective multicenter study to compare the role of these cold-storage solutions on kidney and liver recovery after transplantation. PATIENTS AND METHODS From March 15, 2000 to December 31, 2001, 441 (172 CEL and 269 UW) renal transplants (RT) and 175 (79 CEL and 96 UW) liver transplants (LT) were included in the study. RESULTS Perfusate volume used was significantly lower in the UW group, being 4,732 +/- 796 mL versus 5,826 + 834 mL in the CEL group (P < 0.001). In LT, median total bilirubin serum levels were significantly higher at 5 and 7 posttransplant days in the UW group (90.6 and 92.3 micromol/L, respectively) as compared with CEL (51.3 and 63.4 micromol/L, respectively). After LT, primary nonfunction (PNF) rates in the CEL and UW groups were 3.8% and 4.2% (P = NS) respectively, with 1-year graft and patient survival being 83.3% versus 85.4% (P = NS) and 89.9% versus 90.6% (P = NS). After RT, delayed graft function (DGF) rates were 23.2% and 22.7% (P = NS), respectively; PNF rates were 1.9% and 1.7% (P = NS) respectively, with 1-year graft and patient survival being 92.3% versus 94.2% (P = NS) and 99.4% versus 97.7% (P = NS). CONCLUSIONS CEL solution was shown to be as effective as UW in both liver and kidney preservation. In LT patients, biliary function recovery is significantly better in the CEL group. CEL solution represents an efficacious option in multiorgan harvesting.

BACKGROUND Patients undergoing kidney transplantation demonstrate a higher risk of developing cancer as the result of immunosuppressive treatment and concurrent infections. METHODS The incidence of cancer in a cohort of patients who underwent kidney transplantation between 1990 and 2000, and who survived the acute phase (10 days), was analyzed as part of the North Italy Transplant program. RESULTS A total of 3,521 patients underwent transplantation during a 10-year period in 10 of 13 participating centers; the length of follow-up after kidney transplant was 67.7+/-36.0 months. During the follow-up, 172 patients developed cancer (39 with Kaposi sarcoma, 38 with lymphoproliferative diseases, and 95 with carcinomas [17 kidney, 11 non-basal cell carcinoma of the skin, 10 colorectal, 8 breast, 7 gastric, 7 lung, 6 bladder, and 3 mesothelioma]). The average time to cancer development after transplant was 40.1+/-33.4 months (range 0-134 months). Twenty-four patients developed cancer within 6 months from the transplant (10 with carcinomas, 7 with Kaposi sarcoma, and 7 with lymphoproliferative diseases). Three patients demonstrated a second primary cancer. The average cancer incidence was 4.9%. The incidence of cancer was 0.01 per year. Independent determinants of cancer development were age, gender, and immunosuppressive protocol including induction. Ten-year mortality was significantly higher in patients with cancer (33.1%) than among patients without cancer (5.3%). The relative risk of death in subjects with cancer was 5.5 (confidence interval 4.1-7.4). CONCLUSIONS These preliminary data underline the importance of long-term surveillance of transplant recipients, choice of immunosuppressive treatment, and careful donor selection.

Background: Posttransplant recurrence of focal segmental glomerulosclerosis (FSGS) occurs in a relevant proportion of FSGS patients and represents an important clinical emergency. It is taken as a proof of the existence of circulating permeability plasma factor(s) that are also putative effectors of original proteinuria in these patients. Familial forms of FSGS do not recur, but the discovery of numerous patients with sporadic FSGS and mutations of podocin (NPHS2, that is actually an inherited disease) who received a renal graft require a re-evaluation of the problem. Methods: To evaluate the incidence of posttransplant recurrence of FSGS in patients with NPHS2, the authors screened for podocin mutations in 53 patients with the clinical and pathologic stigmata of FSGS who had renal failure and who had undergone renal transplantation. Results. Twelve children were found to carry a homozygous (n9) or a heterozygous (n4) mutation of podocin and were classified, according to current criteria, as patients with inherited FSGS. In 5 patients of this group (38%), proteinuria recurred after renal graft and in 2, renal biopsy results showed recurrence of FSGS. Prerecurrence serum of 3 patients of this cohort was tested for antipodocin antibodies with indirect immuno-Western utilizing human podocyte extracts and were found negative. The rate of FSGS recurrence was comparable in non-NPHS2-FSGS children (12 of 27) and adults (3 of 13). Also clinical outcome of recurrence and response to plasmapheresis and immunosuppressors were comparable, suggesting a common mechanism. Conclusion: These data show a high rate of FSGS recurrence in patients with NPHS2 mutations that is comparable with idiopathic FSGS and describe the successful therapeutic approach. Recurrence of an apparently inherited disease should stimulate a critical review of the mechanisms of recurrence and of original proteinuria in these cases.

Summary 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.

422 Background: The etiology of renal cell cancer (RCC) is poorly understood, and data from immunosuppressed population may help to highlights risk factors unknown in the immune competent population. To assess incidence and risk factors for renal cell cancer (RCC) after kidney and liver transplant (KT and LT, respectively), we carried out a cohort investigation in 24 Italian transplant centers. Methods: This study is part of an ongoing cohort investigation conducted in 24 transplant centers in all of Italy. Two cohorts have been implemented, including 7,217 KT recipients (64.2% men) and 2,770 LT recipients (74.7% men) transplanted between 1997 and 2009—and followed-up until 2010. Person years (PY) at risk of cancer were computed from 30 days after transplant to cancer diagnosis, death, return to dialysis (for KT) or to study closure. The number of observed cancers was compared to that expected in the general population through standardized incidence ratios (SIR) and 95% confidence intervals (CI). To identify risk factors, incidence rate ratios (IRR) were computed through Poisson regression. Results: Overall, 581 cancers were diagnosed during 61,817 PYs of follow-up, with Kaposi’s sarcoma, non-Hodgkin lymphoma, lung, RCC, and prostate as the most common types. Thirty-eight cases of RCC were diagnosed (36 in KT and 2 in LT). As compared to the general population, the risk of RCC was 4.9-fold significantly higher in KT recipients than expected (95% CI: 3.4-6.8). The increased risk was restricted to the native kidney (31 native kidney OR=4.2, 95% CI:2.9-6.0), and no risk elevation was found in LT recipients (SIR=0.5 95% CI: 0.1-1.9). Use of mTOR inhibitors seemed to exert a 40% reduced risk (IRR=0.6, 95% CI: 0.2–1.4) of RCC, but the difference was not statistically significant. Conclusions: Our study findings confirmed, in Italy, the increased risks for RCC following KT, and they also suggested a possible protective effect of mTORi. The magnitude of the excess risk documented in this cohort study was higher than reported for potential risk factors described in immune competent people—or in people under dialysis—thus suggesting a role for the immune system in the etiology of RCC.

Background. Many attempts have been made to withdraw steroid therapy in renal transplant patients in order to avoid its many side effects. Results have been, so far, controversial. In this randomized prospective study, we compare the efficacy of azathioprine adjuncts to cyclosporine at the time of steroid withdrawal, 6 months after transplantation, versus Cyclosporine monotherapy, in preventing acute rejection. Methods. One hundred and sixteen kidney transplant patients with good and stable renal function (creatininemia

The benefits of kidney transplantation over dialysis on patient survival have been demonstrated without considering the outcomes of patients with graft loss. To determine whether mortality after graft failure reduced the transplantation advantage in patient survival, we retrospectively reviewed the outcomes of 918 first-deceased renal transplant recipients from May 1979 to August 2005. Patient survivals were 88% and 72% at 10 and 20 years; cancer (26%) and cardiovascular disease (25%) were the major causes of death. Graft survivals were 72% and 50% at 10 and 20 years; chronic rejection was the major cause of graft loss (50%). Patient outcomes after return to dialysis were reviewed in 224 of 240 patients. The survivals were 97%, 83%, and 70% at 1, 5, and 10 years, respectively; cardio-cerebrovascular disease (56%), infections (9%), cachexia (9%), and cancer (8%) were the major causes of death. Mortality correlated with patient age at transplantation (P.001). Re-listed patients (96 of 224) were younger (32+/-10 vs 43+/-11 years; P.001), had a shorter dialysis period pretransplant (3.2+/-3.1 vs 4.3+/-3.9 years; P.03), and a better survival at 10 years (98% vs 56%; P.001). Ten-year mortality for patients who returned to dialysis was 20% higher than for patients with a functioning graft (P.001). The reduction in overall patient survival was 2.2% at 10 years (P=NS), 5% at 15 years (P=NS), and 14% at 20 years (P.05). The same results have been demonstrated for patients50 years at transplantation. In conclusion, the mortality rate after return to dialysis did not influence the long-term benefits of kidney transplantation.

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.

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.

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.

The HAART reduces the risk of HIV-related renal disease but the incidence of end-stage renal disease (ESRD). Therefore, efficacy and safety of renal transplantation (Tx) is an important resource in the HIV-infected population. We reported the results of kidney Tx in HIV+patients from deceased donors from June 2007 to March 2012 at our institution. The patients had to have CD4+T-cell counts≥200/mm3 and undetectable plasma HIV-RNA if on HAART. The induction immunosuppressive therapy consisted of metilprednisolone and basilixmab; tacrolimus and/or mycofenolic acid were used for maintenance therapy. The therapeutic drug monitoring (TDM) has been performed for the adjusting of both their doses [1]. A total of 14 patients underwent kidney Tx. They were on dialysis (haemodialysis=13, 92.9%; peritoneal=1, 7.1%) for 5±3.1 years and they were included on the Tx waiting list for 10±8 months. The baseline characteristics are showed in Table 1. Donor at baseline Mean age38±12.5 yearsDeceased14/14 (100%)High/unclassified infectious risk9 (64.29%)RecipientsMean age44 yearsPatients with previous AIDS-defining events3 (21.4%)Median follow-up months (IQR range)42.75 (8.5–55.2)Patient survival at last follow-up14/14 (100%)Graft survival at last follow-up13/14 (92.9%)Mean time of acute rejection since Tx28±20 daysPatients not treated with steroid at last follow-up6 (43%)Plasma creatinine at last follow-up1.87±1.93 mg/dlSevere infectious complications (CMV pneumonia, malaria, Kaposi sarcoma)3 (21.4%)Diabetes3 (21.4%)CMV infection without localization3 (21.4%)Bacterial pneumonia4 (28.6%)Reactivation of HIV RNA3 (21.4%) At the last available point of follow-up (median=42.8 months, IQR=8.5–55.2), 8 out of the 13 patients (61.6%) without steroid had at least one acute rejection episode, but only 1 patient lost the graft, after 43 months (7.1%) due to chronic rejection associated with infectious and vascular complications. After Tx the median CD4+T-cell count increased from 382.5 (IQR range=233–415) to 434 (IQR range=282–605) cells/mm3 (p=0.055). In Figure 1 are reported the CD4+trends of 9 patients with a follow-up of at least 6 months. HIV infection was well controlled, with only 2 (14.3%) cases of virological failure which were promptly resolved after HAART regimen modification. Table 1 shows the observed infectious complications. The skin Kaposi sarcoma has been resolved by switching to immunosuppressive therapy with sirolimus [2]. Kidney Tx appears to be safe in HIV-positive patients undergoing HAART. The viro-immunological parameters remained well controlled with no increases in infectious complications or neoplasm and a satisfactory control of HIV infection. However, the high rejection rate is a serious concern and suggests to consider a steroid-containing immunosuppressive regimen also in these patients.

Limited data exist about cancer prognosis and the development of second cancers in renal transplant recipients. In a retrospective cohort study on 3537 patients incidence rates of the first and, if any, of a second cancer, and standardized incidence ratios [SIR (95% CI)] were computed. Two hundred and sixty-three (7.5%) patients developed a NMSC, and 253 (7.2%) another type of cancer after a median follow-up of 6.5 and 9.0 years, respectively. A statistically significant excess risk, if compared to an age- and sex-matched reference general population, was observed for Kaposi sarcoma and NMSC, followed by non-Hodgkin lymphoma and carcinoma of cervix uteri; a small number of unusual cancers such as tumors of the salivary glands, small intestine and thyroid also were detected at a level worthy of additional scrutiny. Ten-year survival rate of all noncutaneous cancers was 71.3%, with lower rates for lung carcinoma and non-Hodgkin lymphoma (0% and 41.7%, respectively). Patients with NMSC had an increased risk of developing a second NMSC [SIR 8.3 (7.0–10.0)], and patients with a primary noncutaneous cancer had increased risk of developing a second noncutaneous cancer [SIR 1.8 (1.2–2.8)], if compared to the whole cohort. Our study underscore that the high risk of primary and second cancer in renal transplant recipients, including unusual cancers.

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.

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.

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.

We report the occurrence of human herpesvirus (HHV)-8 primary infection in an adult male kidney recipient. Four months after transplantation, the patient developed visceral Kaposi sarcoma, and 1 month later he presented with progressive and severe peripheral cytopenia, in the presence of a normocellular or hypercellular bone marrow (BM) with hemophagocytosis. HHV-8 was the sole pathogen detected by polymerase chain reaction either in the serum or in the BM. HHV-8 latent nuclear antigen was detected in immature progenitor cells from the BM. Immunosuppressive therapy was reduced, and the patient was treated with foscarnet for 2 weeks, leading to a dramatic normalization of blood cell counts, concomitantly with the disappearance of HHV-8 viremia. At the end of antiviral therapy, the patient received chemotherapy, and Kaposi sarcoma regressed in 2 months. Severe peripheral cytopenia may be a posttransplant complication after HHV-8 infection, for which treatment with foscarnet seems appropriate.

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.

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.

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 (P0.01), 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 (P0.01 vs. healthy controls; P0.05 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.