Safety and efficacy of eculizumab in the prevention of antibody-mediated rejection in living-donor kidney transplant recipients requiring desensitization therapy: A randomized trial.

We report results of a phase 2, randomized, multicenter, open-label, two-arm study evaluating the safety and efficacy of eculizumab in preventing acute antibody-mediated rejection (AMR) in sensitized recipients of living-donor kidney transplants requiring pretransplant desensitization (NCT01399593). In total, 102 patients underwent desensitization. Posttransplant, 51 patients received standard of care (SOC) and 51 received eculizumab. The primary end point was week 9 posttransplant treatment failure rate, a composite of: biopsy-proven acute AMR (Banff 2007 grade II or III; assessed by blinded central pathology); graft loss; death; or loss to follow-up. Eculizumab was well tolerated with no new safety concerns. No significant difference in treatment failure rate was observed between eculizumab (9.8%) and SOC (13.7%; P = .760). To determine whether data assessment assumptions affected study outcome, biopsies were reanalyzed by central pathologists using clinical information. The resulting treatment failure rates were 11.8% and 21.6% for the eculizumab and SOC groups, respectively (nominal P = .288). When reassessment included grade I AMR, the treatment failure rates were 11.8% (eculizumab) and 29.4% (SOC; nominal P = .048). This finding suggests a potential benefit for eculizumab compared with SOC in preventing acute AMR in recipients sensitized to their living-donor kidney transplants (EudraCT 2010-019630-28).

Safety and efficacy of eculizumab for the prevention of antibody-mediated rejection after deceased-donor kidney transplantation in patients with preformed donor-specific antibodies.

The presence of preformed donor-specific antibodies in transplant recipients increases the risk of acute antibody-mediated rejection (AMR). Results of an open-label single-arm trial to evaluate the safety and efficacy of eculizumab in preventing acute AMR in recipients of deceased-donor kidney transplants with preformed donor-specific antibodies are reported. Participants received eculizumab as follows: 1200 mg immediately before reperfusion; 900 mg on posttransplant days 1, 7, 14, 21, and 28; and 1200 mg at weeks 5, 7, and 9. All patients received thymoglobulin induction therapy and standard maintenance immunosuppression including steroids. The primary end point was treatment failure rate, a composite of biopsy-proved grade II/III AMR (Banff 2007 criteria), graft loss, death, or loss to follow-up, within 9 weeks posttransplant. Eighty patients received transplants (48 women); the median age was 52 years (range 24-70 years). Observed treatment failure rate (8.8%) was significantly lower than expected for standard care (40%; P < .001). By 9 weeks, 3 of 80 patients had experienced AMR, and 4 of 80 had experienced graft loss. At 36 months, graft and patient survival rates were 83.4% and 91.5%, respectively. Eculizumab was well tolerated and no new safety concerns were identified. Eculizumab has the potential to provide prophylaxis against injury caused by acute AMR in such patients (EudraCT 2010-019631-35).

Incentives for organ donation: proposed standards for an internationally acceptable system.

Incentives for organ donation, currently prohibited in most countries, may increase donation and save lives. Discussion of incentives has focused on two areas: (1) whether or not there are ethical principles that justify the current prohibition and (2) whether incentives would do more good than harm. We herein address the second concern and propose for discussion standards and guidelines for an acceptable system of incentives for donation. We believe that if systems based on these guidelines were developed, harms would be no greater than those to today's conventional donors. Ultimately, until there are trials of incentives, the question of benefits and harms cannot be satisfactorily answered.

Carbon nanobrush-containing poloxamer hydrogel composites for tissue regeneration.

The objective of this study was to examine potential uses for electrically conductive hydrogel composites in tissue engineering and tissue regeneration, and to explore the composites as a growth matrix for clinically relevant cell lines. The composite was comprised of carbon nanobrushes embedded in a biocompatible poloxamer gel. In this study, we assessed the ability of such composite gels to support the growth of fibroblasts and myocytes and eventually serve as a matrix to stimulate wound closure. In such a model, fibroblasts and myocytes are seeded on the hydrogel and bathed in culture medium. The experimental model assesses the ability of fibroblasts and myocytes to grow into and adhere to the gel. The results of this study demonstrate that carbon nanobrushes can be dispersed within poloxamer gels and that fibroblasts and myocytes can proliferate within homogenously dispersed carbon nanobrush-containing poloxamer gels. We also examined the effects of carbon nanobrush content on the rheological properties of the poloxamer gel matrix; improvement occurred in several areas in the presence of carbon nanobrushes. Our future studies will investigate the effects of design parameters such as carbon nanobrush content and matrix structure on wound healing, as well as the growth of tendons and other cell lines within the hydrogel composites. In general, this work has relevance for tissue and cellular engineering and tissue regeneration in clinical medicine.

Transplant tumor registry: donor related malignancies.

BACKGROUND: Transmission of donor malignancies has been intermittently reported since the early days of clinical transplantation. The incidence of United States donor related malignancies has not previously been documented. METHODS: All donor related malignancies reported to the Organ Procurement and Transplantation Network/United Network for Organ Sharing from 4/1/94-7/1/01 in a cohort of 34,933 cadaveric donors and 108,062 recipients were investigated by contacting the transplant centers to verify that the reported tumors were of donor origin. Time and mode of discovery, as well as graft and patient outcome, were determined. The status of other recipients from the donor was investigated. RESULTS: A total of 21 donor related malignancies from 14 cadaveric and 3 living donors were reported. Fifteen tumors were donor transmitted and 6 were donor derived. Transmitted tumors are malignancies that existed in the donor at the time of transplantation. Derived tumors are de novo tumors that develop in transplanted donor hematogenous or lymphoid cells after transplantation. The cadaveric donor related tumor rate is 0.04% (14 of 34,993). The donor related tumor rate among transplanted cadaveric organs is 0.017% (18 of 108,062). Among patients developing donor related malignancies, the overall mortality rate was 38%, with that of transmitted tumors being 46% and derived tumors being 33%. The cadaveric donor related tumor mortality rate is 0.007% (8 of 108,062). CONCLUSIONS: The United States incidence of donor related tumors is extremely small. The donor related tumor death rate is also extremely small, particularly when compared with waiting-list mortality.

Morbid obesity is not a contraindication to kidney transplantation.

BACKGROUND: Concern that morbidly obese (body mass index [BMI] 35) kidney transplant recipients have worse outcomes than non-morbidly obese recipients leads many transplant centers to deny them the benefit of kidney transplantation. These concerns are supported by guidelines recently published by the American Society of Transplantation. However, successfully transplanted morbidly obese persons have a survival advantage over those that remain on dialysis. It is our practice to evaluate morbidly obese transplant candidates for transplantation under the same criteria used for nonobese candidates. This report reviews our experience with morbidly obese kidney transplant recipients having a three year follow-up. METHODS: Outcomes for 23 morbidly obese (BMI 35, range 37 to 56) kidney transplant recipients transplanted between January 1995 and February 2000 were compared with 224 nonobese (BMI 25) kidney recipients transplanted during the same period. RESULTS: Patient and graft survivals were similar between both groups. Although 3-year graft survival for morbidly obese recipients of cadaver organs was 75% compared with 90% for the nonobese group, this finding was not statistically significant, and 3-year graft survival was 100% for morbidly obese recipients of living donor organs compared with 91% for nonobese recipients. Morbidly obese recipients had significantly longer hospital stays, higher readmission rates, and a higher wound infection rate than nonobese recipients. CONCLUSIONS: We found that morbidly obese persons have 3-year graft and patient survivals similar to nonobese persons. Although they also have greater complications and greater numbers of days in the hospital, we believe these reasons are not sufficient to deny morbidly obese persons the survival and quality-of-life advantages of kidney transplantation.

Hydrogel encapsulation to improve cell viability during syringe needle flow.

This work examines pluronic F-127 poloxamer for cell protection during injection through a syringe needle. Direct cell injection is a minimally invasive method for cell transplantation; however, it often results in poor cell viability. We proposed that encapsulating cells in this hydrogel would protect cells from detrimental mechanical forces during injection and increase cell viability. The hydrogel was tested at multiple weights and carbon nanobrush concentrations to determine how gel weight affects cell viability as well as to allow the gels to remain as electrically conductive scaffolds. This work assessed the ability of the hydrogel to prevent cell membrane bursting. We used D1 multipotent mouse bone marrow stromal precursor cells for this study. We found that the pressure drop increases with increasing weight of the gels. However, cell viability also increases as the weight of the gels increases. These results support the proposition that hydrogels can be used to protect cells during syringe needle injection. Since these hydrogels undergo a reverse phase transition, the gels can be used to transplant cells into the body in solution form through injection. The gels will then harden in situ to allow for cell proliferation and tissue regeneration at the desired site.

Tripterygium wilfordii Hook F. versus Sulfasalazine in the treatment of rheumatoid arthritis: a well-designed clinical trial of a botanical demonstrating effectiveness.

Claims that Traditional/Alternative medicine (TM/AM) remedies are effective are routinely ignored by Western Medicine. However, the results of a clinical trial that demonstrated the clinical efficacy of Tripterygium wilfordii Hook F. (TW), a TM used as an anti-inflammatory, were recently published in the Annals of Internal Medicine. Why this article was published in a peer reviewed Allopathic medical journal is an important question that begs examination and may lay the future promise of TM/AM therapeutic interventions.

Identification of a B cell signature associated with renal transplant tolerance in humans.

Establishing long-term allograft acceptance without the requirement for continuous immunosuppression, a condition known as allograft tolerance, is a highly desirable therapeutic goal in solid organ transplantation. Determining which recipients would benefit from withdrawal or minimization of immunosuppression would be greatly facilitated by biomarkers predictive of tolerance. In this study, we identified the largest reported cohort to our knowledge of tolerant renal transplant recipients, as defined by stable graft function and receiving no immunosuppression for more than 1 year, and compared their gene expression profiles and peripheral blood lymphocyte subsets with those of subjects with stable graft function who are receiving immunosuppressive drugs as well as healthy controls. In addition to being associated with clinical and phenotypic parameters, renal allograft tolerance was strongly associated with a B cell signature using several assays. Tolerant subjects showed increased expression of multiple B cell differentiation genes, and a set of just 3 of these genes distinguished tolerant from nontolerant recipients in a unique test set of samples. This B cell signature was associated with upregulation of CD20 mRNA in urine sediment cells and elevated numbers of peripheral blood naive and transitional B cells in tolerant participants compared with those receiving immunosuppression. These results point to a critical role for B cells in regulating alloimmunity and provide a candidate set of genes for wider-scale screening of renal transplant recipients.

Organ donation and utilization in the United States, 2004.

This article discusses issues directly related to the organ donation process, including donor consent, donor medical suitability, non-recovery of organs, organs recovered but not transplanted, expanded criteria donors (ECD), and donation after cardiac death (DCD). The findings and topics covered have important implications for how to evaluate and share best practices of organ donation as implemented by organ procurement organizations (OPOs) and major donor hospitals in the same donation service areas (DSAs). In 2002 and 2003, US hospitals referred more than one million deaths or imminent deaths to the OPOs of their DSA. Referrals increased by nearly 10% from 2002 to 2003 (1,022,280 to 1,121,392). Donor consents have increased by about 5% and the number of total deceased donors has risen from 6,187 to 6,455. Since multiple organs are recovered from most donors, this increase allowed more than 500 additional wait-listed candidates to receive an organ transplant than in the prior year. Non-traditional donor sources have experienced a large rate of increase; in 2003 the number of ECD kidney donors increased by 8% and the number of DCD donors increased by 43%, from 189 donors in year 2002 to 271 donors in 2003.