Efficacy of Prolonged- and Immediate-release Tacrolimus in Kidney Transplantation: A Pooled Analysis of Two Large, Randomized, Controlled Trials.

BACKGROUND: Two large, prospective studies (12-03; OSAKA) compared the efficacy and tolerability of prolonged-release versus immediate-release tacrolimus in kidney transplant patients also receiving mycophenolate mofetil and low-dose corticosteroids (without induction therapy). METHODS: Data were combined into one database to compare results over 24 weeks using 3 alternative endpoints: biopsy-confirmed acute rejection (BCAR); the Food and Drug Administration composite endpoint (graft loss, BCAR, and loss to follow-up), and the European Medicines Agency composite endpoint (graft loss, BCAR, and graft dysfunction). The 95% confidence intervals were calculated (10% noninferiority margin). RESULTS: Overall, 633 patients received prolonged-release tacrolimus (12-03, n = 331; OSAKA, n = 302) and 645 received immediate-release tacrolimus (n = 336; n = 309). Baseline characteristics were comparable. Proportionately more patients receiving prolonged-release tacrolimus had trough levels of 5-15 ng/mL on day 1 (60.8%) and 2 (56.6%) versus immediate-release tacrolimus (42.5% and 43.9%, respectively, both P < .001). Efficacy of prolonged-release and immediate-release tacrolimus were similar as assessed by BCAR (13.9% vs 14.1%, respectively), European Medicines Agency composite endpoint (40.3% vs 38.3%) and US Food and Drug Administration composite endpoint (21.5% vs 19.8%). CONCLUSIONS: Novel efficacy endpoints as required by the European Medicines Agency and US Food and Drug Administration demonstrate noninferiority of prolonged-release versus immediate-release tacrolimus. Significantly more patients treated with prolonged-release tacrolimus versus immediate-release tacrolimus achieved trough levels of 5 to 15 ng/mL early after transplantation. ClinicalTrials.govNCT00189839; NCT00717470.

Coronary Microvascular Dysfunction Predicts Long-Term Outcome in Simultaneous Pancreas-Kidney Transplantation.

BACKGROUND: Patients with diabetes are at increased cardiovascular risk. Simultaneous pancreas-kidney transplantation (SPKT) is the treatment of choice in patients with type 1 diabetes mellitus and diabetic nephropathy. We assessed coronary flow reserve (CFR) by transthoracic echocardiography as a marker of major adverse cardiac events (MACE) in SPKT patients. METHODS: We studied 48 consecutive SPKT patients (28 male, age at SPKT 54 ± 8 years). Time from transplantation was 8.5 ± 3 years. Follow-up was 4.6 ± 1.8 years. Coronary flow velocity in the left anterior descending coronary artery was detected by Doppler echocardiography at rest and during adenosine infusion. CFR was the ratio of hyperemic diastolic flow velocity (DFV) to resting DFV. A CFR ≤ 2 was considered abnormal and a sign of coronary microvascular dysfunction. MACE were cardiac death, myocardial infarction, and heart failure. RESULTS: CFR was 2.55 ± 0.8. CFR was ≤2 in 13 (27%) patients. CFR was lower in SPKT patients with MACE (2.1 ± 0.7 vs 2.7 ± 0.8, P = .03) and patients with MACE had a higher incidence of CFR ≤ 2 (P = .03). Time from transplantation was shorter in patients with MACE (P < .0001). Patients with CFR ≤ 2 had a lower MACE-free survival (P = .03). CFR ≤ 2 predicted the risk of MACE (P = .007) independently from coronary artery disease and metabolic control. However, this predicted role is lost when adjusted for the time from transplantation, which plays a protective role (P = .001). CONCLUSIONS: In SPKT, CFR ≤ 2 may be a reliable marker for MACE, independent of coronary artery disease diagnosis. However, this role seems to be reduced over time. This finding suggests a gradual reduction of cardiovascular risk in SPKT patients.

A randomized trial of everolimus and low-dose cyclosporine in renal transplantation: with or without steroids?

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.

Everolimus associated with low-dose calcineurin inhibitors, an option in kidney transplant recipients of very old donors.

BACKGROUND: Despite potential renal and cardiovascular advantages of proliferation signal inhibitors, their de novo use in kidney transplantation (KT) from elderly donors (ED) is poorly documented. We retrospectively analyzed two consecutive cohorts of KT from ED: low-dose extended-release tacrolimus (Tac) was used from 2010 to 2012 and cyclosporine (Csa) was used from 2008 to 2010. METHODS: Associated maintenance drugs were everolimus (Eve) and steroids. Outcomes were compared between groups over a 12-month follow-up. Fifty-six patients were analyzed in the Tac-Eve group and 54 in the Csa-Eve group. RESULTS: There were no significant differences at baseline with the exception of older donors age in the Tac-Eve cohort (74 vs 71 years, P = .002). There were no deaths, primary non functions, or graft losses. Eight (14%) Tac-Eve and 15 (28%) Csa-Eve patients had delayed graft function (P = .10). Renal function was fairly stable over time (median cGFR 36-49 mL/min and 51-55 mL/min in single kidney transplantation and dual kidney transplantation patients, respectively) with no significant differences between groups at month 12. Surgical complications were infrequent and observed mostly in dual kidney transplantation recipients. Thirty-nine (70%) and 30 (56%) patients remained under their initial Tac-Eve or Csa-Eve regimen, respectively. CONCLUSIONS: Induction with Thymoglobuline and maintenance with Eve and low-dose extended-release Tac and steroids is safe and effective in renal transplant from ED.

Desensitization with plasmapheresis and anti-Cd20 for ABO incompatible kidney transplantation from living donor: experience of a single center in Italy.

OBJECTIVE: Blood group incompatibility in kidney transplants from a living donor can be successfully overcome by using various desensitization protocols: intravenous immunoglobulin, plasmapheresis (PP), immunoadsorption, and double filtration PP. PATIENTS AND METHODS: From July 2010 to October 2013, we performed 10 ABO incompatible kidney transplantation (KT) procedures from a living donor. The desensitization protocol was based on rituximab and PP+cytomegalovirus immune globulin. All patients received induction with basiliximab, except 1 case treated with Thymoglobuline® (ATG) for the simultaneous presence of donor-specific antibody. Tacrolimus and mycophenolate mofetil were initiated at the time of desensitization and continued after the transplant. RESULTS: After a mean follow-up of 11.6±10.4 months, all patients are alive with a functioning graft. The mean serum creatinine concentration at 1 month, 3 months, 6 months, and 1 year was 1.48±0.29, 1.47±0.18, 1.47±0.27, and 1.5±0.27 mg/dl. Three episodes of acute cellular rejection occurred in 2 patients. There was only 1 case of BK virus infection, treated with reduction of immunosuppressive therapy. The protocol biopsy specimens at 1, 3, and 6 months were C4d positive in the absence of acute rejection. CONCLUSIONS: Desensitization with rituximab, PP, and anti-cytomegalovirus immune globulin allowed us to perform transplants from living donors to ABO incompatible recipients with excellent results and reduced costs.

Physical activity in solid organ transplant recipients: organizational aspects and preliminary results of the Italian project.

Most of the difficulties when trying to realize the proposal to prescribe physical activity for transplantation patients come from patient attitudes and cultural beliefs that ignore the benefits of exercise, but there also are organizational aspects arising from the difficulties that these patients face in accessing supervised exercise facilities. To address these difficulties, the Italian study project "Transplant … and Now Sport" was developed based on a model of cooperation among transplantation specialists, sports physicians, and exercise specialists organized as a team combining their specific skills to effectively actuate the physical exercise programs. This preliminary report is based on 26 patients (16 male, 10 female; 47.8±10.0 years old; 21 kidney and 5 liver transplantations; time from transplantation 2.3±1.4 years) who performed prescribed and supervised exercises consisting of 3 sessions per week of aerobic and strengthening exercises for 1 year. Preliminary results show a significant decrease in body mass index (t=1.966; P<.05) and a significant increase in peak aerobic power (t=4.535; P<.01) and maximum workload (t=4.665; P<.01) on the incremental cycling test. Also maximum strength of knee extensors (t=2.933; P<.05) and elbow flexors (t=2.450; P<.05) and countermovement jump performance (t=2.303; P<.05) significantly increased. Creatinine and proteinuria tended to decrease, but the differences were not significant. In health-related quality of life assessed by the SF-36 questionnaire, the Bodily Pain, General Health, Vitality, Social Functioning, and Role Emotional scale scores showed a significant improvement (P<.05). Preliminary results of the study protocol "Transplant…and Now Sport" show the positive effects of the model based on cooperation among transplantation centers, sports medicine centers, and gyms in the administration of a supervised exercise prescription. These data should be considered a contribution to developing and promoting further detailed exercise protocols and to fostering improved posttransplantation health and survival, helping to ensure that physical activity becomes a safe routine medical treatment plan of patient management.

Alefacept combined with tacrolimus, mycophenolate mofetil and steroids in de novo kidney transplantation: a randomized controlled trial.

Memory T cells play a central role in mediating allograft rejection and are a rational target for immunosuppressive therapy. Alefacept is a recombinant LFA3/IgG1 fusion protein that reduces the number of memory T cells in both psoriatic lesions and the peripheral circulation of psoriasis patients. This study evaluated the efficacy and safety of alefacept compared with placebo when combined with tacrolimus, mycophenolate mofetil and corticosteroids in de novo renal transplant recipients. Between December 2007 and March 2009 patients were randomized in a double-blind fashion to receive alefacept (n = 105) or placebo (n = 107) for 3 months and were then followed for a further 3 months. The primary efficacy endpoint was the incidence of biopsy-confirmed acute T cell mediated rejection (Banff grade ≥ 1) through Month 6. Memory T cell counts were significantly reduced in the alefacept group from Week 3 to study end compared with placebo. However, there was no significant difference between the alefacept and placebo groups for the primary efficacy endpoint (alefacept, 11.0% vs. placebo, 7.0%, p = 0.3). Patient and graft survival as well as renal function was similar between treatment groups. Safety and tolerability were generally similar between the treatment arms. Malignancy was higher in the alefacept treatment arm.

Organ donors with small renal cancer: report of 3 cases.

Transmission of donor malignancies has been reported since the early days of clinical transplantation. Up to 1995, the Transplant Tumor Registry created by Penn included 155 cadaver and 29 living donor affected by tumors. The most common, excluding brain tumor, was renal cell carcinoma (RCC). RCC represents 2% of adult cancers, an incidence that increases with advancing age. The expansion of the criteria that define a suitable organ donor has as a consequence included donors that are older than in the past. Small RCCs are found during renal recovery from a cadaveric donor in ∼1% of cases. The use of such donors is a matter of debate; it has been suggested that donor kidneys with small RCC Fuhrman grade I/II may be transplanted after appropriate surgical excision. We report our experience with 3 donors with clear cell RCC: 2 contralateral kidneys were transplanted in 2 recipient and a third recipient received an affected kidney after a wide tumor excision. All of the patients we alive and free from recurrence at 14-48 months (mean 35 mo). In the third case, immunosuppression was achieved with a mammalian target of rapamycin inhibitor, which is currently used not only as an immunosuppressant to prevent rejection, but also as treatment for renal cancer. Our data confirmed that donors with small renal tumors may be used, because the risk of tumor recurrence is small and the benefits of a kidney transplantation are great.

Glomerular c4d immunoreactivity in acute rejection biopsies of renal transplant patients.

In renal transplant patients, glomerulitis may be present in all types of acute rejection, often accompanied by diffuse C4d staining of peritubular capillaries: C4d3 positivity in more than 50% of peritubular capillaries. It may progress to chronic transplant glomerulopathy, characterized by capillary basement membrane multilayering, proteinuria, and progressive loss of renal function. While C4d3 is a recognized marker of an antibody-mediated reaction, the significance of glomerular C4d (GlC4d) staining is unknown. The aim of this study was to evaluate GlC4d immunoreactivity and its correlation with C4d3 in acute rejection biopsies. Paraffin-embedded acute rejection biopsies from 90 renal transplant patients were evaluated according to the Banff classification. Biopsies showing C4d-positive endothelial cells in more than 50% of glomeruli were considered GlC4d-positive. C4d3-positive staining prevalence was 23%. GlC4d-positive staining showed an 89% concordance rate (r = 0.81, P < .0001; Cohen's k = 0.80, P < .0001). GlC4d detection sensitivity was 0.80 and specificity 0.97. C4d3 and GlC4d immunoreactivity was significantly associated with glomerulitis (P < .006 and P < .03, respectively) and with proteinuria at the time of biopsy (P < .03 and P < .01, respectively). Interestingly, GlC4d positivity correlated better than C4d3 positivity with the presence of posttransplant circulating anti-human leukocyte antigen alloantibodies (P < .04 and P = .7, respectively). Patients with C4d3- or GlC4d-positive acute rejections underwent graft loss due to interstitial fibrosis and tubular atrophy more frequently than those with C4d0- or GlC4d-negative rejections (P < .0001 and P < .005, respectively), whereas no differences were observed in graft loss due to death. In conclusion, C4d3 and GlC4d stains showed a high correlation rate. Compared with C4d3, GlC4d staining demonstrated good sensitivity and excellent specificity. Our results suggested that GlC4d staining may indicate glomerular endothelial damage and be of prognostic value.

Nonadherent behaviors after solid organ transplantation.

BACKGROUND AND AIM: The effectiveness of any treatment depends not only on the choice of therapy, but also, to a large extent, on the patient's active cooperation. Adherence to medical prescriptions and particularly to immunosuppressive therapy is crucial to prevent medical complications that negatively influence graft function and patient survival after organ transplantation. The aim of this study was to assess, among patients who underwent solid organ transplantation, nonadherent behaviors (NAB) to immunosuppressive therapy, to correct lifestyle, and to general medical prescriptions. MATERIALS AND METHODS: We evaluated patients who underwent solid organ transplantation from March 2008 to June 2009. All participants completed an anonymous 15-item questionnaire to assess NAB. RESULTS: We enrolled 218 organ transplant patients: 103 liver, 50 kidney, 52 heart, and 13 lung. There were 152 men and the overall age was 52.2 ± 0.8 years (mean ± standard deviation [SD]) time from transplantation, 83.6 ± 4.5 months (mean ± SD). Overall 37.9%, 38.8%, and 12.8% of patients reported nonadherence to immunosuppressive therapy, to correct lifestyle, and to general medical prescriptions, respectively. Considering nonadherence to immunosuppressive therapy and to general prescriptions, the percentage of kidney transplant patients who referred NAB was significantly lower compared with other organ transplant patients (P = .008 and P = .04, respectively). Nonadherent patients to immunosuppressive therapy and to general medical prescriptions displayed a longer interval from transplantation compared with adherent patients (P = .02 and P = .03, respectively). Among patients nonadherent to the correct lifestyle, the rates of men and of patients with disability pension were significantly higher compared to adherent patients (P = .001 and P = .002, respectively). CONCLUSIONS: Poor adherence to medical prescriptions and to adequate lifestyle is common among organ transplant patients, especially those who have undergone liver transplantation. Psychoeducational interventions for transplanted patients and their families are needed to improve adherence.

Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study.

This multicenter, 1:1-randomized, parallel-group, noninferiority study compared the efficacy and safety of twice-daily tacrolimus (Tacrolimus BID; Prograf) and once-daily tacrolimus prolonged release (Tacrolimus QD; Advagraf), combined with steroids and low-dose mycophenolate mofetil without antibody induction, in 667 de novo kidney transplant recipients. A double-blind, double-dummy 24-week period was followed by an open extension of up to 12 months posttransplant. Biopsy-proven acute rejection rate at 24 weeks (primary endpoint, per-protocol analysis) was 15.8% for Tacrolimus BID versus 20.4% for Tacrolimus QD (p = 0.182; treatment difference 4.5%, 95% confidence interval-1.8%, 10.9%, just outside the prespecified 10% noninferiority margin). Kaplan-Meier 12-month patient and graft survival rates were 97.5% and 92.8% for Tacrolimus BID and 96.9% and 91.5% for QD. Both treatment groups showed equally well-maintained renal function at 12 months (mean creatinine clearance approximately 67 mL/min) and similar adverse event profiles. Overall results obtained with either Tacrolimus QD or BID, without antibody induction, were good, supporting use of the once-daily formulation as an effective alternative to the established twice-daily formulation.

C4d-positive renal allograft rejection biopsies in cyclosporine-treated patients: single-center incidence and outcome.

T cell-mediated acute rejection (ATCMR) in renal transplant patients can have an antibody-mediated component. The aim of this study was to evaluate the incidence of renal biopsies showing ATCMR with C4d immunoreactivity and the correlation between C4d-positive ATCMRs and graft outcomes. We studied 216 renal transplant patients receiving cyclosporine-based immunosuppression (mean follow-up = 203.5 +/- 42.5 months). Of these, 79 experienced biopsy-proven ATCMR (group 1), whereas 137 did not show clinical or laboratory evidence of ATCMR (group 2). Mean serum creatinine levels were evaluated at 6 months, as well as 2 and 5 years after transplantation. The number of graft losses due to interstitial fibrosis and tubular atrophy (IF/TA) was greater in group 1 than in group 2 (P < .001 and P < .02, respectively), while graft survival was lower (P < .03). Staining with anti-C4d antibody was performed in 61/77 type I ATCMR biopsies: seven cases showed diffuse C4d positivity with CD68(+) monocytes in peritubular capillaries observed in all cases. Three cases showed focal C4d positivity. Two ATCMRs were steroid, resistant. Graft loss due to IF/TA occurred in 4/7 patients (57.1%) who had previously experienced ATCMRs with diffuse C4d positivity; whereas it occurred in 5/51 patients (9.8%) with previous C4d negative ATCMRs (P < .001). Patients with focal C4d positivity did not undergo graft loss due to IF/TA. In conclusion, at our center the diffuse C4d positivity that occurred in 11.4% of type I ATCMRs was associated with a poor prognosis.

Technical aspects of unilateral dual kidney transplantation from expanded criteria donors: experience of 100 patients.

One option for using organs from donors with a suboptimal nephron mass, e.g. expanded criteria donors (ECD) kidneys, is dual kidney transplantation (DKT). In adult recipients, DKT can be carried out by several techniques, but the unilateral placement of both kidneys (UDKT) offers the advantages of single surgical access and shorter operating time. One hundred UDKT were performed using kidneys from ECD donors with a mean age of 72 years (Group 1). The technique consists of transplanting both kidneys extraperitoneally in the same iliac fossa. The results were compared with a cohort of single kidney transplants (SKT) performed with the same selection criteria in the same study period (Group 2, n = 73). Ninety-five percent of UDKTs were positioned in the right iliac fossa, lengthening the right renal vein with an inferior vena cava patch. In 69% of cases, all anastomoses were to the external iliac vessels end-to-side. Surgical complications were comparable in both groups. At 3-year follow-up, patient and graft survival rates were 95.6 and 90.9% in Group 1, respectively. UDKT can be carried out with comparable surgical complication rates as SKT, leaving the contralateral iliac fossa untouched and giving elderly recipients a better chance of receiving a transplant, with optimal results up to 3-years follow-up.

Sotrastaurin, a novel small molecule inhibiting protein kinase C: first clinical results in renal-transplant recipients.

Sotrastaurin, a novel protein-kinase-C inhibitor, blocks early T-cell activation. In this 12-month, Phase II study, de novo renal-transplant patients were randomized to sotrastaurin (200 mg b.i.d.) + standard-exposure tacrolimus (SET) or reduced-exposure tacrolimus (RET) (SET: n = 76; RET: n = 66), or control (SET + mycophenolic acid [MPA, 720 mg b.i.d.]; n = 74). In both sotrastaurin groups, patients were converted from tacrolimus to MPA after Month 3, achieving calcineurin inhibitor-free immunosuppression. The primary endpoint was composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death or loss to follow-up). The key secondary endpoint was glomerular filtration rate (GFR). Composite efficacy failure rates were: 4.1%, 5.4% and 1.5% at Month 3 (preconversion) and 7.8%, 44.8% and 34.1% at study end in the control, sotrastaurin + SET and sotrastaurin + RET groups, respectively; these results led to premature study discontinuation. Median GFR at Month 6 was: 57.0, 53.0 and 60.0 mL/min/1.73 m(2), respectively. Study-drug discontinuations due to adverse events occurred in 16.2%, 18.4% and 12.1%, respectively. Leukopenia and neutropenia occurred more frequently preconversion in control versus sotrastaurin groups: 13.7%, 5.6%, and 4.6%; and 11.1%, 4.3% and 3.1%, respectively. The initial sotrastaurin + tacrolimus regimen was efficacious and well tolerated but the postconversion sotrastaurin + MPA regimen showed inadequate efficacy. Longer-term evaluation of sotrastaurin + tacrolimus is warranted.

Pharmacokinetics for once- versus twice-daily tacrolimus formulations in de novo kidney transplantation: a randomized, open-label trial.

Tacrolimus, a cornerstone immunosuppressant, is widely available as a twice-daily formulation (Tacrolimus BID). A once-daily prolonged-release formulation (Tacrolimus QD) has been developed that may improve adherence and impart long-lasting graft protection. This study compared the pharmacokinetics (PK) of tacrolimus in de novo kidney transplant patients treated with Tacrolimus QD or Tacrolimus BID. A 6-week, open-label, randomized comparative study was conducted in centers in Europe and Australia. Eligible patients received Tacrolimus QD or Tacrolimus BID. PK profiles were obtained following the first tacrolimus dose (day 1), and twice under steady-state conditions. As secondary objectives, efficacy and safety parameters were also evaluated. Sixty-six patients completed all PK profiles (34 Tacrolimus QD, 32 Tacrolimus BID). Mean AUC(0-24) of tacrolimus on day 1 was approximately 30% lower for Tacrolimus QD than Tacrolimus BID (232 and 361 ng.h/mL, respectively), but was comparable by day 4. There was a good correlation and a similar relationship between AUC(0-24) and C(min) for both formulations. Efficacy and safety data were also comparable over the 6-week period. Tacrolimus QD can be administered once daily in the morning on the basis of the same systemic exposure and therapeutic drug monitoring concept as Tacrolimus BID.

Acute rejection features in dual kidney transplant recipients from elderly donors: comparison of calcineurin inhibitor-based and calcineurin inhibitor-free immunosuppressive protocols.

Features of acute rejection in dual kidney transplant have not been studied. The aim of this study is to compare acute rejections in dual kidney transplant recipients from elderly donors on different immunosuppressive protocols. Sixty-nine patients were evaluated: 28 received calcineurin inhibitor-based (group 1) and 41 received calcineurin inhibitor-free immunosuppression (group 2). Histology of all donor kidneys was evaluated before implantation. All rejections showed tubulitis in both groups, and were classified as T-cell mediated acute rejections. Incidence and Banff grade of rejections in the two groups were not significantly different. Late rejections however, were observed in group 1 (P < 0.01) whereas steroid-resistant rejections occurred in group 2 (P < 0.03). C4d deposition was only observed in group 2. Occurrence of acute rejection was significantly associated with graft loss due to interstitial fibrosis/tubular atrophy in both groups. In group 1 mean serum creatinine levels of patients with rejections at six months and one year were higher than those of patients without rejections (P < 0.03 and P < 0.009, respectively). In group 2 they were higher at six months (P < 0.01) but not at one year. In addition, graft loss due to interstitial fibrosis/tubular atrophy occurred in 3/28 patients in group 1 (10.7%, OR= 1.95, 95%CI 1.02-3.71), and in 1/41 patients in group 2 (2.4%, OR= 0.41, 95%CI 0.07-2.24). Taken together these results suggest better renal function in patients on calcineurin inhibitor-free immunosuppression. In conclusion, acute rejections were detrimental irrespective of the type of immunosuppression, but different features were observed with each therapy. A tailored approach should be advantageous for prevention and treatment of acute rejections.

Post-transplant lymphoproliferative disorders after heart or kidney transplantation at a single centre: presentation and response to treatment.

Post-transplant lymphoproliferative disorders (PTLD) is a serious complication after solid organ transplantation. Reduction of immunosuppression (RI) alone is not able to control the disease. We report a prospective analysis of 30 patients with PTLD after heart or kidney transplantation. Only 5 of 30 patients, treated solely with RI, obtained a complete response. Five patients were treated heterogeneously; in the remaining 20, the efficacy and safety of a weekly anthracycline-based chemotherapy were assessed. Sixteen patients obtained a complete remission. One death was related to treatment. With a median follow-up of 36 months, 3-year overall survival was 63.3% and 57% for the entire group and the chemotherapy-treated group, respectively. Moreover, 4 second neoplasms were observed in the chemotherapeutic group. In this study, we demonstrated that most PTLD need other treatment than RI and a weekly regimen is manageable and has a favourable impact on long-term survival.

Histological markers of humoral rejection in renal transplant patients.

Diagnosis of "suspicious humoral rejection" can be formulated in the presence of peritubular capillary (PTC) C4d deposition and one of the following tissue changes: (1) acute tubular necrosis, (2) glomerulitis or presence of polymophonuclear leukocytes or monocytes in PTC, or (3) arteritis. From January 2004 to October 2006, we performed immunohistochemical staining with anti-C4d antibody on 54 renal biopsies from 39 renal transplant patients. In 25 biopsies we observed diffuse (n = 13) or focal (n = 12) C4d deposition. Based on C4d-positivity, patients were divided into three groups: group 1 included 19 C4d-negative patients; group 2, 10 patients with diffuse C4d-positivity; and group 3, 10 patients with focal C4d-positivity. Panel-reaction antibody-positive tests were associated with diffuse C4d-positivity: 50% of group 2 patients showed a positive test, while no group 1 or 3 patients had a positive test (P < .001). Glomerulitis was observed in six biopsies and associated with diffuse C4d staining. Graft loss occurred in 3/10 group 2 patients (30%); 2/19 group 1 patients (10.5%), and 1/10 group 3 patients (10%). Viral infections were experienced in the year of the biopsy by 50% of group 1 patients 80% of group 2 patients, and 100% of group 3 patients (P < .025), indicating a significantly greater number of infections among patients with C4d-positive biopsies. In eight cases, anti-thymocyte globulin was administered less than 21 days before the biopsy: four had diffuse and four had focal C4d positivity.

Topical photodynamic therapy of actinic keratosis in renal transplant recipients.

Organ transplant recipients (OTRs) show an increased risk of precancerous (mostly actinic keratosis [AK]) and cancerous (mostly squamous cell carcinomas [SCC] and basal cell carcinomas [BCC]) cutaneous lesions. Their frequency increases with time after transplantation. AKs seem to progress more often and faster to invasive SCC in OTRs compared with the general population. The steady increase of risk of cutaneous premalignancies and malignancies with time after transplantation is an alarming figure because the number of organ allograft recipients who live for many years after transplantion is rapidly growing. This points out the need to devote more resources to skin cancer prevention, detection, and management. Various therapies, including cryotherapy, topical 5-fluorouracil, imiquimod, topical diclofenac, curettage, electrosurgery, carbon dioxide laser, and surgical excision, are available for AKs. However, most of these are limited by frequent relapses and the presence of multiple lesions over a wide area. Topical photodynamic therapy (PDT) represents an innovative therapeutic approach for nonsurgical treatment of cutaneous precancerous lesions and skin cancers. In this study we confirmed the usefulness of PDT in the treatment of AKs in OTRs, even in lesions relapsing or unresponsive to conventional treatment. We showed a complete response rate of 71%, after 2 treatments sessions that were 2 weeks apart. The response rate of scalp/facial lesions (72%) was higher compared with acral lesions (40%). Topical PDT could represent a useful therapeutic alternative for AKs in OTRs because large lesions can be treated with excellent cosmetic outcome.

Combined liver and kidney transplantation: analysis of Padova experience.

BACKGROUND/AIM: The main indications for combined liver and kidney transplantation (CLKT) are as follows: (1) cirrhosis with renal damage dependent or not upon liver disease, (2) renal failure with dialysis and concomitant liver end-stage disease, (3) congenital diseases, and (4) enzymatic liver deficiency with concomitant renal failure. The aim of this study was to evaluate our results with CLKT both in adult and pediatric patients. METHODS: From September 1995 to September 2006, 15 CLKT (2.8%) among 541 liver transplantations included 4 pediatric patients (27%). The main indications for CLKT were hepatitis C virus (HCV) and polycystic diseases in adult patients, and primary hyperoxaluria in pediatric patients. RESULTS: The double transplantation was performed from the same donor in all cases. All adult patients received whole liver grafts, whereas 3 split transplants and 1 whole liver graft were transplanted in the pediatric patients. Median liver and kidney cold ischemia times were 468 and 675 minutes, respectively. After a median follow-up of 36 months (range, 1-125), the overall survival rate was 80%. Five-year patient and graft survival rates were 100% for adult CLKT, whereas they were 50% for pediatric patients. We observed only 2 cases (18%) of delayed renal function, requiring temporary hemodialysis with progressive graft improvement. There was only 1 case of kidney retransplantation due to early graft nonfunction in a pediatric patient. CONCLUSION: Although CLKT is related to major surgical risks, results after transplantation are satisfactory with an evident immunological advantage.