Akhtar Khan

Management of the Potential Organ Donor in the ICU: Society of Critical Care Medicine/American College of Chest Physicians/Association of Organ Procurement Organizations Consensus Statement

This document was developed through the collaborative efforts of the Society of Critical Care Medicine, the American College of Chest Physicians, and the Association of Organ Procurement Organizations. Under the auspices of these societies, a multidisciplinary, multi-institutional task force was convened, incorporating expertise in critical care medicine, organ donor management, and transplantation. Members of the task force were divided into 13 subcommittees, each focused on one of the following general or organ-specific areas: death determination using neurologic criteria, donation after circulatory death determination, authorization process, general contraindications to donation, hemodynamic management, endocrine dysfunction and hormone replacement therapy, pediatric donor management, cardiac donation, lung donation, liver donation, kidney donation, small bowel donation, and pancreas donation. Subcommittees were charged with generating a series of management-related questions related to their topic. For each question, subcommittees provided a summary of relevant literature and specific recommendations. The specific recommendations were approved by all members of the task force and then assembled into a complete document. Because the available literature was overwhelmingly comprised of observational studies and case series, representing low-quality evidence, a decision was made that the document would assume the form of a consensus statement rather than a formally graded guideline. The goal of this document is to provide critical care practitioners with essential information and practical recommendations related to management of the potential organ donor, based on the available literature and expert consensus.

Living-Related Donor Renal Transplantation in HIV+ Recipients using Alemtuzumab Preconditioning and Steroid-Free Tacrolimus Monotherapy: A Single Center Preliminary Experience

Background. End-stage renal disease (ESRD) is an increasing problem in patients infected with the human immunodeficiency virus (HIV). The use of highly active antiretroviral therapy (HAART) has decreased the morbidity associated with HIV and has prompted renewed interest in renal transplantation. Methods. We performed four cases of deceased donor renal transplantation in HIV+ recipients and three cases where laparoscopic live donor nephrectomy (LLDN) was utilized to obtain the kidney for transplantation into living-related HIV+ recipients. In the four deceased donor cases, conventional tacrolimus-based immunosuppression, without antibody induction was used. In the three living-related cases, the immunosuppressive regimen was based on two principles: recipient pretreatment and minimal posttransplant immunosuppression. Alemtuzumab 30 mg (Campath 1-H) was used for preconditioning followed by low-dose tacrolimus monotherapy. Results. Of the four deceased donor cases, one patient continues to have good graft function, and another is not yet on dialysis but has significant graft dysfunction. Rejection was observed in three patients (75%). Infectious complications occurred in one patient (25%), all non-acquired immunodeficiency syndrome (AIDs) defining. In the three living-related cases, all had good graft function, and none have experienced acute rejection. HIV viral loads remain undetectable. CD4 counts are slowly recovering. No infectious or surgical complications occurred. There were no deaths in either group. Conclusions. These data suggest that living-related donor renal transplantation with steroid-free tacrolimus monotherapy in a “tolerogenic” regimen can be efficacious. However, long-term follow-up is needed to confirm this observation.

Alemtuzumab induction and tacrolimus monotherapy in pancreas transplantation: One- and two-year outcomes.

Background. Alemtuzumab (Campath-1H) induction with tacrolimus monotherapy has been shown to provide effective immunosuppression for kidney, liver, lung, and small bowel transplantation. This drug combination was evaluated in pancreas transplant recipients. Methods. Sixty consecutive pancreas transplants (30 simultaneous pancreas-kidney, 20 pancreas after kidney, and 10 pancreas alone) were carried out under this protocol between July 2003 to January 2005. The mean follow-up was 22 months (range 17–33). Results. One-year patient, pancreas, and kidney allograft survival were 95%, 93%, and 90%, respectively. With 22 months follow-up, patient, pancreas, and kidney survival were 94%, 89%, and 87%, respectively. The rejection rate was 30% (18/60), with four patients (7%) experiencing steroid-resistant rejection. Major infection occurred in three (5%) patients resulting in two (3.3%) deaths from disseminated histoplasmosis and a herpes virus infection. One patient with cryptococcal meningitis was successfully treated. Seven (11.7%) patients experienced cytomegalovirus infection, all of whom responded to treatment with ganciclovir. One (1.7%) case of polymorphic posttransplant lymphoproliferative disease was seen, which regressed with a temporary discontinuation of tacrolimus and high-dose ganciclovir. The mean serum creatinine of the 30 simultaneous pancreas-kidney transplants at one year posttransplant was 1.37±0.33 mg/ml. The preexisting creatinine in pancreas after kidney transplants was not adversely affected by this immunosuppressive protocol. Conclusion. A single dose of perioperative alemtuzumab followed by daily tacrolimus monotherapy provides effective immunosuppression for pancreas transplantation, but the optimal use of this drug combination is not yet clear.

A Prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone and mycophenolate mofetil in primary adult liver transplantation: a single center report

BACKGROUND Tacrolimus (TAC) and mycophenolate mofetil (MMF) are currently approved immunosuppressants for prevention of rejection in liver transplantation (LTx). They have different modes of action and toxicity profiles, but the efficacy and safety of MMF in primary liver transplantation with TAC has not been determined. METHODS An Institutional Review Board-approved, open-label, single-center, prospective randomized trial was initiated to study the efficacy and toxicity of TAC and steroids (double-drug therapy (D)) versus TAC, steroids, and MMF (triple-drug therapy (T)) in primary adult LTx recipients. Both groups of patients were started on the same doses of TAC and steroids. Patients randomized to T also received 1 gm MMF twice a day. RESULTS Between August 1995 and May 1998, 350 patients were enrolled at a single center-175 in the D and 175 in the T groups. All patients were followed until May 1998, with a mean follow-up of 33.8+/-9.1 months. Using an intention-to-treat analysis, the 1-, 2-, 3-, and 4-year patient survival was 85.1%, 81.6%, 78.6%, and 75.8%, respectively, for D and 87.4%, 85.4%, 81.3%, and 79.9%, respectively, for T. The 4-year graft survival was 70% for D and 72.1% for T. Although the rate of acute rejection in the first 3 months was significantly lower for T than for D (28% for triple vs. 38.9% for double, P=0.03), the overall rate of rejection for T at the end of 1 year was not significantly lower than for the D (38.9% triple vs. 45.2% double). The median time to the first episode of rejection was 14 days for D versus 24 days for T (P=0.008). During the study period, 38 of 175 patients in D received MMF to control ongoing acute rejection, nephrotoxicity, and/or neurotoxicity. On the other hand, 103 patients in the T discontinued MMF for infection, myelosuppression, and/or gastrointestinal disturbances. The need for corticosteroids was less after 6 months for T and the perioperative need for dialysis was lower with use of MMF. CONCLUSION This final report confirms similar patient survival and graft survival up to 4 years with a trend towards fewer episodes of rejection, lower need for steroids, and better perioperative renal function. However, the complex nature of LTx patients and their posttransplantation course prevents the routine application of MMF.

Bone Marrow-derived Endothelial Progenitor Cells and Endothelial Cells May Contribute to Endothelial Repair in the Kidney Immediately After Ischemia-Reperfusion

In ischemic acute kidney injury, renal blood flow is decreased. We have previously shown that reperfused, transplanted kidneys exhibited ischemic injury to vascular endothelium and that preservation of peritubular capillary endothelial integrity may be critical to recovery from ischemic injury. We hypothesized that bone marrow–derived (BMD) endothelial progenitor cells (EPCs) might play an important role in renal functional recovery after ischemia. We tested this hypothesis in recipients of cadaveric renal allografts before and for 2 weeks after transplantation. We found that the numbers of circulating CD34-positive EPCs and CD146-positive endothelial cells (ECs) decreased immediately after ischemia–reperfusion. In renal allograft tissues obtained 1 hr after reperfusion, CD34-positive cells were more frequently observed along the endothelial lining of peritubular capillaries compared with non-ischemic controls. Moreover, 0–17.5% of peritubular capillary ECs were of recipient origin. In contrast, only 0.1–0.7% of tubule cells were of recipient origin. Repeat graft biopsy samples obtained 35 and 73 days after transplant did not contain capillary ECs of recipient origin, whereas 1.4% and 12.1% of tubule cells, respectively, were of recipient origin. These findings suggest that BMD EPCs and ECs may contribute to en-dothelial repair immediately after ischemia–reperfusion.

Proteasome inhibition with bortezomib: an effective therapy for severe antibody mediated rejection after renal transplantation.

Antibody-mediated rejection (AMR) following renal transplantation is less responsive to conventional anti-rejection therapies. Plasmapheresis (PP), intravenous immunoglobulin (IVIg), rabbit antithymocyte globulin (rATG) and rituximab deplete immature B-cells but not mature plasma cells. The proteasome inhibitor bortezomib has activity against mature plasma cell, the source of damaging donor-specific antibody (DSA).We present the successful use of bortezomib in 2 patients who developed AMR following kidney transplantation. The first patient was a 54-year-old white female who received living-unrelated kidney transplantation from her husband. She developed severe AMR early after transplantation with rising DSA titers consistent with an anamnestic immune response by memory cells to the donor antigens. Renal function deteriorated despite treatment with pulse methylprednisolone (MP), PP and IVIg. After initiation of therapy with bortezomib, DSA titers became negative and serum creatinine returned to baseline with histological resolution of AMR. The second patient was a 19-year-old white male who received deceased donor kidney transplantation and developed AMR within 2 weeks, refractory to therapy with pulse MP, PP and IVIg with rising DSA. Bortezomib use resulted in disappearance of DSA and renal function improvement. Both patients tolerated the treatment well with stable renal function at last follow-up. The novel mechanisms of action and preliminary results with bortezomib are encouraging, but require larger studies and longer follow-up.

Outcome of induction immunosuppression for liver transplantation comparing anti‐thymocyte globulin, daclizumab, and corticosteroid

In addition to standard corticosteroid induction, anti‐thymocyte globulin (ATG) or daclizumab as induction immunosuppression has been reported for liver transplantation. However, the effects and long‐term outcomes of antibody induction therapy are not well known, especially for hepatitis C (HCV). The United Network for Organ Sharing (UNOS) database was utilized to analyze 16 898 adult primary liver transplant patients who received ATG alone (n = 452), ATG and steroids (ATG + S) (n = 1758), daclizumab alone (n = 683), or steroid alone (n = 14 005), listed as induction immunosuppression. Graft and patient survival, and donor and recipient factors for survival were analyzed for HCV and all liver diseases. For patients with HCV, ATG + S had significantly inferior graft survival compared with daclizumab (P = 0.01) and steroids (P = 0.03). The Cox proportional hazards model also showed that ATG + S was a marginal risk factor for graft failure (P = 0.05). On the other hand, for patients with all the liver diseases, graft and patient survival were not significantly different between induction regimens. ATG induction appeared to be preferentially used in patients with renal dysfunction, with improvement in renal function after liver transplantation. Thus, ATG induction can be used for patients with renal dysfunction in non‐HCV diseases. Daclizumab induction achieved satisfactory short‐term and long‐term outcomes of liver transplantation in all the liver diseases including HCV disease.

Immune functional assay for immunosuppressive management in post‐transplant malignancy

Uemura T, Riley TR, Khan A, Hollenbeak C, Schreibman I, Ghahramani N, Reeves B, Domen RE, Zander DS, Kadry Z. Immune functional assay for immunosuppressive management in post‐transplant malignancy.
Clin Transplant 2011: 25: E32–E37.

Stereotactic body radiotherapy (SBRT) with or without surgery for primary and metastatic liver tumors

OBJECTIVES We report single center experience on the outcome and toxicity of SBRT alone or in combination with surgery for inoperable primary and metastatic liver tumors between 2007 and 2014. PATIENTS AND METHODS Patients with 1-4 hepatic lesions and tumor diameter ≤9 cm received SBRT at 46.8Gy ± 3.7 in 4-6 fractions. The primary end point was local control with at least 6 months of radiographic followup, and secondary end points were toxicity and survival. RESULTS Eighty-seven assessable patients (114 lesions) completed liver SBRT for hepatoma (39) or isolated metastases (48) with a median followup of 20.3 months (range 1.9-64.1). Fourteen patients underwent liver transplant with SBRT as a bridging treatment or for tumor downsizing. Eight patients completed hepatic resections in combination with planned SBRT for unresectable tumors. Two-year local control was 96% for hepatoma and 93.8% for metastases; it was 100% for lesions ≤4 cm. Two-year overall survival was 82.3% (hepatoma) and 64.3% (metastases). No incidence of grade >2 treatment toxicity was observed. CONCLUSION In this retrospective analysis we demonstrate that liver SBRT alone or in combination with surgery is safe and effective for the treatment of isolated inoperable hepatic malignancies and provides excellent local control rates.

Outcomes of transplantation of single pediatric renal allografts equal to or more than 6 cm in length.

Background. Because of the donor organ shortage, kidneys from smaller pediatric donors are being increasingly used. However, it is unclear whether small pediatric deceased donor kidneys should be used as single grafts or en bloc. We reviewed our outcomes of single kidney transplants from small pediatric donors into adult recipients. Methods. Kidneys equal to or more than 6 cm in length were transplanted as a single kidney in seven adult recipients weighing less than 80 kg. Creatinine clearance, kidney graft size, and glomerular size were followed up at 1, 3, 6, and 12 months after transplantation. Results. All patients and grafts, with the exception of one patient, are currently alive with functional grafts. Two kidneys were procured after cardiac death of the donors, but no delayed graft function was observed. A total of 57% (four of seven) patients developed BK viremia, and 29% (two of seven) patients developed BK virus nephropathy. The graft size significantly increased during follow-up by ultrasonography (P=0.02). The renal allograft function by calculated creatinine clearance also significantly improved at 40.6±6.9 mL/min, 52.7±10.2 mL/min, and 66.2±9.7 mL/min at 1, 3, and 12 month after transplantation, respectively (P=0.01). The size of glomeruli significantly increased from 122±8.4 &mgr;m at 1 to 2 months to 169±22.5 &mgr;m at 3 to 12 months after transplantation (P<0.01). Conclusions. Kidneys equal to or more than 6 cm from small pediatric donors can be successfully transplanted as a single kidney. Single pediatric kidney transplantation can provide adequate renal function with a speedy increase in allograft size.