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Background/Aims: The shortage in organ supply has required the use of expanded criteria donors (ECD) for kidney transplantation. Current pre-transplant evaluations of ECD organs are based on histological, clinical or mixed criteria. This monocentric study investigates the predictivity of Karpinski’s histological score on 3-year graft function in renal transplant. Ex-post classification using Nyberg’s score was carried out to assess the reliability of a purely clinical score and its applicability for organ allocation. Methods: We evaluated 407 deceased donors (251 optimal and 156 ECD) for renal transplants performed between 2001 and 2006. The differences in creatinine levels and MDRD-GFR at transplant and 1, 2 and 3 years post-transplant between optimal donors and ECD were recorded. Amongst ECD organs, the effect of different Karpinski score classes (0–1, 2, 3, 4, double transplants) on 3-year graft outcomes was analyzed. We then compared renal function over time across the Nyberg grades (A, B, C, and D). Results: Karpinski scores 0–1 and 2 and double transplants were associated with improved graft function compared to scores 3 and 4. Nyberg’s clinical score shows a good fit with medium-term outcome and Karpinski’s score, but among the donors with a high Nyberg grade (C and D), it fails to differentiate between allocable or non-allocable organs (due to Karpinski’s score ≥7). Conclusions: Our data demonstrate a correlation of histological damage at the time of transplant with 3-year graft function, but at present we are unable to provide any supposition on the possible outcome of the discarded kidneys.

BACKGROUND: Numerous studies have established the importance of innate immunity, particularly natural killer (NK) cells, in transplantation tolerance. NK cells express killer cell immunoglobulin-like receptors (KIRs) on their surface. By recognizing and binding major histocompatibility complex class I antigens, KIRs prevent autologous cell killing and promote lysis of non-self antigen-presenting cells. This study investigated the role of 16 KIR genes and donor-recipient KIR/HLA combinations on 5-year outcomes in a population of deceased donor kidney transplant recipients. MATERIAL/METHODS: We genotyped 126 renal transplant patients and their donors for HLA A, B, C, DR, and KIR genes. Patients underwent standardized transplantation and immunosuppressive protocols and were followed-up for 5 years. Graft function was evaluated by serum creatinine level and glomerular filtration rate calculated using the 4-variable modification of diet in renal disease (MDRD) equation. RESULTS: The presence of KIR2DS3 in the recipients was associated with better graft function indexes over time (p

Despite their contribution in the success of organ transplantation, calcineurin inhibitors (CNIs) may be responsible for frequent and severe side effects that can affect graft survival and life expectancy. In this article, we have reviewed registry studies and randomized controlled trials (RCTs) that seek to avoid, withdraw, or minimize CNIs in renal transplant recipients. Attempts to completely avoid CNIs by administering mycophenolate mofetil (MMF) and/or sirolimus (SRL) have resulted in increased risks of rejection and side effects, with small advantage to improve renal graft function. Early withdrawal of CNIs after transplantation using administration of MMF can improve graft function but may be associated with a greater risk of acute or chronic rejection and graft failure. RCTs in which CNIs were replaced a few months after transplantation by SRL reported improved graft function among SRL-treated patients, but such a treatment was complicated by iatrogenic toxicity. Late replacement of CNIs with SRL did not produce a particular advantage and again was complicated by more frequent side effects. On the basis of these trials, it seems that CNI elimination can trigger rejection or side effects. Recent RCTs showed that minimization of CNI doses in association with everolimus does not increase the risk of rejection, allows one to obtain good graft function, and is well tolerated. Such an approach seems therefore preferable to complete elimination of CNIs with substitution of the current immunosuppressive drugs.

On all kidney waiting lists the 10% to 20% of patients who have antibodies against more than 80% of a panel of HLA antigens (panel reactive antibody [PRA] >80%) are difficult to transplant. The best solution for these patients is to find a compatible donor, ideally a full match, who yields a negative crossmatch test (CMX). If this is not possible, desensitization treatment (high-dose) intravenous immunoglobulin (IVIG) or plasmapheresis (PP) + low-dose IVIG is possible with good results in living donor kidney transplantation mainly if the antibody titer is low. It may also be offered to patients awaiting cadaveric donors too after a long waiting time; however, when applied for several months, it has the obvious disadvantage of giving the patient the risk for long-lasting immunologic weakness without the certitude of finding a kidney. In one of our recent cases of combined liver plus kidney transplantation, a positive CMX became negative 8 hours after the liver operation; the kidney was transplanted with a good result which lasted over 3 years. This observation suggested the possibility of a quick desensitization protocol in selected patients with a large (but not strong) immunization who probably are the majority. Patients sensitized to IVIG and with low titer PRA could be given a single PP + low-dose IVIG (what can be done within the time limit of cadaveric donor kidney transplantation) with good probability of turning an initial positive CMX to negative with the possibility of performing the operation and the advantage of giving the immunosuppression only when the kidney is present.

Background Metabolic syndrome (MS) includes some risk factors for development of diabetes and cardiovascular disease, obesity (BMI > 30), high triglycerides, low HDL cholesterol, hypertension and impaired glucose tolerance. Following the definition of the Adult Treatment Panel III criteria, a diagnosis of MS was established when 3 or more factors were present. In renal transplan patients MS has been reported to negatively influence both patient and graft survivals. The present study sought to verify the effect of MS among our cases. Methods 298 cadaveric renal transplant recipients operated between January 1, 1996 and December 31, 2001 with absence of diabetes before transplantation, stable renal function 1 year posttransplantation and at least 4 years follow up were retrospectively evaluated from the end of the first post-operative year. Results 50 patients out of 298 (16,7%) had MS at the beginning of the study, including 37 of them with 3 and 13 with 4 risk factors. Only one patient with MS died of cardiovascular disease. Graft failure was observed in 23.5% MS patients versus 9,7% patients without the Syndrome (p:n.s.) Only Creatinine and the incidence of Cardiovascular Diseases at 4 years were statistically higher in MS patients ( P Conclusions These results suggested that MS is a risk factor for increasing CVD morbidity and decreased graft function, but early treatment of risk factors as soon as they become apparent can limit the adverse effects on patient and graft survival.

Introduction It is widely accepted that the risk of malignancies is significantly increased among patients with end-stage kidney disease (ESKD) and after kidney transplantation compared with the general population. Only a few data are available on kidney transplantation waiting list patients. The aim of this study was to investigate solid organ cancer incidence among subjects on the waiting list at a single center. Materials and Methods We retrospectively reviewed the records of all patients enrolled on our kidney transplantation waiting list between August 1, 2008 and July 31, 2010, seeking to evaluate the causes of withdrawal from the list, incidence of cancer, type of neoplasm, and its correlation with clinical features. We estimated the ratio of observed to expected numbers of cancers, the standardized incidence ratio (SIR). Results Among 1184 patients, we excluded 569 patients from the waiting list including 26 (4.56%) who displayed malignancies. The overall incidence of cancer was 0.11 events/person-months and the overall prevalence of cancer was 2.2%. In 97% of patients, the malignant disease was confined to the primitive organ of origin without secondary dissemination. We observed a prevalence of cancers related to ESKD (17; 65.38%). The SIR for all cancer types in our population compared with the general population was 2.22. The SIR for native kidney and thyroid cancers among our population compared with the general population was >10. Conclusion The incidence of cancer was significantly increased among kidney transplantation waiting list patients compared with the general population. Our study highlighted the importance of a careful, targeted neoplastic screening. It could be particularly important for ESKD-related malignancies like native kidney tumors or thyroid cancers.

Background: Short-term results of renal transplantation have shown a drastic improvement over time mainly due to changes in immunosuppressive therapy. Non-compliance to therapy is one of the causes of graft loss. Tacrolimus is a cornerstone of immunosuppressive therapy: recently became available Tacrolimus once a day formulation (Advagraf) that could improve the compliance of patients to immunosuppressive therapy. Few are published data about its use in clinical practice. We therefore compared the efficacy and pharmacokinetics of once-daily formulation compared to the classic twice-daily dosing tacrolimus in de novo kidney transplant patients. Methods: Retrospectively evaluation of 30 de novo transplant recipients treated with Advagraf in 2009-2012 (on dose daily of 0.2-0.3 mg/kg) and 30 treated with Prograf (2 doses daily of 0.2 mg /kg). Comparison between the two groups regarding drugs dose, blood level and clinical variables. Result: Both Advagraf and Prograf patients reached the drug target level, even if initially with a higher drug dose for Advagraf. Creatinine levels were initially higher in Advagraf group, no differences are detectable two weeks after transplant. There were no differences between groups for rejection episodes, graft loss and adverse events. Lipid metabolism was significantly better in Advagraf patients. Discussion: Advagraf confirm to offer a similar short-term efficacy compared with the twice a day administration in de novo kidney transplant, with a higher drug dose compared to tacrolimus. The safety profile is comparable with twice-daily administration. Interestingly a better lipid metabolism is present in Advagraf group.

Background Kidney transplant recipients (KTRs) manifest hypercoagulable state that contributes to an increased incidence of deep vein thrombosis (DVT), not only early but also late in their course. KTRs display an imbalance of hemostatic mechanisms with a multifactorial rise in procoagulant factors, partly related to traditional risk factors and partly to transplantation. The aim of this study was to evaluate the incidence of first episodes of DVT among KTRs, focusing on risk factors. Methods From 2008 to 2011, we evaluated 30 kidney transplant patients who ≥4 months there after transplantation developed DVT in the lower limbs only, lower limbs complicated by pulmonary embolism or retinal thrombosis. We analyzed causes of primary nephropathy, immunosuppressive regimen, post-transplantation infections, and erythrocytosis. DVT was diagnosed by color Doppler ultrasound or eye examination. Results A significantly increased incidence of DVT was observed among patients receiving cyclosporine or cyclosporine + mammalian target of rapamycin inhibitors, affected by polycystic kidney diseases, systemic lupus erythematosus or nephrotic syndrome, or displaying rapid and/or excessive correction of hematocrit values. DVT was not significantly related to an acute infection (cytomegalovirus) or to the prior dialysis modality. Conclusions Hypercoagulability is a multifactorial condition in KTRs, representing a severe complication in stable patients. Prevention may consist of either accurate pretransplantation screening for thrombophilia or identification of patients at higher DVT risk.

BACKGROUND The progressive deterioration of kidney allograft function leads in most cases to transplant failure. Polymorphisms in genes encoding for inflammatory and apoptosis molecules may be one possible explanation for interindividual differences in kidney transplant outcomes. The objective of our work was to identify the possible effect of interleukin 6 (IL-6), transforming growth factor beta 1 (TGFB1), and Fas on graft function. MATERIAL AND METHODS A case-control study was carried out to assess potential associations between polymorphisms in inflammation- and apoptosis-related genes and the risk for chronic impairment of kidney graft function. The study included 376 cadaveric kidney recipients, 256 of them with stable graft function and 120 who experienced renal deterioration during the follow-up period of 2.6 ± 1.4 years. Genotyping of IL-6/G-174C, TGFB1/L10P, TGFB1/R25P, and Fas/G-670A polymorphisms was performed by PCR-RFLP and direct sequencing. RESULTS Considering the single IL-6, TGFB1, and Fas polymorphisms, we found similar allelic and genotype frequencies between the 2 groups. To test the hypothesis of mutual effects of polymorphisms, multiple logistic regression was performed incorporating data for all the possible dual genotypic associations. The association of IL-6 high producer and Fas low producer genotype resulted in a protective effect against graft dysfunction (OR=0.79; 95% C.I.=0.72-0.86). CONCLUSIONS This study did not find significant associations of apoptosis and inflammation gene polymorphisms with transplanted kidney function in Italian renal transplant recipients. However, our data seem to indicate that the carriage of IL-6 high producer/Fas low producer genotype has a protective effect against graft function loss.

A 55-year-old Caucasian man who had received a second kidney graft in July 1993, was switched from cyclosporine to tacrolimus in June 2000 due to deterioration of renal function. Thereafter, he began to complain of muscle cramps in both quadriceps with an increased CPK and EMG findings of polyneuropathy. A muscle biopsy demonstrated acute myositis. Prednisone was administered with amelioration of the patient's symptoms, but with persistently increased CPK and myoglobin levels. In February 2001, mycophenolate mofetil was introduced and tacrolimus tapered to 3 mg daily to seek a toxic role of this immunosuppressant, since there was no other cause of myositis. A sudden decrease in CPK was observed, but the complete normalization took place only after its withdrawal in September 2002. This case represents a tacrolimus-associated myositis.

Presso il Centro Trapianti di Rene del Policlinico S. Orsola di Bologna nel corso del 2011 sono stati sottoposti a trapianto 62 pazienti di cui 51 da donatore cadavere (43 singoli reni, 3 doppi trapianti di rene, 4 trapianti combinati rene/fegato, 1 trapianto combinato rene/cuore) e 11 da donatore vivente; per la realizzazione dell’attività sono stati utilizzati complessivamente 65 reni. Complessivamente si è registrata una riduzione dell’attività trapiantologica rispetto al 2010 (-10%); in linea con la media Nazionale che risulta in calo di circa il 10%. Si è assistito ad un incremento dell’attività di trapianto da donatore vivente del 30% rispetto ai dati del 2010 e al continuo sviluppo di programmi di trapianto combinato. Anche nel 2011 si è confermata una buona collaborazione con il Centro Regionale Trapianto, con il Centro Interregionale AIRT e con le altre strutture trapiantologiche nazionali (NITp, OCST); non si sono registrati rifiuti di organi per motivi di carattere organizzativo o logistico. Anche nel 2011 le strutture logistiche e le procedure operative utilizzate dal Centro Trapianti di Bologna sono stati sottoposti a verifiche dei requisiti di qualità; nel corso dell’anno il Dipartimento di cui fa parte il Centro Trapianti ha superato la fase di accreditamento regionale. Nel corso dell’anno è stata divulgata ai pazienti candidati a trapianto renale la guida al trapianto che fornisce informazioni sugli aspetti gestionali e pratici delle diverse fasi del Programma del Trapianto (lista di attesa, trapianto, follow-up post-trapianto) con l’intento di rispondere ai più frequenti quesiti dei pazienti. L’esperienza del Centro Trapianto di Rene del S. Orsola nelle diverse fasi (inserimento in lista di attesa, terapia immunosoppressiva, follow-up post trapianto) è stata oggetto di pubblicazione su riviste Nazionali ed Internazionali e di comunicazione in Congressi di Nefrologia, Chirurgia ed Immunologia. L’Unità Operativa di Nefrologia Dialisi e Trapianto del Policlinico S. Orsola è sede della Lista Unica Regionale per il trapianto di rene (circolare dell’Assessorato alla Sanità della Regione Emilia-Romagna n. 12 del 30 maggio 2001); coordina, in collaborazione con i colleghi dei Centri Trapianto di Modena e di Parma, la valutazione di idoneità al trapianto dei reni proposti dal Centro Regionale Trapianti e, in collaborazione con la Unità Operativa di Genetica Medica di Parma, l’allocazione degli stessi. L’attività complessiva attinente alla Lista Unica è riportata in dettaglio in una specifica sezione del presente report regionale. Gli obiettivi del Centro per l’anno 2012 sono costituiti dal mantenimento di un’attività di trapianto da donatore cadavere in linea con i dati storici del Centro, dall’incremento dei Trapianti da donatore vivente con lo sviluppo di programmi di informazione sul territorio regionale, dalla periodica rivalutazione dei pazienti con comorbidità note (in particolare patologia cardiovascolare) o da più tempo inseriti in lista e dal consolidamento dei programmi di trapianto combinato.

Background/Aims: DNA fragmentation is one of the typical features of apoptosis, frequently induced by oxidative stress. Increased oxidative stress is known to be related to several pathological processes. In this study, we assessed oxidative damage in the early follow-up period after kidney transplantation measuring DNA oxidation and fragmentation of mononuclear cells and the circulating levels of inflammatory cytokines. Methods: Blood samples from 30 kidney transplant recipients were collected before transplantation and after 2 days, 1 month and 6 months. Oxidative DNA fragmentation was measured by Comet Assay, whereas DNA oxidation was evaluated measuring 8-OHdG leukocyte levels. Serum IL-1β, IL-4, IL-6, IL-8, IL-10, IFN-γ and TNF-α were assayed using a multiplex ELISA analysis. Results: At 6 months after transplantation, a significant reduction in DNA fragmentation and IL-6 plasma levels was observed; DNA oxidation was higher in patients with a worse outcome, with delayed graft function and low nutritional status. We also found a correlation of IL-6 and IL-10 levels with DNA fragmentation and of IL-10 levels with DNA oxidation. Conclusion: Low levels of oxidation and apoptosis at 6 months after transplantation correlate with a better recovery of renal function in kidney allografts. The measurement of cytokine levels confirmed a reduction of inflammatory parameters within 6 months of follow-up.

Polyomavirus-associated nephropathy (PVAN) has become an important cause of graft loss in the last few years. The typical course of PVAN is characterized by an asymptomatic period of viruria followed, within weeks, by the development of viremia in the context of stable renal function. The persistence of viral replication characterized by high viremia, leads to parenchymal injuries and causes the development, within months, of PVAN that could lead to deterioration in graft function and graft loss. We reported, in a patient who received a renal transplant, an unusual presentation of PVAN characterized by the development of acute renal failurte earlier than would be expected after transplantation, where the histological presentation alone could be confused with an acute rejection. We underline the importance of the association of histological findings with the viral load in urine and blood and with ancillary techniques such as immunohistochemistry and polymerase chain reaction (PCR) in situ for virus detection. We also want to emphasize that decoy cells and PCR for BK virus DNA research could be considered among the diagnostic tools for possible acute renal failure in kidney transplant.

Viene valutata la capacità predittiva della funzione renale a distanza dei sistemi più in uso per la valutazione istologica pre trapianto (Karpinsky-Nyberg) dei reni di donatori marginali

There is increasing proof that organ preserva- tion by machine perfusion is able to limit ischemia/ reperfusion injury in kidney transplantation. This study was designed to compare the efficiency in hypothermic organ preservation by machine perfusion or cold storage in an animal model of kidney autotransplantation.Twelve pigs underwent left nephrectomy after warm ischemic time; the organs were preserved in machine perfusion (n = 6) or cold storage (n = 6) and then autotransplanted with immediate contralateral nephrectomy. The following parameters were compared between the two groups of animals: hematologi- cal and urine indexes of renal function, blood/gas analysis values, histological features, tissue adenosine-5'- triphosphate (ATP) content, perforin gene expression in kidney biopsies, and organ weight changes were compared before and after preservation. The amount of cellular ATP was significantly higher in organs preserved by machine perfusion; moreover, the study of apoptosis induction revealed an enhanced perforin expression in the kidneys, which underwent simple hypothermic preservation com- pared to the machine-preserved ones. Organ weight was significantly decreased after cold storage, but it remained quite stable for machine-perfused kidneys. The present model seems to suggest that organ preservation by hypothermic machine perfusion is able to better control cellular impairment in comparison with cold storage. Key Words: Renal transplantation—Kidney function—Organ preservation—Machine perfusion—Ischemia/reperfusion injury—Delayed graft function.

Stem cells are a potential source for the regeneration of many tissues, including damaged kidneys. The present study describes the adoption of hyaluronic- butyric acid monoesters (HB) to induce expression of nephrogenic genes by mesenchymal cells isolated from human placental membranes. HB at a concentration of 1 mg/mL induces chromatin opening and increases the expression of the observed markers (cadherin 11, CD24, RAR-alpha, stearoyl-CoA desaturase 2, 14-3-3 0, Ewing sarcoma homolog.). These results open new routes toward cell regeneration after kidney injury.

Chronic allograft nephropathy (CAN) leads to the majority of late graft loss following renal transplantation. Detection of CAN is often too late to permit early intervention and successful management. Most current strategies for managing CAN rely on minimizing or eliminating calcineurin inhibitors (CNIs) once CAN has become established. The proliferation signal inhibitors everolimus and sirolimus have potent immunosuppressive and antiproliferative actions, with the potential to alter the natural history of CAN by reducing CNI exposure whilst avoiding acute rejection. Whilst data will be forthcoming from a number of clinical trials investigating this potential, we discuss early detection of CAN and the rationale for a role for this class of agent.

DESCRIZIONE DI UN RARO CASO DI INFEZIONE DA PARVOVIRUS B19 IN UNA PAZIENTE PORTATRICE DI TRAPIANTO RENALE DA DONATORE CADAVERE.

Cardiovascular disease is the leading cause of mortality and morbidity in renal transplant recipients as well as the leading cause of death with a functioning graft. The high cardiovascular risk is attributable to the prolonged exposure to multiple traditional and nontraditional risk factors in the pretransplant and posttransplant period. Particular attention must be paid to cardiovascular screening of candidates for kidney transplantation. After a transplant, treatment and prevention strategies should be focused on the modifiable risk factors including smoking, dietary habits, physical activity, weight control, hypertension, and dyslipidemia. Further studies on these factors are needed to better define the pharmacological approaches (hypotensive or hypolipemic drugs) and therapeutic targets. In view of the role of immunosuppressive therapy in the onset or worsening of several risk factors, it is important to tailor the treatment approach and dosage to the cardiovascular risk profile of the individual patient.

Transplantation offers a unique opportunity to demonstrate the complementary roles of randomized controlled trials and outcome research. The surgery and collaboration necessary for the transplant procedure makes randomization and blinding difficult. Because essentially every recipient is included in a transplant registry, sampling bias is minimized. Regulatory agencies generally do not consider outcomes research when assessing efficacy of new drugs or medical interventions. This workgroup summary examines the suitability of outcomes research to complement results of randomized controlled trials and related issues: efficacy versus effectiveness, internal versus external validity, data types, limitations, and analysis methodologies. Many advances in outcomes research have been pioneered in transplantation. A case is made for regulatory and reimbursement authorities to use outcomes research when making efficacy, effectiveness, and coverage decisions in transplantation.

Renal transplantation is the treatment of choice for patients with end-stage renal disease. In recent years a major improvement has been observed in short-term graft survival, but there has been no corresponding improvement in long-term survival. Chronic allograft dysfunction (CAD) is an anatomical and clinical alteration that can lead to the loss of the transplanted organ without any specific cause. The pathogenesis of CAD, which still remains to be fully clarified, involves both immunological factors (acute rejection, subclincial rejection, HLA mismatches between donor and recipient, noncompliance, etc) and non-immunological factors (marginal donor ischemia/reperfusion injury, infection, cardiovascular risk factors, nephrotoxicity, etc). Immunosuppressive therapy represents one of the strategies for the prevention of CAD. The introduction into clinical practice of novel immunosuppressive agents with no or lower nephrotoxicity, like mycophenolate mofetile, rapamycin and everolimus, will make therapeutic strategies aimed at decreasing the incidence of CAD feasible.