Kenneth E. Lamb

Long-Term Renal Allograft Survival in the United States: A Critical Reappraisal

Renal allograft survival has increased tremendously over past decades; this has been mostly attributed to improvements in first‐year survival. This report describes the evolution of renal allograft survival in the United States where a total of 252 910 patients received a single‐organ kidney transplant between 1989 and 2009. Half‐lives were obtained from the Kaplan–Meier and Cox models. Graft half‐life for deceased‐donor transplants was 6.6 years in 1989, increased to 8 years in 1995, then after the year 2000 further increased to 8.8 years by 2005. More significant improvements were made in higher risk transplants like ECD recipients where the half‐lives increased from 3 years in 1989 to 6.4 years in 2005. In low‐risk populations like living‐donor‐recipients half‐life did not change with 11.4 years in 1989 and 11.9 years in 2005. First‐year attrition rates show dramatic improvements across all subgroups; however, attrition rates beyond the first year show only small improvements and are somewhat more evident in black recipients. The significant progress that has occurred over the last two decades in renal transplantation is mostly driven by improvements in short‐term graft survival but long‐term attrition is slowly improving and could lead to bigger advances in the future.

Solid Organ Allograft Survival Improvement in the United States: The Long‐Term Does Not Mirror the Dramatic Short‐Term Success

Organ survival in the short‐term period post‐transplant has improved dramatically over the past few decades. Whether this has translated to a long‐term survival benefit remains unclear. This study quantifies the progression of nonrenal solid organ transplant outcomes from 1989 to 2009 in liver, lung, heart, intestine and pancreas transplants. Long‐term graft survival was analyzed using data on adult solid organ transplant recipients from the UNOS/SRTR database and is reported as organ half‐life and yearly attrition rates. Liver, lung, heart, intestine and pancreas half‐lives have improved from 5.8 to 8.5, 1.7 to 5.2, 8.8 to 11, 2.1 to 3.6 and 10.5 to 16.7 years, respectively. Long‐term attrition rates have not shown the same consistent improvement, with the yearly attrition rate 5–10 years post‐transplant for liver, lung, heart and pancreas changing from 4.7 to 4.3, 10.9 to 10.1, 6.4 to 5.1 and 3.3 to 4.2, respectively. Attrition rates for intestine and pancreas transplantation alone display more variability due to smaller sample size but exhibit similar trends of improved first‐year attrition and relatively stagnant long‐term attrition rates. With first‐year survival and attrition rates almost at a pinnacle, further progress in long‐term survival will come from targeting endpoints beyond first‐year rejection and survival rates.

Associations between EBV serostatus and organ transplant type in PTLD risk: an analysis of the SRTR National Registry Data in the United States.

In a prior multiorgan transplant database study, recipient Epstein–Barr virus (EBV) seronegativity was not associated with increased risk for posttransplant lymphoproliferative disorders (PTLD) in liver transplants (LTX), at variance with prior single center reports and with data from kidney and heart transplants (KTX and HTX). The Scientific Registry of Transplant Recipients (SRTR) in the United States is the only other registry with data on the required variables for comparison.Our study set comprised 112 756 KTX (580 PTLDs; 0.51%), 13 937 HTX (140 PTLDs; 1.0%) and 40 437 LTX (383 PTLDs; 0.95%) performed January 2003 onward. The unadjusted hazard ratio (HR) for PTLD if recipient EBV seronegative was 5.005 for KTX, 6.528 for HTX and 2.615 for LTX (p < 0.001 for all). In models adjusted for multiple covariates, the adjusted HR was 3.583 (p < 0.001) for KTX, 4.037 (p < 0.001) for HTX, 1.479 (p = 0.03) for LTX. Interaction models using EBV seropositive KTX as reference group showed significantly higher risk for all other EBV seronegative organ transplant groups and also for EBV seropositive LTX (AHR 2.053, p < 0.0001).Recipient EBV seronegativity is still significantly associated with risk for PTLD in LTX, though less so because of higher baseline risk in the EBV seropositive LTX group.

An inducible system for highly efficient production of recombinant adeno-associated virus (rAAV) vectors in insect Sf9 cells

Production of clinical-grade gene therapy vectors for human trials remains a major hurdle in advancing cures for a number of otherwise incurable diseases. We describe a system based on a stably transformed insect cell lines harboring helper genes required for vector production. Integrated genes remain silent until the cell is infected with a single baculovirus expression vector (BEV). The induction of expression results from a combination of the amplification of integrated resident genes (up to 1,200 copies per cell) and the enhancement of the expression mediated by the immediate-early trans-regulator 1 (IE-1) encoded by BEV. The integration cassette incorporates an IE-1 binding target sequence from wild-type Autographa californica multiple nuclear polyhedrosis virus, a homologous region 2 (hr2). A feed-forward loop is initiated by one of the induced proteins, Rep78, boosting the amplification of the integrated genes. The system was tested for the coordinated expression of 7 proteins required to package recombinant adeno-associated virus (rAAV)2 and rAAV1. The described arrangement provided high levels of Rep and Cap proteins, thus improving rAAV yield by 10-fold as compared with the previously described baculovirus/rAAV production system.

Pulsatile Pump Decreases Risk of Delayed Graft Function in Kidneys Donated After Cardiac Death

Organ storage techniques have been under scrutiny to determine the best preservation method, particularly in donation after cardiac death (DCD) kidneys. Conflicting literature on the benefit of pulsatile perfusion (PP) over cold storage (CS) warrants further investigation. We analyzed the risk of developing delayed graft function (DGF) in recipients of DCD and donation after brain death (DBD) kidneys undergoing PP or CS. We stratified on basis of cold ischemic time (CIT) to determine the interaction of preservation techniques, CIT and DCD kidneys on developing DGF. Of 54 136 recipients, 4923 received DCD kidneys of which 3330 (67%) underwent PP. Of 49 213 DBD recipients, 7531 (15%) underwent PP. DCD had a higher risk of DGF versus DBD (adjusted odds ratio, AOR 3.2; 3.0–3.5). PP kidneys had less DGF (AOR 0.59; 0.56–0.63) compared to CS. Interaction models of method by donor type referenced to PP/DBD revealed CS/DBD kidneys had higher DGF (AOR 1.8; 1.7–1.9), whereas CS/DCD kidneys had the highest risk of DGF (AOR 5.01; 4.43–5.67). Even though suggestive for a benefit of PP on DGF, this retrospective analysis cannot address whether this is an intrinsic effect of PP or is associated with the logistics of PP such as discard of DCD kidneys based on pump parameters.

Across all solid organs, adolescent age recipients have worse transplant organ survival than younger age children: A US national registry analysis.

Univariate analyses suggest that adolescents have worse long‐term allograft survival versus younger children across different SOT. This studys objective was to determine whether multivariate analyses of a large national database recording all deceased SOT (KI; LI; HR; LU) also show worse adolescent allograft survival in the different organs. Using data from the national Scientific Registry for Transplant Recipients in the USA for pediatric primary SOT from 1989 to 2010, we calculated median half‐lives and constructed K–M graft survival curves. Recipient age at transplant (<12 or adolescent 12–17 yr) was fitted with other identical covariates into multivariate Cox proportional hazards models. In all SOT recipients, unadjusted graft survival curves demonstrated better graft survival for adolescents initially, followed by crossing of the lines, such that adolescent SOT recipients had worse survival after one yr (KI), 4.6 yr (LI), 4.4 yr (HR), and 1.6 yr (LU). Multivariate models of the post‐cross period showed a significantly higher AHR for worse graft survival in adolescent age across all four SOTs: AHR 1.400 (KI), 1.958 (LI), 1.414 (HR), and 1.576 (LU). Improving adolescent long‐term outcomes across all four organs will be a defining issue in the future.

Improving Long-Term Outcomes for Transplant Patients: Making the Case for Long-Term Disease-Specific and Multidisciplinary Research

We thank Dr. De Geest and coauthors for their letter corresponding to our paper and certainly agree to the principles they outlined (1). Improvements in posttransplant outcomes are often defined by discrete quantifiable variables such as rejection rates and 1-year survival. Characterizing aspects of transplantation such as quality of life, overall cost of care and long-term survival require longer follow-up and detailed tracking of numerous variables. Although we can describe relative success in the short-term, the longer term and more complex areas of needed improvement are limited by our capacity to track and identify specific areas of intervention. The longer the posttransplant phase grows, the more intricate the interplay of chronic disease, immunosuppression and socioeconomic risk becomes.

Lack of significant improvements in long-term allograft survival in pediatric solid organ transplantation: A US national registry analysis

Improvements across many facets of transplantation have led to better 1‐yr outcomes of transplanted organs. In this study, we assessed whether longer‐term attrition rates improved in pediatric kidney (KI), liver (LI), heart (HR) and lung (LU) transplant (TX) survival. We analyzed data between 1989 and 2008 from 5747 KI, 7348 LI, 5103 HR, and 715 LU TXs (under 18 yr of age at transplant, first solitary transplant only), from the National Scientific Registry of Transplant Recipients database in the USA. Kaplan–Meier (K‐M) or ordinary least square (OLS) estimates were used to calculate median and projected survival half‐lives. Attrition rates, defined as percent failing within a given time period, were stratified by year of TX. Median half‐lives from 1989 TX year to 2005 TX year have shown a major improvement only in LI TX, remaining unchanged in HR and KI TX, or remaining very low in LU TX. All four organ TX types have shown a dramatic drop in first‐year attrition rates from 1989 to 2008. However, longer‐term attrition rates (1–3, 3–5, 5–10 yr) have remained largely unchanged for all four organ TX types. Further progress in long‐term survival will need targeting end‐points beyond first‐year rejection and survival rates.

Stem‐cell therapy for dilated cardiomyopathy: a pilot study evaluating retrograde coronary venous delivery

OBJECTIVE To evaluate retrograde coronary venous stem-cell delivery for Dobermanns with dilated cardiomyopathy. METHODS Retrograde coronary venous delivery of adipose-derived mesenchymal stem cells transduced with tyrosine mutant adeno-associated virus 2 to express stromal-derived factor-1 was performed in Dobermanns with dilated cardiomyopathy. Cases were followed for 2 years and electrocardiograms (ECG), echocardiograms and Holter monitoring were performed. RESULTS Delivery of cells was feasible in 15 of 15 dogs. One dog died following the development of ventricular fibrillation 24 hours after cell delivery. The remaining 14 dogs were discharged the following day without complications. Echocardiographic measurements of left ventricular size and function showed continued progression of disease. On the basis of Kaplan-Meier product limit estimates, median survival for dogs following stem-cell delivery was 620 days (range of 1-799 days). When including only the occult-dilated cardiomyopathy population and excluding those dogs already in congestive heart failure, median survival was 652 days (range of 46-799 days). CLINICAL SIGNIFICANCE Retrograde venous delivery of tyrosine mutant adeno-associated virus 2-stromal-derived factor-1 adipose-derived mesenchymal stem cells appears safe. Stem-cell therapy in dogs with occult-dilated cardiomyopathy does not appear to offer advantage compared to recently published survival data in similarly affected Dobermanns.

Best allograft survival from share-35 kidney donors occurs in middle-aged adults and young children-an analysis of OPTN data.

Background On October 2005, the Organ Procurement and Transplant Network implemented a new allocation policy for kidney transplants (KTX) from deceased donors (DD) ages <35 years to increase an access to transplantation from young donors for pediatric (ages <18 years) recipients, which is known as Share-35 (S35). However, many of these kidneys were allocated to adult recipients. The intent of this study was to analyze the graft outcomes from S35 kidneys in pediatric and adult recipients, stratified further by recipient age, to assess if recipient age affects the outcome from these presumably ideal kidneys. Methods The Organ Procurement and Transplant Network database from October 2005 to November 2010 involving 18,461 S35-KTX was used to calculate cumulative graft survival (CGS), death-censored graft survival, and patient survival using Kaplan-Meier estimates. The differences between survival curves were tested for significance by log-rank method after adjusting for various donor, recipient, and transplant-associated variables. Results With S35 implementation, children received a higher proportion of DD ages <35 years. Within the pediatric age group, adolescents (ages 13–17 years) had the worst CGS. Among adults, the highest CGS was obtained in middle-aged adults, whereas young adults (ages 18–25 years) showed worse CGS. CGS in young children (ages <12 years) was comparable with those in middle-aged adults. In older adults (ages >55 years), CGS was lowered by higher patient death rates. Conclusions Recipient age affects allograft survival from high-quality young DD kidneys, such as S35 kidneys. Best survival occurs in middle-aged adults and in children ages <12 years, whereas adolescents and young adults do not derive an optimal benefit.