Gene Expression in Biopsies of Acute Rejection and Interstitial Fibrosis/Tubular Atrophy Reveals Highly Shared Mechanisms That Correlate With Worse Long-Term Outcomes.

Interstitial fibrosis and tubular atrophy (IFTA) is found in approximately 25% of 1-year biopsies posttransplant. It is known that IFTA correlates with decreased graft survival when histological evidence of inflammation is present. Identifying the mechanistic etiology of IFTA is important to understanding why long-term graft survival has not changed as expected despite improved immunosuppression and dramatically reduced rates of clinical acute rejection (AR) (Services UDoHaH. http://www.ustransplant.org/annual_reports/current/509a_ki.htm). Gene expression profiles of 234 graft biopsy samples were obtained with matching clinical and outcome data. Eighty-one IFTA biopsies were divided into subphenotypes by degree of histological inflammation: IFTA with AR, IFTA with inflammation, and IFTA without inflammation. Samples with AR (n = 54) and normally functioning transplants (TX; n = 99) were used in comparisons. A novel analysis using gene coexpression networks revealed that all IFTA phenotypes were strongly enriched for dysregulated gene pathways and these were shared with the biopsy profiles of AR, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. These molecular biopsy profiles correlated with future graft loss in IFTA samples without inflammation.

What's hot, what's new in clinical organ transplantation: report from the American Transplant Congress 2015.

Innovative and exciting advances in the clinical sciences in organ transplantation were presented at the American Transplant Congress 2015. The full spectrum of transplantation was covered, with important developments in many topics. Key areas covered by presentations included living donor outcomes, optimal utilization and allocation of deceased donors, new immunosuppression regimens, antibody-mediated rejection and tolerance induction. This review highlights some of the most interesting and noteworthy clinical presentations from the meeting.

Time-trends in publication productivity of young transplant surgeons in the United States.

To further clarify whether the transplant surgical research workforce is adequately poised to further scientific achievement, we have investigated the publication productivity of young transplant surgeons. Our hypothesis is that recent young transplant surgeons write fewer academic manuscripts than their senior colleagues did when they were young surgeons. We compared the number of first and senior author publications in the first 5 years after completion of fellowship among recent transplant surgeons (completed fellowship 2000-2004) and former young surgeons (completed fellowship 1990-1994). Recent young surgeons wrote fewer overall manuscripts (0.94 vs. 1.67, p < 0.05), as well as basic science manuscripts (0.21 vs. 0.54, p < 0.05) and clinical manuscripts (0.73 vs. 1.14, p < 0.05). Adjusting for the number of trainees, we note that recent young surgeons published 59% fewer basic science publications (IRR 0.41, 95% CI 0.29-0.57, p < 0.001) and 33% fewer clinical publications (IRR 0.67, 95% CI 0.56-0.82, p < 0.001). Among fellows in the 2000-2004 cohort, there was a 32% lower chance of publishing at least one paper compared with fellows in the 1990-1994 cohort (IRR 0.68, 95% CI 0.51-0.89, p = 0.006). These findings raise concerns about the future place of transplant surgeons within the science that shapes our own field.

Utilization of kidneys with similar kidney donor risk index values from standard versus expanded criteria donors.

With the shortage of standard criteria donor (SCD) kidneys, efficient expanded criteria donor (ECD) kidney utilization has become more vital. We investigated the effects of the ECD label on kidney recovery, utilization and outcomes. Using data from the Scientific Registry of Transplant Recipients from November 2002 to May 2010, we determined recovery and transplant rates, and modeled discard risk, for kidneys within a range of kidney donor risk index (KDRI) 1.4-2.1 that included both SCD and ECD kidneys. To further compare similar quality kidneys, these kidneys were again divided into three KDRI intervals. Overall, ECD kidneys had higher recovery rates, but lower transplant rates. However, within each KDRI interval, SCD and ECD kidneys were transplanted at similar rates. Overall, there was increased risk for discard for biopsied kidneys. SCD kidneys in the lower two KDRI intervals had the highest risk of discard if biopsied. Pumped kidneys had a lower risk of discard, which was modulated by KDRI for SCD kidneys but not ECD kidneys. Although overall ECD graft survival was worse than SCD, there were no differences within individual KDRI intervals. Thus, ECD designation adversely affects neither utilization nor outcomes beyond that predicted by KDRI.

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.

Young transplant surgeons and NIH funding.

Transplant surgeons have historically been instrumental in advancing the science of transplantation. However, research in the current environment inevitably requires external funding, and the classic career development pathway for a junior investigator is the NIH K award. We matched transplant surgeons who completed fellowships between 1998 and 2004 with the NIH funding database, and also queried them regarding research effort and attitudes. Of 373 surgeons who completed a fellowship, only 6 (1.8%) received a K award; of these, 3 subsequently obtained R-level funding. An additional 5 individuals received an R-level grant within their first 5 years as faculty without a K award, 3 of whom had received a prior ASTS-sponsored award. Survey respondents reported extensive research experience during their training (78.8% spent median 24 months), a high proportion of graduate research degrees (36%), and a strong desire for more research time (78%). However, they reported clinical burdens and lack of mentorship as their primary perceived barriers to successful research careers. The very low rate of NIH funding for young transplant surgeons, combined with survey results that indicate their desire to participate in research, suggest institutional barriers to access that may warrant attention by the ASTS and the transplant surgery community.

Systematic evaluation of pancreas allograft quality, outcomes and geographic variation in utilization.

Pancreas allograft acceptance is markedly more selective than other solid organs. The number of pancreata recovered is insufficient to meet the demand for pancreas transplants (PTx), particularly for patients awaiting simultaneous kidney-pancreas (SPK) transplant. Development of a pancreas donor risk index (PDRI) to identify factors associated with an increased risk of allograft failure in the context of SPK, pancreas after kidney (PAK) or pancreas transplant alone (PTA), and to assess variation in allograft utilization by geography and center volume was undertaken. Retrospective analysis of all PTx performed from 2000 to 2006 (n = 9401) was performed using Cox regression controlling for donor and recipient characteristics. Ten donor variables and one transplant factor (ischemia time) were subsequently combined into the PDRI. Increased PDRI was associated with a significant, graded reduction in 1-year pancreas graft survival. Recipients of PTAs or PAKs whose organs came from donors with an elevated PDRI (1.57-2.11) experienced a lower rate of 1-year graft survival (77%) compared with SPK transplant recipients (88%). Pancreas allograft acceptance varied significantly by region particularly for PAK/PTA transplants (p < 0.0001). This analysis demonstrates the potential value of the PDRI to inform organ acceptance and potentially improve the utilization of higher risk organs in appropriate clinical settings.

DonorNet and the potential effects on organ utilization.

The evolution of communication as donor data flows from organ procurement organization to transplant centers has evolved with the incorporation of DonorNet 2007 into the UNet(SM) system. The ensuing study looks at DonorNet's impact on this process. We established defined time periods for comparison purposes. The study looked at match number for organ placement and overall organ utilization with a focus on ischemia time and graft outcomes. The results of the study demonstrate no significant change in the median match number of organ placement in liver or kidney transplantation. Changes in discard rates were varied amongst transplanted organs and there were noticeable changes in organ sharing with an increase in local allocation for kidney and liver and an ensuing decrease in regional and national distribution. There were no significant differences in the outcomes of livers and kidneys with low offer numbers compared with those with high offer numbers. Overall the study suggests a modest impact by DonorNet on organ placement and utilization, but a longer term study would need to be done to fully evaluate its impact.

Organ donation and utilization in the United States: 1998-2007.

Organ transplantation remains the only life-saving therapy for many patients with organ failure. Despite the work of the Organ Donation and Transplant Collaboratives, and the marked increases in deceased donors early in the effort, deceased donors only rose by 67 from 2006 and the number of living donors declined during the same time period. There continue to be increases in the use of organs from donors after cardiac death (DCD) and expanded criteria donors (ECD). This year has seen a major change in the way organs are offered with increased patient safety measures in those organ offers made by OPOs using DonorNet. Unfortunately, the goals of 75% conversion rates, 3.75 organs transplanted per donor, 10% of all donors from DCD sources and 20% growth of transplant center volume have yet to be reached across all donation service areas (DSAs) and transplant centers; however, there are DSAs that have not only met, but exceeded, these goals. Changes in organ preservation techniques took place this year, partly due to expanding organ acceptance criteria and increasing numbers of ECDs and DCDs. Finally, the national transplant environment has changed in response to increased regulatory oversight and new requirements for donation and transplant provider organizations.

Solving the organ shortage crisis: the 7th annual American Society of Transplant Surgeons' State-of-the-Art Winter Symposium.

The 2007 American Society of Transplant Surgeons' (ASTS) State-of-the-Art Winter Symposium entitled, 'Solving the Organ Shortage Crisis' explored ways to increase the supply of donor organs to meet the challenge of increasing waiting lists and deaths while awaiting transplantation. While the increasing use of organs previously considered marginal, such as those from expanded criteria donors (ECD) or donors after cardiac death (DCD) has increased the number of transplants from deceased donors, these transplants are often associated with inferior outcomes and higher costs. The need remains for innovative ways to increase both deceased and living donor transplants. In addition to increasing ECD and DCD utilization, increasing use of deceased donors with certain types of infections such as Hepatitis B and C, and increasing use of living donor liver, lung and intestinal transplants may also augment the organ supply. The extent by which donors may be offered incentives for donation, and the practical, ethical and legal implications of compensating organ donors were also debated. The expanded use of nonstandard organs raises potential ethical considerations about appropriate recipient selection, informed consent and concerns that the current regulatory environment discourages and penalizes these efforts.

Organ donation and utilization in the United States, 1997-2006.

Deceased organ donation has increased rapidly since 2002, coinciding with implementation of the Organ Donation Breakthrough Collaborative. The increase in donors has resulted in a corresponding increase in the numbers of kidney, liver, lung and intestinal transplants. While transplants for most organs have increased, discard and nonrecovery rates have not improved or have increased, resulting in a decrease in organs recovered per donor (ORPD) and organs transplanted per donor (OTPD). Thus, the expansion of the consent and recovery of incremental donors has frequently outpaced utilization. Meaningful increases in multicultural donation have been achieved, but donations continue to be lower than actual rates of transplantation and waiting list registrations for these groups. To counteract the decline in living donation, mechanisms such as paired donation and enhanced incentives to organ donation are being developed. Current efforts of the collaborative have focused on differentiating ORPD and OTPD targets by donor type (standard and expanded criteria donors and donors after cardiac death), utilization of the OPTN regional structure and enlisting centers to increase transplants to match increasing organ availability.

Proceedings of Consensus Conference on Simultaneous Liver Kidney Transplantation (SLK).

A consensus conference sponsored by the American Society of Transplant Surgeons (ASTS), American Society of Transplantation (AST), United Network for Organ Sharing (UNOS) and American Society of Nephrology (ASN) convened to examine simultaneous liver-kidney transplantation (SLK). Directors from the 25 largest liver transplant programs along with speakers with recognized expertise attended. The purposes of this conference were to propose indications for SLK, to establish a prospective data registry and, most importantly, to recommend standard listing criteria for these patients. Scientific registry of transplant recipients data, and single center data regarding chronic kidney disease (CKD) and acute kidney injury (AKI) in conjunction with liver failure as a basis for SLK was presented and discussed. The consensus was that Regional Review Boards (RRB) should determine listing for SLK, as with other MELD exceptions, with automatic approval for: (i) End-stage renal disease with cirrhosis and symptomatic portal hypertension or hepatic vein wedge pressure gradient >/= 10 mm Hg (ii) Liver failure and CKD with GFR /= 2.0 mg/dL and dialysis >/= 8 weeks (iv) Liver failure and CKD and biopsy demonstrating > 30% glomerulosclerosis or 30% fibrosis. The RRB would evaluate all other requests to determine appropriateness.

The effects of donor and recipient practices on transplant center finances.

Over the past several years we have noted a marked decrease in this profitability of our kidney transplant program. Our hypothesis is that this reduction in kidney transplant institutional profitability is related to aggressive donor and recipient practices. The study population included all adults with Medicare insurance who received a kidney transplant at our center between 1999 and 2005. Adopting the hospital perspective, multi-variate linear regression models to determine the independent effects of donor and recipient characteristics and era effects on total reimbursements and total hospital margin. We note statistically significant decreased medical center incremental margins in cases with ECDs (-$5887) and in cases of DGF (-4937). We also note an annual change in the medical center margin is independently associated with year and changes at a rate of -$5278 per year, related to both increasing costs and decreasing Medicare reimbursements. The financial loss associated with patient DGF and the use of ECD kidneys may resonate with other centers, and could hinder efforts to expand kidney transplantation within the United States. The Centers for Medicare and Medicaid Services (CMS) should consider risk-adjusted reimbursement for kidney transplantation.

Determinants of discard of expanded criteria donor kidneys: impact of biopsy and machine perfusion.

We examined factors associated with expanded criteria donor (ECD) kidney discard. Scientific Registry of Transplant Recipients (SRTR)/Organ Procurement and Transplantation Network (OPTN) data were examined for donor factors using logistic regression to determine the adjusted odds ratio (AOR) of discard of kidneys recovered between October 1999 and June 2005. Logistic and Cox regression models were used to determine associations with delayed graft function (DGF) and graft failure. Of the 12,536 recovered ECD kidneys, 5139 (41%) were discarded. Both the performance of a biopsy (AOR = 1.21, p = 0.02) and the degree of glomerulosclerosis (GS) on biopsy were significantly associated with increased odds of discard. GS was not consistently associated with DGF or graft failure. The discard rate of pumped ECD kidneys was 29.7% versus 43.6% for unpumped (AOR = 0.52, p < 0.0001). Among pumped kidneys, those with resistances of 0.26-0.38 and >0.38 mmHg/mL/min were discarded more than those with resistances of 0.18-0.25 mmHg/mL/min (AOR = 2.5 and 7.9, respectively). Among ECD kidneys, pumped kidneys were less likely to have DGF (AOR = 0.59, p < 0.0001) but not graft failure (RR = 0.9, p = 0.27). Biopsy findings and machine perfusion are important correlates of ECD kidney discard; corresponding associations with graft failure require further study.

Simultaneous kidney-pancreas transplantation.

Simultaneous kidney-pancreas transplantation is the most commonly performed type of pancreas transplant. Recipients with functioning pancreas transplants have normal glycemic control without the need for exogenous insulin, and are free of hypoglycemic events. While pancreas transplantation has a beneficial impact on a number of diabetic complications, and kidney-pancreas transplant prolongs survival compared to remaining on the transplant waiting list, the contribution of the pancreas to survival beyond that achieved by kidney transplant alone is controversial. Candidates generally have type 1 diabetes refractory to intensive insulin therapy; selection criteria are more stringent that for kidney transplant alone. Most pancreas transplants are performed with enteric exocrine drainage and systemic venous drainage, although portal venous drainage is also employed. Complications are more frequent and more severe than for kidney transplant alone, which is a consideration when selecting appropriate candidates. Immunosuppression usually includes induction therapy and triple-drug maintenance therapy, but early outcomes using steroid-free regimens are encouraging. Rejection is difficult to accurately detect noninvasively, but the use of percutaneous biopsy in diagnosis is increasing. Outcomes are generally good; the kidney and pancreas graft survival rates are 92% and 85%, respectively at one year. Patient survival exceeds 85% after five years. Although the benefit of the pancreas transplant on mortality is uncertain, most studies demonstrate a significant improvement in quality of life.

Preliminary analysis of early outcomes of a prospective, randomized trial of complete steroid avoidance in liver transplantation.

Steroids are a mainstay in liver transplantation for induction and maintenance immunosuppression but are associated with significant adverse effects. While prior studies have successfully limited the use of steroids, whether complete steroid avoidance will improve outcomes remains unclear. To further evaluate the need for steroids, consenting patients who underwent liver transplantation between June 2002 and May 2004 were entered into a prospective, randomized trial to receive either standard therapy (tacrolimus, mycophenolate mofetil, steroid induction/maintenance) or complete steroid avoidance (standard therapy without steroid induction/maintenance). Clinically suspected rejection was confirmed by biopsy and treated with pulse steroid therapy. Outcomes were compared on an intention to treat basis. Of the 72 patients enrolled, 36 (50%) were randomized to the steroid avoidance group with a mean follow up of 412 +/- 41 days. Donor and recipient characteristics were similar between groups. The steroid avoidance group was more likely to have significant infections (52% vs 28%, P = .03). There was a trend toward an increased rate of acute rejection (25% vs 14%, P = .23). Twelve of 36 recipients (33%) enrolled in the steroid avoidance group later received steroids. The incidence of recurrent hepatitis C was similar between groups. The 1-year patient (90% vs 83%, P = .44) and graft survivals (90% vs 81%, P = .27) were similar between groups. These data suggest complete steroid avoidance in liver transplantation results in acceptable patient and graft survival. However, the potential long-term benefits of steroid avoidance, including a decrease in severity of recurrent hepatitis C, remain under investigation.

Peripheral vascular occlusive disease in renal transplant recipients: risk factors and impact on kidney allograft survival.

BACKGROUND: This study evaluated the relationship between renal transplantation and the evolution of lower extremity peripheral vascular occlusive disease (PVOD). METHODS: A total of 664 adult renal allograft recipients from 1985-1995 were retrospectively reviewed for atherosclerotic risk factors and peripheral vascular occlusive disease (PVOD). PVOD events were defined as bypass, major amputation, claudication, or percutaneous angioplasty. Follow-up ranged from 2-12 years. RESULTS: The cumulative 5- and 10-year incidences of lower extremity PVOD after renal transplantation were 4.2 and 5.9%. Eight of 14 patients (57%) with pretransplant PVOD had additional PVOD events versus de novo appearance of PVOD in 21/650 patients (3.2%; P<0.0001). In a proportional hazards model, age, preoperative PVOD, diabetes, and postoperative smoking were independent risk factors for the development of PVOD after transplantation. Recipients with lower extremity PVOD had significantly lower 10-year patient and graft survival. Increased graft failure was due to an excess of deaths with a functioning graft. A total of 34 major interventions were performed. One- and two-year limb salvage rates were 64.2 and 53.8%. CONCLUSIONS: Lower extremity PVOD after renal transplantation is associated with diminished patient survival, and affects kidney graft survival via disproportionate patient attrition. Age, preoperative PVOD, diabetes, and postoperative smoking are important risk factors. Transplantation does not appear to either accelerate or retard the progression of disease. An aggressive approach towards limb salvage in properly selected patients is justifiable.

Excess risk of renal allograft loss associated with cigarette smoking.

BACKGROUND: Cigarette smoking contributes to a number of health-related problems, but its impact on renal transplant survival beyond accelerated patient death is unclear. METHODS: We performed a cohort study of 645 adult renal allograft recipients from 1985 to 1995 to evaluate the relationship between smoking and graft outcome. RESULTS: Twenty-four percent of recipients (156/645) were smokers at the time of transplant evaluation. Of these, 90% continued to smoke after transplantation. Pretransplant smoking was significantly associated with reduced overall graft and death-censored graft survival. Patients who were smokers at the time of pretransplant evaluation had kidney graft survival of 84%, 65%, and 48% at 1, 5, and 10 years, respectively, compared with graft survival in nonsmokers of 88%, 78%, and 62% (P=0.007). Pretransplant smoking adversely affected death-censored graft survival in recipients of cadaveric (P=0.02) and of living donor kidneys (P=0.02). Reduced graft survival in pretransplant smokers could not be accounted for by differences in rejection (64% vs. 61%, P=0.35). In a multivariate analysis, pretransplant smoking was associated with a relative risk of 2.3 for graft loss. Among patients with a smoking history before transplantation, death-censored graft survival was significantly higher for those who quit smoking before transplant evaluation. CONCLUSIONS: Cigarette smoking before kidney transplantation contributes significantly to allograft loss. The effect of smoking on graft outcome is not explained by increases in rejection or patient death. Smoking cessation before renal transplantation has beneficial effects on graft survival. These effects should be emphasized to patients with end-stage renal disease who are considering renal transplantation.

Transthoracic, transdiaphragmatic excision of simultaneous lung and adrenal lesions.

Simultaneous adrenal and pulmonary lesions frequently present a therapeutic challenge to the thoracic surgeon. We describe 2 cases in which a transthoracic, transdiaphragmatic approach was used to establish tissue diagnosis and complete removal of gross tumor. In 1 case an intraoperative decision to perform a pneumonectomy was dictated by the tissue diagnosis of the adrenal mass, which was obtained with relative ease via this method. In both cases the morbidity of traditional approaches for adrenal operation was avoided.