Effect of Replacing Race With Apolipoprotein L1 Genotype in Calculation of Kidney Donor Risk Index.

Renal allografts from deceased African American donors with two apolipoprotein L1 gene (APOL1) renal-risk variants fail sooner than kidneys from donors with fewer variants. The Kidney Donor Risk Index (KDRI) was developed to evaluate organ offers by predicting allograft longevity and includes African American race as a risk factor. Substituting APOL1 genotype for race may refine the KDRI. For 622 deceased African American kidney donors, we applied a 10-fold cross-validation approach to estimate contribution of APOL1 variants to a revised KDRI. Cross-validation was repeated 10 000 times to generate distribution of effect size associated with APOL1 genotype. Average effect size was used to derive the revised KDRI weighting. Mean current-KDRI score for all donors was 1.4930 versus mean revised-KDRI score 1.2518 for 529 donors with no or one variant and 1.8527 for 93 donors with two variants. Original and revised KDRIs had comparable survival prediction errors after transplantation, but the spread in Kidney Donor Profile Index based on presence or absence of two APOL1 variants was 37 percentage points. Replacing donor race with APOL1 genotype in KDRI better defines risk associated with kidneys transplanted from deceased African American donors, substantially improves KDRI score for 85-90% of kidneys offered, and enhances the link between donor quality and recipient need.

AST/ASTS workshop on increasing organ donation in the United States: creating an "arc of change" from removing disincentives to testing incentives.

The American Society of Transplantation (AST) and American Society of Transplant Surgeons (ASTS) convened a workshop on June 2-3, 2014, to explore increasing both living and deceased organ donation in the United States. Recent articles in the lay press on illegal organ sales and transplant tourism highlight the impact of the current black market in kidneys that accompanies the growing global organ shortage. We believe it important not to conflate the illegal market for organs, which we reject in the strongest possible terms, with the potential in the United States for concerted action to remove all remaining financial disincentives for donors and critically consider testing the impact and acceptability of incentives to increase organ availability in the United States. However, we do not support any trials of direct payments or valuable considerations to donors or families based on a process of market-assigned values of organs. This White Paper represents a summary by the authors of the deliberations of the Incentives Workshop Group and has been approved by both AST and ASTS Boards.

Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure.

Apolipoprotein L1 gene (APOL1) nephropathy variants in African American deceased kidney donors were associated with shorter renal allograft survival in a prior single-center report. APOL1 G1 and G2 variants were genotyped in newly accrued DNA samples from African American deceased donors of kidneys recovered and/or transplanted in Alabama and North Carolina. APOL1 genotypes and allograft outcomes in subsequent transplants from 55 U.S. centers were linked, adjusting for age, sex and race/ethnicity of recipients, HLA match, cold ischemia time, panel reactive antibody levels, and donor type. For 221 transplantations from kidneys recovered in Alabama, there was a statistical trend toward shorter allograft survival in recipients of two-APOL1-nephropathy-variant kidneys (hazard ratio [HR] 2.71; p = 0.06). For all 675 kidneys transplanted from donors at both centers, APOL1 genotype (HR 2.26; p = 0.001) and African American recipient race/ethnicity (HR 1.60; p = 0.03) were associated with allograft failure. Kidneys from African American deceased donors with two APOL1 nephropathy variants reproducibly associate with higher risk for allograft failure after transplantation. These findings warrant consideration of rapidly genotyping deceased African American kidney donors for APOL1 risk variants at organ recovery and incorporation of results into allocation and informed-consent processes.

Kidneys at higher risk of discard: expanding the role of dual kidney transplantation.

Half of the recovered expanded criteria donor (ECD) kidneys are discarded in the United States. A new kidney allocation system offers kidneys at higher risk of discard, Kidney Donor Profile Index (KDPI)>85%, to a wider geographic area to promote broader sharing and expedite utilization. Dual kidney transplantation (DKT) based on the KDPI is a potential option to streamline allocation of kidneys which otherwise would have been discarded. To assess the clinical utility of the KDPI in kidneys at higher risk of discard, we analyzed the OPTN/UNOS Registry that included the deceased donor kidneys recovered between 2002 and 2012. The primary outcomes were allograft survival, patient survival and discard rate based on different KDPI categories (<80%, 80-90% and >90%). Kidneys with KDPI>90% were associated with increased odds of discard (OR=1.99, 95% CI 1.74-2.29) compared to ones with KDPI<80%. DKTs of KDPI>90% were associated with lower overall allograft failure (HR=0.74, 95% CI 0.62-0.89) and better patient survival (HR=0.79, 95% CI 0.64-0.98) compared to single ECD kidneys with KDPI>90%. Kidneys at higher risk of discard may be offered in the up-front allocation system as a DKT. Further modeling and simulation studies are required to determine a reasonable KDPI cutoff percentile.

Report of a consensus conference on transplant program quality and surveillance.

Public reports of organ transplant program outcomes by the US Scientific Registry of Transplant Recipients have been both groundbreaking and controversial. The reports are used by regulatory agencies, private insurance providers, transplant centers and patients. Failure to adequately adjust outcomes for risk may cause programs to avoid performing transplants involving suitable but high-risk candidates and donors. At a consensus conference of stakeholders held February 13-15, 2012, the participants recommended that program-specific reports be better designed to address the needs of all users. Additional comorbidity variables should be collected, but innovation should also be protected by excluding patients who are in approved protocols from statistical models that identify underperforming centers. The potential benefits of hierarchical and mixed-effects statistical methods should be studied. Transplant centers should be provided with tools to facilitate quality assessment and performance improvement. Additional statistical methods to assess outcomes at small-volume transplant programs should be developed. More data on waiting list risk and outcomes should be provided. Monitoring and reporting of short-term living donor outcomes should be enhanced. Overall, there was broad consensus that substantial improvement in reporting outcomes of transplant programs in the United States could and should be made in a cost-effective manner.

Report of a joint ESOT and AST meeting: highlights in biologic agents and transplantation.

A joint meeting organized by the European (ESOT) and American (AST) Societies of Transplantation occurred in Nice, France, October 1-3, 2010. Focused on emerging use of biologic agents in solid organ transplantation, it served as a venue for state-of-the-art updates in basic immunology and clinical science, with an emphasis on the interrelatedness of the two. This meeting summary is designed to highlight important insights communicated in Nice, offer an overview of novel therapeutics in development, and entice members of all societies to consider attending a second joint symposium, under consideration for 2012.

Inflammation in areas of tubular atrophy in kidney allograft biopsies: a potent predictor of allograft failure.

The Banff scoring schema provides a common ground to analyze kidney transplant biopsies. Interstitial inflammation (i) and tubulitis (t) in areas of viable tissue are features in scoring acute rejection, but are excluded in areas of tubular atrophy (TA). We studied inflammation and tubulitis in a cohort of kidney transplant recipients undergoing allograft biopsy for new-onset late graft dysfunction (N = 337). We found inflammation ('iatr') and tubulitis ('tatr') in regions of fibrosis and atrophy to be strongly correlated with each other (p < 0.0001). Moreover, iatr was strongly associated with death-censored graft failure when compared to recipients whose biopsies had no inflammation, even after adjusting for the presence of interstitial fibrosis (Hazard Ratio = 2.31, [1.10-4.83]; p = 0.0262) or TA (hazard ratio = 2.42, [1.16-5.08]; p = 0.191), serum creatinine at the time of biopsy, time to biopsy and i score. Further, these results did not qualitatively change after additional adjustments for C4d staining or donor specific antibody. Stepwise regression identified the most significant markers of graft failure which include iatr score. We propose that a more global assessment of inflammation in kidney allograft biopsies to include inflammation in atrophic areas may provide better prognostic information. Phenotypic characterization of these inflammatory cells and appropriate treatment may ameliorate late allograft failure.

Use of cardioprotective medications in kidney transplant recipients.

Death with function causes half of late kidney transplant failures, and cardiovascular disease (CVD) is the most common cause of death in these patients. We examined the use of potentially cardioprotective medications in a prospective observational study at seven transplant centers in the United States and Canada. Among 935 patients, 87% received antihypertensive medications at both 1 and 6 months after transplantation. Similar antihypertensive regimens were used for patients with and without diabetes and CVD, but with wide variability among centers. In contrast, while 44% of patients were on angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) at the time of transplantation, the proportion taking these agents dropped to 12% at month 1, then increased to 24% at 6 months. Fewer than 30% with CVD or diabetes received ACEI/ARB therapy 6 months posttransplant. Aspirin use was uncommon (<40% of patients). Even among those with diabetes and/or CVD, fewer than 60% received aspirin and only half received a statin at 1 and 6 months. This study demonstrates marked variability in the use of cardioprotective medications in kidney transplant recipients, a finding that may reflect, among several possible explanations, clinical uncertainty due the lack of randomized trials for these medications in this population.

Fixed- or controlled-dose mycophenolate mofetil with standard- or reduced-dose calcineurin inhibitors: the Opticept trial.

Mycophenolate mofetil (MMF) was developed with cyclosporine as a fixed-dose immunosuppressant. More recent data indicate a relationship between mycophenolic acid (MPA) exposure in individuals and clinical endpoints of rejection and toxicity. This 2-year, open-label, randomized, multicenter trial compared the efficacy and safety of concentration-controlled MMF (MMF(CC)) dosing with a fixed-dose regimen in 720 kidney recipients. Patients received either (A) MMF(CC) and reduced-level calcineurin inhibitor (MMF(CC)/CNI(RL)); (B) MMF(CC) and standard-level CNI (MMF(CC)/CNI(SL)); or (C) fixed-dose MMF and CNI(SL) (MMF(FD)/CNI(SL)). Antibody induction and steroid use were according to center practice. The primary endpoint was noninferiority (alpha= 0.05) of group A versus group C for treatment failure (including biopsy-proven acute rejection [BPAR], graft loss and death) at 1 year. Although mean CNI trough levels in group A did not reach the prespecified targets, they were statistically lower than those in groups B and C (p < or = 0.01 for each comparison). BPAR rates (8.5%) were low across groups. Group A had 19% fewer treatment failures (23% vs. 28%, p = 0.18). MMF doses were highest (p < 0.05), with withdrawals for adverse events the fewest (p = 0.02), in group A. Of the 80% of subjects taking tacrolimus (Tac), those with higher MPA exposure had significantly less rejection (p < 0.001) and diarrhea correlated with Tac, but not with MPA levels. Thus, MMF(CC) with low-dose CNI resulted in outcomes not inferior to those with standard CNI exposure and MMF(FD), indicating potential utility of MMF(CC) in CNI-sparing regimens.

Limiting financial disincentives in live organ donation: a rational solution to the kidney shortage.

Availability of kidney transplantation is limited by an inadequate supply of organs, with no apparent remedy on the immediate horizon and increasing reliance on living donors (LDs). While some have advocated financial remuneration to stimulate donation, the National Organ Transplant Act (NOTA) of 1984 expressly forbids the offer of 'valuable consideration.' However, recent developments indicate some fluidity in the definition of valuable consideration while evolving international standards highlight deficiencies (particularly regarding long-term care and follow-up) in the current American system. Recognizing that substantial financial and physical disincentives exist for LDs, we propose a policy change that offers the potential to enhance organ availability as well as address concerns regarding long-term care. Donors assume much greater risk than is widely acknowledged, risk that can be approximated for the purpose of determining appropriate compensation. Our proposal offsets donor risk via a package of specific benefits (life insurance, health insurance and a small amount of cash) to minimize hazard and ensure donor interests are protected after as well as before nephrectomy. It will fund medical follow-up and enable data collection so that long-term risk can be accurately assessed. The proposal should be cost effective with only a small increase in the number of LDs, and the net benefit will become greater if removal of disincentives stimulates even further growth. As importantly, by directly linking compensation to risk, we believe it preserves the essence of kidney donation as a gift, consistent with NOTA and implementable in the United States without altering current legal statutes.

Report of a National Conference on Donation after cardiac death.

A national conference on organ donation after cardiac death (DCD) was convened to expand the practice of DCD in the continuum of quality end-of-life care. This national conference affirmed the ethical propriety of DCD as not violating the dead donor rule. Further, by new developments not previously reported, the conference resolved controversy regarding the period of circulatory cessation that determines death and allows administration of pre-recovery pharmacologic agents, it established conditions of DCD eligibility, it presented current data regarding the successful transplantation of organs from DCD, it proposed a new framework of data reporting regarding ischemic events, it made specific recommendations to agencies and organizations to remove barriers to DCD, it brought guidance regarding organ allocation and the process of informed consent and it set an action plan to address media issues. When a consensual decision is made to withdraw life support by the attending physician and patient or by the attending physician and a family member or surrogate (particularly in an intensive care unit), a routine opportunity for DCD should be available to honor the deceased donor's wishes in every donor service area (DSA) of the United States.

Maintenance immunosuppression in the renal transplant recipient: an overview.

Managing maintenance immunosuppressive regimens after kidney transplantation is often challenging and confusing, requiring careful attention to efficacy, dosing, adverse effects, and costs of multiple medications. Most protocols combine a primary immunosuppressant (cyclosporine or tacrolimus) with one or two adjunctive agents (azathioprine, mycophenolate mofetil, sirolimus, corticosteroids). Avoiding drug-drug interactions is a major part of effective immunosuppressant management, and special situations (eg, pregnancy, intravenous dosing, caring for minority patients) can prove especially daunting. This review summarizes available data regarding current practices in maintenance immunosuppression, emphasizing issues that arise in day-to-day management of renal transplant recipients.

Tolerance in renal transplantation after allogeneic bone marrow transplantation-6-year follow-up.

Despite significant advancements in clinical transplantation, very few reports describe the long-term acceptance of transplanted solid organs without indefinite immunosuppression. The immunosuppressive agents used are nonspecific and have serious potential side effects. We present a patient who received a living-donor renal allograft from the same person who had donated bone marrow to her several years earlier. Tolerance was expected based on previous acceptance of full-thickness skin grafts from the donor. Indeed, there has been no evidence of rejection during a 6-year follow-up period, and no induction or maintenance immunosuppression has been given. All noninvasive parameters of graft function remain normal. This and similar reports prove that genetically disparate solid organs can coexist without pharmacological immunosuppression.

Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation.

Many complications after renal transplantation can be prevented if they are detected early. Guidelines have been developed for the prevention of diseases in the general population, but there are no comprehensive guidelines for the prevention of diseases and complications after renal transplantation. Therefore, the Clinical Practice Guidelines Committee of the American Society of Transplantation developed these guidelines to help physicians and other health care workers provide optimal care for renal transplant recipients. The guidelines are also intended to indirectly help patients receive the access to care that they need to ensure long-term allograft survival, by attempting to systematically define what that care encompasses. The guidelines are applicable to all adult and pediatric renal transplant recipients, and they cover the outpatient screening for and prevention of diseases and complications that commonly occur after renal transplantation. They do not cover the diagnosis and treatment of diseases and complications after they become manifest, and they do not cover the pretransplant evaluation of renal transplant candidates. The guidelines are comprehensive, but they do not pretend to cover every aspect of care. As much as possible, the guidelines are evidence-based, and each recommendation has been given a subjective grade to indicate the strength of evidence that supports the recommendation. It is hoped that these guidelines will provide a framework for additional discussion and research that will improve the care of renal transplant recipients.

[Sertraline. Adverse effects due to the superposition of serotonic and malignant neuroleptic syndromes]. / Sertralina. Efectos adversos por superposición de manifestaciones de síndromes serotóninico y neuroléptico maligno.

A 57 year-old man chronically treated with 50 mg daily of sertraline was admitted to the emergency room with mental status changes, rigidity, seizure activity and autonomic instability. He was rapidly transferred to the Intensive Care Unit. Laboratory determinations revealed increases in serum enzymes, prevailing creatine phosphokinase with a peak level by the third day of 35,000 Ui/L. Initial low serum sodium (10 mEq/L) was attributed to inadequate antidiuretic hormone secretion. Supportive care included discontinuation of sertraline and lorazepam administration. Mental status, and rigidity returned to baseline within 60 hours. Differential diagnosis between the neuroleptic malignant syndrome and the serotonin syndrome could not be determined accurately because of the striking overlap of signs and symptoms of both syndromes.

Prediction of renal transplant survival from early postoperative radioisotope studies.

UNLABELLED: It has been routine at the University of Alabama Medical Center to obtain a radionuclide renal function study immediately after transplantation (usually within 3 d) that includes estimation of effective renal plasma flow (ERPF) from a single plasma sample in addition to imaging. We present here the correlation between baseline measurements and the 1-y graft survival. METHODS: Two cohort years were reviewed: 1988, when 131I-orthoiodohippurate (OIH) was used; and 1995, when 99mTc-mercaptoacetyltriglycine (MAG3) was used. ERPF was measured concurrently with gamma-camera imaging by previously published single-injection, single-sample methods (converting MAG3 clearance to ERPF by means of a correction factor). RESULTS: Graft survival during the first postoperative year improved significantly in the interval between cohort years, from 74% of 147 cadaver (CD) grafts in 1988 to 91% of 200 CD grafts in 1995 (log rank test, P < 0.05). In contrast, for living related donor (LRD) grafts there was no significant change, from 91% of 66 in 1988 to 91% of 83 in 1995. The baseline ERPF was a significant predictor of graft survival in both 1988 and 1995 (Wilcoxon test, P > 0.05). For LRD grafts the association was not significant in either year. Using MAG3 (1995), the peak time and the ratio of counting rate (R) at 20 min to that at 3 min (R20:3) were also significant predictors for CD graft survival. Using OIH (1988 cohort), the correlation with peak time did not reach significance, and the R20:3 measurement was not available. Although multivariate combinations (Cox proportional hazards model) did not have significantly more predictive value at the 95% confidence level than ERPF or R20:3 alone, some statisticians suggest a 75% confidence level for adding an additional covariate to a multivariate model. Use of this level led to a model including both ERPF and R20:3. CONCLUSION: Single-sample ERPF measured in the immediate post-transplant period, whether from OIH clearance or MAG3 clearance, was a statistical predictor of graft survival for CD transplants. For MAG3, the peak time and R20:3 were also significant predictors. These associations held only for CD transplants and not for LRD transplants.