Financial Neutrality for Living Organ Donors: Reasoning, Rationale, Definitions, and Implementation Strategies.

In the United States, live organ donation can be a costly and burdensome undertaking for donors. While most donation-related medical expenses are covered, many donors still face lost wages, travel expenses, incidentals, and potential for future insurability problems. Despite widespread consensus that live donors (LD) should not be responsible for the costs associated with donation, little has changed to alleviate financial burdens for LDs in the last decade. To achieve this goal, the transplant community must actively pursue strategies and policies to eliminate unreimbursed out-of-pocket costs to LDs. Costs should be more appropriately distributed across all stakeholders; this will also make live donation possible for people who, in the current system, cannot afford to proceed. We propose the goal of LD "financial neutrality," offer an operational definition to include the coverage/reimbursement of all medical, travel, and lodging costs, along with lost wages, related to the act of donating an organ, and guidance for consideration of medical care coverage, and wage and other expense reimbursement. The intent of this report is to provide a foundation to inform discussion within the transplant community and to advance initiatives for policy and resource allocation.

Living and deceased organ donation should be financially neutral acts.

The supply of organs­particularly kidneys­donated by living and deceased donors falls short of the number of patients added annually to transplant waiting lists in the United States. To remedy this problem, a number of prominent physicians, ethicists, economists and others have mounted a campaign to suspend the prohibitions in the National Organ Transplant Act of 1984 (NOTA) on the buying and selling of organs. The argument that providing financial benefits would incentivize enough people to part with a kidney (or a portion of a liver) to clear the waiting lists is flawed. This commentary marshals arguments against the claim that the shortage of donor organs would best be overcome by providing financial incentives for donation. We can increase the number of organs available for transplantation by removing all financial disincentives that deter unpaid living or deceased kidney donation. These disincentives include a range of burdens, such as the costs of travel and lodging for medical evaluation and surgery, lost wages, and the expense of dependent care during the period of organ removal and recuperation. Organ donation should remain an act that is financially neutral for donors, neither imposing financial burdens nor enriching them monetarily.

Consensus conference on best practices in live kidney donation: recommendations to optimize education, access, and care.

Live donor kidney transplantation is the best treatment option for most patients with late-stage chronic kidney disease; however, the rate of living kidney donation has declined in the United States. A consensus conference was held June 5-6, 2014 to identify best practices and knowledge gaps pertaining to live donor kidney transplantation and living kidney donation. Transplant professionals, patients, and other key stakeholders discussed processes for educating transplant candidates and potential living donors about living kidney donation; efficiencies in the living donor evaluation process; disparities in living donation; and financial and systemic barriers to living donation. We summarize the consensus recommendations for best practices in these educational and clinical domains, future research priorities, and possible public policy initiatives to remove barriers to living kidney donation.

Organ transplantation for nonresidents of the United States: a policy for transparency.

A policy proposal relating to transplantation of deceased donor organs into nonresidents of the United States was jointly sponsored by the Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) International Relations and Ethics Committees and approved by the OPTN/UNOS Board in June 2012. The proposal followed prior acceptance by the Board of the definitions of "travel for transplantation" and "transplant tourism" and the introduction in March 2012 of revised data collection categories for transplant candidates who are neither citizens nor residents. The most important aspect of the new policy concerns replacement of the previous so-called "5% rule" with the review of all residency and citizenship data and the preparation of a public annual report. The new policy does not prohibit organ transplantation in nonresidents. However, the policy and public data report will ensure transparency and support transplant center responsibility to account for their practices. Since the adoption of the policy, the first 19 months of data show that less than 1% of new deceased donor waitlist additions and less than 1% of transplantation recipients were non-US citizen/nonresidents candidates who traveled to the United States for purposes of transplantation. By adopting this policy, the US transplant community promotes public trust and serves as an example to the international transplant community.

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.

Simultaneous liver-kidney transplantation summit: current state and future directions.

Although previous consensus recommendations have helped define patients who would benefit from simultaneous liver-kidney transplantation (SLK), there is a current need to reassess published guidelines for SLK because of continuing increase in proportion of liver transplant candidates with renal dysfunction and ongoing donor organ shortage. The purpose of this consensus meeting was to critically evaluate published and registry data regarding patient and renal outcomes following liver transplantation alone or SLK in liver transplant recipients with renal dysfunction. Modifications to the current guidelines for SLK and a research agenda were proposed.

The use of executed prisoners as a source of organ transplants in China must stop.

Internationally accepted ethical standards are unequivocal in their prohibition of the use of organs recovered from executed prisoners: yet this practice continues in China despite indications that Ministry of Health officials intend to end this abhorrent practice. Recently published articles on this topic emphasize the medical complications that result from liver transplantation from executed 'donors' but scant attention is given to the source of the organs, raising concern that the transplant community may be becoming inured to unacceptable practice. Strategies to influence positive change in organ donation practice in China by the international transplant community are discussed. They include an absolutist policy whereby no clinical data from China is deemed acceptable until unacceptable donation practices end, and an incremental policy whereby clinical data is carefully evaluated for acceptability. The relative advantages and drawbacks of these strategies are discussed together with some practical suggestions for response available to individuals and the transplant community.

Associations of body mass index and weight loss with mortality in transplant-waitlisted maintenance hemodialysis patients.

A body mass index (BMI) below morbid obesity range is often a requirement for kidney transplant wait-listing, but data linking BMI changes to mortality during the waitlist period are lacking. By linking the 6-year (7/2001-6/2007) national databases of a large dialysis organization and the Scientific Registry of Transplant Recipients, we identified 14 632 waitlisted hemodialysis patients without kidney transplantation. Time-dependent survival models examined the mortality predictability of 13-week-averaged BMI, pretransplant serum creatinine as a muscle mass surrogate and their changes over time. The patients were on average 52 ± 13 years old, 40% women and had a BMI of 26.9 ± 6.3 kg/m². Each kg/m² increase of BMI was associated with a death hazard ratio (HR) of 0.96 (95%CI: 0.95-0.97). Compared to the lowest creatinine quintile, the 4th and 5th quintiles had death HRs of 0.75 (0.66-0.86) and 0.57 (0.49-0.66), respectively. Compared to minimal (< ± 1 kg) weight change over 6 months, those with 3 kg- < 5 kg and ≥ 5 kg weight loss had death HRs of 1.31 (1.14-1.52) and 1.51 (1.30-1.75), respectively. Similar associations were observed with creatinine changes over time. Transplant-waitlisted hemodialysis patients with lower BMI or muscle mass and/or unintentional weight or muscle loss have higher mortality in this observational study. Impact of intentional weight change remains unclear.

Disparities in the utilization of live donor renal transplantation.

Despite universal payer coverage with Medicare, sociodemographic disparities confound the care of patients with renal failure. We sought to determine whether adults who realize access to kidney transplantation suffer inequities in the utilization of live donor renal transplantation (LDRT). We identified adults undergoing primary renal transplantation in 2004-2006 from the United Network for Organ Sharing (UNOS). We modeled receipt of live versus deceased donor renal transplant on multilevel multivariate models that examined recipient, center and UNOS region-specific covariates. Among 41 090 adult recipients identified, 39% underwent LDRT. On multivariate analysis, older recipients (OR 0.62, 95% CI 0.56-0.68 for 50-59 year-olds vs. 18-39 year-old recipients), those of African American ethnicity (OR 0.54, 95% CI 0.50-0.59 vs. whites) and of lower socioeconomic status (OR 0.72, 95% CI 0.67-0.79 for high school-educated vs. college-educated recipients; OR 0.78, 95% CI 0.71-0.87 for lowest vs. highest income quartile) had lower odds of LDRT. These characteristics accounted for 14.2% of the variation in LDRT, more than recipient clinical variables, transplant center characteristics and UNOS region level variation. We identified significant racial and socioeconomic disparities in the utilization of LDRT. Educational initiatives and dissemination of processes that enable increased utilization of LDRT may address these disparities.

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 recipient's 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.

Increased T cell immunosenescence and accelerated maturation phenotypes in older kidney transplant recipients.

Older kidney transplant recipients experience increased rates of infection and death, and less rejection, compared with younger patients. However, little is known about immune dysfunction in older compared with younger kidney transplant recipients and whether it is associated with infection. We evaluated T cell phenotypes including maturation, immune senescence, and exhaustion in a novel investigation into differences in older compared with younger patients receiving identical immune suppression regimens. We evaluated PBMC from 60 kidney transplant recipients (23 older and 37 matched younger patients) by multiparameter immune phenotyping. Older kidney transplant recipients demonstrated decreased frequency of naïve CD4+ and CD8+ T cells, and increased frequency of terminally differentiated, immune senescent, and NK T cells expressing KLRG1. There was a trend towards increased frequency of T cell immune senescence in patients experiencing infection in the first year after transplantation, which reached statistical significance in a multivariate analysis. This pilot study reveals immune dysfunction in older compared with younger transplant recipients, and suggests a likely mechanism for increased vulnerability to infection. The ability to assess T cell maturation and immune senescence in transplant recipients offers the potential for risk stratification and customization of immune suppression to prevent infection and rejection after transplantation.

Military antishock trousers. Effect on hemodialysis-induced hypotension.

To evaluate the effect of military antishock trousers (MAST) on hemodialysis-induced hypotension, we observed seven patients undergoing maintenance hemodialysis treatment. We saw each patient on two separate occasions during four-hour hemodialysis treatments. On one occasion , we inflated the MAST to a pressure of 45 mm Hg over the lower extremities and 15 mm Hg over the abdomen; on the second occasion, the MAST were not inflated. Blood pressure was recorded at 15-minute intervals. We found no significant difference between the mean arterial pressure with MAST inflation and that in the control studies. The weight losses during the two studies were also similar. We suggest that, despite their reported efficacy in post-trauma hypotension, MAST are not effective in managing dialysis-induced hypotension.

Catecholamine responses to central volume expansion produced by head-out water immersion and saline infusion.

To delineate plasma catecholamine responses to central volume expansion, four salt-replete healthy adults were subjected to 4 h of thermoneutral head-out water immersion (WI) and infusion of 2 liters normal saline (SI) over 4 h on two separate occasions. Each study was preceded and followed by a control hour. Both of these maneuvers resulted in significant increases in urinary sodium excretion and suppression of PRA and plasma aldosterone levels. During WI studies, plasma norepinephrine levels fell steadily from a prestudy value of 453 +/- 74 pg/ml to a nadir of 254 +/- 71 pg/ml (P less than 0.05) during the fourth immersion hour. In response to SI, plasma norepinephrine fell steadily from a prestudy level of 328 +/- 56 pg/ml to a nadir of 261 +/- 47 pg/ml during the fourth hour of infusion. Plasma dopamine levels rose and epinephrine levels were unchanged in response to WI as well as SI. When the mean urinary sodium excretion was plotted against the mean dopamine to norepinephrine ratio, there was a direct relationship in WI studies (r = 0.90) as well as SI studies (r = 0.92). These data suggest that plasma norepinephrine levels fall and plasma dopamine levels rise in response to volume expansion. These data also suggest that relative concentrations of dopamine vs those of norepinephrine may have a role in mediating natriuresis in response to volume expansion.

Mediation of the antiproliferative effect of cyclosporine on human lymphocytes by blockade of interleukin 2 biosynthesis.

Normal human peripheral blood mononuclear cells (PBMC) were cultured with phytohemagglutinin-P (PHAP) and cyclosporine (CsA) to investigate the mode of action of CsA on cellular proliferation. CsA at 1 microgram/ml exerted a marked inhibitory effect on PBMC responsiveness to PHAP. An antiproliferative effect of CsA was observed at the inductive phase of the cell cycle, but the drug was ineffective when it was added to cultures 24 hr after stimulation. In parallel with this inhibitory effect interleukin 2 (IL-2) production was inhibited. In contrast, IL-2 receptor was expressed on the CsA-treated cells, and the antiproliferative influence of the drug was completely reversed by addition of highly purified human IL-2 to the CsA-treated cells. Exogenous IL-2, however, did not restore cellular capacity to produce IL-2. This study suggests that CsA acts by inhibiting IL-2 production (via blockade of IL-2 gene expression) rather than by preventing the expression of the IL-2 receptor.

Gamma-interferon gene expression in human renal allograft fine-needle aspirates.

Cytokines appear to play a major role in acute transplant rejection (AR); however, the specific cytokines initiating AR are not known. To investigate gamma-interferon messenger RNA (mRNA) as a key factor in AR induction, we performed reverse transcription-polymerase chain reaction (RT-PCR) on renal allograft fine-needle aspirates (FNA). Fifteen FNA from 15 patients were processed and interpreted in the standard fashion, the percent of tubular cells with MHC class II expression (DR) quantitated, and aliquots of FNA obtained for RT-PCR. RT-PCR was performed with primers to gamma-IFN with cyclophylin and insulin primers as controls. Retrospective clinical diagnoses were made for each FNA sample. Following RT-PCR, all FNA and FNAs from control normal and AR nephrectomy specimens had cyclophylin present, and in the 9 samples tested insulin was absent. Five patients had AR clinically and by FNA criteria; all 5 had elevated DR and gamma-IFN mRNA present in FNA. Five patients had tubular necrosis or cyclosporine toxicity clinically, and FNA without immune activation or elevated DR and negative gamma-IFN mRNA. Two patients had immune activation by FNA with elevated DR; both FNA expressed gamma-IFN mRNA by Southern blot, one only weakly, and both patients subsequently developed clinical AR. Two patients had recently treated AR, one with persistent DR elevation without-immune activation and negative gamma-IFN mRNA in FNAs. This study demonstrates that RT-PCR can be performed with renal allograft FNA samples. The findings suggest intragraft gamma-IFN mRNA expression occurs in active AR preceding clinical AR, thus defining incipient AR. Detection of gamma-IFN mRNA may offer an early diagnostic tool for detection of AR.

Cyclosporine microemulsion- and mycophenolate mofetil-related lymphoid aggregates are not associated with acute rejection.

BACKGROUND: Microemulsion cyclosporine, mycophenolate mofetil, and prednisone have become a common immunosuppressive protocol in renal transplantation. We identified lymphocytic infiltrates in transplant fine-needle aspirates and core biopsies from patients on this regimen without acute rejection clinically or by standardized morphological criteria and investigated this inflammatory response. METHODS: Twenty-eight aspirates from 21 patients were included and assessed in the standard fashion. Nine core biopsies showing interstitial lymphocytic infiltration were evaluated with antibodies against CD3, CD4, CD8, CD20, CD30, CD56, KP1, and epithelial membrane antigen (EMA). Aspirates and biopsies were assessed for tubular cell major histocompatibility complex (MHC) class II antigen and for gamma-interferon (gamma-IFN), interleukin-4 (IL-4), and IL-10 mRNAs by reverse transcription-polymerase chain reaction. RESULTS: Fifteen aspirates showed immune activation solely due to mature lymphocytes and monocytes; 13 had no immune activation. All aspirates were negative for MHC class II antigens. Of 6 activated aspirates assessed for gamma-IFN mRNA, 5 were negative. All 21 patients had similar clinical characteristics and recovered renal function without rejection treatment. The core biopsies had lymphocytes in 5-30% of the interstitium. The cells were 70-85% CD3+, with 50-85% CD4+, 3-10% KP1+, and rare cells CD56+. No T-cell activation was present (EMA- and CD30-). Seven biopsies were assessed and were negative for gamma-IFN mRNA; only one biopsy had weakly positive MHC class II staining. Two activated aspirates were negative for IL-4 and IL-10 mRNA, while three biopsies each contained IL-4 and IL-10 mRNAs. CONCLUSIONS: Inactive interstitial lymphoid infiltrates are frequent in patients on this drug regimen and should not be interpreted as acute rejection, particularly in aspirate samples. These lymphocytes may play a role in long-term allograft acceptance.

Histopathological features of hepatitis C in renal transplant candidates [see comment].

BACKGROUND: Although hepatitis C virus (HCV) infection is common in renal transplant candidates, its clinical significance remains unclear in this population. Little detailed information is available about the histological severity of HCV infection in these patients. We evaluated the liver biopsy features of chronic HCV in a large population of renal transplant candidates and investigated associations between histopathological changes and host- and virus-related factors. METHODS: Thirty-seven patients seropositive for anti-HCV with chronic renal failure (CRF) referred to UCLA Medical Center for kidney or kidney/liver transplantation during the period 1992-1997 were included. HCV genotype and viral load were measured. A multivariate analysis by logistic regression model was performed: age, gender, race, HCV load and genotype, CRF level, aspartate and alanine aminotransferase activity, duration of HCV infection, underlying nephropathy, and alcohol abuse were independent variables; liver histology score was assumed a dependent variable. RESULTS: Liver disease was present in all HCV-infected patients. Logistic regression analysis revealed that histological damage was (P = 0.0017) independently associated with the CRF level; the severity of liver disease, as shown by univariate analysis, being significantly higher in CRF patients not requiring dialysis than among dialysis population. All patients on dialysis showed mild or moderate necroinflammatory activity; the majority (22/28 = 79%) of these individuals had fibrosis, three (3/28 = 11%) dialysis patients had established cirrhosis. Thirty-one (84%) of 37 patients were tested by polymerase chain reaction, 25 (81%) patients had detectable HCV RNA in serum, the mean HCV load among viremic patients was 10.9x10(5) copies/ ml. The most frequent HCV genotypes were la (8/24 = 33%) and 1b (7/24 = 29%), followed by genotype 2b (3/24 = 12%). CONCLUSIONS: Pathological changes on liver biopsy were observed in all HCV-infected patients awaiting renal transplantation. The severity of histologic damage observed on liver biopsy was less in dialysis than predialysis CRF patients. All dialysis patients had mild or moderate necroinflammatory activity; fibrosis was frequent with 11% of them having cirrhosis. The HCV viral load was rather low; no relationship between liver histology changes and virological features of HCV or aminotransferase activity was apparent. Further studies with repeat liver biopsies after kidney transplantation to observe the evolution of HCV-related liver disease after immunosuppressive therapy are indicated. We suggest including liver biopsy in the evaluation of the HCV-infected renal transplant candidate.

Angiotensin-converting enzyme inhibition in the treatment of renal transplant erythrocytosis. Clinical experience and observation of mechanism.

Recent observations indicate that angiotensin-converting enzyme (ACE) inhibition corrects renal transplant erythrocytosis (RTE). The mechanism for this association is not known. We examined the effect of ACE inhibition on hematocrit, erythropoietin (EPO), and renin substrate. ACE inhibition has been reported to suppress renin substrate, which is known to stimulate EPO and erythropoiesis. In 15 patients with RTE, hematocrit dropped from 52.8 +/- 0.6 (SEM) to 45.8 +/- 1.4% after 8 weeks of treatment with Enalapril, 2.5-20 mg/day. Serum EPO (normal range: 9-30 mU/ml) was high in one, normal in seven, and low in seven patients. ACE inhibition reduced EPO in patients with initial high or normal levels but induced no change in patients with initial low levels. ACE inhibition had no significant effect on renin substrate. In one patient who rejected his first graft, erythrocytosis recurred following a second, successful transplant. Treatment was discontinued because of cough in two patients and symptomatic drop in blood pressure in one patient. We conclude RTE is not caused by hypererythropoietinemia. In patients with normal circulating EPO, erythrocytosis may result from an increase sensitivity to EPO, and ACE inhibition lowered hematocrit by further reduction of this hormone. However, the finding of erythrocytosis in half our patients with suppressed EPO, suggests the participation of non-EPO-mediated mechanism(s). The recurrence of RTE in a patient after a second transplant raises the additional possibility of patient-specific factors in the pathogenesis of this disorder. In contrast to other reports, we documented side-effects (cough, hypotension) in three (20%) of our patients. Our clinical experience, coupled with prior reports of spontaneous resolution of RTE in some patients, suggests that intermittent courses of ACE-inhibition may be the optimal strategy in the use of this form of therapy for RTE.