Ramasamy Bakthavatsalam

Impact of cytomegalovirus in organ transplant recipients in the era of antiviral prophylaxis.

Background. Antiviral prophylaxis has been shown to decrease the incidence of cytomegalovirus (CMV) disease in organ transplant recipients, but whether CMV disease that occurs despite prophylaxis is associated with mortality remains unknown. Methods. The clinical features and risk factors for CMV disease in a cohort of liver transplant recipients who received antiviral prophylaxis were assessed retrospectively. Cox proportional hazard regression was used to assess the relationship of CMV to mortality during the first posttransplant year. Results. CMV disease developed in 37 of 437 (8.5%) recipients at a median of 4.5 (range, 2.5 to 12) months posttransplant and was associated only with donor-seropositive/recipient-seronegative serostatus in multivariate analysis (P<0.0001). Mortality at 1 year was 12% (51 of 437) and was infection-associated in 49% of cases. In multivariate analysis, CMV disease was independently associated with overall mortality at 1 year (HR, 5.1, P=0.002) and even more strongly with infection-associated mortality (HR 11, P=0.002). There was no association of CMV with noninfection-associated mortality (P>0.05). Conclusions. Late CMV disease is an important clinical problem in liver transplant recipients who receive antiviral prophylaxis, and is strongly and independently associated with mortality. Strategies to prevent late CMV disease are warranted.

Ischemic cholangiopathy following liver transplantation from donation after cardiac death donors

The use of donation after cardiac death (DCD) donor hepatic allografts is becoming more widespread; however, there have been published reports of increased graft failure from specific complications associated with this type of allograft. The complication of ischemic cholangiopathy (IC) has been reported to occur more frequently after the use of DCD hepatic allografts. We report the results of 52 liver transplants from DCD donors and the factors that influenced the development of IC. We conducted a retrospective review of all DCD and donation after brain death (DBD) donor liver recipients from September 2003 through December 2006 at a single institution. Survival and complication rates were compared between the 2 groups. The Cox proportional hazards model was then used to identify recipient and donor factors that predict the development of IC in the DCD group. There was no difference in 1‐year patient or graft survival rates between the 2 groups. There was no incidence of primary nonfunction from the DCD allografts. Hepatic artery complications and anastomotic bile duct complications were comparable in the 2 groups. There was, however, an increased risk for the development of IC in the DCD group (13.7% versus 1%, P = 0.001). Donor weight >100 kg and total ischemia times ≥9 hours, in donors older than 50 years of age, predicted the development of IC in the DCD group. In conclusion, there is a higher incidence of IC in recipients receiving DCD donor livers; however, patient and graft outcomes with DCD donors remain comparable to those with DBD donors. Careful donor selection may improve utilization of these grafts. Liver Transpl 14:604–610, 2008.

The biopsied donor liver: Incorporating macrosteatosis into high-risk donor assessment†

To expand the donor liver pool, ways are sought to better define the limits of marginally transplantable organs. The Donor Risk Index (DRI) lists 7 donor characteristics, together with cold ischemia time and location of the donor, as risk factors for graft failure. We hypothesized that donor hepatic steatosis is an additional independent risk factor. We analyzed the Scientific Registry of Transplant Recipients for all adult liver transplants performed from October 1, 2003, through February 6, 2008, with grafts from deceased donors to identify donor characteristics and procurement logistics parameters predictive of decreased graft survival. A proportional hazard model of donor variables, including percent steatosis from higher‐risk donors, was created with graft survival as the primary outcome. Of 21,777 transplants, 5051 donors had percent macrovesicular steatosis recorded on donor liver biopsy. Compared to the 16,726 donors with no recorded liver biopsy, the donors with biopsied livers had a higher DRI, were older and more obese, and a higher percentage died from anoxia or stroke than from head trauma. The donors whose livers were biopsied became our study group. Factors most strongly associated with graft failure at 1 year after transplantation with livers from this high‐risk donor group were donor age, donor liver macrovesicular steatosis, cold ischemia time, and donation after cardiac death status. In conclusion, in a high‐risk donor group, macrovesicular steatosis is an independent risk factor for graft survival, along with other factors of the DRI including donor age, donor race, donation after cardiac death status, and cold ischemia time. Liver Transpl 16:874–884, 2010.

Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation

Orthotopic liver transplantation (OLT) is the only effective treatment for end‐stage liver disease due to primary sclerosing cholangitis (PSC). Recurrence of PSC has recently emerged as a leading cause of allograft failure in the long term. There is limited data on risk factors for recurrence of PSC. We performed a retrospective analysis of 69 consecutive patients who underwent a first OLT for PSC over a 14‐year period. Baseline characteristics and clinical and laboratory test results post‐LT were recorded. Cholangiograms and liver histopathology were reviewed in a blinded manner by an experienced radiologist and hepatopathologist. Recurrent PSC was diagnosed using previously published Mayo Clinic cholangiographic or histologic criteria. Of 69 patients, 7 (10%) developed recurrent PSC at a median of 68 months (range, 24‐134 months) post‐LT. The following variables were associated with recurrent PSC in our cohort: presence of human leukocyte antigen (HLA)‐DRB1*08 (29% versus 2%; P= 0.026; odds ratio [OR], 24.4; 95% confidence interval [CI], 1.8‐318.1), acute cellular rejection (ACR) (71% versus 22%; P= 0.015; OR, 8.7; 95% CI, 1.5‐49.9), and steroid‐resistant ACR (29% versus 0%; P= 0.012). Despite the strong linkage disequilibrium between DRB1*08 and DQB1*04, DRB1*08‐positive subjects with recurrence were negative for DQB1*04, whereas the single DRB1*08‐positive subject without recurrent PSC was positive for DQB1*04. A history of ACR and presence of HLA‐DRB1*08 are associated with increased risk of recurrent PSC, suggesting an immunologic mechanism for this syndrome. Further studies are required to confirm these observations and to understand the underlying mechanisms. Liver Transpl 14:245–251. 2008.

Identifying risk for recurrent hepatocellular carcinoma after liver transplantation: Implications for surveillance studies and new adjuvant therapies

The recurrence of hepatocellular carcinoma (HCC) is a major cause of mortality for patients transplanted with HCC. There currently exists no standard method for identifying those patients with a high risk for recurrence. Identification of factors leading to recurrence is necessary to develop an efficient surveillance protocol and address new potential adjuvant therapies. We conducted a retrospective review of 834 consecutive liver transplants from 1/1/1996 to 12/31/2005 (mean follow‐up 1303 ± 1069 days) at one institution and 352 consecutive transplants from 1/2/2002 to 12/31/2005 (mean follow‐up 836 ± 402 days) at a second institution. The test cohort comprised patients identified with HCC in their explanted livers from 1/1/2001 to 12/31/2005 at the first institution. Explant pathology and donor and recipient characteristics were reviewed to determine factors associated with HCC recurrence. These predictors were validated in the remaining liver transplant recipients. The test cohort had 116 patients with findings of HCC in their explanted livers. Twelve patients developed recurrent HCC. Stepwise logistic regression identified 4 independent significant explant factors predictive of recurrence. Size of one tumor (>4.5 cm), macroinvasion, and bilobar tumor were positive predictors of recurrence, whereas the presence of only well‐differentiated HCC was a negative predictor. Designating each significant factor with points in relation to its odds ratio, a Predicting Cancer Recurrence Score (PCRS) with results ranging from −3 to 6 was developed that accurately determined risk of recurrence. These findings were then applied to the two validation cohorts, which confirmed the high predictive value of this model. In conclusion, patients transplanted for HCC with a PCRS of ≤0 have a low risk of recurrence. Patients with a PCRS of 1 or 2 have a moderate risk of recurrence, and those with a PCRS of ≥3 have a high risk for recurrence. Liver Transpl 14:956–965, 2008.

A Randomized Clinical Trial Testing the Anti-Inflammatory Effects of Preemptive Inhaled Nitric Oxide in Human Liver Transplantation

Decreases in endothelial nitric oxide synthase derived nitric oxide (NO) production during liver transplantation promotes injury. We hypothesized that preemptive inhaled NO (iNO) would improve allograft function (primary) and reduce complications post-transplantation (secondary). Patients at two university centers (Center A and B) were randomized to receive placebo (n = 20/center) or iNO (80 ppm, n = 20/center) during the operative phase of liver transplantation. Data were analyzed at set intervals for up to 9-months post-transplantation and compared between groups. Patient characteristics and outcomes were examined with the Mann-Whitney U test, Student t-test, logistic regression, repeated measures ANOVA, and Cox proportional hazards models. Combined and site stratified analyses were performed. MELD scores were significantly higher at Center B (22.5 vs. 19.5, p<0.0001), surgical times were greater at Center B (7.7 vs. 4.5 hrs, p<0.001) and warm ischemia times were greater at Center B (95.4 vs. 69.7 min, p<0.0001). No adverse metabolic or hematologic effects from iNO occurred. iNO enhanced allograft function indexed by liver function tests (Center B, p<0.05; and p<0.03 for ALT with center data combined) and reduced complications at 9-months (Center A and B, p = 0.0062, OR = 0.15, 95% CI (0.04, 0.59)). ICU (p = 0.47) and hospital length of stay (p = 0.49) were not decreased. iNO increased concentrations of nitrate (p<0.001), nitrite (p<0.001) and nitrosylhemoglobin (p<0.001), with nitrite being postulated as a protective mechanism. Mean costs of iNO were

Unexpected surgical difficulties leading to hemorrhage and gas embolus during laparoscopic donor nephrectomy: a case report

1,020 per transplant. iNO was safe and improved allograft function at one center and trended toward improving allograft function at the other. ClinicalTrials.gov with registry number 00582010 and the following URL:http://clinicaltrials.gov/show/NCT00582010.

Should Liver Transplantation in Patients with Model for End-Stage Liver Disease Scores < 14 Be Avoided? A Decision Analysis Approach

PurposeTo report the case of a laparoscopic donor nephrectomy in which the preoperative evaluation of the patient gave no indication of the surgical difficulties that were encountered intraoperatively, resulting in substantial bleeding, a suspected gas embolism, and emergency conversion of the procedure from laparoscopic to open donor nephrectomy.Clinical featuresA 59-yr-old man - height: 175 cm, weight: 85.5 kg, American Society of Anesthesiologists physical status I - presented as kidney donor for laparoscopic donor nephrectomy. He was healthy, on no medication, and had no previous abdominal surgery or diseases of the urinary tract. The preoperative computed tomography (CT) scan evaluation of his kidneys confirmed this by reporting a normal bilateral renal and renal vascular anatomy. In contradiction to the preoperative CT scan findings, the surgeon discovered abnormalities in the operative field. This included extensive scarring surrounding the left kidney, adenopathy near the right hilum, and a large branch lumbar vein entering the renal vein. The large branch lumbar vein was clipped but the clips dislodged, causing significant blood loss, and a suspected gas embolus. The procedure was converted to an emergency open donor nephrectomy. Postoperatively the patient made a full recovery.ConclusionLaparoscopic donor nephrectomies, though usually performed on healthy individuals, have their pitfalls, and complications during this procedure can be sudden and serious. As shown in this case, although CT scan results are regarded as reliable, they can be misleading. As an anesthetic precaution for possible gas emboli during laparoscopic procedures, nitrous oxide should be avoided and the patient be ventilated with 100% oxygen.RésuméObjectifPrésenter le cas d’une néphrectomie laparoscopique chez un donneur, Lévaluation préopératoire du patient n’avait donné aucune indication des difficultés chirurgicales peropératoires rencontrées qui ont causé un important saignement, une embolie gazeuse probable et la conversion d’urgence de la technique laparoscopique en néphrectomie ouverte.Éléments cliniquesUn homme de 59 ans, 175 cm, 85,5 kg et d’état physique ASA I, s’est présenté comme donneur de rein pour une néphrectomie laparoscopique. Il était en bonne santé, ne prenait aucun médicament et n’avait pas d’antécédent chirurgical abdominal ou de maladies des voies urinaires. L’évaluation préopératoire par tomodensitométrie des reins a confirmé la situation en montrant une anatomie rénale et vasculaire rénale normale bilatérale. Pourtant, le chirurgien a découvert des anomalies au niveau du site opératoire. Elles comprenaient une cicatrisation importante autour du rein gauche, des adénopathies près du hile droit et un grand rameau de la veine lombaire pénétrant dans la veine rénale. Ce rameau a été clippé, mais les clips se sont détachés, ce qui a provoqué une perte de sang significative et une embolie gazeuse probable. La laparoscopie a été convertie en néphrectomie ouverte d’urgence. Le patient s’est complètement rétabli par la suite.ConclusionLes néphrectomies laparoscopiques chez les donneurs d’organes, quoique réalisées habituellement chez des personnes en bonne santé, ont aussi leurs pièges. Les complications qui peuvent survenir sont parfois soudaines et critiques. Comme ce cas le montre, même les résultats de la tomodensitométrie, considérés comme fables, peuvent être trompeurs. Le protoxyde d’azote devrait être évité et le patient ventilé avec de l’oxygène à 100% afin de prévenir une possible embolie gazeuse pendant les interventions chirurgicales laparoscopiques.

Treatment of severe lactic acidosis during the pre-anhepatic stage of liver transplant surgery with intraoperative hemodialysis

Studies have shown that liver transplantation offers no survival benefits to patients with Model for End‐Stage Liver Disease (MELD) scores ≤ 14 in comparison with remaining on the waitlist. The consensus of a 2003 transplant community national conference was that a minimum MELD score should be required for placement on the liver waitlist, but no minimum listing national policy was enacted at that time. We developed a Markov microsimulation model to compare results under the present US liver allocation policy with outcomes under a “Rule 14” policy of barring patients with a MELD score of ≤14 from the waitlist or transplantation. For probabilities in the microsimulation model, we used data on all adult patients (≥18 years) listed for or undergoing primary liver transplantation in the United States for chronic liver disease from 1/1/2003 through 12/31/2007 with follow‐up until 2/1/2008. The “Rule 14” policy gave a 3% improvement in overall patient survival over the present system at 1, 2, 3, and 4 years and predicted a 13% decrease in overall waitlist time for patients with MELD scores of 15 to 40. Patients with the greatest benefit from a “Rule 14” policy were those with MELD scores of 6 to 10, for whom a 17% survival advantage was predicted from waiting on the list versus undergoing transplantation. Our analysis supports changing the national liver allocation policy to not allow liver transplantation for patients with MELD ≤ 14. Liver Transpl 15:242–254, 2009.

Postrenal transplant non-EBV multiple myeloma of donor origin.

Severe uncompensated lactic acidosis manifesting during the pre-anhepatic stage of orthotopic liver transplant surgery is an uncommon event, but it poses serious concern because of the additional lactate production and impaired elimination by the liver that develops during the anhepatic and allograft reperfusion stages of the procedure. A man with end-stage liver disease secondary to hepatitis C and hemochromatosis and normal renal function, who developed severe lactic acidosis in the pre-anhepatic stage of liver transplantation, was treated successfully with intraoperative, continuous venovenous hemodialysis. Hemodialysis effectively corrected the patients lactic acidosis and removed lactate, which contributed to hemodynamic stability during the anhepatic and graft reperfusion stages of his liver transplant surgery.