Early corticosteroid withdrawal under modern immunosuppression in renal transplantation: multivariate analysis of risk factors for acute rejection.

UNLABELLED: Early corticosteroid withdrawal has been shown to be effective in low-risk patient populations in a number of US and European multicenter trials. However, patient populations traditionally considered to be at high risk for acute rejection (eg, African Americans, repeat transplant recipients, sensitized patients) are usually excluded from these trials. Since our initial experience with early withdrawal almost 10 years ago, we have included high-immunologic-risk patients. We have accumulated enough high-risk patients with early withdrawal to allow the first multivariate analysis of risk factors for acute rejection in early withdrawal under modern immunosuppression. METHODS: Early withdrawal was performed under prospective IRB-approved protocols. Statistical analysis included chi square test and logistic regression. All rejection episodes were biopsy proven and graded by Banff 1997 criteria. RESULTS: A total of 164 patients underwent early withdrawal: 82% had at least one mismatched DR antigen, 17% had delayed graft function, 33% were African American, and 18% were repeat transplant recipients. Multivariate analysis of risk factors for acute rejection indicated that two factors induced a statistically significant alteration in acute rejection risk: repeat transplant recipients (4.3-fold increased risk) and thymoglobulin induction (0.30 risk (ie, 70% reduction in risk compared to patients not receiving thymoglobulin induction). Sensitized recipients and African Americans were also at increased risk but did not quite reach statistical significance. These data strongly support the use of T-cell depleting antibody induction therapy in high-risk patients undergoing early withdrawal under modern immunosuppression.

A prospective, pilot study of early corticosteroid cessation in high-immunologic-risk patients: the Cincinnati experience.

BACKGROUND: The first prospective trial of steroid withdrawal dedicated to high-immunologic-risk patients is reported herein. METHODS: Twenty-five patients were enrolled prospectively in an IRB-approved HIPAA-compliant protocol. Immunosuppression included corticosteroid withdrawal (CSWD) at 7 days, tacrolimus (target trough level 4 to 8 ng/mL), sirolimus (target trough level 8 to 12 ng/mL), and Mycophenolate Mofetil (2 g/d). Induction with daclizumab (2 mg/kg) on posttransplant days (PTD) 0 and 14 was administered to the first 10 patients. The protocol for the next 15 patients was modified because of high acute rejection rates to include received T-cell-depleting antibody induction therapy with thymoglobulin (1.5 mg/kg) on PTDs 0 and 2 followed by daclizumab on Postoperative day (POD) 14. Recipient inclusion criteria included: (1) repeat transplant recipients; or (2) patients with a peak PRA > or =25%. All rejection episodes were diagnosed by biopsy and graded using Banff '97 criteria. RESULTS: Twenty-five patients were enrolled and median follow-up was 402 days. Forty percent of recipients were black, 68% of patients were repeat transplant recipients, 68% received deceased donor kidneys, and 36% had a peak flow PRA >25%. Overall acute rejection, graft survival, and patient survival rates of 40%, 88%, and 96%, respectively, were observed for the duration of the study. Acute rejection occurred in 6 of 10 patients (60%) with daclizumab induction; however, acute rejection rates fell to 27% when thymoglobulin was introduced (P = .1). CONCLUSIONS: This study supports our previous observations in a multivariate analysis of early CSWD patients, wherein polyclonal antibody induction therapy reduced acute rejection. High-immunologic-risk patients may be able to undergo early CSWD with acceptable rates of acute rejection.

Histocompatibility testing predicts acute rejection risk in early corticosteroid withdrawal regimens.

UNLABELLED: Histocompatibility testing has been shown to predict acute rejection risk in steroid-based immunosuppression. However, little evidence exists of its ability to predict acute rejection risk in corticosteroid-free patients, with no evidence in early corticosteroid withdrawal (CSWD) under modern immunosuppression. The purpose of this study was to evaluate the ability of histocompatibility testing to identify patients at high risk for acute rejection after early CSWD. METHODS: One hundred eighty-one patients were entered into six IRB-approved early CSWD regimens. Histocompatibility testing included serologic PRA, flow cytometric PRA testing by Class I and Class II MHC beads, and B cell crossmatching with pronase treatment. All rejection episodes were biopsy proven, and grading was assigned using Banff criteria. Influence of individual tests was examined using Chi square univariate and multivariate logistic regression analysis. RESULTS: Median follow-up was 23.5 months (range 7-48 months). Of 181 patients, 16% were repeat transplant recipients, 36% received deceased donor renal transplants, 48% received living related donor renal transplants, and 16% received living unrelated transplants. Overall patient survival was 97%, and death-censored graft survival was 96.5%. Acute rejection rates in the entire follow-up period were 17.7%. 12.4% in primary transplant recipients and 37% in repeat transplant recipients. Multivariate analysis revealed that HLA AB and DR locus mismatching were associated with increased acute rejection risk. Similarly, serologic PRA analysis predicted acute rejection risk; however, flow cytometry crossmatching did not predict acute rejection risk. The greatest single influence on acute rejection risk appeared to be a flow cytometric B cell crossmatch (7.94-fold increased risk). In conclusion, histocompatibility testing can identify patients at high risk for acute rejection following early CSWD. HLA matching, serologic PRA testing, and flow cytometry-based B cell crossmatching can all be used to predict acute rejection risk.

Global cardiovascular risk under early corticosteroid cessation decreases progressively in the first year following renal transplantation.

UNLABELLED: A primary reason to eliminate corticosteroids from immunosuppressive regimens in solid organ transplant recipients is improved cardiovascular risk profiles. Although a number of studies have documented that corticosteroid withdrawal (CSWD) regimens reduce hypertension, hyperlipidemia, diabetes, and weight gain, global assessments of cardiovascular risk under CSWD have not been reported. The purpose of this study was to document cardiovascular risk under CSWD using a global risk assessment by Framingham risk assessment. METHODS: Framingham global cardiovascular risk assessments were performed at baseline and 3, 6, and 12 months posttransplant on patients enrolled in prospective, IRB-approved early (<7 days of corticosteroids) CSWD trials. Framingham score was based on age, sex, presence of diabetes, HDL and total cholesterol, and systolic blood pressure. All patients were nonsmokers. Left ventricular hypertrophy assessment by EKG criteria was not available at all time points and therefore were not included. RESULTS: One hundred eighty-three patients were included in the analysis. Fourteen percent of patients had evidence of coronary heart disease (prior MI, CABG, PTCA, or significant cardiovascular disease as evidenced by angiography) prior to transplant. Complete information was available for 160 patients at baseline, 132 at 1, 3, and 6 months, and 93 at 12 months posttransplant. Mean 10-year risk (expressed as percent) for developing coronary heart disease decreased over time: 8.03 at baseline, 8.31 at 3 months, 7.40 at 6 months, and 7.20 at 12 months, indicating that global cardiovascular risk fell at 1 year posttransplant by about 10% in renal transplant recipients undergoing early CSWD. CONCLUSIONS: Estimation of cardiovascular risk by Framingham risk factor assessment allows incorporation of several cardiovascular risk factors into a single estimate, thereby accounting for differential effects of each individual factor on global cardiovascular risk. This experience indicates that global cardiovascular risk decreases by approximately 10% at 1 year posttransplant in renal transplant recipients who undergo early corticosteroid withdrawal (CSWD).

Posttransplant lymphoproliferative disorder: significance of central nervous system involvement.

BACKGROUND: Few data exist regarding central nervous system (CNS) involvement in patients with posttransplant lymphoproliferative disorder (PTLD). The purpose of this study was to review the Israel Penn International Transplant Tumor Registry (IPITTR) experience with CNS involvement by PTLD. METHODS: Nine hundred ten PTLD cases from the United States were reported to the IPITTR and reviewed for CNS involvement. RESULTS: One hundred thirty-six transplant recipients with PTLD (15%) had CNS involvement. The highest incidence of CNS involvement occurred in pancreas (3 of 11; 27%) and kidney transplant recipients (76 of 429; 18%). Fifteen cases occurred in children and 121 cases in adults. For both children and adults, isolated CNS disease was associated with better survival when compared with multiple-site involvement (children: 29% vs 0%; adults: 12% vs 6%; P < .05). Three-year survival in PTLD patients with CNS involvement was 9.4% and without CNS involvement was 49.4% (P < .01). Radiation therapy alone appeared to provide the best survival rates (25%). CONCLUSIONS: CNS involvement in transplant recipients with PTLD carries an ominous prognosis; however, isolated CNS involvement has a better prognosis than CNS plus extracranial involvement. Radiation therapy alone provides the best results, but this may be a reflection of isolated CNS disease.

Chemotherapy for posttransplant lymphoproliferative disorder: the Israel Penn International Transplant Tumor Registry experience.

INTRODUCTION: Very little published data exist regarding the results of chemotherapy treatment of posttransplant lymphoproliferative disorder (PTLD). The purpose of the study was to review the Israel Penn International Transplant Tumor Registry experience with PTLD treated with chemotherapy. METHODS: Patients with PTLD who received chemotherapy were identified and data collected regarding demographics, tumor characteristics, recurrence rates, and survival. RESULTS: One hundred ninety three solid organ transplant recipients with PTLD who received chemotherapy were identified. Most patients were male (142:51) and Caucasian (148; 16 AA, 29 unspecified). Most PTLD were B-cell predominant (81%), monoclonal (71), and CD 20+ (60% of patients tested). Organ transplanted included: kidney, 92 (48%); heart, 54 (28%); liver, 30 (16%); pancreas, 8 (4%); and lung, 9 (5%). Median time to presentation posttransplant was 24.5 months (range 0.8 to 226.5 months). Ninety patients received CHOP, 12 ProMACE, 65 other multidrug regimens, and 23 patients received single-agent chemotherapy. Five-year survival for these four regimens were: 24%, 25%, 32%, and 5%. PTLD-specific death rates were 34%, 34%, 40%, and 48%. CONCLUSIONS: Single-agent chemotherapy appears to be inferior to other chemotherapy regimens for PTLD as it is associated with lower survival.

Prostate cancer prior to solid organ transplantation: the Israel Penn International Transplant Tumor Registry experience.

INTRODUCTION: Prostate adenocarcinoma (PCA) is the second leading cause of cancer-related deaths in men, and with routine prostrate specific antigen (PSA) screening, is being diagnosed with increasing frequency. To date, reported experiences with transplantation in men with a history of PCA are limited to only a few patients. This study presents the first series of transplant recipients with a history of PCA. METHODS: Analysis of transplant recipients with a history of pretransplant PCA was performed on the Israel Penn International Transplant Tumor Registry database. PCA were staged using American Joint Committee on Cancer criteria. Statistics analysis was performed by chi-square and Student t tests. RESULTS: Ninety patients with preexisting PCA were identified: 77 renal, 10 heart, and three liver transplant recipients. Mean age at PCA diagnosis was 61.3 +/- 6.3 years. Median interval between diagnosis and transplantation was 19.3 months, and median follow-up after transplantation was 20.5 months. Median time to PCA recurrence was 10.6 months after transplantation and median survival time with recurrent PCA was 49.2 months after transplant. Patient mortality was 28.8%, and PCA-related death rate was 7.8%. PCA recurrence rate was 17.7%. Tumor recurrence rates in stage I and II disease (14 and 16%) were lower than in stage III disease (36%). CONCLUSIONS: In conclusion, death rate to disease other than PCA is three times that due to PCA. PCA recurrence rates are relatively low in patients who initially presented with stage I and II disease, and are half that of patients with stage III disease.

De novo colorectal cancer: five-year survival is markedly lower in transplant recipients compared with the general population.

INTRODUCTION: The biological behavior of most solid tumors in transplant recipients has not been adequately compared to the general population. The purpose of the present study was to compare outcomes in de novo colorectal cancer (CRC) following solid organ transplantation to those observed in the general population (SEER) database. METHODS: All transplant recipients with de novo CRC in the Israel Penn International Transplant Tumor Registry were identified and analyzed and the data were compared to CRC patients in the SEER National Cancer Institute (NCI) database. RESULTS: One hundred and fifty transplant recipients with de novo CRC were identified, among which were 93 (62%) kidney, 29 (19.3%) heart, 27 (18%) liver, and 1 (0.7%) lung recipients. Median age of transplant recipients was 54 years, compared to a median age of 72 years for patients in the SEER NCI database. However, compared to patients from the SEER NCI database, recipients with Duke's A through C stage disease were noted to experience a significant decrease in 5-year survival. The results in Duke's C patients were particularly dismal. CONCLUSIONS: The early age at presentation of CRC in transplant recipients suggests that the development of de novo CRC may be effected by immunosuppression. Decreased 5-year survival rates in transplant recipients compared to the general population suggest that CRC in transplant patients is biologically more aggressive. These data cannot distinguish whether the lower survival rates are because the CRC are inherently biologically more aggressive or whether immunosuppression allows for more aggressive clinical behavior of CRC.

Skin cancer following transplantation: the Israel Penn International Transplant Tumor Registry experience.

UNLABELLED: The purpose of this study was to analyze a large series of skin cancers in solid organ transplant recipients to determine their biologic behavior. METHODS: A retrospective review of all US transplant recipients with skin cancer reported to the Israel Penn International Transplant Tumor Registry was performed. RESULTS: Transplant recipients from the United States with skin malignancies were identified (n = 2018) and assigned to 1 of 3 groups: squamous cell cancer (SCC), basal cell cancer (BCC), or combined malignancies (BCC/SCC). Squamous cell to basal cell cancer ratio was found to be 1.9 to 1. The ratio of extrarenal to renal allograft recipients was identical for all 3 groups (3:1). The median interval from transplant to skin cancer diagnosis was greater than 4 years in each group and longest in those with isolated SCC lesions. In the SCC group, there was a 9% incidence of nodal or secondary site involvement affecting the cervix, perineum, or lung. The highest recurrence rate was demonstrated in the combined malignancy group. Cancer-specific deaths were significantly higher in the SCC (8%) and BCC/SCC (6.8%) groups compared to the BCC (3.6%) group. CONCLUSIONS: This large experience indicates that SCC is more common than BCC in transplant recipients. SCC alone or in combination with BCC appears aggressive and is associated with significant mortality.

Methicillin-resistant Staphylococcus aureus infection in liver transplantation: a matched controlled study.

UNLABELLED: The purpose of this study was to evaluate the clinical impact of methicillin-resistant Staphylococcus aureus (MRSA) infections on transplant recipients. METHODS: Liver and kidney recipients with MRSA infections were retrospectively identified and compared to an age, gender, UNOS status, organ transplanted, and transplant date matched (2:1) non-MRSA-infected recipient control group. All MRSA infections were initially treated with vancomycin, and four (33%) liver recipients were converted to linezolid therapy after failing to improve with vancomycin. RESULTS: The overall MRSA infection incidence was 1.4% (24/1770) with MRSA more common in liver (3.75%; 12/320) than kidney transplants (0.8%; 12/1450) (P < .001). The most common sites of MRSA infection were blood (42%), lung (38%), and abdomen (29%). The MRSA group had a greater percentage of prior antibiotic usage (79% vs 40%; P < .0015). The MRSA group experienced more posttransplant complications (52% vs 19%; P < .011)), and exhibited a trend toward greater length of stay in the intensive care unit (7.8 vs 4.6 days; P = .09), but not overall length of stay. Survival was similar in MRSA and non-MRSA groups (75% vs 88%; P = .17). No significant differences in mortality were noted between liver and kidney recipients infected with MRSA (P = .6). CONCLUSION: MRSA infection is associated with a higher incidence of posttransplant complications and antibiotic usage in both liver and kidney recipients compared to patients with MRSA infection.

Pilot study of early corticosteroid elimination after pancreas transplantation.

UNLABELLED: Early corticosteroid withdrawal has recently been shown to be possible in recipients of simultaneous pancreas kidney transplants; however, its feasibility in solitary pancreas recipients has not been documented. In the present study, we provide evidence that early withdrawal can be achieved in pancreas as well as pancreas-kidney recipients. METHODS: Twenty type I diabetics underwent 13 pancreas-kidney transplants and 7 pancreas-only transplants with early withdrawal (methylprednisone 6-day taper). Additional immunosuppression consisted of tacrolimus, mycophenolate mofetil, and thymoglobulin induction (five doses). RESULTS: Transplants included 13 pancreas-kidney, 6 pancreas after kidney transplant, and 1 pancreas after islet transplant. Overall mean follow-up was 7.3 months. One episode of pancreas transplant rejection after pancreas-only transplant was detected on protocol biopsy without biochemical abnormalities. One renal allograft rejection occurred 65 days posttransplant in a pancreas-kidney recipient and was graded as a Banff IA rejection. A single pancreas graft loss occurred due to thrombosis 6 days after pancreas-kidney transplantation. CONCLUSIONS: These results indicate that relatively short thymoglobulin induction (five doses) with tacrolimus and mycophenolate mofetil can allow early withdrawal in both pancreas-kidney and pancreas-only transplant recipients.

Donor kidneys with small renal cell cancers: can they be transplanted?

INTRODUCTION: The purpose of this study was to determine whether incidentally discovered, small renal cell cancers (RCC) in donor kidneys can be excised and safely transplanted. METHODS: The Israel Penn International Transplant Tumor Registry database was searched and all small RCC that were identified and resected prior to transplantation of deceased and living donor kidneys were reviewed. Patient demographics, tumor characteristics, recurrence, and survival were examined. RESULTS: Fourteen kidneys were identified in which small RCC were noted at the time of procurement and where the tumors were excised ex vivo and then transplanted. Eleven kidneys were obtained from living related donors and three were from deceased donors. Median tumor size was 2 cm (range 0.5 to 4 cm). All 14 tumors were of histological Furhman grade II/VI (n = 8) or Furhman grade I/VI (n = 6). All kidneys had pathologically confirmed negative margins. The mean age of the recipients was 40.8 +/- 9.2 years, with the majority being men (11 men; 3 women). Median follow-up for this group was 69 months (range 14 to 200 months). There have been no recurrences of tumor in these recipients and the 1-, 3-, and 5-year patient and graft survivals are 100%, 100%, and 93%. CONCLUSIONS: These data represent the only data available (to our knowledge) on this issue. This experience indicates that donor kidneys with small, incidental RCC and low histological grade (Furhman grade I and II/IV) can be managed with excision and transplantation, with a low risk of tumor recurrence in the recipient.

Laparoscopic living donor nephrectomy for kidneys with multiple arteries.

INTRODUCTION: Laparoscopic donor nephrectomy (LDN) involving kidneys with multiple arterial vessels is limited to a small number of reports, with all but two series reporting fewer than 25 patients. Moreover, outside of the pioneering centers at the University of Maryland and Johns Hopkins, no series of at least 25 patients has been published confirming these experience. The present study presents the largest series of LDN of donor kidneys with multiple arterial vessels outside of these two pioneering programs. METHODS: All LDN performed at the University of Cincinnati from 2000 to 2004 were reviewed. Results between LDN kidneys with a single vessel and those with multiple vessels were compared. Statistical analysis included chi-square and Student t test. RESULTS: Of 240 LDN, 37 were performed for kidneys with multiple vessels (15%): nine right kidneys (25%) and 28 left kidneys (75%). Cold ischemia time was longer for the multiple vessel organs (46 +/- 24 minutes) than for single vessel organs (35 +/- 13 minutes; P = .001), and warm ischemia time was longer for the multiple vessel kidneys (4:20 +/- 2:05 minutes) than single vessel kidneys (3:13 +/- 0:47 minutes; P = .001). Recipient renal function (serum creatinine) was similar for multiple and single artery donors at postoperative day 7 (1.76 +/- 1.38 and 1.7 +/- 1.47) and at postoperative day 365 (1.06 +/- 0.3 and 1.34 +/- 0.44). CONCLUSIONS: This experience confirms results from other series in documenting the safety and reproducibility of LDN for kidneys with multiple arterial vessels.

Laparoscopic right living donor nephrectomy.

INTRODUCTION: Left laparoscopic donor nephrectomy (LDN) is preferred over right LDN due to technical ease. The purpose of this study was to compare results between right and left LDN and thereby determine whether substantial experience with right LDN can provide results equivalent to left LDN. METHODS: All LDN from 2000 to 2004 were reviewed, and right LDN data compared to left LDN data. Statistical analyses included chi-square and Student t tests. RESULTS: Two hundred thirteen left LDN (84%) were compared to 40 right LDN (16%). Donor age, gender, race, and body mass index, and multiple arteries were similar in right and left LDN groups. Operative and cold ischemia times were similar, but warm ischemia was longer for right LDN (3:55 +/- 1:22 minutes) than left LDN (3.18 +/- 1:06 minutes; P = .004). Despite this, renal allograft function was similar on postoperative day 7 (creatinine 1.77 +/- 1.21 for right LDN, 1.7 +/- 1.5 for left LDN) and at 1 year (right LDN 1.5 +/- 0.4, left LDN 1.23 +/- 0.28). Graft survival rate in the right LDN at 1 year was 97.5%. CONCLUSIONS: This large experience with right LDN indicates that results comparable to left LDN can be obtained. This observation increases the options for LDN in patients with multiple left renal arteries, or with right renal cysts, or with right kidneys that are smaller in size compared to the contralateral left kidney.