Umberto Valente

Performance of Different Prediction Equations for Estimating Renal Function in Kidney Transplantation

Numerous formulas have been developed to estimate renal function from biochemical, demographic and anthropometric data. Here we compared renal function derived from 12 published prediction equations with glomerular filtration rate (GFR) measurement by plasma iohexol clearance as reference method in a group of 81 renal transplant recipients enrolled in the Mycophenolate Mofetil Steroid Sparing (MY.S.S.) trial. Iohexol clearances and prediction equations were carried out in all patients at months 6, 9 and 21 after surgery. All equations showed a tendency toward GFR over‐estimation: Walser and MDRD equations gave the best performance, however not more than 45% of estimated values were within ±10% error. These formulas showed also the lowest bias and the highest precision: 0.5 and 9.2 mL/min/1.73 m2 (Walser), 2.7 and 10.4 mL/min/1.73 m2 (MDRD) in predicting GFR. A significantly higher rate of GFR decline ranging from −5.0 mL/min/1.73 m2/year (Walser) to −7.4 mL/min/1.73 m2/year (Davis–Chandler) was estimated by all the equations as compared with iohexol clearance (−3.0 mL/min/1.73 m2/year). The 12 prediction equations do not allow a rigorous assessment of renal function in kidney transplant recipients. In clinical trials of kidney transplantation, graft function should be preferably monitored using a reference method of GFR measurement, such as iohexol plasma clearance.

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

BackgroundThe potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC.Methods/DesignThe study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating.DiscussionIf our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC.Trial RegisterTrial registered at http://www.clinicaltrials.gov: NCT00355862(EudraCT Number: 2005-005362-36)

Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial

BACKGROUND Mycophenolate mofetil has replaced azathioprine in immunosuppression regimens worldwide to prevent graft rejection. However, evidence that its antirejection activity is better than that of azathioprine has been provided only by registration trials with an old formulation of ciclosporin and steroid. We aimed to compare the antirejection activity of these two drugs with a new formulation of ciclosporin. METHODS The mycophenolate steroids sparing multicentre, prospective, randomised, parallel-group trial compared acute rejections and adverse events in recipients of cadaver-kidney transplants over 6-month treatment with mycophenolate mofetil or azathioprine along with ciclosporin microemulsion (Neoral) and steroids (phase A), and over 15 more months without steroids (phase B). The primary endpoint was occurrence of acute rejection episodes. Analysis was by intention to treat. FINDINGS 168 patients per group entered phase A. 56 (34%) assigned mycophenolate mofetil and 58 (35%) assigned azathioprine had clinical rejections (risk reduction [RR] on mycophenolate mofetil compared with azathioprine 13.7% [95% CI -25.7% to 40.7%], p=0.44). 88 patients in the mycophenolate mofetil group and 89 in the azathioprine group entered phase B. 14 (16%) taking mycophenolate mofetil and 11 (12%) taking azathioprine had clinical rejections (RR -16.2%, [-157.5% to 47.5%], p=0.71). Average per-patient costs of mycophenolate mofetil treatment greatly exceeded those of azathioprine (phase A 2665 Euros [SD 586] vs Euros 184 [62]; phase B 5095 Euros [2658] vs 322 Euros [170], p<0.0001 for both). INTERPRETATION In recipients of cadaver kidney-transplants given ciclosporin microemulsion, mycophenolate mofetil offers no advantages over azathioprine in preventing acute rejections and is about 15 times more expensive. Standard immunosuppression regimens for transplantation should perhaps include azathioprine rather than mycophenolate mofetil, at least for kidney grafts.

Treatment of EBV-Related Post-Renal Transplant Lymphoproliferative Disease with a Tailored Regimen Including EBV-Specific T Cells

The treatment of EBV‐associated post‐transplant lymphoproliferative disease (PTLD) poses a considerable challenge. Efforts have been made to define regimens based on combination of the available therapeutic agents, chosen and tailored on a patient‐by‐patient basis, with the aim of augmenting event‐free patient and graft survival. Recently, autologous EBV‐specific cytotoxic T‐lymphocytes (CTL) have proved effective in enhancing EBV‐specific immune responses and reducing viral load in organ transplant recipients with active infection. We investigated the use of a tailored combined approach including autologous EBV‐specific CTL for the treatment of EBV‐related PTLD developing after pediatric kidney transplantation.

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial.

Background We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). Methods In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor–free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor–free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. Results Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ⩽60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). Conclusions Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.

Split and whole liver transplantation outcomes: A comparative cohort study

A specific split liver transplantation (SLT) program has been pursued in the North Italian Transplant program (NITp) since November 1997. After 5 yr, 1,449 liver transplants were performed in 7 transplant centers, using 1,304 cadaveric donors. Whole liver transplantation (WLT) and SLT were performed in 1,126 and 323 cases, respectively. SLTs were performed in situ as 147 left lateral segments (LLS), 154 right trisegment liver (RTL) grafts, and 22 modified split livers (MSL), used for couples of adult recipients. After a median posttransplant follow‐up of 22 months, SLTs achieved a 3‐yr patient and graft survival not significantly different from the entire series of transplants (79.4 and 72.2% vs. 80.6 and 74.9%, respectively). Recipients receiving a WLT or a LLS showed significantly better outcomes than patients receiving RTL and MSL (P < 0.03 for patients and P < 0.04 for graft survival). At the multivariate analysis, donor age of >60 yr, RTL transplant, <50 annual transplants volume, urgent transplantation (United Network for Organ Sharing (UNOS) status I and IIA), ischemia time of >7 hours, and retransplantation were factors independently related to graft failure and to significantly worst patient survival. Right grafts procured from RTL and either split procured as MSL had a similar outcome of marginal whole livers. In conclusion, in 5 yr, the increased number of pediatric transplants due to split liver donation reduced to 3% the in‐list children mortality, and a decrease in the adult patient dropout rate from 27.2 to 16.2% was observed. Such results justify a more widespread adoption of SLT protocols, organizational difficulties not being a limit for the application of such technique. Liver Transpl 12:402–410, 2006.

A new splitting technique for liver grafts

The in-situ split-liver (ISSL) technique allows the division of the liver of a cadaver donor in two parts that can be transplanted in two different patients. The two grafts obtained are different in size, the left one being generally suitable for transplantation only in small children. We describe here the successful use of an alternative technique, generating two grafts more similar in size, both of which are transplantable into adults or large children. The donor was a brain-dead 33-year-old man 164 cm tall and weighing 60 kg. The multiple organ harvesting was done with standard technique apart from division of the liver. After a cholecistectomy the right and left portal and hepatic arterial branches were identified. The left hepatic duct was sectioned. The right lobe was then mobilised and freed from the inferior vena cava (IVC); the right vein was encircled at its confluence with the IVC. Parenchyma transection was then done along a plane directed from the right border of the gallbladder fossa, to the division of the portal vein and to the right margin of the median hepatic vein, leaving the right lobe connected only with its vascular attachments (figure). After flushing of the organs the heart was retrieved, then came the right lobe of the liver, including the five to eight segments, the right branches of the hepatic artery and of the portal vein, the common bile duct, and the right hepatic vein with a patch of IVC. The left lobe of the liver, including the segments one to four was then removed, with the coeliac axis and the hepatic artery, the portal trunk, the left hepatic duct, and the median and left hepatic veins in continuity with the IVC. Finally, the kidneys were removed. During the 4 h operation, seven units of packed red blood cells were transfused. The right and left grafts weighed 685 g and 480 g, respectively, and were transplanted in a 53-year-old man, 178 cm tall and weighing 79 kg, with alcoholic cirrhosis, and in a 13-year-old girl 155 cm tall and weighed 48 kg, with autoimmune cirrhosis and hepatitis C virus infection. Both the grafts had immediate good function and the patients had rapid recovery. They were discharged on the 15th and 24th postoperative day, respectively, and are alive and well with normal liver function at 5 months. This alternative technique of ISSL provided two grafts of similar size, showing excellent function in two recipients of adult size. The blood loss during the split was similar to that reported from harvesting a right-lobe graft from a living donor, with a similar technique. With increasing experience this figure can be reduced. ISSL has proved a safe and effective way to increase the number of liver transplants with the available donor pool, dividing the liver mass between the large right lobe and the small left lateral segment. The minimum amount of liver tissue needed to achieve sufficient immediate function in a given patient is not well known, but should probably not be lower then 25–50% of his predicted liver volume. The left lateral segment seldon exceeds 300 g in weight, being therefore inadequate for most adults and large children. The net benefit from standard ISSL is therefore only for small children, representing a limited percentage of candidates for liver transplantation. The extension of ISSL to increase the number of adult transplants can be a further step in optimising the use of cadaver donors. Our technique increases the flexibility of the procedure and can virtually double the pool of liver grafts for adult recipients.

Incidence of Bleeding Following Invasive Procedures in Patients With Thrombocytopenia and Advanced Liver Disease

BACKGROUND & AIMS Patients with advanced liver disease often undergo invasive procedures, so the combination of thrombocytopenia, coagulopathy, and bleeding should be carefully assessed. We evaluated the prevalence of thrombocytopenia in a series of patients with liver cirrhosis who were being evaluated for orthotopic liver transplantation (OLT) and determined the number of invasive procedures and procedure-related incidences of bleeding in patients with thrombocytopenia. METHODS We studied 121 consecutive patients who were being evaluated for OLT. Thrombocytopenia was defined as a platelet count <150,000/μL and severe thrombocytopenia as a platelet count <75,000/μL. The presence of significant coagulopathy was defined as an international normalized ratio >1.5. Invasive procedures and incidences of procedure-related bleeding were recorded for each patient. RESULTS The prevalence of thrombocytopenia and severe thrombocytopenia were 84% and 51%, respectively. Among the 102 thrombocytopenic patients, 50 (49%) underwent an invasive procedure (32 with severe thrombocytopenia; 64%). Bleeding occurred in 10 of the patients who underwent an invasive procedure (20%). Among the 50 patients who underwent invasive procedure, 32 had severe thrombocytopenia and 18 had moderate thrombocytopenia. Bleeding occurred in 10 of the 32 patients (31%) with severe thrombocytopenia and in none of those with moderate thrombocytopenia. There was no difference in prevalence of significant coagulopathy between patients with severe thrombocytopenia who underwent invasive procedure and bled (3/10; 30%) and those who did not bleed (10/22; 45%). CONCLUSIONS Thrombocytopenia has a high prevalence among patients with advanced liver disease. Bleeding related to invasive procedures occurs most frequently in patients with severe thrombocytopenia, whereas significant coagulopathy does not seem to be associated with bleeding.

Dendritic cells pulsed with polyomavirus BK antigen induce ex vivo polyoma BK virus-specific cytotoxic T-cell lines in seropositive healthy individuals and renal transplant recipients

Polyoma BK virus (BKV)-associated interstitial nephritis has emerged as a relevant complication of immunocompromise after kidney transplantation, leading to reduced survival of the renal allograft. The limitations of current antiviral treatment and the high probability of rejection in kidney graft recipients when control of viral replication is attempted by reduction of immunosuppression warrant further efforts to develop alternative therapeutic tools. Cellular immunotherapy has proved to be a successful approach for prevention and/or treatment of other viral complications in the immunocompromised host. For assessing the feasibility of translating this strategy to the prevention of BKV-associated disease, a procedure for ex vivo reactivation of BKV-specific cytotoxic T cells (CTL) was developed from BKV-seropositive healthy donors and allograft recipients through stimulation with dendritic cells pulsed with inactivated BKV. The CTL lines thus obtained showed BKV specificity, as an efficient lysis of BKV-infected targets was accompanied by little or no reactivity against mock-infected autologous or allogeneic targets. In vitro killing of allogeneic BKV-infected targets, likely as a result of populations of TCRgammadelta+/CD3+ displaying MHC class I unrestricted cytotoxicity, was also displayed. Application of this culture system may allow a preemptive therapy approach to BKV-related complications in transplant recipients, based on CTL treatment guided by BKV DNA levels.

Liver Match, a prospective observational cohort study on liver transplantation in Italy: Study design and current practice of donor-recipient matching

BACKGROUND The Liver Match is an observational cohort study that prospectively enrolled liver transplantations performed at 20 out of 21 Italian Transplant Centres between June 2007 and May 2009. Aim of the study is to investigate the impact of donor/recipient matching on outcomes. In this report we describe the study methodology and provide a cross-sectional description of donor and recipient characteristics and of graft allocation. METHODS Adult primary transplants performed with deceased heart-beating donors were included. Relevant information on donors and recipients, organ procurement and allocation were prospectively entered in an ad hoc database within the National Transplant Centre web-based Network. Data were blindly analysed by an independent Biostatistical Board. RESULTS The study enrolled 1530 donor/recipient matches. Median donor age was 56 years. Female donors (n = 681, median 58, range 12-92 years) were older than males (n = 849, median 53, range 2-97 years, p < 0.0001). Donors older than 60 years were 42.2%, including 4.2% octogenarians. Brain death was due to non-traumatic causes in 1126 (73.6%) cases. Half of the donor population was overweight, 10.1% was obese and 7.6% diabetic. Hepatitis B core antibody (HBcAb) was present in 245 (16.0%) donors. The median Donor Risk Index (DRI) was 1.57 (>1.7 in 35.8%). The median cold ischaemia time was 7.3h (≥ 10 in 10.6%). Median age of recipients was 54 years, and 77.7% were males. Hepatocellular carcinoma (HCC) was the most frequent indication overall (44.4%), being a coindication in roughly 1/3 of cases, followed by viral cirrhosis without HCC (28.2%) and alcoholic cirrhosis without HCC (10.2%). Hepatitis C virus infection (with or without HCC) was the most frequent etiologic factor (45.9% of the whole population and 71.4% of viral-related cirrhosis), yet hepatitis B virus infection accounted for 28.6% of viral-related cirrhosis, and HBcAb positivity was found in 49.7% of recipients. The median Model for End Stage Liver Disease (MELD) at transplant was 12 in patients with HCC and 18 in those without. Multivariate analysis showed a slight but significant inverse association between DRI and MELD at transplant. CONCLUSIONS The deceased donor population in Italy has a high-risk profile compared to other countries, mainly due to older donor age. Almost half of the grafts are transplanted in recipients with HCC. Higher risk donors tend to be preferentially allocated to recipients with HCC, who are usually less ill and older. No other relevant allocation strategy is currently adopted at national level.