Paolo Muiesan

Vascular Hypertrophy and Remodeling in Secondary Hypertension

It has been proposed that several neurohumoral factors may be involved in the genesis of vascular structural changes (remodeling or hypertrophy) frequently observed in essential hypertension. Therefore, in this study we investigated vascular structural alterations of subcutaneous small resistance arteries in patients with secondary forms of hypertension. The study included 70 participants: 11 with pheochromocytoma, 13 with primary aldosteronism, and 17 with renovascular hypertension; 13 normotensive subjects and 16 patients with essential hypertension served as controls. All subjects were submitted to a biopsy of subcutaneous fat. Small resistance arteries were dissected and mounted on a micromyograph, and media-lumen ratio, media thickness, remodeling index, and growth index were evaluated. Endothelial function was evaluated according to the dose-response curve to acetylcholine. In patients with either primary aldosteronism or renovascular hypertension, a marked increase in media-lumen ratio was observed, whereas in patients with pheochromocytoma, the extent of vascular structural alterations was similar to that observed in patients with essential hypertension. The increase in media-lumen ratio in patients with essential hypertension and with pheochromocytoma was mainly due to vascular remodeling (remodeling index, 93% to 94%), whereas in patients with renovascular hypertension, there was vascular growth (remodeling index, 70%; growth index, 53%). Patients with primary aldosteronism had an intermediate pattern compared with the other two forms of secondary hypertension. An evident impairment of endothelial function was observed in all four hypertensive groups. In conclusion, the renin-angiotensin-aldosterone system seems to be more powerful than the adrenergic system in inducing vascular growth.

Split liver transplantation: King's College Hospital experience.

BACKGROUND The purpose of split liver transplantation is to increase the source of pediatric grafts without compromising the adult donor pool. Early results have been discouraging because of technical complications and selection of poor risk patients. METHODS The results of a single center experience of 41 split liver transplantations were analyzed. Patient and graft survival and complications related to the technique were analyzed. RESULTS Patient and graft survival for the whole group was 90% and 88% respectively at a median follow up of 12 months (range 6-70 months). Patient and graft survival for the right lobe graft was 95% and the left lateral segment 86% and 82% respectively. Four patients died, of which two of the patients were first two splits following technical complications. Two others died, one from cerebral lymphoma and the other of multiorgan failure secondary to sepsis. One patient has been retransplanted for chronic biliary sepsis. CONCLUSION Split liver transplantation has now become an acceptable treatment option for both adult and pediatric recipients with end stage liver disease. Right lobe recipients are not disadvantaged by the procedure. Good results can be achieved with better patient selection and by the use of good quality organs.

Single-center experience with liver transplantation from controlled non-heartbeating donors: a viable source of grafts.

Background:To increase the number of livers available for transplantation a non-heartbeating donor (NHBD) liver transplant program was started after obtaining hospital ethical committee approval. Methods:Controlled donors with a warm ischemia of <30 minutes were considered. A 5-minute stand-off period was observed from asystole to skin incision. A super-rapid technique was used for the retrieval. Methods used to assess the suitability for transplantation included liver function tests, morphologic and histologic assessment, and hepatocyte viability testing. Results:Sixty livers were retrieved from NHBDs. Of these, 33 were judged suitable for transplantation. Of these one was exported and transplanted, and one could not be matched to a suitable recipient. A further 27 were not used because of liver appearance in 21, prolonged hypoxia and hypotension in 4, poor perfusion in 1, and donor malignancy in 1. Mean donor age was 39.4 years (range, 0.75–67 years). Causes of death were head trauma in 10 donors, intracranial bleed in 24, and anoxic/ischemic brain injury in 26. Mean warm ischemia time was 14.7 minutes (range, 7–40 minutes). Thirty-two patients were transplanted (one split liver), and the mean age of the recipients was 38.4 years (range, 0.7–72 years). All grafts had good early function except one right lobe split. There were 4 deaths resulting from ischemic brain injury, chronic rejection, biliary sepsis, and multiorgan failure following retransplantation for primary nonfunction. Overall patient and graft survival is 87% and 84%, respectively, at a median follow-up of 15 months. Conclusions:Early results suggest that controlled NHBDs are a significant new source of grafts, but careful donor selection and short cold ischemia are mandatory.

Pregnancy outcome after liver transplantation: A single‐center experience of 71 pregnancies in 45 recipients

Infertility is common in women with end‐stage liver disease. Successful liver transplant (LT), however, can restore childbearing potential. Controversy exists regarding the most appropriate immunosuppressive regimen and timing of conception following LT. We report the outcomes of a review of all pregnancies occurring following LT at Kings College Hospital, London, from 1988 to 2004. Seventy‐one pregnancies were recorded in 45 women. Tacrolimus (60%) and cyclosporin A (38%) were the predominant primary immunosuppressive agents used. Median age at conception was 29 years (range, 19–42), with a median time from LT to conception of 40 months (range, 1–111). There were 50 live births, and no maternal or fetal deaths related to pregnancy. There were no graft losses. Median gestation was 37 weeks (range, 24–42) with a median birth weight of 2,690 g (range, 554–4,260). Caesarean section was performed in 40% of pregnancies. Complications included pregnancy‐induced hypertension in 20%, preeclampsia in 13%, acute cellular rejection in 17%, and renal impairment in 11%. There was no statistically significant difference in complication rates observed between immunosuppressive groups. Pregnancies occurring within 1‐year posttransplant had an increased incidence of prematurity, low birth weight, and acute cellular rejection compared to those occurring later than 1 year. In conclusion, this study confirms that favorable outcomes of pregnancy post‐LT can be expected for the majority of patients. However, delaying pregnancy until after 1‐year post‐LT is advisable, since doing so maybe associated with a lower risk of prematurity. Liver Transpl 12:1138–1143, 2006.

Liver transplantation in adults coinfected with HIV

OBJECTIVE To report our experience of prospectively identifying and transplanting livers into HIV-positive patients. DESIGN Liver transplantation in HIV-positive patients remains controversial. The finding of HIV is usually considered a contraindication to any form of transplantation. Previously reported cases are few and refer to patients who tested HIV positive after they had their liver transplantations or who seroconverted in the posttransplantation period. This is, to our knowledge, the only report of patients who were known to be HIV positive at the time of decision for listing for transplantation. METHODS The medical records of five HIV-positive patients who received liver transplants in Kings College Hospital, London, during a 5-year period (January 1995-December 1999) were reviewed. All five were known to be HIV positive at the time of listing for liver replacement. Three of them had end-stage liver disease due to hepatitis C (two of them had underlying Hemophilia A) while the other two had acute liver failure, one due to hepatitis B infection and one due to nonA-nonB-nonC hepatitis. In all but one patient the HIV infection had been asymptomatic. RESULTS All patients survived the immediate posttransplantation period, but the three patients with hepatitis C died of complications of recurrent hepatitis C between 6 and 25 months posttransplantation. The other two patients are currently alive 4 and 34 months posttransplantation with good graft function and without complications from their HIV infection. CONCLUSION The early outcome of liver transplantation in HIV seropositive patients can be good, and patients should not be excluded from transplantation if their liver disease determines their prognosis. More effective antiviral therapy for hepatitis C given posttransplantation, and for hepatitis B reinfection, should improve the longer-term outcome of HIV patients with end-stage liver disease due to hepatitis.

The impact of diabetes mellitus on fibrosis progression in patients transplanted for hepatitis C.

Despite the recognition of numerous factors for aggressive hepatitis C virus (HCV) recurrence after liver transplantation (LT) our understanding of this phenomenon is incomplete. We tested the hypothesis that diabetes mellitus (DM) was implicated. One hundred sixty‐three patients undergoing primary LT for HCV from 1990 to 2004 were evaluated and biopsies were scored according to the modified Ishak score. Severe recurrence of HCV was defined as a fibrosis score ≥4 within 6 years of LT. Risk factors assessed included recipient, donor and transplant variables. Fifty‐four patients (33.1%) had a fibrosis score ≥4 at the end of the study period. Factors associated with progression to severe fibrosis was donor age (p = 0.008) especially donor age >55 (p = 0.038, HR 2.43), pre‐LT DM (p = 0.039, HR 2.68) and DM post‐LT (p = 0.004, HR 3.28). The combination of receiving a liver from a donor older than 55 years and having DM post‐LT was associated with an 8.38‐fold risk of progression to severe fibrosis (p = 0.000124) when compared to patients not diabetic post‐LT who received livers from donors aged <55 years. These data indicate that diabetic status is one of the more important variables determining the severity of HCV recurrence and is synergistic with donor age. This observation may provide an additional management opportunity to modify the impact of HCV recurrence.

Media: lumen ratio in human small resistance arteries is related to forearm minimal vascular resistance.

Background For the evaluation in humans of structural alterations in resistance arteries, most studies have used an indirect index, the measurement of minimal vascular resistance (mean blood pressure divided by maximal postischaemic blood flow) in suitable vascular beds. A sensitive and specific micromyographic technique was recently made available for the study of human small resistance arteries. Whether a correlation really exists between results obtained with the two techniques has not yet been investigated. Objective To evaluate both forearm minimal vascular resistance and media: lumen ratio of omental or subcutaneous small arteries in normotensive subjects and hypertensive patients. Design and methods Thirty-four individuals were included in the study (age range 35–74 years; 24 hypertensive, 10 normotensive). Twenty-five had elective abdominal surgery and nine hypertensive patients had a gluteal biopsy. Omental and subcutaneous small arteries were dissected and mounted on a wire micromyograph (Mulvanys technique), and media: lumen ratio and media thickness were measured. The dose-response curve to noradrenaline was constructed at cumulative concentrations from 3 ± 10–9 to 3 ± 10–5 mol/l. Venous occlusion plethysmography was used to measure blood flow in the forearm, and minimal vascular resistance was calculated from mean blood pressure and postischaemic maximal blood flow (13 min ischaemia plus exercise). Results A statistically significant correlation was found between media: lumen ratio and minimal vascular resistance (r = 0.74, P < 0.001) as well as between media: lumen ratio and systolic (r = 0.44, P < 0.01) and diastolic (r = 0.38, P < 0.05) blood pressures. Similar correlations were observed between media thickness and systolic and diastolic blood pressures. Small arteries from hypertensive patients had a significantly increased reactivity to noradrenaline (by analysis of variance) compared with those from normotensive subjects, in terms of wall tension but not of active media stress. Conclusions The present study demonstrated that the media: lumen ratio of small resistance vessels is significantly related to forearm minimal vascular resistance, suggesting that direct and indirect evaluations of vascular morphology will give similar results.

Human hepatocyte isolation and relationship of cell viability to early graft function.

Hepatocyte transplantation is emerging as an additional modality of treatment for patients with acute liver failure or liver-based metabolic disorders. The procedure requires isolation of high-quality hepatocytes from unused donor livers. Hepatocytes were isolated from 20 donor livers (11 right lobes, 3 left lateral segments, 6 whole livers) using a collagenase perfusion technique. Cell viability (median 56%, range 13–95%) and yield (median 1.4 × 109 cells, range 2.0 × 106–1.8 × 1010 cells) varied according to the tissue available. Fatty livers rejected for transplantation gave lower cell viability (median 45%, range 25–59%). There was a significant correlation between age of donor (median 21 years, range 7–66 years) and viability of isolated hepatocytes in vitro (r = −0.683, p = 0.001). The 13 segments of livers were from reduced/split grafts used for clinical transplantation in 9 children and 4 adults. There was no significant correlation between in vitro cell viability and clinical parameters including intensive care stay, serum aspartate aminotransferase, and international normalized ratio (in the first 7 days), and allograft rejection or other early posttransplant complications, in patients transplanted with the corresponding tissue.

Results of split liver transplantation in children

ObjectiveTo analyze the outcome of 80 consecutive pediatric split liver transplants performed at the authors’ center between 1994 and 2000. Summary Background DataSplit liver transplantation has become an accepted method of increasing the number of available grafts for pediatric liver transplant recipients. MethodsThe age of the patients at the time of transplantation ranged from 5 days to 16 years (median 3 years). Sixteen transplants were performed for acute liver failure and 64 for chronic liver failure. The ex situ splitting technique was used for all but four grafts. Fourteen livers were split for two pediatric recipients. Posttransplant follow-up ranged from 6 to 84 months (median 42 months). ResultsOverall patient survival at 6 months follow-up was 96.2%. Graft survival at six months was 93.7%. The Kaplan-Meier patient survival rates at 1 and 3 years were 93.5% and 88.1%, and the graft survival rates were 89.7% and 86.1%, respectively. Four patients required retransplantation. In the acute group (n = 16), the patient survival rates were 93.7% at 1 year and 76.4% at 3 years; there were three deaths due to posttransplant lymphoproliferative disease (PTLD), sepsis, and chronic rejection. In the chronic group (n = 64), the 1- and 3-year patient survival rates were 93.6% and 90.9%, respectively. There were six deaths in this group. Four patients died in the first year after the transplant due to intracranial bleeding, cerebral tumor recurrence, PTLD, and chronic rejection. There were two deaths at 3 years, one due to progressive renal failure secondary to cyclosporin toxicity and the other due to sepsis, portal hypertension, and recurrent bleeding. Vascular complications occurred in six (7.5%) patients and biliary complications in seven (8.7%). ConclusionsThese results, which represent the experience of a single institution over the last 6 years, indicate that ex situ split liver transplantation can be performed in children with good overall outcome and acceptable morbidity.

Outcomes of liver transplantation in HIV‐infected individuals: The impact of HCV and HBV infection

Liver transplantation (LT) in human immunodeficiency virus (HIV)‐positive individuals is considered to be an experimental therapy with limited reported worldwide experience, and little long‐term survival data. Published data suggest that the short‐term outcome is encouraging in selected patients. Here, we report our experience in 14 HIV‐infected liver allograft recipients, and compare outcomes between those coinfected with hepatitis C virus (HCV) and the non‐HCV group. A total of 14 HIV‐infected patients (12 male, 2 female, age range 26‐59 years) underwent LT between January 1995 and April 2003. Indications for LT were HCV (n = 7), hepatitis B virus (HBV; n = 4), alcohol‐induced liver disease (n = 2), and seronegative hepatitis (n = 1); 3 patients presented with acute liver failure. At LT, CD4 cell counts (T‐helper cells that are targets for HIV) ranged from 124 to 500 cells/μL (mean 264), and HIV viral loads from <50 to 197,000 copies/mL. Nine of 12 patients were exposed to highly active antiretroviral therapy (HAART) before LT. In the non‐HCV group (n = 7), all patients are alive, all surviving more than 365 days (range 668‐2,661 days). No patient has experienced HBV recurrence, and graft function is normal in all 7 patients. However, 5 of 7 HCV‐infected patients died after LT at 95‐784 days (median 161 days). A total of 4 patients died of complications due to recurrent HCV infection and sepsis, despite antiviral therapy in 3 of them. A total of 3 patients experienced complications relating to HAART therapy. In conclusion, outcome of LT in HIV‐infected patients with HBV or other causes of chronic liver disease indicates that LT is an acceptable therapeutic option in selected patients. However, longer follow‐up in larger series is required before a conclusive directive can be provided for HCV / HIV coinfected patients requiring LT. (Liver Transpl 2004;10:1271–1278.)