Munci Kalayoglu

Risk factors for primary dysfunction after liver transplantation - A multivariate analysis

In a retrospective analysis on 323 orthotopic liver transplant procedures performed between July 1984 and October 1991 the incidence of two forms of primary dysfunction (PDF) of the liver: primary nonfunction (PNF), and initial poor function (IPF) were studied. The incidence of PDF was 22% (73/323) with 6% PNF (20/323) and 16% IPF (53/323), while 78% (250/323) had immediate function (IF). Occurrence of both IPF and PNF resulted in a higher graft failure rate (P < 0.001), retransplantation rate (P < 0.001), and patient mortality (P < 0.003) within the first three months after OLTx. Univariate analyses of donor and recipient factors and their influence on PDF demonstrated that longer donor hospitalization (> 3 days), older donor age (> 49 years), extended preservation times (> 18 hr), and fatty changes in the donor liver biopsy, as well as reduced-size livers, younger recipient age, and renal insufficiency prior to OLTx, significantly affected the incidence of IPF and PNF. Multivariate analysis of potential risk factors showed that reduced-size liver (P = 0.0001), fatty changes on donor liver biopsy (P = 0.001), older donor age (P = 0.009), retransplantation (P = 0.01), renal insufficiency (P = 0.02), and prolonged cold ischemia times (P = 0.02) were independently associated with a higher incidence of IPF and PNF. No statistical correlation was found between PDF and etiology of ESLD, nutritional status of the recipient, UNOS status, and Child-Pugh classification in this study. We conclude that PNF and IPF are both separate clinical entities that have a significant effect on outcome after OLTx. Routine donor liver biopsies are recommended to decrease the rate of IPF and PNF. The combination of risk factors shown to be significant for PDF should be avoided--and, if that is not possible, the only variable that can be controlled, the preservation time, should be kept as short as possible.

Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study.

Campath‐1H, an anti‐CD52 monoclonal antibody, was used as induction therapy (40 mg i.v. total dose) in 29 primary human renal transplants, and the patients were maintained on rapamycin monotherapy (levels 8–15 ng/mL) post‐transplant. Campath‐1H profoundly depletes lymphocytes long‐term and more transiently depletes B cells and monocytes. All patients are alive and well at 3–29 months of follow up. One graft was lost because of rejection. There have been no systemic infections and no malignancies. Eight of 29 patients have experienced rejection, which was successfully treated in seven of eight patients. Five of these patients had pathological evidence of a humoral component of their rejection. Seven of the 29 patients were converted to standard triple therapy on account of rejection. Rapamycin was generally well tolerated in that there were no significant wound‐healing problems; two lymphoceles required surgical drainage; and most patients were treated with a lipid‐lowering agent. Flow crossmatch testing post‐transplant revealed evidence of alloantibody in two patients tested with previous combined cellular and humoral rejection. Biopsies have shown no chronic allograft nephropathy to date. In view of the relatively high incidence of early humoral rejection, we plan to modify the immunosuppressive regimen in subsequent pilot studies. This clinical trial provides insight into the use of Campath‐1H induction in combination with rapamycin maintenance monotherapy.

Donation After Cardiac Death: The University of Wisconsin Experience With Liver Transplantation

Objective:To determine whether the outcomes of liver transplantation (LTx) from donation after cardiac death (DCD) donors are equivalent to those from donation after brain death (DBD) donors. Summary Background Data:Because of the significant donor organ shortage, more transplant centers are using livers recovered from DCD donors. However, long-term, single-center outcomes of liver transplantation from DCD donors are limited. Methods:From January 1, 1993, to July 31, 2002, 553 liver transplants were performed from DBD donors and 36 were performed from DCD donors. Differences in event rates between the groups were compared with Kaplan-Meier estimates and the log-rank test. Differences in proportion and differences of means between the groups were compared with Fisher exact test and the Wilcoxon rank sum test, respectively. Results:Mean warm ischemic time at recovery in the DCD group was 17.8 ± 10.6 minutes. The overall rate of biliary strictures was greater in the DCD group at 1 year (33% versus 10%) and 3 years (37% versus 12%; P = 0.0001). The incidence of hepatic artery thrombosis, portal vein stenosis/thrombosis, ischemic-type biliary stricture (ITBS), and primary nonfunction were similar between groups. However, the incidence of both hepatic artery stenosis (16.6% versus 5.4%; P = 0.001) and hepatic abscess and biloma formation (16.7% versus 8.3%; P = 0.04) were greater in the DCD group. Trends toward worse patient and graft survival and increased incidence of ITBS were seen in DCD donors greater than 40 years compared with DCD donors less than 40 years. Overall patient survival at 1 year (DCD, 80%; versus DBD, 91%) and 3 years (DCD, 68%; versus DBD, 84%) was significantly less in the DCD group (P = 0.002). Similarly, graft survival at 1 year (DCD, 67%; versus DBD, 86%) and 3 years (DCD, 56%; versus DBD, 80%) were significantly less in the DCD group (P = 0.0001). Conclusions:Despite similar rates of primary nonfunction, LTx after controlled DCD resulted in worse patient and graft survival compared with LTx after DBD and increased incidence of biliary complications and hepatic artery stenosis. However, overall results of LTx after controlled DCD are encouraging; and with careful donor and recipient selection, LTx after DCD may successfully increase the donor liver pool.

Experience with 500 simultaneous pancreas-kidney transplants.

METHODS From December 1985 to October 1997, 500 simultaneous pancreas-kidney transplants (SPKs) were performed at the University of Wisconsin. Bladder drainage (BD) was used in 388 and enteric drainage (ED) in 112. All pancreas transplants were preserved in UW solution. RESULTS Patient survival at 1, 5, and 10 years was 96.4%, 88.6%, and 76.3%; kidney function, 88.6%, 80.3%, and 66.6%; and pancreas function, 87.5%, 78.1%, and 67.2%. Thrombosis of the pancreas occurred in three to four (0.6% to 0.8%) and primary nonfunction in one (0.2%). There was a 4.2% acute tubular necrosis rate for the kidney. Conversion from BD to ED was required in 24% of cases. Primary indications for enteric conversion (EC) were leak (14%), urethritis and extravasation (7%), and chronic hematuria (3%). No graft was lost as a result of EC. There was no difference in 1-year graft survival between ED and BD. Leading causes of pancreas loss were rejection in 45 patients and death with a functioning graft in 27 patients. Since June 1995, mycophenolate mofetil was used for immunosuppression (n = 109). One-year survival rates with mycophenolate mofetil are patient, 98.1 %; kidney, 94.2%; and pancreas, 93.1%. Steroid-resistant rejections decreased from 48% to 15%. CONCLUSIONS This series represents the worlds largest experience with SPK, including the longest follow-up for BD pancreatic transplants. Ten-year graft survival rates exceed those of all other transplants, with the exception of HLA-identical living-related grafts. This series confirms that SPK is a highly successful procedure for selected diabetic patients with renal failure.

Successful extrarenal transplantation from non-heart-beating donors.

The current organ shortage has made utilization of organs from less-than-ideal donors more common. Although several transplant centers use kidneys from non-heart-beating donors (NHBDs), there has been reluctance to extend the use of these donors to extrarenal organs. Of the 130 donors referred to our organ procurement organization between January 1993 and May 1994, 16 (12.3%) were NHBDs. Organ retrieval from 10 of these resulted in extrarenal donation, 5 resulted in renal donation only, and 1 resulted in no retrieval as a result of prolonged warm ischemia (> 2 hr). A total of 39 organs were transplanted from these NHBDs. A rapid en bloc retrieval technique was used for extrarenal NHBDs. The mean warm ischemic time was 15.4 min; preservation times were similar for both NHBDs and heart-beating donors. After liver transplantation (n = 5), one episode of primary nonfunction that was technical in origin required retransplantation. Following simultaneous pancreas-kidney transplantation (n = 6), all patients were insulin independent and free of graft pancreatitis; one patient required hemodialysis (16.7%). After isolated renal transplantation (n = 21), 3 patients (14.3%) required hemodialysis. Three of 4 liver recipients are alive after a mean follow-up period of 12.7 months; all simultaneous pancreas-kidney and renal transplant recipients are alive after a mean follow-up period of 8.4 and 8.3 months, respectively. Three liver allografts, 5 pancreas and kidney allografts, and 19 renal allografts are functioning. The lung allograft was lost to rejection 81 days after transplantation; however, the recipient is alive 3 months after retransplantation. Our results demonstrate that in controlled situations, extrarenal organs can be utilized from NHBDs and can be expected to function similarly to organs retrieved from heart-beating donors. We increased the number of transplanted organs by 8.6% using NHBDs for both renal and extrarenal donation. Continued application of these techniques will likely further increase the number of organs retrieved for transplantation.

Determinants of graft survival after renal transplantation

We studied multiple determinants of graft survival at a single center and the effects of nonimmunologic graft loss on transplant survival. This retrospective study examined the results of 589 cadaver donor transplants performed between 1986 and 1992. Graft survival rates were calculated using Kaplan-Meier estimates for both overall graft survival (all causes of graft loss) and immunologic graft survival (function lost due to acute or chronic rejection and noncompliance). Cadaver graft survival was significantly poorer with an increasing degree of DR mismatch (P=0.02). An analysis of pretransplant variables showed graft loss risk was highest with greater DR mismatches, two B-antigen mismatch, higher donor serum creatinine, and younger recipient age. After transplantation, acute rejection was the most significant factor associated with long-term graft survival. Our data demonstrate a significant advantage for zero DR and one DR mismatch cadaver donor transplants, with excellent immunologic graft survival. This study suggests that a combination of immediate graft function, prevention of acute rejection by appropriate early immunosuppressive therapy, and acceptable DR match enhances cadaveric graft survival.

Donation After Cardiac Death: The University of Wisconsin Experience with Renal Transplantation

Owing to the shortage of organ donors, there is renewed interest in donation after cardiac death (DCD), formerly referred to as nonheart‐beating donation. From January 1984 until August 2000, 382 renal transplants were performed from DCD donors. These were compared with 1089 renal transplants performed from donation after brain death (DBD) donors. The mean warm ischemic time in DCD donors was 16.5 min. There was no statistical difference in cold ischemic time, rate of primary nonfunction, or graft loss in the first 30 days after transplantation. The rate of delayed graft function (DGF) was higher for DCD donors (27.5% vs. 21.3%; p = 0.016) and discharge creatinine was higher in DCD donors (1.92 mg/dL vs. 1.71 mg/dL; p = 0.001). There was no statistical difference in the 5‐, 10‐, or 15‐year allograft survival when DCD donors were compared with DBD donors (64.8%, 44.8%, 27.8% vs. 71.3%, 48.3%, 33.8%; p = 0.054). Likewise, no statistical difference in the rate of technical complications was seen. Our long‐term data indicate that the results of renal transplantation from DCD donors are equivalent to long‐term allograft survival from DBD donors despite an increase in the rate of DGF. Organ procurement organizations, transplant centers, and hospitals should work to expand the implementation of DCD policies.

Treatment of severe Epstein-Barr virus-induced lymphoproliferative syndrome with ganciclovir: Two cases of after solid organ transplantation

A lymphoproliferative syndrome following organ transplantation has been described that results from infection with the Epstein-Barr virus (EBV) [1,2]. EBV infection in the immunosuppressed host can induce B-cell proliferation and clinical disease that varies from benign infectious mononucleosis to a fulminant polyclonal or monoclonal lymphoid proliferation [2-51. Successful treatment has been accomplished by reducing immunosuppression and initiating therapy with acyclovir [2,6-81. Recently, anti-B-cell antibodies have also been successfully employed in two children after HLA-mismatched bone marrow transplantation [9]. Despite the use of these modalities, treatment failures have occurred, especially if the lymphoproliferation is monoclonal [lo]. Ganciclovir, 9-(1,3-dihydroxy-2-propoxymethyl) guanine, is a powerful inhibitor of herpes viruses including herpes simplex virus, cytomegalovirus, varicella-zoster virus, and EBV [ll-141. In vitro assays have demonstrated that ganciclovir is more potent than acyclovir in inhibiting EBV virus and may be more effective in the treatment of this infection [13]. Experience with ganciclovir in patients with cytomegalovirus infections has demonstrated the drug’s efficacy and low incidence of side effects [15-181. To our knowledge, the use of ganciclovir in patients with the lymphoproliferative syndrome has not been reported. We describe two cases of a severe lymphoproliferative disorder with EBV infection following transplantation. Both patients received ganciclovir after a poor initial response to intravenous acyclovir and reduction of immunosuppression.

Retransplantation of the liver - A seven-year experience

Three hundred and four patients underwent 362 liver transplants between July 1984 and April 1992. Fifty-eight retransplants were performed in 44 patients (14.5%). Thirty-four patients underwent two (77.3%), seven patients three (15.9%), two patients four (4.5%), and one patient five (2.3%) transplants. Poor function accounted for 23 retransplants (6.4%), technical problems for 19 retransplants (5.2%), and rejection for 15 retransplants (4.1%). One-month patient survivals after retransplantation for poor function, technical problems, or rejection were similar (79.0%, 73.4%, and 80.0%, respectively). No difference in retransplantation rates were seen between adults and children receiving whole liver transplants (WLT) (11.6% versus 19.1%). However, retransplantation for poor function was more common in pediatric recipients receiving reduced-size liver transplants (RLT) (20.0% versus 0.0%, P<0.01), while retransplantation for hepatic artery thrombosis (HAT) was more common in pediatric recipients receiving WLT (16.7% versus 2.8%, P<0.05). The presence of multiorgan system failure of greater than four was associated with a high mortality (90%), whereas patients undergoing emergent retransplantation who had less than four systems fail had a survival of 73.9% and patients who underwent elective retransplantation had a survival rate of 81.8%. Length of stay and cost of liver transplantation was higher in patients undergoing retransplantation when compared with primary transplants (29.7±14.9 days versus 58.4±38.9 days and ±122,358± 59,782 versus ±289, 302±126, 907, P<0.01). The overall actuarial one-year patient survival in primary transplants was 86.6% and in retransplants 74.8%, and at five years these were 71.4% versus 62.5%, respectively (P<0.05). Our results support continued retransplantation of the liver unless the patients medical condition dictates otherwise.

Liver Transplantation for Hepatoblastoma the American Experience

The current role of liver transplantation in treating malignant tumors of the liver is uncertain, except for select histologic types. Pooled data on the results of liver transplantation in 12 children with hepatoblastoma is presented here. One half of the children are alive 24 to 70 (44 +/- 19) months after transplantation with no evidence of recurrence. Three patients (25%) died of tumor recurrence and three (25%) died of other causes. Unifocal and intrahepatic tumors were associated with better prognosis compared to the multifocal tumors and tumors with extrahepatic spread (p = 0.04 and 0.13). Microscopically vascular invasion and the predominance of embryonal and/or anaplastic epithelium were associated with a poor prognosis compared to the tumors with no vascular invasion and with predominantly fetal epithelium (p = 0.08 and 0.1). It is concluded that continued efforts to treat unresectable hepatoblastomas by liver transplantation is justified and the role of adjuvant chemotherapy in improving the results needs to be better defined.