Roberta Angelico

Prospective multicenter clinical trial of immunosuppressive drug withdrawal in stable adult liver transplant recipients

Lifelong immunosuppression increases morbidity and mortality in liver transplantation. Discontinuation of immunosuppressive drugs could lessen this burden, but the safety, applicability, and clinical outcomes of this strategy need to be carefully defined. We enrolled 102 stable liver recipients at least 3 years after transplantation in a single‐arm multicenter immunosuppression withdrawal trial. Drugs were gradually discontinued over a 6 to 9‐month period. The primary endpoint was the development of operational tolerance, defined as successful immunosuppressive drug cessation maintained for at least 12 months with stable graft function and no histopathologic evidence of rejection. Out of the 98 recipients evaluated, 57 rejected and 41 successfully discontinued all immunosuppressive drugs. In nontolerant recipients rejection episodes were mild and resolved over 5.6 months (two nontolerant patients still exhibited mild gradually improving cholestasis at the end of follow‐up). In tolerant recipients no progressive clinically significant histological damage was apparent in follow‐up protocol biopsies performed up to 3 years following drug withdrawal. Tolerance was independently associated with time since transplantation (odds ratio [OR] 1.353; P = 0.0001), recipient age (OR 1.073; P = 0.009), and male gender (OR 4.657; P = 0.016). A predictive model incorporating the first two clinical variables identified subgroups of recipients with very high (79%), intermediate (30%‐38%), and very low (0%) likelihood of successful withdrawal. Conclusion: When conducted at late timepoints after transplantation, immunosuppression withdrawal is successful in a high proportion of carefully selected liver recipients. A combination of clinical parameters could be useful to predict the success of this strategy. Additional prospective studies are now needed to confirm these results and to validate clinically applicable diagnostic biomarkers. (Hepatology 2013;58:1824–1835)

Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation.

Following organ transplantation, lifelong immunosuppressive therapy is required to prevent the host immune system from destroying the allograft. This can cause severe side effects and increased recipient morbidity and mortality. Complete cessation of immunosuppressive drugs has been successfully accomplished in selected transplant recipients, providing proof of principle that operational allograft tolerance is attainable in clinical transplantation. The intra-graft molecular pathways associated with successful drug withdrawal, however, are not well defined. In this study, we analyzed sequential blood and liver tissue samples collected from liver transplant recipients enrolled in a prospective multicenter immunosuppressive drug withdrawal clinical trial. Before initiation of drug withdrawal, operationally tolerant and non-tolerant recipients differed in the intra-graft expression of genes involved in the regulation of iron homeostasis. Furthermore, as compared with non-tolerant recipients, operationally tolerant patients exhibited higher serum levels of hepcidin and ferritin and increased hepatocyte iron deposition. Finally, liver tissue gene expression measurements accurately predicted the outcome of immunosuppressive withdrawal in an independent set of patients. These results point to a critical role for iron metabolism in the regulation of intra-graft alloimmune responses in humans and provide a set of biomarkers to conduct drug-weaning trials in liver transplantation.

Conversion to rapamycin immunosuppression for malignancy after kidney transplantation

INTRODUCTION Malignancies are a well-known complication of immunosuppressive therapy among renal transplant recipients, representing an important cause of long-term morbidity and mortality. Rapamycin has been shown to limit the proliferation of a number of malignant cell lines in vivo and in vitro. METHODS Fifteen patients developed the following malignancies at a mean of 90.3 months (range = 10-252) after kidney transplantation: metastatic gastric cancer (n = 1), metastatic colon cancer (n = 1), bilateral nephrourothelioma (n = 1), skin cancer (n = 2), Kaposis sarcoma (n = 2), posttransplant lymphoproliferative disorder (PTLD; n = 4), renal cell carcinoma T1 (n = 1), MALT lymphoma (n = 1), intramucous colon carcinoma (n = 1), liposarcoma of the spermatic cord (n = 1). After the diagnosis of malignancy, the patients were switched from calcineurin inhibitor-based immunosuppression to rapamycin (monotherapy, n = 3), or associated with steroids (n = 6) or with mycophenolate mofetil (n = 6). RESULTS Both patients with metastatic cancer underwent chemotherapy but succumbed after 6 and 13 months. Two patients with PTLD who underwent chemotherapy died after 12 and 36 months. At a mean follow-up of 32.7 months (range = 7-56), the remaining 11 patients are cancer-free. Two patients lost their grafts after 24 and 36 months after the switch due to chronic rejection. Renal graft function remained stable in all other patients from diagnosis throughout follow-up. CONCLUSION Our observations suggested that rapamycin-based immunosuppression offers the possibility for regression of nonmetastatic tumors. Nevertheless, it is difficult to assess whether tumor regression was due to rapamycin treatment or to the reduced immunosuppression.

Glycogen Storage Disease Type Ia and VI Associated With Hepatocellular Carcinoma: Two Case Reports

Glycogen storage diseases (GSD) are inherited metabolic disorders of glycogen metabolism due to intracellular enzyme deficiency resulting in abnormal storage of glycogen in tissues. GSD represents an indication for liver transplantation (OLT) when medical treatment fails to control the metabolic dysfunction and/or there is an high risk of malignant transformation of hepatocellular adenomas (HCA). Herein we have reported two cases of GSD, type Ia and type VI, which were both associated with rapidly growing HCA, and underwent OLT because of suspect changes in their radiological features. Final histological findings in the explanted liver showed the presence of hepatocellular carcinoma (HCC) in both cases. In GSD type Ia and VI, OLT is considered to be the treatment of choice when a liver neoplasm is suspected. While the association of HCC with GSD type Ia is well known, this is the first case of HCC in GSD type VI so far reported to the best of our knowledge.

Long-term, maintenance MMF monotherapy improves the fibrosis progression in liver transplant recipients with recurrent hepatitis C.

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (LT) is universal. We designed a retrospective case–control study to evaluate the effect of mycophenolate mofetil (MMF) monotherapy in patients with recurrent hepatitis C. Fifteen patients with histologically proven hepatitis C recurrence after LT were switched from calcineurin inhibitors (CNIs) to MMF monotherapy because of impairment of kidney function and/or metabolic side effects, and treated for 48 months (MMF group). Fifteen well‐matched LT recipients who continued to receive CNIs therapy over the same period served as control group. Demographics, clinical data, time after LT, and baseline liver biopsies were similar in the two groups. There was no worsening of hepatic fibrosis during the study in the MMF group [2.6 ± 1.5 (baseline) Ishak Units vs. 2.7 ± 1.8 (after 48 months of MMF treatment), P = 0.6]. In contrast, a significant increase in the fibrosis score [2 ± 1.1 (baseline) vs. 3.2 ± 1.7 (after 48 months of CNI treatment), P = 0.0002] was observed in the control group. The yearly fibrosis progression rate was of 0.05 ± 0.44 in the MMF group and 0.33 ± 0.24 in the CNI group (P = 0.04). MMF monotherapy is associated with a favourable effect on hepatic fibrosis progression in HCV liver transplant recipients.

The Tor Vergata weaning of immunosuppression protocols in stable hepatitis C virus liver transplant patients: the 10-year follow-up.

We report herein the 10‐year outcome of the Tor Vergata weaning off immunosuppression protocol in hepatitis C virus (HCV) liver transplant patients. Thirty‐four patients who had received a liver graft for HCV‐related cirrhosis were enrolled in a prospective study in which they were progressively weaned off immunosuppression. The primary endpoints were feasibility and safety of the weaning; the second aim was to assess fibrosis progression. At the 10‐year follow‐up, of the eight original tolerant patients, six remained IS‐free. Of the 26 individuals who could not be weaned, 22 were alive. When the baseline biopsies were compared with the 10‐year biopsies, the tolerant group showed no differences in staging, whereas the nontolerant group showed a significant increase in staging. The fibrosis progression rates calculated for the tolerant and the nontolerant groups were −0.06 ± 0.12 and 0.1 ± 0.2, respectively (P = 0.04). Furthermore, with the last taken biopsies, nine nontolerant patients were showing frank cirrhosis versus no cirrhosis among the tolerant patients. After a 10‐year follow‐up of a Tor Vergata weaning protocol, 6/34 patients completed follow‐up without reinstitution of immunosuppression and this appeared beneficial regarding a reduction in fibrosis progression.

Switch from Twice-Daily Tacrolimus (Prograf) to Once-Daily Prolonged-Release Tacrolimus (Advagraf) in Kidney Transplantation

Advagraf is a new modified-release once-daily formulation of tacrolimus. The aim of this study was to define the efficacy and safety of switching from Prograf to Advagraf immunosuppression in kidney transplant recipients. The switched dose ratio of Prograf to Advagraf was 1:1. Forty-one patients (34 men and 7 women) were switched at 36.6 ± 16.1 months after kidney transplantation. All patients maintained stable renal function and the conversion. In 16 subjects it was possible to withdraw steroid administration after obtaining adequate Advagraf blood levels, among whom 14 remained steroid free. Adverse events, including dizziness and tinnitus, were reported in 1 patient, who was reverted to Prograf. One patient who was receiving triple therapy with low tacrolimus blood levels experienced are acute rejection episode. The switch to Advagraf was safe and efficacious in kidney transplant recipients with or without steroid administration. Moreover, interruption of steroid was possible and well tolerated after achieving adequate stable blood levels with Advagraf.

The efficacy and safety of mammalian target of rapamycin inhibitors ab initio after liver transplantation without corticosteroids or induction therapy

BACKGROUND Mammalian target of rapamycin inhibitors have been used along with corticosteroids and/or induction therapy immediately after liver transplantation. Our aim was to assess the safety and tolerability of everolimus ab initio after liver transplantation without corticosteroids or induction, as well as efficacy in terms of liver function, rejection and graft loss. METHODS A retrospective observational study of 50 adult patients (86% males, median age 54 years, range 25-68) who were liver transplanted between 2009 and 2013 and followed for 12 months. All recipients received everolimus plus low doses of calcineurin inhibitors (n=38) or mycophenolate (n=12) without corticosteroids and/or induction from the day of transplant. RESULTS The overall patient and graft survival was 80%. Liver function was stable during one year follow-up. No rejections or graft loss were observed. Only five patients (10%) required therapy for onset dyslipidemia. CONCLUSION Everolimus-based immunosuppression regimen without corticosteroids and/or induction immediately after liver transplantation seems to be safe and effective when administered with low doses of calcineurin-inhibitor or mycophenolate; although these findings require further investigation, these regimens could avoid adverse effects of standard immunosuppression regimens with higher doses.

One-shot versus multidose perioperative antibiotic prophylaxis after kidney transplantation: A randomized, controlled clinical trial

BACKGROUND There is no consensus on the optimal perioperative antibiotic prophylaxis regimen for renal transplant recipients. Some studies have reported that irrigation of the wound at the time of closure without systemic antibiotics may suffice to minimize the risk for surgical site infection (SSI), but many centers still use long-term, multidose regimens in which antibiotics are administered until removal of foreign bodies occur, such as the urethral catheter, drain and central line. METHODS We designed a prospective, randomized, multicenter, controlled trial to compare a single dose versus a multidose regimen of systemic antibiotic prophylaxis in adult, nondiabetic, non-morbidly obese patients undergoing renal transplantation. The primary endpoint was the incidence of SSI; the assessment of other infection in the first postoperative month was the secondary endpoint. RESULTS Two hundred five patients were enrolled and randomized to receive either a single (n = 103) or multidose antibiotic regimen (n = 102) for prophylaxis. The incidences of SSI and urinary tract infection were similar in both groups. CONCLUSION As the dramatic increase in antibiotic resistance has mandated the implementation of global programs to optimize the use of antibiotic agents in humans, we believe that the single dose regimen is preferred, at least in nondiabetic, non-morbidly obese, adult renal transplant recipients.

Hepatitis C virus recurrence and immunosuppression-free state after liver transplantation

HCV-related disease is the most common indication for liver transplantation (LT). HCV recurrence, which is almost universal, has a significant impact on patient and graft survival after LT and still represents a great unsolved issue for the liver transplant community. Several treatment strategies have been proposed. Since antiviral therapy has limited efficacy and can be administrated only in selected transplant recipients and additionally that immunosuppressive drugs have a negative impact on HCV re-infection, the achievement of an immunosuppression-free state after LT could play a central role in the avoidance of rapid HCV recurrence.