Steven M. Rudich

Long‐term survival after liver transplantation in children with metabolic disorders

Abstract: Background: Liver transplantation for inherited metabolic disorders aims to save the patients life when the disorder is expected to progress to organ failure, and to cure the underlying metabolic defect. Methods: We retrospectively analyzed 146 pediatric liver transplants (28 metabolic; 118 non‐metabolic) performed between 1986 and 2000. Results: Twenty‐eight transplants were performed in 24 children with metabolic disease (8 females; 16 males; age range 3u2003months to 17u2003yr). Indications included α−1‐antitrypsin deficiency (nu2003=u20038), two cases each of hyperoxaluria type 1, Wilsons disease, hereditary tyrosinemia type I, citrullinemia, methylmalonic acidemia, and one case each of propionic acidemia, Crigler–Najjar syndrome type I, neonatal hemachromatosis, hemophilia B, Niemann–Pick disease type B, and cystic fibrosis. Eighteen transplants were whole organ grafts and 10 were lobar or segmental. Auxiliary liver transplants were performed in two patients and three received combined liver‐kidney transplants. There were three deaths from sepsis, two from chronic rejection, and one from fulminant hepatitis. Seven of 10 patients currently of school age are within 1u2003yr of expected grade and three who had pretransplant developmental delay have remained in special education. Actuarial survival rates at 5 and 10u2003yr are 78% and 68%, respectively, with mean follow‐up in excess of 5u2003yr. These results compare favorably to 100 pediatric patients transplanted for non‐metabolic etiologies (65% and 61%, respectively) (p=u200aNS). Conclusions: Pediatric liver transplantation for metabolic disorders results in excellent clinical and biochemical outcome with long survival and excellent quality of life for most recipients.

Interaction Between Donor and Recipient Age in Determining the Risk of Chronic Renal Allograft Failure

OBJECTIVESnDonor age is a known risk factor for chronic allograft failure (CAF) in renal transplant recipients. We have recently shown that advanced recipient age is also a risk factor for CAF. To investigate the interaction between donor and recipient age, we analyzed 40,289 primary solitary Caucasian adult renal transplants registered at the United States Renal Data System (USRDS) from 1988 to 1997.nnnDESIGNnCAF was defined as allograft loss beyond 6 months posttransplantation, censored for death, recurrent disease, acute rejection, thrombosis, noncompliance, infection, or technical problems. Cox proportional hazards models were used to investigate the risk of allograft loss secondary to CAF. All models were corrected for 15 covariates including donor and recipient demographics, ischemic time, and human leukocyte antigen match. Donor and recipient age were categorized, and relative risk for allograft loss of the interaction between the obtained categorical covariates was evaluated.nnnSETTINGnRetrospective data analysis using the USRDS.nnnPARTICIPANTSnAll primary Caucasian renal transplant recipients from 1988 to 1997.nnnRESULTSnPatients aged 55 and older who received donor kidneys had a 110% increased risk of CAF (relative risk (RR) = 2.1, 95% confidence interval (CI) = 1.9-2.3, P< .001) and recipients aged 65 and older had a 90% increased risk for CAF (RR = 1.9, 95% CI = 1.61-2.1, P< .001), compared with the youngest reference groups. In addition, there was an additive and, in the long term, synergistic interaction between donor and recipient age in determining allograft loss.nnnCONCLUSIONSnDonor and recipient age had an independent, equivalently detrimental effect on renal allograft survival. An overall additive and, in the long term (beyond 36 months posttransplant), synergistic deleterious effect on renal allograft survival was observed for the interaction of donor and recipient age.

Preparation and characterization of implantable sensors with nitric oxide release coatings

The widespread use of miniaturized chemical sensors to monitor clinically important analytes such as PO2, PCO2, pH, electrolytes, glucose and lactate in a continuous, real-time manner has been seriously hindered by the erratic analytical results often obtained when such devices are implanted in vivo. One major factor that has influenced the analytical performance of indwelling sensors is the biological response they elicit when in contact with blood or tissue (e.g. thrombus formation on the device surface, inflammatory response, encapsulation, etc.). Nitric oxide (NO) has been shown to be a potent inhibitor of platelet adhesion and activation as well as a promoter of wound healing in tissue. Herein, we review recent work aimed at the development of hydrophobic NO-releasing polymers that can be employed to coat catheter-type amperometric oxygen sensors without interfering with the analytical performance of these devices. Such modified sensors are shown to exhibit greatly enhanced hemocompatibility and improved analytical performance when implanted within porcine carotid and femoral arteries for up to 16 h. Further, results from preliminary studies also demonstrate that prototype fluorescent oxygen sensors, catheter-style potentiometric carbon dioxide sensors and subcutaneous needle-type enzyme-based amperometric glucose sensors can also be fabricated with new NO-release outer coatings without compromising the analytical response characteristics of these devices. The NO-release strategy may provide a solution to the lingering biocompatibility problems encountered when miniature chemical sensors are implanted in vivo.

Epithelioid hemangioendothelioma of the liver disseminated to the peritoneum treated with liver transplantation and interferon alpha-2B.

Epithelioid hemangioendothelioma (EH) is a rare, low-grade, malignant neoplasm of vascular origin that may develop at different sites, such as in the soft tissue, lungs, or liver. We report the case of a 21-year-old female with primary EH of the liver treated by liver transplantation and review the available literature on EH. This patient developed symptomatic recurrence of the tumor in the pelvis 2 months posttransplant. Treatment with interferon alpha-2b resulted in substantial regression of the pelvic metastases and alleviation of symptoms, but the patient developed graft rejection and died of associated complications 16 months posttransplant. This report is the first showing the efficacy of interferon in this setting.

Gender imbalance in living donor renal transplantation

BACKGROUNDnPrevious studies have shown more women than men among living donors (LD) and more men among recipients of those kidneys. In this study, we compared the evolving demographics of LD transplants.nnnMETHODSnWe retrospectively analyzed all LD transplants performed in our center between 1964 and 2000.nnnRESULTSnAmong 1182 LD cases, 1035 (88%) were biologically related (LRD) and 147 (12%) were unrelated (LURD). LURD donors and recipients were significantly older than LRD donors and recipients, respectively (P=0.0001). More LURD allograft recipients were male (71%) compared with LRD recipients (57%) (P=0.0013). The proportion of female donors was 55% in both groups. Spousal donations were predominantly wife-to-husband (69%). Compared with the LRD group, there was a greater proportion of female-to-male LURD transplants (46 vs. 30%) and a smaller proportion of female-to-female LURD transplants (10 vs. 25%) (P=0.0001). When spousal pairs were excluded from the analysis, there was a higher proportion of male-to-male (48 vs. 27%) donations and a lower proportion of male-to-female (18 vs. 9%) and female-to-female (25 vs. 17%) transplants in the LURD group (P=0.001).nnnCONCLUSIONSnGender disparities in LD transplantation are primarily due to a higher proportion of wife-to-husband donations and a lower incidence of male-to-female grafts among nonspousal LURD transplants. Strategies should be devised to ensure access for women to renal transplantation and to encourage and facilitate donation by men.

INTERACTION OF MYCOPHENOLATE MOFETIL AND HLA MATCHING ON RENAL ALLOGRAFT SURVIVAL

Introduction. The importance of HLA matching for renal transplantation outcomes has been appreciated for several decades. It has been hypothesized that as pharmacologic immunosuppression becomes stronger and more specific, the impact of HLA matching may be vanishing. Mycophenolate Mofetil (MMF) has been demonstrated to both decrease acute rejection and improve three-year graft survival. It is possible that with new immunosuppressive regimens containing MMF the relative effect of HLA matching may be altered. To determine the relative impact of HLA matching in patients on MMF we undertook an analysis of the United States Renal Transplant Data Registry (USRDS). Methods. All primary, solitary renal transplants registered at the USRDS between January 1995 and June 1997, on initial immunosuppression that included either MMF or AZA were followed until June 1998. Primary study end points were graft and patient survival. Kaplan-Meier analysis was performed to compare AZA vs. MMF treated patients by HLA mismatch. Cox proportional hazard models were used to investigate the interaction between HLA mismatch and AZA versus MMF therapy on the study endpoints. All multivariate analyses were corrected for 13 potential confounding pretransplant variables including intention to treat immunosuppression. Results. A total of 19,675 patients were analyzed (8,459 on MMF and 11,216 on AZA). Overall three year graft survival was higher in the MMF group when compared to the AZA group (87% vs. 84% respectively P <0.001). For both AZA and MMF three-year graft survival improved with fewer HLA donor-recipient mis-matches. Comparing zero antigen mismatches to six antigen mismatches, the relative improvement was comparable for both patients on AZA (92.4% vs. 80.6%) and MMF (95.2% vs. 82.9%). By Cox proportional hazard model the relative risk for graft loss decreased significantly in both the AZA and MMF treated patients with increased HLA matching. Conclusion. The use of MMF does not obviate the benefits of HLA matching, while HLA matching does not minimize the benefits of MMF on long term graft survival. Our study would suggest that HLA matching and MMF therapy are additive factors in decreasing the risk for renal allograft loss.

Improved planar amperometric nitric oxide sensor based on platinized platinum anode. 2. Direct real-time measurement of NO generated from porcine kidney slices in the presence of l-arginine, l-arginine polymers, and protamine.

Nitric oxide generation from porcine kidney slices is assessed using a new planar NO-selective amperometric sensor. The planar shape of the sensor allows for direct NO measurements near the surface (10 microm) of renal tissue slices in real time. Renal NO production may be modulated by the addition of L-arginine, arginine homopolymers (R2, R6, R10), and protamine, all of which can potentially transport across cellular membranes and provide a substrate for nitric oxide synthase within kidney parenchyma. Real-time amperometric measurements demonstrate that most L-arginine species can translocate across the cell membrane and rapidly increase NO production. However, no increase in NO generation is observed when the dimer of L-arginine (R2) is added to the solution bathing the tissue, suggesting that this species cannot permeate cell membranes. The degree of enhancement in NO generation observed for L-arginine and the larger peptides depends on the structure and follows the following sequence: R10 (decamer) > protamine > R6 (hexamer) > L-arginine. Protamine and the R10 decamer, especially, induce the largest increases in NO generation owing to their apparent rapid translocation into cells and subsequent cleavage by proteases to create high intracellular levels of L-arginine. The effect of sensor size (for sensor dimensions of 0.15- and 1-mm outer diameters) on the measured surface NO levels is also examined. The larger sensor traps more NO but hinders access of the L-arginine species to the tissue area between the flat distal plane of the sensor and the surface of the kidney slice. The use of such NO-generating peptides may be important in numerous biological systems that depend on NO production, such as ischemia-reperfusion injury and thrombogenesis.

Liver Transplantation in Children with Metabolic Disorders in the United States

We studied pediatric liver transplantation for metabolic disease in a large national cohort to determine whether smaller studies suggesting a survival advantage for these recipients could be corroborated. We also hoped to determine whether higher survival rates in recipients with metabolic disease are associated with lack of structural liver disease, and to evaluate these recipients risk factors for mortality. Data from the Scientific Registry of Transplant Recipients were used to analyze nationwide results (1990–99) of pediatric liver transplantation for patients with biliary atresia and metabolic disease. Adjusted patient survival rates for children with metabolic disease at 1 and 5u2003years were 94% and 92%, respectively, – significantly higher than for recipients with biliary atresia (90% and 86%) (pu200a=u200a0.008). Cox regression models identified recipient black race [relative risk (RR)u2003=u20035.1] and simultaneous transplantation of other organs (RRu2003=u20033.2) as significant risk factors for mortality in the metabolic group. Adjusted survival rates for metabolic patients with structural and nonstructural liver diseases were similar to each other at both 1 and 5 years. Children with metabolic disease had significantly higher adjusted short‐ and long‐term post‐transplant survival rates than those with biliary atresia. Structural disease was not a risk factor for worse outcomes.

Evaluation of pancreatic allograft dysfunction by laparoscopic biopsy.

Background. Histologic evaluation of a failing pancreatic allograft is necessary for accurate classification of graft dysfunction. Unlike percutaneous or transcystoscopic techniques, laparoscopic biopsy allows visualization of the allograft in addition to obtaining tissue for histologic examination. Methods. We retrospectively reviewed all laparoscopic pancreas transplant biopsies performed over a 15-month period ending February 2002. Results. There were 12 laparoscopic pancreas biopsies performed in 11 patients between 6 weeks and 8 years (mean 2.5±2.8 years) after transplant. Indications for biopsy were hyperglycemia (n=8), hyperamylasemia (n=3), and graft tenderness (n=1). Adequate tissue was obtained in 11 of 12 biopsies. Two patients received definitive treatment at the time of laparoscopy (pseudocyst debridement, ovarian cyst excision). Conclusions. Laparoscopic pancreas transplant biopsy allows safe visualization of the allograft and effective specimen retrieval, and in some cases provides the opportunity for therapeutic intervention.