Gastrointestinal Side Effects of Post-Transplant Therapy.

Modern immunosuppressive therapy has produced a real revolution in renal and organ transplantation but it comes with the price of multiple side effects. There are many gastrointestinal (GI) complications that are the consequence of transplant immunosuppressant medication. In fact, for any immunosuppressant therapy, certain standardized precepts and attitudes that aim to reduce the incidence and the impact of the medication side effects must be applied. Many patients undergo renal transplantation and the physicians have to be aware of the advantages and the risks associated. This article reviews the main GI complications that may arise as a consequence of immunosuppressive therapy after solid organ transplantation, focusing on renal and renal/pancreas transplantation, as well as the ways in which the incidence of these complications can be reduced. Management of the post-transplant therapy is mandatory in order to increase not only the grafts' and the patients' survival, but also their quality of life by the occurrence of fewer complications.

[Surgical overview on kidney and pancreas transplantation]. / Problemi chirurgici nel trapianto di rene e di pancreas - Position paper.

The main purpose of this paper, written by a group of Italian expert transplant surgeons, is to provide clinical support and to help through the decision-making process over pre-transplant surgical procedures in potential kidney recipients, as well as selection of pancreas transplant candidates and perioperative management of kidney recipient. Current topics such as different approaches in minimally invasive donor nephrectomy, methods of graft preservation and treatment of failed allograft were addressed.

Acute allograft rejection following interferon therapy for hepatitis C in recipients who have returned to dialysis after kidney transplant failure: case study.

Interferon-based therapy remains the gold standard for hepatitis C in patients with chronic kidney disease; however, due to the high rate of IFN-induced rejection after transplant, treatment of HCV-infected kidney transplant recipients is recommended only in particular circumstances. We report the case of a 45-year-old Caucasian female with chronic hepatitis C (genotype 1b) who returned to hemodialysis following the complete functional loss of her kidney transplant. She started combination antiviral therapy with peg-IFN-α2a (135 mcg sc weekly) plus ribavirin (200 mg daily) nine months after the re-initiation of hemodialysis. Antiviral therapy was neither effective nor safe; ribavirin was stopped at week 38 due to hemolytic anemia; on-treatment HCV breakthrough was observed at week 48; and acute rejection occurred after four months of IFN-based therapy. Diagnosis of acute allograft rejection was suspected on the grounds of clinical, radiographic, and laboratory data. Allograft nephrectomy was then performed and histology showed acute-on-chronic rejection. This is an uncommon case of IFN-associated kidney rejection in an allograft recipient who had functional loss of her graft and had returned to hemodialysis. In view of the risk of rejection of renal allograft, and the limited efficacy of IFN-based treatment of hepatitis C, physicians should be aware of effective treatment with oral anti-viral agents and avoid the use of IFN in patients on maintenance dialysis with failed renal allograft.

What has changed in more than 40 years of activity and 3000 kidney transplants at Policlinico University Hospital, Milan.

The activity of kidney transplantation at Policlinico University Hospital, now the Ca' Granda Foundation, was established by Professor Edmondo Malan, who performed the first deceased donor transplantation in Milan, Italy, in 1969. Since then, 2989 kidney transplant procedures (2760 first, 219 second, 10 third transplants) have been performed through the end of November 2011, 2617 of them coming from deceased donors and 372 from living donors. Patient and graft survival have increased since the introduction of cyclosporine and tacrolimus in the last 28 years: 323 living donor-recipients under calcineurin inhibitors (CNI) show patient survival of 95.4% at five years and 88% at 10 years, not significantly different when compared with those of 1968 deceased donor-recipients (93.5% and 86.2%, respectively, at the same time points). Crude graft survival for living donor-recipients under CNI is 84.2% at 5 years and 70.2% at 10 years, not significantly different from those of deceased donor-recipients (80.3% and 64.3% for at the same time points). Actuarial graft survival censored by death is 87.2% at 5 years and 76.5% at 10 years for living donor-recipients vs. 84.4% and 72.2% for deceased donor-recipients, respectively. Previously unacceptable living or deceased kidneys are now successfully transplanted after being repaired with microsurgical techniques at bench. The rate of donors over 60 years of age has increased from 3.8% in the period of 1983-1995 to 20.8% in the last 15 years. It is interesting to note that 306 older kidneys (living donor, deceased donor, first, second, third transplants, with mean donor age of 64.6 +/- 4.0 yrs. and range 60-77 yrs.), always transplanted singularly, have similar behavior if compared with organs coming from donors aging 11-49 years. Survival rates are 93.1%, 90.1%, 88.4%, and 73.2% at 1, 3, 5, and 10 years post-transplant for the older donor grafts vs. 91.2%, 88.1%, 85.4%, and 74.4% for the younger donor grafts at the same time points. Perhaps the practice of dual transplant should be revisited and reserved to very old and ECD-donors. An open subcostal mini-incision (MINI) has been utilized in 177 living donors since 1996. This technique offers the same advantages of hand assisted videolaparoscopic technique, no disadvantages, and no major complications. Although more older and unrelated living donors are included in the MINI-group, very good results are obtained in these recipients, with graft survival censored by death of 97.2%, 95.3%, 93.8%, and 86.3% at 1, 3, 5, and 10 years post-transplant.

Improved treatment feasibility in children with hemophilia using arteriovenous fistulae: the results after seven years of follow-up.

BACKGROUND: An easy and stable venous access is essential in hemophilic children who receive regular prophylaxis or immune tolerance induction treatment. Central venous access devices improve treatment feasibility, but their use is complicated by infection and/or thrombosis. Arteriovenous fistula (AVF) has been evaluated as an alternative to central venous access devices in hemophilic children since 1999. DESIGN AND METHODS: This study provides results obtained in a large series after seven years of follow-up. RESULTS: From 1999 to 2008, 43 procedures were performed in 38 children (median age: 2.7 years). Thirty-five AVFs (81%) achieved maturation after a median of 58 days and were used for a median of five years (range: 0.4-8.5). A brachial artery caliber larger than 1.2 mm was associated with successful maturation (p<0.05). Complications with some impact on arteriovenous fistula use or duration were observed in 14/43 procedures (32%) and in 13/38 children (34%). Age at arteriovenous fistula creation was younger in children who lost arteriovenous fistula patency (p<0.05) and aneurysms were more frequent in children who were on daily treatment regimen and thus had a greater cumulative number of arteriovenous fistula accesses (p<0.05). At the end of the follow-up period, 22 AVFs were still in use and 9 had been surgically dismantled. Arteriovenous fistula use allowed long-term prophylaxis (up to 8.5 years) in 11 children and the completion of immune tolerance induction without interruptions in 18 children. CONCLUSIONS: This study confirms the feasibility of arteriovenous fistula with an acceptable rate of complications and suggests that its use is particularly favorable in children with inhibitors in whom it should be considered as first-choice venous access.

Longitudinal evaluation of mycophenolic acid pharmacokinetics in pediatric kidney transplant recipients. The role of post-transplant clinical and therapeutic variables.

This longitudinal study assessed the influence of post-transplant clinical and therapeutic variables in 50 kidney transplant recipients aged 2-19 yr receiving a triple immunosuppressive regimen consisting of cyclosporine microemulsion (CsA), steroids and MMF (300-400 mg/m(2) body surface area twice daily), the full pharmacokinetic profile (10 points) of which was investigated on post-transplant days 6, 30, 180 and 360. Total plasma MPA was measured by Enzyme Multiplied Immunoassay Technique. CsA therapeutic drug monitoring (TDM) was performed via C2 blood monitoring, while MPA TDM via C0. MPA Cmax, tmax, AUC0-12 and AUC0-4 pharmacokinetic profile changed significantly during the first post-transplant year. C0 was a poor predictor of the total MPA exposure [as measured by the area under the concentration-time curve AUC)], while a truncated AUC was a good surrogate of the 12-h profile (r = 0.91; p < 0.001) Graft function and cyclosporine therapy influenced MPA pharmacokinetics, as shown by the univariate and multivariate analyses. We conclude that because after transplantation MPA exposure varied over time, a strict TDM is advisable in the pediatric population.

Combined liver-kidney transplantation in glycogen storage disease Ia: a case beyond the guidelines.

Glycogen storage disease type Ia (GSD Ia) is a rare metabolic disorder due to hepatic glucose-6-phosphatase deficiency. Although great progress has been made in managing affected patients, severe hypoglycemia, lactic acidosis, hyperlipidemia, hepatic cytolysis, and impaired kidney function are frequent. Liver transplantation is the only radical treatment, for which the main indications are hepatic adenomatosis, hepatocellular carcinoma, or severe hepatic dysfunction. We present the case of a patient with end-stage renal disease without focal hepatic lesions and with moderate hepatic metabolic control, and we explain how combined liver-kidney transplantation (LKT) made it possible to correct the metabolic defects responsible for the impaired glucose homeostasis, liberalize the diet, and give birth to a healthy child after an uneventful pregnancy. Patients with end-stage renal disease that resulted from GSD Ia should be considered for LKT even in the absence of hepatic lesions with the aim of improving their quality of life.

C0 or C2 driven cyclosporine monitoring in long-term pediatric kidney transplant recipients: is there any threat for chronic rejection development?

The clinical management of cyclosporine has evolved greatly during the last decade thanks to the use of pharmacokinetic (PK) studies which confirmed the dose relationship between drug exposure and its biological effects. Therefore, cyclosporine PK monitoring during the early phase of the post-transplant period became essential to avoid over or underexposure to the drug thus preventing the risk of nephrotoxicity or acute rejection episodes. More recently, a simple PK determination based on cyclosporine blood concentration measured 2 h after the morning dose, has proven to be very effective for monitoring cyclosporine exposure in the early postoperative period. In this paper, the authors present a set of PK profiles obtained from a stable, long-term pediatric kidney transplant population and correlate these parameters with the risk of chronic rejection development. The study shows how cyclosporine monitoring based on the sole trough level determination misled a correct therapeutic behavior, as revealed by the PK parameters that were constantly below the therapeutic threshold in a small patient cohort who eventually developed chronic rejection. The C2 determination should be considered as the gold standard for cyclosporine monitoring in long-term pediatric recipients.

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

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

Long-term safety and feasibility of arteriovenous fistulae as vascular accesses in children with haemophilia: a prospective study.

Infectious and thrombotic complications limit the long-term use of subcutaneous ports as venous accesses for children with haemophilia. This study has evaluated for the first time the safety and feasibility of internal arteriovenous fistulae (AVF) as alternative accesses. During the 3-year study period, 27 severe haemophiliacs, 14 with factor VIII inhibitors (52%), underwent the creation of 31 proximal AVF in the forearm. Mild forearm haematomas were observed after five procedures (16%) in five patients who had or developed inhibitors after surgery. Inadequate AVF maturation was observed after five of 31 procedures (16%) in four children. AVF were first accessed after a median of 42 d and regularly used at home by 26 patients (96%) for a median follow-up period of 29 months. Thrombosis of a venous branch occurred in one AVF (3%) after 9 months of uncomplicated use in a child with inhibitor who spontaneously recovered from the symptoms and still used AVF for nine additional months. Mild symptoms, referable to distal ischaemia, were transiently reported by two children (7%) who needed no remedial intervention. This study demonstrates that the use of AVF in haemophiliacs enabled long-term treatment at home in all patients but one.

Conversion from cyclosporine to tacrolimus in pediatric kidney transplant recipients.

In pediatric kidney transplant recipients, tacrolimus has been proposed either for primary immunosuppression or as a rescue agent for refractory acute rejection, chronic rejection, and cyclosporine toxicity. This paper describes our experience with tacrolimus conversion from cyclosporine-based therapy in six selected cases: four due to refractory acute rejections unresponsive to conventional therapy, one to chronic graft rejection, and one to cyclosporine-related hypertrichosis. A "simple-switch" conversion was used without any overlap, starting with a dose of 0.2 mg/kg per day. The time to conversion varied from 10 to 730 days after the transplant. In the patients with acute rejection, the median time to reversal after tacrolimus conversion was 12 days. The symptoms of the patient with cyclosporine toxicity completely resolved without any loss of allograft function. The patient with chronic rejection maintained stable renal function for more than 1 year after conversion. A new onset of post-transplant diabetes mellitus and dose-related nephrotoxicity were recorded as adverse events. In conclusion, our experience suggests that tacrolimus can play an important role in the salvage treatment of pediatric kidney transplantations with deteriorating graft function due to acute rejection refractory to standard therapy. Tacrolimus conversion also provides excellent results in the presence of cyclosporine toxicity.