E Shaharabani

Kidney transplantation from living-unrelated donors: comparison of outcome with living-related and cadaveric transplants under current immunosuppressive protocols

OBJECTIVES Living-unrelated donors may become an additional organ source for patients on the kidney waiting list. We studied the impact of a combination of calcineurin inhibitors and mycophenolate-mofetil together with steroids on the outcomes of living-related (LRD), unrelated (LUR), and cadaver transplantation. METHODS Between September 1997 and January 2000, 129 patients underwent LRD (n = 80) or LUR (n = 49) kidney transplantation, and another 173 patients received a cadaveric kidney. Immunosuppressive protocols consisted of mycophenolate-mofetil with cyclosporine-Neoral (41%) or tacrolimus (59%) plus steroids. We compared the patient and graft survival data, rejection rate, and graft functional parameters. RESULTS LRD recipients were younger (33.6 years) than LUR (47.8 years) and cadaver (43.7 years) donor recipients (P <0.001). HLA matching was higher in LRD patients (P <0.001). Acute rejection developed in 28.6% of LUR versus 27.5% of LRD transplants and 29.7% of cadaver kidney recipients (P = not significant). The creatinine level at 1, 2, and 3 years after transplant was 1.63, 1.73, and 1.70 mg% for LRD patients; 1.48, 1.48, and 1.32 mg% for LUR patients; and 1.75, 1.68, and 1.67 mg% for cadaver kidney recipients (P = not significant), respectively. No difference in patient survival rates was found among the groups. The 1, 2, and 3-year graft survival rates were significantly better in recipients of LRD (91.3%, 90.0%, and 87.5%, respectively) and LUR transplants (89.8%, 87.8%, and 87.8%, respectively) than in cadaver kidney recipients (81.5%, 78.6%, 76.3%, respectively; P <0.01). CONCLUSIONS Despite HLA disparity, the rejection and survival rates of LUR transplants under current immunosuppressive protocols are comparable to those of LRD and better than those of cadaveric transplants.

Hepatic artery thrombosis in pediatric liver transplantation: Graft salvage after thrombectomy

Abstract: Hepatic artery thrombosis (HAT) is a devastating complication that may occur after orthotopic liver transplantation (OLT). A higher incidence has been reported in children. Salvage of the graft by thrombectomy has been suggested as an alternative to re‐transplantation. In this study we report the outcome of three children who underwent thrombectomy for HAT. Between January 1992 and June 1998, 14 children (< 17 yrs of age) underwent liver transplantation. Three developed HAT (one a whole‐liver graft recipient, age 17; two living‐related graft recipients, ages 4 and 4.5 yr). In the first patient, thrombosis of the hepatic artery was associated with scattered areas of parenchymal necrosis on computed tomography. In the two living‐related patients, HAT was found incidentally during re‐exploration for bleeding (day 2 and day 10). Thrombectomy was performed in all three patients. At 18–24 months after thrombectomy, all three children had normal graft function. In the first patient, complete regeneration of the liver has been documented by computed tomography and a late asymptomatic recurrent thrombosis is suggested by absence of arterial flow on Doppler examination. The hepatic artery is patent in the two living‐related recipients. One of these living‐related recipients developed ischemic bile duct stricture and underwent successful percutaneous balloon dilatation. We conclude that long‐term normal graft function can be achieved by thrombectomy in pediatric liver recipients with HAT, even in the presence of limited parenchymal damage.

Serum cholestasis markers as predictors of early outcome after liver transplantation

Abstract:  Background:  Early cholestasis is not uncommon after liver transplantation and usually signifies graft dysfunction. The aim of this study was to determine if serum synthetic and cholestatic parameters measured at various time points after transplantation can predict early patient outcome, and graft function.

BK polyoma virus nephropathy in kidney transplant recipient: the role of new immunosuppressive agents.

BK POLYOMA virus (BKV) is a newly described agent causing renal dysfunction and failure among kidney transplant recipients. The virus remains latent following primary exposure at childhood and becomes activated in immunocompromised states. Clinically, the virus rarely causes symptoms such as hemorrhagic cystitis in bone marrow transplant recipients. Although viral shedding is detected in urine specimens of many renal transplant recipients, only a few will develop BKV transplant nephropathy. This disease process is characterized by a rapidly progressive loss of graft function. Introduction of new and more aggressive immunosuppressive protocols may explain the emergence of this new infectious complication. We describe our experience with 7 patients with BKV nephropathy with specific attention to possible risk factors.

Defibrotide for the treatment of veno-occlusive disease after liver transplantation.

Background. Veno-occlusive disease (VOD) after liver transplantation is associated with acute rejection and poor outcome. The use of antithrombotic and thrombolytic agents is limited by their toxicity. Defibrotide is a polydeoxyribonucleotide with thrombolytic and antithrombotic properties and no systemic anticoagulant effect. Methods. Defibrotide, 35–40 mg/kg/day, was administered intravenously for 21 days on a compassionate-use basis to two patients aged 66 and 49 years. VOD had developed 6 weeks and 4 months after orthotopic liver transplantation for hepatitis C and hepatitis B infection, respectively. VOD was diagnosed clinically by findings of weight gain (8.5% and 16%), ascites, jaundice (serum bilirubin 5.4 mg/dl and 21.7 mg/dl), and severe coagulopathy (in one patient), and histologically by the presence of hemorrhagic centrilobular necrosis and fibrous stenosis of the hepatic venules. One of the patients had received azathioprine as part of the immunosuppressive regimen. There was no evidence of acute cellular rejection histologically. Results. After 3 weeks of defibrotide administration, the first patient showed complete clinical resolution of the VOD, and serum bilirubin level normalized. He is alive 6 months after transplantation. The second patient, treated at a later stage of disease, showed marked improvement in the coagulopathic state, but there was no resolution of the VOD. He died 2 months later of multiorgan failure due to Escherichia coli sepsis. Neither patient had side effects from the drug. Conclusions. Defibrotide is a promising drug for the treatment of VOD after liver transplantation and needs to be evaluated in large, prospective studies.

Magnetic resonance cholangiopancreatography for the accurate diagnosis of biliary complications after liver transplantation: comparison with endoscopic retrograde cholangiography and percutaneous transhepatic cholangiography – long‐term follow‐up

Katz LH, Benjaminov O, Belinki A, Geler A, Braun M, Knizhnik M, Aizner S, Shaharabani E, Sulkes J, Shabtai E, Pappo O, Atar E, Tur‐Kaspa R, Mor E, Ben‐Ari Z. Magnetic resonance cholangiopancreatography for the accurate diagnosis of biliary complications after liver transplantation: comparison with endoscopic retrograde cholangiography and percutaneous transhepatic cholangiography – long‐term follow‐up.
Clin Transplant 2010: 24: E163–E169.

Neuregulins rescue PC12-ErbB-4 cells from cell death induced by β-amyloid peptide

Neuregulins (NRGs), which are highly expressed in the nervous system, bind and activate two receptor tyrosine kinases, ErbB-3 and ErbB-4. We previously showed that NRG mediates survival of PC12-ErbB-4 cells from apoptosis induced by serum deprivation, tumor necrosis factor-α treatment, or H2O2. These effects of NRGs are mediated by the phosphoinositide 3-kinase (PI3K) signaling pathway. In the present study, we show that NRG induces a significant protective effect from β-amyloid 25–35 (Aβ[25–35]) peptide-induced cell death. The PI3K signaling pathway might be involved in this effect of NRG as the downstream effector of PI3K, protein kinase B (PKB/AkT), is activated by NRG in the presence of Aβ, and PKB/AkT activation is inhibited by the PI3K inhibitor, LY294002. In addition, our results demonstrate that Aβ-induced cell death is reduced by expression of activated PI3K. These results suggest that PI3K-dependent pathways might regulate the toxic effect of Aβ. In addition, Aβ induced alteration in the levels of the proapoptotic protein Bax. Neuregulin (NRG) treatment however, induced elevation in the levels of the antiapoptotic protein BclxL. The NRG-mediated BclxL elevation is regulated by protein kinase C (PKC), as NRG failed to elevate BclxL in the presence of the PKC inhibitor, GF109203X. Moreover, activation of PKC by phorbol 12-myristate 13-acetate markedly attenuated cell death induced by Aβ and induced elevation in BclxL levels. The results suggest that NRG might affect cell viability using two signaling pathways: activation of PI3K/PKB/AkT pathway and activation of PKC, which results in increasing levels of the antiapoptotic protein BclxL.

Postshunt hepatic encephalopathy in liver transplant recipients.

Background. Preexisting spontaneous portosystemic shunts increase the risk of posttransplantation portal vein thrombosis. Portosystemic shunts may also be placed surgically to manage posttransplant portal vein stenosis/thrombosis. Both types may be complicated by hepatic encephalopathy. Methods. The database of a major tertiary medical center from 1999 to 2006 was searched for liver transplant recipients with hepatic encephalopathy and stable liver function. The medical and imaging files were reviewed for risk factors, management, and outcome. Results. Of the 244 patients who underwent liver transplantation during the study period, four (1.6%) met the inclusion criteria. Median age at transplantation was 49 years (range 39–54); median time to the first episode of hepatic encephalopathy after transplantation was 23 months (range 2–40). In two patients, a distal splenorenal shunt placed at 1 and 7 months after transplantation to treat portal vein thrombosis led to hepatic encephalopathy at 1 and 33 months later. Both responded to medical therapy. The other two patients had spontaneous splenorenal shunts, and hepatic encephalopathy appeared 33 months and 12 months after transplantation. Treatment consisted of transhepatic percutaneous portal vein dilatation with stent insertion in the first patient and interposition of a venous graft between the superior mesenteric and left intrahepatic portal veins to reroute splanchnic flow in the second patient. Conclusions. Portosystemic shunts in liver transplant recipients with stable graft function may be associated with hepatic encephalopathy. Pretransplant assessment to detect unknown spontaneous shunts is important. Restoration of portal flow is the preferred procedure in this setting.

Sequential liver and kidney transplantation from a single living donor in two young adults with primary hyperoxaluria type 1

Using living donor organs for sequential liver and kidney transplantation (SeqLKT) in patients with primary hyperoxaluria type 1 (PH1) has emerged as a viable approach. Taking both organs from a single donor, however, is rare. There are 8 reported cases of SeqLKT in the literature, and in all but 1 case, children were the recipients. We present our experience with SeqLKT in 2 young adults with PH1. In the first case, with an interval between procedures of 4.5 months, SeqLKT was performed with a right liver lobe from a 47‐year‐old father for his 19‐year‐old son with PH1 who was on dialysis for 2 years before transplantation. Both the donor and the recipient had an uneventful recovery, although there was re‐exploration for the control of bleeding in the recipient after liver transplantation. Thirty‐three months after transplantation, the patient had normal liver and renal function. In the second case, with an interval between procedures of 22 days, SeqLKT was performed with organs from a 45‐year‐old father for his 19‐year‐old daughter with PH1 who was on dialysis for 8 months. The recipient procedures, including right liver lobe transplantation and kidney transplantation, were uneventful. The donor underwent percutaneous drainage of a subphrenic collection and subsequently fully recovered. Eighteen months after transplantation, the recipients liver and renal allograft function was normal. In conclusion, because of the severe organ shortage, living related SeqLKT using the same donor should be carefully considered for young adults with PH1. Liver Transpl 19:646–648, 2013.

Recurrent hepatitis C virus disease after liver transplantation and concurrent biliary tract complications: poor outcome.

Abstract:  Recurrent hepatitis C virus (HCV) infection is particularly aggressive in the post‐liver transplantation setting, with rapid progression of liver fibrosis. Biliary complications remain a significant cause of morbidity following liver transplantation. Post‐cholecystectomy biliary strictures are associated with advanced hepatic fibrosis. The aim of this retrospective study was to determine whether the presence of biliary complications affects survival in liver transplant recipients with recurrent HCV disease. The files of liver transplant recipients (53.7% male; mean age 52.7 ± 10.3 yr) were reviewed for incidence, type and treatment of biliary complications, and findings were compared between those who developed recurrent HCV disease (n = 47, 83.9%) and those who did not (n = 9). Twenty‐one biliary complications developed in 12 patients with recurrent HCV (25.5%). Treatment with endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography with balloon dilatation and stent placement or surgical revision was successful in nine (75%). Three biliary complications developed in three patients with no recurrence (p = NS). There was no statistically significant association between recurrent HCV disease and biliary complications. However, among those with recurrent disease, the recurrence was severe in nine of 12 recipients with biliary complications (75%) but in only nine of 35 without biliary complications (26%) (p = 0.001). Death was documented in eight patients with severe recurrence (44.4%), including three (37.5%) with biliary complications and two (7%) with non‐severe recurrence, neither of whom had biliary complications (p = 0.003). Antiviral treatment was successful in nine of 25 patients (36%) who received it. On multivariate analysis, biliary complications were a significant predictor of severe recurrence (OR 27.0, 95% confidence interval 2.07–351.4) (p = 0.012). Fibrosis stage in the second biopsy was significantly correlated with serum alanine aminotransferase (p = 0.01) and with duration of biliary obstruction (p = 0.07). In conclusion, biliary complications of liver transplantation strongly affect outcome in patients with recurrent HCV disease despite attempts to relieve the biliary obstruction and to treat the recurrent HCV disease.