Jeffrey Veale

Transporting live donor kidneys for kidney paired donation: initial national results.

Optimizing the possibilities for kidney‐paired donation (KPD) requires the participation of donor–recipient pairs from wide geographic regions. Initially it was envisaged that donors would travel to the recipient center; however, to minimize barriers to participation and simplify logistics, recent trends have involved transporting the kidneys rather than the donors. The goal of this study was to review outcomes of this practice. KPD programs throughout the United States were directly queried about all transplants involving live donor kidney transport. Early graft function was assessed by urine output in the first 8 h, postoperative serum creatinine trend, and incidence of delayed graft function. Between April 27, 2007 and April 29, 2010, 56 live donor kidneys were transported among 30 transplant centers. Median CIT was 7.2 h (IQR 5.5–9.7, range 2.5–14.5). Early urine output was robust (>100 cc/h) in all but four patients. Creatinine nadir was <2.0 mg/dL in all (including the four with lower urine output) but one patient, occurring at a median of 3 days (IQR 2–5, range 1–49). No patients experienced delayed graft function as defined by the need for dialysis in the first week. Current evidence suggests that live donor kidney transport is safe and feasible.

Anti-HLA antibodies can induce endothelial cell survival or proliferation depending on their concentration.

Patients exhibiting a humoral immune response to the transplanted organ are at increased risk of antibody-mediated rejection and development of transplant vasculopathy. Historically, antibodies were thought to elicit transplant rejection through complement mediated damage of the endothelium of the graft. More recently, studies from our laboratory and others have shown that antibody ligation of class I molecules on the surface of endothelial cells transduces signals resulting in functional changes including expression of cell survival proteins and cell proliferation. The intracellular events initiated by antibody ligation are dependent upon the degree of molecular aggregation and influenced by the concentration of the antibody and level of human leukocyte antigen (HLA) expression. Herein we describe our recent findings on the effect of molecular aggregation on the class I signaling pathway in human endothelial cells.

Chain Transplantation: Initial Experience of a Large Multicenter Program

We report the results of a large series of chain transplantations that were facilitated by a multicenter US database in which 57 centers pooled incompatible donor/recipient pairs. Chains, initiated by nondirected donors, were identified using a computer algorithm incorporating virtual cross‐matches and potential to extend chains. The first 54 chains facilitated 272 kidney transplants (mean chain length = 5.0). Seven chains ended because potential donors became unavailable to donate after their recipient received a kidney; however, every recipient whose intended donor donated was transplanted. The remaining 47 chains were eventually closed by having the last donor donate to the waiting list. Of the 272 chain recipients 46% were ethnic minorities and 63% of grafts were shipped from other centers. The number of blood type O‐patients receiving a transplant (n = 90) was greater than the number of blood type O‐non‐directed donors (n = 32) initiating chains. We have 1‐year follow up on the first 100 transplants. The mean 1‐year creatinine of the first 100 transplants from this series was 1.3 mg/dL. Chain transplantation enables many recipients with immunologically incompatible donors to be transplanted with high quality grafts.

Asynchronous, Out-of-Sequence, Transcontinental Chain Kidney Transplantation: A Novel Concept

The organ donor shortage has been the most important hindrance in getting listed patients transplanted. Living kidney donors who are incompatible with their intended recipients are an untapped resource for expanding the donor pool through participation in transplant exchanges. Chain transplantation takes this concept further, with the potential to benefit even more recipients. We describe the first asynchronous, out of sequence transplant chain that was initiated by transcontinental shipment of an altruistic donor kidney 1 week after that recipients incompatible donor had already donated his kidney to the next recipient in the chain. The altruistic donor kidney was transported from New York to Los Angeles and functioned immediately after transplantation. Our modified‐sequence asynchronous transplant chain (MATCH) enabled eight recipients, at four different institutions, to benefit from the generosity of one altruistic donor and warrants further exploration as a promising step toward addressing the organ donor shortage.

Should pediatric patients wait for HLA-DR-matched renal transplants?

Graft survival rates from deceased donors aged 35 years or less among all primary pediatric kidney transplant recipients in the United States between 1996 and 2004 were retrospectively examined to determine the effect of HLA‐DR mismatches on graft survival. Zero HLA‐DR‐mismatched kidneys had statistically comparable 5‐year graft survival (71%), to 1‐DR‐mismatched kidneys (69%) and 2‐DR‐mismatched kidneys (71%). When compared to donors less than 35 years of age, the relative rate of allograft failure was 1.32 (p = 0.0326) for donor age greater than or equal to age 35. There was no statistical increase in the odds of developing a panel‐reactive antibody (PRA) greater than 30% at the time of second waitlisting, based upon the degree of HLA‐A, ‐B or ‐DR mismatch of the first transplant, nor was there a ‘dose effect’ when more HLA antigens were mismatched between the donor and recipient. Therefore, pediatric transplant programs should utilize the recently implemented Organ Procurement and Transplantation Networks (OPTN)allocation policy, which prioritizes pediatric recipients to receive kidneys from deceased donors less than 35 years of age, and should not turn down such kidney offers to wait for a better HLA‐DR‐matched kidney.

Specific binding and magnetic concentration of CD8+ T-lymphocytes on electrowetting-on-dielectric platform

In the quest to create a low-power portable lab-on-a-chip system, we demonstrate the specific binding and concentration of human CD8+ T-lymphocytes on an electrowetting-on-dielectric (EWOD)-based digital microfluidic platform using antibody-conjugated magnetic beads (MB-Abs). By using a small quantity of nonionic surfactant, we enable the human cell-based assays with selective magnetic binding on the EWOD device in an air environment. High binding efficiency (∼92%)of specific cells on MB-Abs is achieved due to the intimate contact between the cells and the magnetic beads (MBs) produced by the circulating flow within the small droplet. MBs have been used and cells manipulated in the droplets actuated by EWOD before; reported here is a cell assay of a clinical protocol on the EWOD device in air environment. The present technique can be further extended to capture other types of cells by suitable surface modification on the MBs.

Kidney Transplant Chains Amplify Benefit of Nondirected Donors

IMPORTANCE Despite the potential for altruistic nondirected donors (NDDs) to trigger multiple transplants through nonsimultaneous transplant chains, concerns exist that these chains siphon NDDs from the deceased donor wait list and that donors within chains might not donate after their partner receives a transplant. OBJECTIVE To determine the number of transplantations NDDs trigger through chains. DESIGN Retrospective review of large, multicenter living donor-recipient database. SETTING Fifty-seven US transplant centers contributing donor-recipient pairs to the database. PARTICIPANTS The NDDs initiating chain transplantation. MAIN OUTCOMES MEASURE Number of transplants per NDD. RESULTS Seventy-seven NDDs enabled 373 transplantations during 46 months starting February 2008. Mean chain length initiated by NDDs was 4.8 transplants (median, 3; range, 1-30). The 40 blood type O NDDs triggered a mean chain length of 6.0 (median, 4; range, 2-30). During the interval, 66 of 77 chains were closed to the wait list, 4 of 77 were ongoing, and 7 of 77 were broken because bridge donors became unavailable. No chains were broken in the last 15 months, and every recipient whose incompatible donor donated received a kidney. One hundred thirty-three blood type O recipients were transplanted. CONCLUSION AND RELEVANCE This large series demonstrates that NDDs trigger almost 5 transplants on average, more if the NDD is blood type O. There were more blood type O recipients than blood type O NDDs participating. The benefits of transplanting 373 patients and enabling others without living donors to advance outweigh the risk of broken chains that is decreasing with experience. Even 66 patients on the wait list without living donors underwent transplantation with living-donor grafts at the end of these chains.

Serum Creatinine Detection by a Conducting-Polymer-Based Electrochemical Sensor To Identify Allograft Dysfunction

Kidney transplant recipients who have abnormally high creatinine levels in their blood often have allograft dysfunction secondary to rejection. Creatinine has become the preferred marker for renal dysfunction and is readily available in hospital clinical settings. We developed a rapid and accurate polymer-based electrochemical point-of-care (POC) assay for creatinine detection from whole blood to identify allograft dysfunction. The creatinine concentrations of 19 blood samples from transplant recipients were measured directly from clinical serum samples by the conducting polymer-based electrochemical (EC) sensor arrays. These measurements were compared to the traditional clinical laboratory assay. The time required for detection was <5 min from sample loading. Sensitivity of the detection was found to be 0.46 mg/dL of creatinine with only 40 μL sample in the creatinine concentration range of 0 mg/dL to 11.33 mg/dL. Signal levels that were detected electrochemically correlated closely with the creatinine blood concentration detected by the UCLA Ronald Reagan Medical Center traditional clinical laboratory assay (correlation coefficient = 0.94). This work is encouraging for the development of a rapid and accurate POC device for measuring creatinine levels in whole blood.

Kidney paired donation in the presence of donor-specific antibodies.

Incompatible donor/recipient pairs with broadly sensitized recipients have difficulty finding a crossmatch-compatible match, despite a large kidney paired donation pool. One approach to this problem is to combine kidney paired donation with lower-risk crossmatch-incompatible transplantation with intravenous immunoglobulin. Whether this strategy is non-inferior compared with transplantation of sensitized patients without donor-specific antibody (DSA) is unknown. Here we used a protocol including a virtual crossmatch to identify acceptable crossmatch-incompatible donors and the administration of intravenous immunoglobulin to transplant 12 HLA-sensitized patients (median calculated panel reactive antibody 98%) with allografts from our kidney paired donation program. This group constituted the DSA(+) kidney paired donation group. We compared rates of rejection and survival between the DSA(+) kidney paired donation group with a similar group of 10 highly sensitized patients (median calculated panel reactive antibody 85%) that underwent DSA(-) kidney paired donation transplantation without intravenous immunoglobulin. At median follow-up of 22 months, the DSA(+) kidney paired donation group had patient and graft survival of 100%. Three patients in the DSA(+) kidney paired donation group experienced antibody-mediated rejection. Patient and graft survival in the DSA(-) kidney paired donation recipients was 100% at median follow-up of 18 months. No rejection occurred in the DSA(-) kidney paired donation group. Thus, our study provides a clinical framework through which kidney paired donation can be performed with acceptable outcomes across a crossmatch-incompatible transplant.

Managing Finances of Shipping Living Donor Kidneys for Donor Exchanges

Kidney donor exchanges enable recipients with immunologically incompatible donors to receive compatible living donor grafts; however, the financial management of these exchanges, especially when an organ is shipped, is complex and thus has the potential to impede the broader implementation of donor exchange programs. Representatives from transplant centers that utilize the National Kidney Registry database to facilitate donor exchange transplants developed a financial model applicable to paired donor exchanges and donor chain transplants. The first tenet of the model is to eliminate financial liability to the donor. Thereafter, it accounts for the donor evaluation, donor nephrectomy hospital costs, donor nephrectomy physician fees, organ transport, donor complications and recipient inpatient services. Billing between hospitals is based on Medicare cost report defined costs rather than charges. We believe that this model complies with current federal regulations and effectively captures costs of the donor and recipient services. It could be considered as a financial paradigm for the United Network for Organ Sharing managed donor exchange program.