Brahm Vasudev

Donor‐Transmitted Malignancies in Organ Transplantation: Assessment of Clinical Risk

The continuing organ shortage requires evaluation of all potential donors, including those with malignant disease. In the United States, no organized approach to assessment of risk of donor tumor transmission exists, and organs from such donors are often discarded. The ad hoc Disease Transmission Advisory Committee (DTAC) of the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) formed an ad hoc Malignancy Subcommittee to advise on this subject. The Subcommittee reviewed the largely anecdotal literature and held discussions to generate a framework to approach risk evaluation in this circumstance. Six levels of risk developed by consensus. Suggested approach to donor utilization is given for each category, recognizing the primacy of individual clinical judgment and often emergent clinical circumstances. Categories are populated with specific tumors based on available data, including active or historical cancer. Benign tumors are considered in relation to risk of malignant transformation. Specific attention is paid to potential use of kidneys harboring small solitary renal cell carcinomas, and to patients with central nervous system tumors. This resource document is tailored to clinical practice in the United States and should aid clinical decision making in the difficult circumstance of an organ donor with potential or proven neoplasia.

Successful Treatment of BK Viremia Using Reduction in Immunosuppression Without Antiviral Therapy

Background. Treatment of BK virus (BKV) infection in renal transplant recipients remains controversial. This retrospective analysis evaluated efficacy and safety of reducing immunosuppression without antiviral therapy. Methods. This single center analysis included 24 patients diagnosed with BK viremia between September 2001 and December 2003. Sixteen patients (66%) presented with BKV nephritis and eight patients (34%) presented with viremia without evidence of nephritis on renal biopsy. Results. At time of diagnosis, mean plasma BKV DNA (copies/mL) was 460,409 (range 10,205–1,920,691). Mean doses reduction of mycophenolate mofetil and tacrolimus were 44% and 41%, respectively, from time of diagnosis of BKV infection to complete resolution of viremia. A decline in BK viral load was noticed within 15 to 30 days, with successful elimination of viremia over a mean period of 5.8 months (range, 1–9.5). Mean serum creatinine at time of diagnosis of BK viremia was 1.8 mg/dL (range, 1.2–2.8). Mean follow-up period is 30.9 months postdiagnosis. At the most recent visit, serum creatinine was 2.0 mg/dL (range, 1.0–3.6) (P=0.14). With reduction in immunosuppressive therapy, three patients (13%) developed acute cellular rejection and were treated successfully with intravenous bolus steroids. During follow-up, one patient had a relapse of BKV nephritis during pregnancy and lost her graft. After mean follow-up period of 43.5 months posttransplantation, all 24 patients are alive and 23 have a functioning graft. Seventeen patients (71%) have stable or improved graft function. Conclusion. Our analysis shows that reduction in immunosuppression therapy alone results in clearance of the BK viremia with good long-term outcome.

BK virus-specific antibodies and BKV DNA in renal transplant recipients with BKV nephritis.

We evaluated twenty renal transplant subjects at various stages of BKV nephritis (BKVN) for BKV‐specific IgG and IgM antibodies using ELISA technique and BKV‐DNA using PCR. They were divided as early onset (n = 7), stabilizing (n = 3), resolved (n = 8) and late onset (n = 2) BKVN. BKV‐specific antibodies and BKV‐DNA were simultaneously determined. The mean BKV‐specific IgG level in early onset and stabilizing BKVN were 64 and 39 EIA units, and were significantly lower than 138 EIA units seen in resolved BKVN, P = 0.007, P = 0.008. The mean BKV‐specific IgM levels in stabilizing BKVN was higher than resolved BKVN (130 vs 51 EIA units), P = 0.006. Mean plasma BKV loads for each group were 955 925, 5642 and 42 copies/mL of plasma, respectively. Prospective study in six BKVN cases revealed mean IgG, IgM levels and BKV‐DNA at the time of diagnosis of BKVN as 39, 110 EIA units and 586 758 copies/mL of plasma, respectively. After a mean period of 5.2 months, IgG level increased to 120 EIA units (p = 0.0058) and had no detectable viral copies in circulation.

Cancer after renal transplantation.

Purpose of reviewProlonged waiting times for renal transplantation, an increase in the average age of recipients, decreased acute rejection rates due to use of newer potent immunosuppressives and improving long-term transplant survival have raised concerns in the transplant community regarding posttransplant cancer. In view of the fact that transplant recipients are living longer, it is of paramount importance that we continue to translate discoveries at the bench to the bedside and document cancers in the posttransplant recipient registries. Analysis of data will help in optimizing patient management. Recent findingsRecent evidence indicates that sirolimus is associated with a decreased incidence of posttransplant de-novo cancer and remission of Kaposis sarcoma and nonmelanoma skin cancer. Mycophenolate mofetil has been shown to have an antiproliferative activity against leukemia and lymphoma and an anti-tumor effect against colon and prostate cancer. Clinically it has been shown to be associated with a reduced incidence of cancers like posttransplant lymphoproliferative disorder. SummaryAppropriate selection of transplant candidates, pretranspant and posttransplant cancer surveillance and judicious evidence-based use of newer immunosuppressants may help reduce the incidence and improve the outcome of posttransplant cancer.

Conversion From Twice-Daily Tacrolimus to Once-Daily Extended Release Tacrolimus (LCPT): The Phase III Randomized MELT Trial

Phase III noninferiority trial examining efficacy and safety of converting stable renal transplant recipients from twice‐daily tacrolimus to a novel extended‐release once‐daily tacrolimus formulation (LCPT) with a controlled agglomeration technology. Controls maintained tacrolimus twice daily. The primary efficacy endpoint was proportion of patients with efficacy failures (death, graft failure, locally read biopsy‐proven acute rejection [BPAR], or loss to follow‐up) within 12 months. Starting LCPT dose was 30% lower (15% for blacks) than preconversion tacrolimus dose; target trough levels were 4–15 ng/mL. A total of 326 patients were randomized; the mITT population (n = 162 each group) was similar demographically in the two groups. Mean daily dose of LCPT was significantly (p < 0.0001) lower than preconversion tacrolimus dose at each visit; mean trough levels between groups were similar. There were four efficacy failures in each group; safety outcomes were similar between groups. Frequency of premature study drug discontinuation was LCPT: 12% versus tacrolimus twice daily: 5% (p = 0.028). LCPT demonstrated noninferiority to tacrolimus twice daily in efficacy failure rates. LCPT may offer a safe and effective alternative for converting patients to a once‐daily formulation. Compared to currently available tacrolimus formulation, LCPT requires lower doses to achieve target trough levels.

Communication gaps associated with donor-derived infections

The detection and management of potential donor‐derived infections is challenging, in part due to the complexity of communications between diverse labs, organ procurement organizations (OPOs), and recipient transplant centers. We sought to determine if communication delays or errors occur in the reporting and management of donor‐derived infections and if these are associated with preventable adverse events in recipients. All reported potential donor‐derived transmission events reviewed by the Organ Procurement and Transplantation Network Ad Hoc Disease Transmission Advisory Committee from January 2008 to June 2010 were evaluated for communication gaps between the donor center, OPO and transplant centers. The impact on recipient outcomes was then determined. Fifty‐six infection events (IEs; involving 168 recipients) were evaluated. Eighteen IEs (48 recipients) were associated with communication gaps, of which 12 resulted in adverse effects in 69% of recipients (20/29), including six deaths. When IEs and test results were reported without delay, appropriate interventions were taken, subsequently minimizing or averting recipient infection (23 IEs, 72 recipients). Communication gaps in reported IEs are frequent, occur at multiple levels in the communication process, and contribute to adverse outcomes among affected transplant recipients. Conversely, effective communication minimized or averted infection in transplant recipients.

Acute kidney injury requiring dialysis secondary to adenovirus nephritis in renal transplant recipient

K. Sujeet, B. Vasudev, P. Desai, J. Bellizzi, L. Novoa‐Takara, C. He, A. El‐Meanawy. Acute kidney injury requiring dialysis secondary to adenovirus nephritis in renal transplant recipient
Transpl Infect Dis 2011: 13: 174–177. All rights reserved

Lower prevalence of BK virus infection in African American renal transplant recipients: a prospective study.

Background. Because the occurrence of BK virus (BKV) nephritis is far less frequent than BK viremia or viruria, analysis of risk factors for BKV nephritis as an endpoint could lead to erroneous findings. We undertook a prospective study to evaluate the risk factors for the occurrence of BKV infections using BK viruria and viremia as endpoints. Methods. Two hundred forty renal only transplant recipients were prospectively enrolled into our institutional review board-approved single center study to evaluate various aspects of posttransplant BKV infection. All patients were followed up for a minimum of 6 months posttransplant. Results. Of the 240 subjects, 154 were whites, 61 African Americans, and 25 belonged to other races. A total of 94 developed BKV infection (any degree of BK viruria or viremia) whereas 146 developed no infection. Among these, 33 had BK viruria alone, 61 had BK viremia with viruria and 25 had significant viremia defined as BKV DNA more than 10,000 copies/mL of plasma. Lower proportion of African Americans developed BKV infection, 14 of 61 (23%), as opposed to whites, 67 of 154 (47%). Logistic regression model showed lower risk of any BKV infection in African American recipient race (OR, 0.38; 95% CI, 0.17–0.82; P=0.016) and higher risk of significant BKV infection with occurrence of acute rejection (OR, 3.9; 95% CI, 1.31–11.8; P=0.015). The Kaplan-Meier analysis shows a trend toward greater freedom from BKV infection in African Americans as opposed to other racial groups (P=0.33). Conclusion. Renal transplant recipients of African American race had a lower risk of posttransplant BKV infection compared with whites, independent of other confounding risk factors.

Kidney Transplant Outcomes

A 25-year-old African-American man with past medical history of systemic lupus erythematosus (SLE) received a 0/6 HLA matched kidney transplant from a deceased donor. Four months post transplantation on routine screening his serum creatinine was elevated from a baseline value of 1.2–1.6 mg/dL. A kidney biopsy performed to elucidate the cause of transplant renal dysfunction revealed acute cellular rejection, BANFF 1a. He received three doses of IV solumedrol and 4 weeks later his serum creatinine was back to 1.2 mg/dL.