Polyomavirus-associated nephropathy: update of clinical management in kidney transplant patients.

Over the last decade, polyomavirus-associated nephropathy (PVAN) has occurred with increasing frequency after renal transplantation, leading to significant renal dysfunction and graft loss. More than 95% of all cases are caused by the human polyomavirus type 1 called the BK virus. The primary treatment for PVAN is immunosuppression reduction, which must be carefully balanced against increased risks of rejection. Although no validated protocols exist, a first step commonly involves reduction of calcineurin inhibitors with antiproliferative agents by more than one-third, e.g., reaching trough levels of tacrolimus <6 ng/mL, of cyclosporine <150 ng/mL, dosing of mycophenolate mofetil to <1 g/day, and azathioprine <75 mg/day. When rejection is diagnosed together with PVAN, a transient pulse treatment is recommended before subsequent reduction in immunosuppression. No antiviral treatments for PVAN have been approved by the United States Food and Drug Administration. The antiviral drug cidofovir has shown in vitro activity against murine polyomaviruses, and has been used in some patients in lower doses in an effort to minimize the nephrotoxic effects of cidofovir while treating PVAN. Small series of PVAN patients treated with leflunomide, intravenous immune globulin therapy, and fluoroquinolones have also been reported recently.

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.

Corticosteroid avoidance ameliorates lymphocele formation and wound healing complications associated with sirolimus therapy.

INTRODUCTION: Sirolimus (RAPA) and corticosteroids (CS) both inhibit wound healing. To evaluate the possibility that RAPA and CS have additive effects on wound healing, we evaluated the effects of corticosteroid avoidance (CSAV) on wound healing complications in patients treated with RAPA. METHODS: One hundred nine patients treated with a CSAV regimen (no pretransplantation or posttransplantation CS) were compared with a historical control group (n = 72) that received cyclosporine (CsA), mycophenolate mofetil (MMF), and CS. The CSAV group received low-dose CsA, MMF, RAPA, and thymoglobulin induction. Complications were classified as follows: wound healing complications (WHC) or infectious wound complications (IWC). WHC included lymphocele, hernia, dehiscence, diastasis, and skin edge separation. IWC included wound abscess and empiric antibiotic therapy for wound erythema. RESULTS: The CSAV group was largely CS-free: 11% of patients received CS for rejection, 12% of patients received CS for recurrent disease, and 85% of patients are currently off CS. The CSAV group had a significantly lower incidence of WHC (13.7% vs 28%; P = .03) and lymphoceles (5.5% vs 16%; P = .02) than the control group. There was no difference in the incidence of IWC between the 2 groups. Patients who received CSAV were 18% less likely (P = .57) to develop any type of complication, 41% less likely (P = .20) to develop a WHC, and 71% less likely (P = .018) to develop a lymphocele. CONCLUSIONS: CSAV in a RAPA-based regimen results in a marked reduction in WHC and lymphoceles. Therefore, CSAV provides a promising approach for addressing WHC associated with RAPA therapy.

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.

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).

African American renal transplant recipients benefit from early corticosteroid withdrawal under modern immunosuppression.

African Americans have historically been considered high-risk renal transplant recipients due to increased rejection rates and reduced long-term graft survival. Modern immunosuppression has reduced rejections and improved graft survival in African Americans and may allow successful corticosteroid withdrawal. Outcomes in 56 African Americans were compared to 56 non-African Americans enrolled in early withdrawal protocols. Results are reported as African American versus non-African American. Acute rejection at 1 year was 23% and 18% (P = NS), while patient and graft survival was 96% versus 98% and 91% versus 91% (P = NS), respectively. In conclusion, early withdrawal in African Americans is associated with acceptable rejection rates and excellent patient and graft survival, indicating that the risks and benefits of early withdrawal are similar between African Americans and non-African Americans. Additional followup is needed to determine long-term renal function, graft survival, and cardiovascular risk in African Americans with early steroid withdrawal.

Early steroid withdrawal does not increase risk for recurrent focal segmental glomerulosclerosis.

UNLABELLED: Experience with early corticosteroid withdrawal (CSWD) in renal transplant recipients with focal segmental glomerulosclerosis (FSGS) has not been previously reported. Since corticosteroids are used to treat primary FSGS, concern exists as to whether early CSWD regimens will be associated with an increased risk of FSGS recurrence posttransplant. The purpose of the present study was to evaluate the results of early CSWD in FSGS recipients and compare these results to a historic control group of FSGS patients who underwent renal transplantation under corticosteroid-based immunosuppression. METHODS: Forty-three patients with FSGS underwent renal transplantation with early CSWD. Results in these patients were compared to FSGS patients that underwent renal transplantation with chronic corticosteroid therapy. All rejection episodes were biopsy proven with grading by Banff criteria. Statistical analyses included Student's t test and chi square tests. RESULTS: Results in 43 patients with a median follow-up of 569 days were analyzed and compared to control patients. There was no significant difference in recurrent FSGS, time to recurrence, or graft loss. CONCLUSION: CSWD does not increase risk for recurrence of FSGS. These observations indicate that ECSW can be achieved in FSGS patients, thereby affording them the benefits of steroid elimination.

Outcomes of patients with rejection post-polyomavirus nephropathy.

INTRODUCTION: We sought to determine the effects of rejection in renal transplant recipients with polyomavirus nephropathy (PVN). METHODS: SCr, biopsy findings, BKV serum and urine loads (Taqman PCR), and BKV antibody titers (HA inhibition assay) were analyzed by two-sample median tests and z tests in 11 patients with median follow-up of 7.3 (2.0 to 31.5) months post-PVN. All patients underwent immunosuppression reduction (ISR) as PVN treatment. RESULTS: Post-PVN, 3 (27%) patients had five rejection episodes, with 80% being mild. Median time to rejection was 18 (2 to 60) weeks. One hundred percent of patients who experienced post-PVN rejection also experienced rejection pre-PVN. Rejection episode treatments consisted of: none in one, increased tacrolimus in two, IVIG in one, IVIG and increased tacrolimus in one. Median viral loads in patients with post-PVN rejection versus those without rejection were not different in serum (2.01 x 10(4) vs 9.00 x 10(4) BKV copies/mL; P = .22) or urine (5.37 x 10(5) vs 8.93 x 10(6) BKV copies/mL; P = .28). Median BKV antibody titers were slightly lower (16384 vs 32768 HA units; P = .02) and median SCr values were significantly higher (2.7 vs 1.9 mg/dL, P = .0003) in patients who had experienced post-PVN rejection. Graft losses occurred in one rejection-free patient (chronic allograft nephropathy) and in one patient who experienced multiple acute rejection episodes, humoral rejection, and worsening PVN. CONCLUSIONS: Patients who experience rejection prior to PVN are at high risk of developing rejection post-ISR and post-PVN; however, low graft loss rates may still be achieved.

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.

Central nervous system tumors in donors: misdiagnosis carries a high morbidity and mortality.

INTRODUCTION: The cost of misdiagnosis of central nervous system (CNS) tumors in donors has not been previously described. The purpose of this study was to examine the Israel Penn International Transplant Tumor Registry experience with these donors. METHODS: All cases where an error in diagnosis was made due to intracranial hemorrhage from undiagnosed CNS tumors and where CNS metastases were misdiagnosed as primary brain tumor were examined. RESULTS: Forty-two organ recipients with misdiagnosed primary brain deaths from 29 donors were examined. After transplantation these donors were identified with: melanoma (23%), renal cell carcinoma (19%), choriocarcinoma (12%), sarcoma (10%), Kaposi's sarcoma (7%), and variable tumors (22%). The majority of patients were renal allograft recipients (84%) followed by liver (n = 4) and lung recipients (n = 1). The most commonly diagnostic error was with intracranial hemorrhage (ICH) (62%). A donor-related transmission rate of 74% (31/42) was identified among those patients with a misdiagnosed brain death. The majority of donor-transmitted cancers were identified in the recipient allograft (71%). Sixty-four percent of recipients suffered diffuse metastatic disease. Overall survival was poor, with a 5-year survival rate of 32% (10/31). Explantation was performed in 17 patients with confirmed donor-transmitted cancer, and in these patients a survival benefit was noted (10/17, 59%, vs 0/14, 0%; P < .01). CONCLUSIONS: Error in the diagnosis of donor brain death due to CNS tumors has significant and often fatal consequences. Allograft explantation for kidney recipients or retransplantation for extrarenal recipients may provide a survival benefit. Potential donors with unclear etiologies for brain death, particularly ICH, should be considered for a limited brain autopsy after donation.

Polyomavirus in kidney and kidney-pancreas transplant recipients.

PURPOSE: To report the incidence and clinical characteristics of polyomavirus (PV) nephritis in kidney (KTX) and kidney-pancreas transplant (KPTX) recipients. METHODS: Single center retrospective analysis of all cases of PV nephritis in KTX and KPTX patients transplanted between 1994 and 1999. RESULTS: Thirteen (5 KTX and 8 KPTX) patients (2.1%) had PV nephritis diagnosed on multiple biopsies (n = 22) among 504 KTX and 106 KPTX recipients. The incidence of PV nephritis was higher in cadaver donor transplants (2.6% cadaver vs. 0.7% living donors), after KPTX (1% KTX vs. 7.5% KPTX), in males (3.3% male vs. 0.7% female), and in diabetic patients (4.4% diabetic vs. 0.8% nondiabetic). The mean time to diagnosis of PV nephritis was 18 (range 6-48) months after KTX and 17 (range 9-31) months after KPTX. Three KTX patients and 5 KPTX patients had calcineurin inhibitor toxicity on biopsy prior to developing PV nephritis. Reduction in immunosuppression occurred in 100% of KTX and 63% of KPTX patients. Three patients (23%) developed rejection within 3 months of diagnosis of PV, 1 after a reduction in immunosuppression. Despite multiple antiviral treatment regimens, renal allograft failure requiring dialysis occurred in 60% of KTX and 50% of KPTX patients. All KPTX patients remain insulin independent and 2 were successfully retransplanted with living donor kidneys. 2 patients (15%) died but there was no mortality directly related to the virus. CONCLUSIONS: Polyomavirus nephritis may be increasing in incidence and appears to be unresponsive to either conventional antiviral agents or a reduction in immunosuppression. Most of our cases occurred in male diabetic patients undergoing cadaveric donor transplantation and were preceded by biopsy-proven nephrotoxicity. Further studies are needed to better define the pathogenesis of PV and effective antiviral treatment.

Evolving experience of hepatitis B virus prophylaxis in liver transplantation.

Passive immunoprophylaxis with hepatitis B immunoglobulin (HBIG) is important to prevent recurrence of hepatitis B virus (HBV) after orthotopic liver transplantation (OLT) for chronic HBV cirrhosis. With availability of lamivudine (3TC), the use of combination prophylaxis with long-term HBIG/3TC has been shown to prevent short-term HBV recurrence. This report compares HBV recurrence rates between groups receiving no/short-term HBIG, long-term HBIG alone, or HBIG/3TC prophylaxis, and describes HBIG requirements during the first 6 and 12 months in the latter two groups. This study involved patients undergoing OLT at the University of Tennessee-Memphis between May 1990 and July 2001. During this period, 388 liver transplants were performed at our center. All hepatitis B surface antigen (HBsAg)-positive recipients (n = 27) were included in this retrospective analysis. The groups were similar with regard to pre-transplant demographic characteristics such as age, gender, weight, and pre-transplant diagnosis. Owing to the retrospective study design, median follow-up was longer for the no-prophylaxis (5.6 years) and the HBIG-alone (6.0 years) groups compared to the HBIG/3TC group (4.2 years). Patient survival was 50% in the no-prophylaxis and 71% in the HBIG-alone groups compared to 100% in the HBIG/3TC group (P = 0.09). When censored for death with a functioning graft, graft survival was 50% in the no-prophylaxis and 86% in the HBIG-alone group compared to 100% in the HBIG/3TC group (P = 0.07). The overall incidence of HBV recurrence in the no-prophylaxis era was 100% and 21% in the HBIG-alone era compared to 0% in the HBIG/3TC era (P < 0.001), despite similar mean and median HBIG trough titers in the HBIG-alone and HBIG/3TC groups. The incidence of HBV recurrence in HBV DNA-positive recipients was 100% in the no-prophylaxis era, 30% in the HBIG-alone era, and 0% in the HBIG/3TC era (P < 0.001). Recipients in the HBIG-alone group had a nearly two-fold increase in HBIG requirement at 6 and 12 months in order to maintain similar HBIG trough titers post-transplant compared to recipients in the HBIG/3TC group despite similar pre-transplant HBV serology. This increased HBIG requirement in the HBIG-alone group resulted in a marked increase in the mean overall cost of HBV prophylaxis in this group ($47,367 US dollars at 6 months; $84,280 US dollars at 12 months) compared to the HBIG/3TC group ($25,931 US dollars at 6 months; $49,599 US dollars at 12 months). These data demonstrate an improvement in patient and graft survival rates in the group receiving combination HBIG/3TC prophylaxis compared to the HBIG-alone and no-prophylaxis groups. There was a significant reduction in HBV recurrence in the group receiving combination HBIG/3TC when compared to the groups receiving HBIG alone or no prophylaxis. Furthermore, we demonstrated that the addition of 3TC to the long-term HBIG regimen led to elimination of the disparity previously described in HBV recurrence rates between HBV DNA-positive and HBV DNA-negative recipients. Importantly, our data demonstrates a complete lack of HBV recurrence in the HBIG/3TC group at a median follow-up of 4.2 years. Additionally, the data show that the addition of 3TC to the post-operative prophylaxis regimen resulted in a reduction in the requirement of HBIG at 6 and 12 months, which markedly reduced the overall cost of post-transplant HBV prophylaxis.

Rhodococcus equi pulmonary infection in a pancreas-alone transplant recipient: consequence of intense immunosuppression.

We report the case of a pancreas-alone transplant recipient who developed Rhodococcus equi pneumonia after receiving multiple courses of antilymphocyte therapy for the treatment of recurrent acute pancreas allograft rejection. We also review and discuss the diagnosis, clinical course, and treatment of 18 cases of R. equi infection reported in solid organ transplant recipients. The lung is the most common primary site of infection, but R. equi infection is difficult to diagnose because of the pleomorphic, gram-positive, and partially acid-fast nature of the organism. Treatment usually involves a combination of antibiotics including rifampin, macrolides, vancomycin, and ciprofloxacin. The optimal duration of therapy is unknown, but relapse is common if the duration of treatment is less than 14 days. The duration of therapy should be guided by clinical recovery, culture results, and radiographic findings. Monitoring levels of immunosuppressive agents-such as tacrolimus and cyclosporine-is needed in order to avoid clinically significant drug interactions with rifampin or the macrolides when these agents are used in order to treat R. equi infection in the transplant population.