Fabrice Muscari

Prevalence, incidence and risk factors for donor-specific anti-HLA antibodies in maintenance liver transplant patients.

Although large retrospective studies have identified the presence of donor‐specific antibodies (DSAs) to be a risk factor for rejection and impaired survival after liver transplantation, the long‐term predicted pathogenic potential of individual DSAs after liver transplantation remains unclear. We investigated the incidence, prevalence and consequences of DSAs in maintenance liver transplant (LT) recipients. Two hundred sixty‐seven LT recipients, who had undergone transplantation at least 6 months previously and had been screened for DSAs at least twice using single‐antigen bead technology, were included and tested annually for the presence of DSAs. At a median of 51 months (min–max: 6–220) after an LT, 13% of patients had DSAs. At a median of 36.5 months (min–max: 2–45) after the first screening, 9% of patients have developed de novo DSAs. The sole predictive factor for the emergence of de novo DSAs was retransplantation (OR 3.75; 95% CI 1.28–11.05, pu2009=u20090.025). Five out of 21 patients with de novo DSAs (23.8%) developed an antibody‐mediated rejection. Fibrosis score was higher among patients with DSAs. In conclusion, monitoring for the development of DSAs in maintenance LT patients is useful in case of graft dysfunction and to identify patients with a high risk of developing liver fibrosis.

Duodenal Villous Atrophy: A Cause of Chronic Diarrhea After Solid-Organ Transplantation

Persistent diarrhea is commonly observed after solid organ transplantation (SOT). A few cases of mycophenolate mofetil (MMF)‐induced duodenal villous atrophy (DVA) have been previously reported in kidney‐transplant patients with chronic diarrhea. Herein, we report on the incidence and characteristics of DVA in SOT patients with chronic diarrhea. One hundred thirty‐two SOT patients with chronic diarrhea underwent an oesophago‐gastroduodenoscopy (OGD) and a duodenal biopsy after classical causes of diarrhea have been ruled out. DVA was diagnosed in 21 patients (15.9%). It was attributed to mycophenolic acid (MPA) therapy in 18 patients (85.7%) (MMF [n = 14] and enteric‐coated mycophenolate sodium [n = 4]). MPA withdrawal or dose reduction resulted in diarrhea cessation. The incidence of DVA was significantly higher in patients with chronic diarrhea receiving MPA compared to those who did not (24.6% vs. 5.1%, p = 0.003). DVA was attributed to a Giardia lamblia parasitic infection in two patients (9.5%) and the remaining case was attributed to azathioprine. In these three patients, diarrhea ceased after metronidazole therapy or azathioprine dose reduction. In conclusion, DVA is a frequent cause of chronic diarrhea in SOT recipients. MPA therapy is the most frequent cause of DVA. An OGD should be proposed to all transplant recipients who present with persistent diarrhea.

De novo donor-specific anti-HLA antibodies mediated rejection in liver-transplant patients.

The incidence and consequences of de novo donor‐specific anti‐HLA antibodies (DSAs) after liver transplantation (LT) are not well known. We investigated the incidence, risk factors, and complications associated with de novo DSAs in this setting. A total of 152 de novo liver‐transplant patients, without preformed anti‐HLA DSAs, were tested for anti‐HLA antibodies, with single‐antigen bead technology, before, at transplantation, at 1, 3, 6 and 12 months after transplantation, and thereafter annually and at each time they presented with increased liver‐enzyme levels until the last follow‐up, that is, 34 (1.5–77) months. Twenty‐one patients (14%) developed de novo DSAs. Of these, five patients had C1q‐binding DSAs (24%). Younger age, low exposure to calcineurin inhibitors, and noncompliance were predictive factors for de novo DSA formation. Nine of the 21 patients (43%) with de novo DSAs experienced an acute antibody‐mediated rejection (AMR). Positive C4d staining was more frequently observed in liver biopsies of patients with AMR (9/9 vs. 1/12, P < 0.0001). Eight patients received a B‐cell targeting therapy, and one patient received polyclonal antibodies. Only one patient required retransplantation. Patient‐ and graft‐survival rates did not differ between patients with and without DSAs. In conclusion, liver‐transplant patients with liver abnormalities should be screened for DSAs and AMR.

Inhibition of T-cell activation and proliferation by mycophenolic acid in patients awaiting liver transplantation: PK/PD relationships.

Mycophenolic acid (MPA) plasma concentrations were reported to be associated with a decrease in T-cell proliferation, and in both IL-2 α-chain (CD25) and transferin receptor (CD71) expression. The aim of this study was to confirm, quantify and model these PK/PD relationships. Full profiles of MPA plasma concentrations, T-cell proliferation, intracytoplasmic IL-2 and TNF-α expression, and both CD71 and CD25 expression were collected over the 12h after dosing in 10 patients on the waiting list for liver transplantation. Data were analyzed using NONMEM(®). Both CD25 and CD71 expression and T cell proliferation clearly decreased (median of decrease from baseline 62%, 68% and 94%, respectively) with increasing MPA concentrations, in contrast to IL-2 and TNF-α expression. The CD25 and CD71 baseline expression (E(0)) and maximum effect (E(max)) were correlated with the E(0) and E(max) values of T-cell proliferation (r(2)=0.509 and r(2)=0.622, respectively). The CD25, CD71 expression and T-cell proliferation profiles were adequately fitted using a sigmoid inhibitory E(max) model. Low estimated values (≤2 mg/L) for 50% inhibitory MPA concentrations were obtained. This study confirmed a transient MPA concentration-dependent decrease in T-cells expressing CD25 and CD71 and a strong reduction of T-cell proliferation and showed that CD25 and CD71 expression was correlated with T-cell proliferation.

Successful treatment of fibrosing cholestatic hepatitis with pegylated interferon, ribavirin and sofosbuvir after a combined kidney–liver transplantation

Fibrosing cholestatic hepatitis (FCH) is a classical but rare and severe form of recurrent hepatitis C virus (HCV) after liver transplantation. Classical anti‐HCV therapy, that is pegylated‐interferon (peg‐interferon) and ribavirin, has been shown to have limited efficacy in treating FCH. Herein, we report on the first case of successful use of peg‐interferon, ribavirin, plus sofosbuvir to treat HCV‐induced FCH in a combined liver–kidney transplant patient. Antiviral therapy was given for 24 weeks. HCV clearance occurred within 4 weeks after starting therapy and was maintained until 4 weeks after the end of therapy. Antiviral tolerance was good. We conclude that the use of sofosbuvir‐based anti‐HCV therapy can be successfully used to treat FCH after a liver or combined kidney–liver transplantation.

Impact of molecular adsorbent recirculating system on renal recovery in type-1 hepatorenal syndrome patients with chronic liver failure

Liver transplantation remains the best option for treating type‐1 hepatorenal syndrome (HRS1). The aim of this retrospective study was to determine whether the molecular adsorbent recirculation system (MARS) can improve renal function in HRS1 patients.

Donor-specific antibodies and liver transplantation.

In contrast to other types of organ transplantation, liver-transplant recipients used to be considered highly resistant to donor-specific antibodies (DSAs). Consequently, most transplant programs did not consider the presence of DSAs at transplantation or during the follow-up. However, since the early 1990s, antibody-mediated pathological lesions have been recognized in ABO-incompatible liver-transplant recipients. Recent data confirm the detrimental effect of preformed and de novo DSAs in ABO-compatible liver transplantation, with inferior clinical outcomes in patients presenting with circulating antibodies. Acute antibody-mediated rejection (AMR), plasma-cell hepatitis, biliary stricture, but also long-term complications, such as chronic rejection, liver ductopenia, and graft fibrosis, are now recognized to be associated with DSAs. Moreover, some non-HLA DSAs are suspected to induce graft dysfunction. Clinical, biological, and histological patterns within AMR need to be clarified. Treatment of these complications has yet to be defined. This article summarizes recent advances concerning the impact of preformed and de novo DSAs in liver transplantation, it defines the complications associated with DSAs, and discusses the potential strategies to manage patients with such complications.

Kidney histology and function in liver transplant patients

BACKGROUNDnChronic kidney disease is a common complication after liver transplantation. However, few reports regarding kidney histology exist for this setting.nnnMETHODSnInulin clearance was measured and a kidney biopsy was performed in 99 patients at 60 ± 48 months after liver transplantation. Kidney biopsies were scored according to the Banff classification, and interstitial fibrosis was measured by a computerized quantitative method.nnnRESULTSnThere was a steep decrease in kidney function within the first 6 months following transplantation, but this lessened thereafter. At kidney biopsy, inulin clearance and estimated glomerular filtration rate (eGFR) (using the abbreviated Modification of Diet in Renal Disease equation) were highly correlated (r(2) = 0.47, P < 0.0001). A decrease in eGFR at 6 months post-transplant was the sole predictive factor for inulin clearance of < 60 mL/min/1.73 m(2) at 5 years post-transplant. Few patients had a specific pattern of kidney histopathology and all patients had complex primary lesions. Lowered eGFR at 6 months post-transplant was a predictive factor for > 50% sclerotic glomeruli on the kidney biopsy. The duration of tacrolimus therapy, as compared to cyclosporine A, was a protective factor for < 20% interstitial fibrosis on the kidney biopsy.nnnCONCLUSIONnIn the setting of liver transplantation, this is the largest kidney-histology study to confirm that histological kidney lesions are complex, multiple and interrelated. Kidney function at 6 months post-transplant can predict long-term kidney function and histology.

Outcomes of patients with hepatocellular carcinoma are determined in multidisciplinary team meetings

To analyze overall survival (OS) rates for the three curative treatments of hepatocellular carcinoma (HCC) on an intention‐to‐treat (ITT) basis.

Histological long‐term outcomes from acute antibody‐mediated rejection following ABO‐compatible liver transplantation

Acute antibody‐mediated rejection (aAMR) is an unusual complication after orthotopic ABO‐compatible liver transplantation. To date, the clinical and histological long‐term outcomes after aAMR are not well known.