Search

Summary: Although rapid discontinuation of prednisone (RDP) after kidney transplantation has been successful in low‐risk recipients, there is concern about RDP use in recipients at increased risk for rejection or recurrent disease. Using SRTR, we compared outcomes for RDP versus maintenance prednisone‐treated recipients for all adult 1st and 2nd transplants (n = 169 479) and the following 1st transplant subgroups: African American (AA); highly sensitized; those with a potentially recurrent disease; and pediatric recipients. For all adult 1st LD and DD transplants, RDP was associated with better patient and graft survival. For all LD subgroups, RDP and maintenance prednisone were associated with similar patient, graft, and death‐censored (DC) graft survival. For 1st transplant DD subgroups, RDP was associated with better patient survival in AA, those with potentially recurrent disease, and pediatric recipients; graft survival with RDP was better in AAs. For adult 2nd DD transplants, RDP was associated with worse DC‐graft survival. Importantly, for all differences, the effect size was small. With the exception of 2nd DD transplants, RDP protocols can be used without decreasing patient or graft survival for subgroups of 1st DD and LD kidney transplant recipients and for 2nd LD transplant recipients, at increased risk of rejection or recurrent disease. [ABSTRACT FROM AUTHOR]

The first successful kidney transplant occurred in 1954. Since then, long-term graft survival has been an elusive idealistic goal of transplantation. Yet 62 years later, we know of only 6 kidney transplant recipients who have achieved ≥ 50-year graft survival while being on no immunosuppression or a substantially reduced regimen. Herein, we report graft survival ≥ 50 years in 2 living donor recipients who have been maintained on standard-of-care immunosuppression the entire time. For our 2 recipients, their living donor's altruism altered the course, length, and quality of their life, which by all accounts can be deemed normal: They attended college, held jobs, had successful pregnancies, raised families, and were productive members of society. Both donors are still alive and well, more than 50 years post-donation; both have an acceptable GFR and normal blood pressure, with hyperlipidemia as their only medical problem. These 2 intertwined stories illustrate the tremendous potential of a successful kidney transplant: long-term survival with a normal lifestyle and excellent quality of life, even after more than 5 decades on full-dose immunosuppression. [ABSTRACT FROM AUTHOR]

Living donor kidney transplantation benefits the recipient. However, kidney failure can occur in a small fraction of donors — the risk is not uniform but varies according to donor characteristics. Studies to date have failed to match on important factors, such as era, environment or family history. Long-term studies with well-matched healthy controls are therefore needed. [ABSTRACT FROM AUTHOR]

Matas AJ, Granger D, Kaufman DB, Sarwal MM, Ferguson RM, Woodle ES, Gill JS. Steroid minimization for sirolimus-treated renal transplant recipients. Clin Transplant 2011: 25: 457-467. © 2010 John Wiley & Sons A/S. Steroids are associated with a myriad of post-transplant side effects. Therefore, as new immunosuppressive drugs have been developed, attempts have been made to minimize steroid exposure. Sirolimus (SRL) has been demonstrated to have efficacy in early and late post-transplant immunosuppression. Accordingly, numerous trials have studied steroid minimization (early and late post-transplant) in the context of SRL-containing protocols (either with or without a calcineurin inhibitor). We herein review these trials and show that recent studies have determined that both late steroid withdrawal and early rapid discontinuation can be successful with SRL immunosuppression. [ABSTRACT FROM AUTHOR]

The goal of steroid minimization trials has been to minimize or eliminate steroid-related side-effects while simultaneously not increasing the rate of acute rejection (AR) and chronic graft loss. Early trials of late steroid withdrawal (≥3 months post-transplant) were associated with significantly increased AR rates and late graft loss. More recent trials of rapid discontinuation of prednisone (RDP) (≤7 days post-transplant) have been associated with little or no increase in AR rates and no difference in graft survival (versus maintenance prednisone). Of note, induction therapy appears to be important for success; however, it is not clear if any single maintenance protocol is superior. Intermediate-term follow-up (5–7 years) is now available for some randomized and nonrandomized trials; graft survival and renal function remain excellent. Most of these trials have been done in low immunologic risk recipients, but there are reports of success of RDP in children, black recipients, sensitized recipients, recipients with potentially recurring disease, and kidney–pancreas recipients. Of critical importance, steroid-related side-effects have been minimized. Steroid minimization protocols can clearly be recommended for low-risk patients; additional trials are necessary for those at higher risk. Additional research is also necessary on integrating calcineurin inhibitor minimization with steroid minimization. [ABSTRACT FROM AUTHOR]

The pros and cons of a regulated system of financial incentives for living donors are being actively debated. To date, a detailed proposal on how such a system could work has not been developed. Herein, the specifics of a potential model, using the infrastructure already in place for deceased donor evaluation and allocation, are outlined. [ABSTRACT FROM AUTHOR]

Background: Pancreas graft thrombosis remains the leading non-immunologic cause of graft loss after pancreas transplantation. We studied the role of hypercoagulable states (HCS) in pancreas graft thrombosis (pthx). Methods: Between January 1, 1994, and January 1, 2003, 131 pancreas transplant recipients experienced a pthx (n = 67) or other thrombotic events. Fifty-six recipients consented to have their blood drawn and tested for the HCS. These results were compared with a control group of pancreas transplant recipients who did not experience a thrombotic event. Fisher's exact test was used to compare the groups. Results: We found 18% of the recipients with pancreas thrombosis to have a HCS. Factor V Leiden (FVL) was found in 15% vs. 4% in the control group (p = ns) vs. 3–5% in the general white population. We found 3% of the pancreas thrombosis patients to have a prothrombin gene mutation (PGM) vs. 0% in the control group (p = ns) vs. 1–2% in the general white population. Conclusions: Of pancreas transplant recipients with thrombosis, 18% had one or more of the most common factors associated with a HCS (FVL or PGM). This can be compared with 4% in a control group and 4–7% in the general white population, respectively. Although the differences are not statistically significant due to small numbers, we feel that the findings may be clinically relevant. While this is only a pilot study, it may be reasonable to screen select pancreas transplant candidates for HCS, especially FVL and PGM, until more data become available. [ABSTRACT FROM AUTHOR]

Kidney transplants have become common surgical procedures, with thousands performed yearly around the world. The surgical techniques for the transplant are well established and the procedure is associated with high success rates. The complication rate associated with the procedure is low, especially when compared to other abdominal organ transplants such as liver and pancreas transplants. Nonetheless, the detection, accurate diagnosis, and timely management of surgical complications occurring after kidney transplant are important tasks of the team managing these patients. A delay in the diagnosis or management of these complications can result in significant morbidity to the recipient, with risk of graft loss and mortality. Most surgical complications involve either the wound or one of the three anastomoses (renal artery, renal vein, or ureter). Examples include wound infection, renal artery or vein thrombosis, and urine leak. Most of these complications will require surgical or radiologic intervention for appropriate management. [ABSTRACT FROM AUTHOR]

Five preventable causes of kidney graft loss in the 1990s: A single-center analysis. Background. Despite improvements in immunosuppressive protocols and patient care, kidney allografts continue to fail. We studied causes of graft loss for primary kidney transplants in the 1990s to determine major causes and potential interventions. Methods. Causes of graft loss were reviewed for 1467 primary kidney transplants done at our institution between January 1, 1990, and December 31, 1999. Graft loss for that entire population was studied and then the causes of loss selectively examined at <1 year, 1 to 5 years, and>5 years post-transplant. Finally, causes of loss in the 1990s versus the 1980s were compared. Results. Five major causes of graft loss were noted in the 1990s: thrombosis, acute rejection (either alone or combined with delayed graft function or infection), chronic rejection, death with function, and noncompliance. In the first year post-transplant, thrombosis (25%) and death with function (41%) were the major causes of graft loss. After the first year, chronic rejection and death with function predominated. For recipients dying with graft function, cardiovascular disease was the major cause of death. Conclusions. This study identified the five major causes of kidney graft loss in the 1990s. Different interventions are required to decrease loss from each of these causes. Future research needs to be directed at such interventions. [ABSTRACT FROM AUTHOR]

Introduction: Previous cross-sectional analyses have identified significant associations between quality of life (QOL), comorbidities and adverse effects in renal transplant recipients. This report examines the longitudinal relationship between adverse effects and QOL, with particular attention to the relative impact of adverse effects associated with immunosuppression. Methods: The Transplant Learning Center (TLC) is a program designed to improve QOL and preserve graft function in transplant recipients. Self-selected enrollees filled out questionnaires at roughly 3-month intervals. Each questionnaire included QOL scales developed for the program. Repeated measures multiple regression analysis was used to examine the relationship between the QOL scales, comorbidities, adverse effects, adjusting for other factors. Results: A total of 4247 TLC enrollees were included in the analysis, with a mean time since transplant of 5.1 yr. Comorbidities and adverse effects were common, with high blood pressure reported by 87% of respondents and unusual hair growth reported by 69.6%. In bivariate analysis, emotional/psychological problems and headaches had the largest impact on QOL. In multivariate analysis, emotional/psychological problems decreased sexual interest or ability, and headache had the largest adverse QOL effect. Conclusions: We have identified QOL issues that have been previously underemphasized in transplant recipients. These findings open new areas of research to further explore and define these issues. They provide new opportunities for interventions to address factors adversely impacting QOL and to develop strategies to improve QOL in these patients. Clinicians should actively solicit information about adverse effects of medications, particularly information about sexual and relationship issues, when evaluating renal recipients. These issues should be taken into account when making therapeutic decisions. [ABSTRACT FROM AUTHOR]

Given the constant flux in caseload and the number of personnel available in the OR, waiting for a final XM often prolongs organ preservation time (a room available at the time a XM is started is not available when the XM is completed). Longer preservation is associated with increased DGF and decreased graft survival. We have shown in a retrospective analysis that final XMs on 0% PRA recipients were always negatitve (Transplantation, 1999). We now describe a policy of: a) not doing screening XM and b) proceeding to the OR without a XM, in situations where the recipients's PRA has been documented to be 0% and when there have not been any interim transfusions (and the OR is ready before XM completion). Final XM is completed after the transplant. All patients send sera every 6 weeks for PRA (antiglobulin technique). If ≥3 consecutive PRAs are 0%, no donar-specific screening XM is done prior to calling the patient in for tx (UNOS allocation algorithm used). If there have not been any interim transfusions, we have proceeded to tx prior to completion of the final XM. Between 1/1/98-12/31/99, we did 109 CAD kidney (K) and 79 simultaneous kidney pancreas (SPK) tx; 67 (61%) K and 56 (71%) SPK had 0% PRA. Of the 0% PRA, 25/67 (37%) K and 28/56 (50%) SPK had no pretx XM. For K with no XM, cold ischemia was shorter (13.2±0.2 vs. 18±0.9 hrs, p=0.01) and DGF less (12% vs. 24%, p=0.3); for SPK with no XM, cold ischemia was shorter (15.2±2 vs. 18±0.9 hrs, p=0.1); no diff in DGF. All post-XM were negative and there were no hyperacute rejections; there was no diff in acute rejection episodes. Actuarial 1 yr graft survival: no XM-K=87.5%, SKP=82%; Yes XM-K=88%, SKP=86% (NS). Our data suggests it is safe, in select circumstances, to proceed to the OR without a XM. Elimination of the screening XM for 0% PRA candidates saves money. Proceeding of the OR (if available) without a final XM shortens cold ischemia time. [ABSTRACT FROM AUTHOR]

Examines graft and patient survival in elderly kidney transplant recipients in Minnesota. Identification of pre-transplant risk factors; Incidence of end-stage renal disease in the elderly; Factors predicting outcome of transplantation in a group of patients with shortened life expectancy.

Abstract: For pediatric kidney transplant recipients, chronic rejection has become the predominant cause of graft loss. This article reviews risk factors for chronic rejection and what can be done to lower the risk of chronic rejection for future transplant recipients. [ABSTRACT FROM AUTHOR]

Background. Transplant candidates frequently ask whether they should, based on information available at the time, accept a cadaver kidney or wait for a potentially better one.Methods. We analyzed 937 first and second cadaver transplants done between January 1, 1984 and December 31, 1997 to determine if information available at the time an offer is made could be used to predict long-term graft survival.Results. By Cox regression, risk factors for worse long-term graft survival were older donor age, cardiovascular or cerebrovascular cause of donor death, and delayed graft function (DGF). HLA-ABDR mismatch was marginally significant. Whether DGF will occur is not known at the time of an offer, but risk factors can be determined; we found these to be older donor age and> 10% panel-reactive antibodies (PRA) at transplantation (by Cox regression). Using these variables (PRA, ABDR mismatch, donor age, and donor cause of death) known at the time of an offer, we calculated the relative risk of worse long-term graft survival for each subgroup (Table 3 in manuscript). In general, older age and donor death from cardiovascular or cerebrovascular disease were associated with worse outcome. Kidneys from donors of <50 yr had the best outcome, irrespective of match.Conclusion. The data provided can be used to help guide patients as to whether they are better off accepting an offered kidney or waiting for a potentially better one. If an offer is declined, the next kidney may have a potentially worse outcome. [ABSTRACT FROM AUTHOR]

The article reports on the shortage of organ donation for transplantation in the U.S. The impact of the implemented state policies on the rate of organ donation and transplantation from January 1, 1998 to December 31, 2010 including public education programmes, revenue pools and paid leaves of absence for living donors are assessed. The establishment of revenue pools promoting organ donation is found to have a moderate effect on the number of transplants.

Chronic rejection (CR) is the most common cause of graft loss beyond the 1st posttransplant year. The aim of this analysis was to identify the risk factors for the development of CR in pediatric renal transplant recipients. Between June 1984 and March 1994, 217 renal transplants were performed in children at our center. Immunosuppression included prednisone, azathioprine, cyclosporine (CsA), and prophylactic antibody. Using multivariate analysis, we studied the impact of the following variables on the development of biopsy-proven CR: age at transplant (≤5 years, >5 years), gender, race, transplant number (primary, retransplant), donor source (cadaver, living donor), donor age (<20 years, 20-49 years, >49 years), number of ABDR mismatches (0, 1-2, 3-4, 5-6), number of DR mismatches (0, 1, 2), percentage peak panel reactive antibody (PRA) (≤50%, >50%), percentage PRA at transplantation (≤50%, >50%), dialysis pretransplant, preservation time >24 h, acute tubular necrosis requiring dialysis, initial CsA dosage (≤5 mg/kg per day, >5 mg/kg per day), CsA dosage at 1 year posttransplant (≤5 mg/kg per day, >5 mg/kg per day), acute rejection (AR), number of AR episodes (ARE) (1, >1), timing of AR (≤6 months, >6 months), reversibility of AR (complete, partial), and infection [cytomegalovirus (CMV), non-CMV viral, bacterial]. Risk factors for the development of CR in pediatric renal transplant recipients were: AR (P <0.0001, odds ratio 19.4), multiple ARE (>1 vs. 1) (P <0.0001, odds ratio 30.1), and high percentage peak PRA (>50%) (P <0.03, odds ratio 3.6). [ABSTRACT FROM AUTHOR]

Infants are thought to be more immunoreactive and at a greater risk for developing irreversible rejection compared with older children. We investigated this by analyzing patient and graft survival rates, incidence of acute rejection, reversibility of acute rejection, development of a subsequent acute rejection, and incidence of graft loss due to rejection in 154 children (<18 years of age) after primary renal transplantation. Most patients (n = 139) were treated with quadruple immunosuppression (antibody, azathioprine, prednisone, cyclosporine). Treatment of the first acute rejection episode (ARE) consisted of antibody and increased prednisone (68%) or increased prednisone alone (30%), and was not significantly different between the age groups. Transplants were from living donors (LRD) in 80% of cases. Patients were followed for at least 1 year (mean 58±30 months); 68% (105/154) of recipients experienced 1 or more ARE. The incidence of ARE was significantly lower in patients <2 years of age (45%) compared with patients 2 – 5 (76%, P = 0.01), 6 – 12 (78%, P = 0.005), and 13 – 17 (76%, P = 0.009) years of age. There was no significant difference in the 1-, 2- and 5-year patient or graft survival rates, the development of a subsequent acute rejection, or the incidence of graft loss due to acute rejection when analyzed by age group. These data suggest that the impact of an ARE is similar for younger and older children in our population receiving predominantly LRD transplants and quadruple immunosuppression. [ABSTRACT FROM AUTHOR]

The article presents a letter to the editor by the authors of "Long-term consequences of kidney donation" in response to letters about their research published in the issue.

Presents an editorial about organ donation in the United States. Assertion that people with end-stage renal disease can choose between dialysis or a kidney transplant for treatment options; Choice that patients must make about whether they want organs from a living or deceased donor; How a living donor transplant leads to better outcomes; Way that patients must be put on a waiting list if there is not a living donor available; Efforts to increase donations from living donors; Description of a study in this issue by Montgomery about the success of paired organ exchange.

Iliac artery stenosis is a rare cause of renal dysfunction in renal allograft recipients. Its presence can mimic renovascular hypertension and yet alter the very radiologic tests used to diagnose renal artery stenosis. We investigate a case of iliac artery stenosis that presented with diuretic resistant fluid overload, hypertension and limb claudication that exposed the pitfalls in the diagnosis and management of this condition. Successful stent placement, 8 months after transplant, resulted in return of the serum creatinine below the post-transplant nadir. [ABSTRACT FROM AUTHOR]

Aims: Tacrolimus, metabolized by CYP3A4 and CYP3A5 enzymes, is susceptible to drug–drug interactions (DDI). Steroids induce CYP3A genes to increase tacrolimus clearance, but the effect is variable. We hypothesized that the extent of the steroid–tacrolimus DDI differs by CYP3A4/5 genotypes. Methods: Kidney transplant recipients (n = 2462) were classified by the number of loss of function alleles (LOF) (CYP3A5*3, *6 and *7 and CYP3A4*22) and steroid use at each tacrolimus trough in the first 6 months post‐transplant. A population pharmacokinetic analysis was performed by nonlinear mixed‐effect modelling (NONMEM) and stepwise covariate modelling to define significant covariates affecting tacrolimus clearance. A stochastic simulation was performed and translated into a Shiny application with the mrgsolve and Shiny packages in R. Results: Steroids were associated with modestly higher (3%–11.8%) tacrolimus clearance. Patients with 0‐LOF alleles receiving steroids showed the greatest increase (11.8%) in clearance compared to no steroids, whereas those with 2‐LOFs had a negligible increase (2.6%) in the presence of steroids. Steroid use increased tacrolimus clearance by 5% and 10.3% in patients with 1‐LOF and 3/4‐LOFs, respectively. Conclusions: Steroids increase the clearance of tacrolimus but vary slightly by CYP3A genotype. This is important in individuals of African ancestry who are more likely to carry no LOF alleles, may more commonly receive steroid treatment, and will need higher tacrolimus doses. [ABSTRACT FROM AUTHOR]

Obese transplant recipients (BMI ≥ 30 kg/m2) have decreased posttransplant patient and graft survival compared with their nonobese counterparts. At the same time, many prednisone‐related side effects (eg, new‐onset diabetes) are similar to those associated with obesity. Using SRTR data, we studied outcomes associated with prednisone‐free maintenance immunosuppression (rapid discontinuation of prednisone—RDP). Between January 1, 2000, and December 31, 2014, 44 635 first transplant recipients with BMI ≥ 30 kg/m2 had a first kidney transplant (28 176 DD; 16 459, LD); 12,994 (29%) were discharged from the hospital on a prednisone‐free protocol. We compared outcomes to those discharged on a protocol incorporating maintenance prednisone (intention‐to‐treat analysis). RDP‐treated obese first DD recipients had significantly better patient survival (HR, 0.88; CI, 0.81‐0.96) and graft survival (HR, 0.93; CI, 0.88‐0.99) compared with their counterparts on maintenance immunosuppression. Although not statistically significant, the same trends were seen for LD recipients. For both DD and LD recipients, there was no difference between groups for death‐censored graft survival, suggesting that the benefit of RDP was due to improved patient survival. Our findings suggest that kidney transplant recipients with BMI ≥ 30 kg/m2 benefit from a protocol that incorporates RDP. [ABSTRACT FROM AUTHOR]

Background: Chronic immunosuppression following pancreas transplantation carries significant risk, including posttransplant lymphoproliferative disease (PTLD). We sought to define the incidence, risk factors, and long‐term outcomes of PTLD following pancreas transplantation at a single center. Methods: All adult pancreas transplants between February 1, 1983 and December 31, 2023 at the University of Minnesota were reviewed, including pancreas transplant alone (PTA), simultaneous pancreas–kidney transplants (SPK), and pancreas after kidney transplants (PAK). Results: Among 2353 transplants, 110 cases of PTLD were identified, with an overall incidence of 4.8%. 17.3% were diagnosed within 1 year of transplant, 32.7% were diagnosed within 5 years, and 74 (67.3%) were diagnosed after 5 years. The overall 30‐year incidence of PTLD did not differ by transplant type—7.4% for PTA, 14.2% for SPK, and 19.4% for PAK (p = 0.3). In multivariable analyses, older age and Epstein‐Barr virus seronegativity were risk factors for PTLD, and PTLD was a risk factor for patient death. PTLD‐specific mortality was 32.7%, although recipients with PTLD had similar median posttransplant survival compared to those without PTLD (14.9 year vs. 15.6 year, p = 0.9). Conclusions: PTLD following pancreas transplantation is associated with significant mortality. Although the incidence of PTLD has decreased over time, a high index of suspicion for PTLD following PTx should remain in EBV‐negative recipients. [ABSTRACT FROM AUTHOR]

Major gaps remain in our understanding of antibody‐mediated rejection (AMR) after kidney transplant. We examined the incidence, risk factors, response to treatment, and effects on outcomes of AMR at seven transplant programs in the long‐term Deterioration of Kidney Allograft Function prospective study cohort. Among 3131 kidney recipients, there were 194 observed AMR cases (6.2%) during (mean ± SD) 4.85 ± 1.86 years of follow‐up. Time to AMR was 0.97 ± 1.17 (median, 0.48) years. Risk factors for AMR included younger recipient age, human leukocyte antigen DR mismatches, panel‐reactive antibody >0%, positive T‐ or B‐cell cross‐match, and delayed graft function. Compared with no AMR, the adjusted time‐dependent hazard ratio for death‐censored graft failure is 10.1 (95% confidence interval, 6.5‐15.7) for all AMR patients, 4.0 (2.5, 9.1) for early AMR (<90 days after transplant), and 24.0 (14.0‐41.1) for late AMR (≥90 days after transplant). Patients were treated with different therapeutic combinations. Of 194 kidney transplant recipients with AMR, 50 (25.8%) did not respond to treatment, defined as second AMR within 100 days or no improvement in estimated glomerular filtration rate by 42 days. Long‐term outcomes after AMR are poor, regardless of the initial response to treatment. Better prevention and new therapeutic strategies are needed to improve long‐term allograft survival. [ABSTRACT FROM AUTHOR]

Background: Acute rejection (AR) after kidney transplantation is an important allograft complication. To reduce the risk of post-transplant AR, determination of kidney transplant donor-recipient mismatching focuses on blood type and human leukocyte antigens (HLA), while it remains unclear whether non-HLA genetic mismatching is related to post-transplant complications. Methods: We carried out a genome-wide scan (HLA and non-HLA regions) on AR with a large kidney transplant cohort of 784 living donor-recipient pairs of European ancestry. An AR polygenic risk score (PRS) was constructed with the non-HLA single nucleotide polymorphisms (SNPs) filtered by independence (r2 < 0.2) and P-value (< 1×10−3) criteria. The PRS was validated in an independent cohort of 352 living donor-recipient pairs. Results: By the genome-wide scan, we identified one significant SNP rs6749137 with HR = 2.49 and P-value = 2.15×10−8. 1,307 non-HLA PRS SNPs passed the clumping plus thresholding and the PRS exhibited significant association with the AR in the validation cohort (HR = 1.54, 95% CI = (1.07, 2.22), p = 0.019). Further pathway analysis attributed the PRS genes into 13 categories, and the over-representation test identified 42 significant biological processes, the most significant of which is the cell morphogenesis (GO:0000902), with 4.08 fold of the percentage from homo species reference and FDR-adjusted P-value = 8.6×10−4. Conclusions: Our results show the importance of donor-recipient mismatching in non-HLA regions. Additional work will be needed to understand the role of SNPs included in the PRS and to further improve donor-recipient genetic matching algorithms. Trial registry: Deterioration of Kidney Allograft Function Genomics (NCT00270712) and Genomics of Kidney Transplantation (NCT01714440) are registered on ClinicalTrials.gov. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "The high cost of organ transplant commercialism," by G. M. Danovitch in the 2014 issue.

A letter to the editor is presented in response to the article "Risk of End-Stage Renal Disease Following Live Kidney Donation," by A. D. Muzaale et al which was published in a 2014 issue.

The article discusses the results of a study which showed the increased risk to the donor in the living donor transplantation for end-stage renal disease (ESRD), referencing a research published in the journal "Kidney International." The results include the right of a fully informed donor candidates to make an autonomous decision about kidney donation and immunological disease as the main cause of ESRD in donors and risk for healthy young donors of developing ESRD late in life.

A difficult decision for patients in need of kidney–pancreas transplant is whether to seek a living kidney donor or wait to receive both organs from one deceased donor. The framework of dynamic treatment regimes (DTRs) can inform this choice, but a patient‐relevant strategy such as "wait for deceased‐donor transplant" is ill‐defined because there are multiple versions of treatment (i.e., wait times, organ qualities). Existing DTR methods average over the distribution of treatment versions in the data, estimating survival under a "representative intervention." This is undesirable if transporting inferences to a target population such as patients today, who experience shorter wait times thanks to evolutions in allocation policy. We, therefore, propose the concept of a generalized representative intervention (GRI): a random DTR that assigns treatment version by drawing from the distribution among strategy compliers in the target population (e.g., patients today). We describe an inverse‐probability‐weighted product‐limit estimator of survival under a GRI that performs well in simulations and can be implemented in standard statistical software. For continuous treatments (e.g., organ quality), weights are reformulated to depend on probabilities only, not densities. We apply our method to a national database of kidney–pancreas transplant candidates from 2001–2020 to illustrate that variability in transplant rate across years and centers results in qualitative differences in the optimal strategy for patient survival. [ABSTRACT FROM AUTHOR]

Background Nonadherence to posttransplant immunosuppressive medication is associated with increased rates of rejection and graft loss, yet it is unknown to what degree ideal adherence is associated with the sequelae of overimmunosuppression. Specifically, we questioned whether excellent adherence increased the posttransplant cancer risk. Methods Between August 1998 and August 2006, 195 consenting kidney transplant recipients had electronic monitoring of theirimmunosuppressive medication adherence. Results Based on their average quantitative adherence to a single immunosuppressant drug over the first 6 months posttransplant, recipients were grouped into adherence tertiles (highest, >97.9% adherence; middle, 91–97.8%; lowest, <91%). The cumulative incidence of cancer was calculated for patients in each tertile, treating death as a competing risk. The association between adherence and cancer rate was calculated after adjusting for recipient risk factors, using a competing risk proportional hazards model. The median duration of follow-up was 10.1 years. The 10-year estimated cumulative cancer incidence was 59.4% in the most adherent, 36.1% in the middle group and 38.1% in the least adherent group (P = 0.006). Excluding nonmelanocytic skin cancers, cancer incidence remained significantly higher in the highest adherence group (P = 0.002). Conclusions These data provide additional support for the need to individualize immunosuppression to minimize both rejection and immunosuppressive drug–related complications including cancer. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article in the previous issue about the effects of kidney donation including cardiovascular death and end-stage renal disease (ESRD).

The author reflects on the question of whether organ donors should be paid in an effort to increase the supply of organs which is available for transplantation. He suggests that they should because each year the waiting lists for people waiting for organs gets longer. He argues that a change in organ donation law which allowed donors to be paid would increase the supply of organs and protect the health and dignity of waiting patients.

A letter to the editor is presented in response to an article on ethical incentives and organ donation by researcher Francis L. Delmonico and colleagues in the June 20, 2002 issue.

Discusses the policy for nondirected donation, or donation by a living person to someone they do not know, of kidneys at the University of Minnesota at Minneapolis. Evaluation of donors and recipients; The ethics involved in nondirected donations, such as the risk to the donor; Studies that show that donors experience increased self-esteem and feelings of well-being.

Kidney transplant recipients carrying the CYP3A5*1 allele have lower tacrolimus troughs, and higher dose requirements compared to those with the CYP3A5*3/*3 genotype. However, data on the effect of CYP3A5 alleles on post‐transplant tacrolimus management are lacking. The effect of CYP3A5 metabolism phenotypes on the number of tacrolimus dose adjustments and troughs in the first 6 months post‐transplant was evaluated in 78 recipients (64% Caucasians). Time to first therapeutic concentration, percentage of time in therapeutic range (TTR), and estimated glomerular filtration rate (eGFR) were also evaluated. Fifty‐five kidney transplant recipients were CYP3A5 poor metabolizers (PM), 17 were intermediate metabolizers (IM), and 6 were extensive metabolizers (EM). Compared to PMs, EMs/IMs had significantly more dose adjustments (6.1 vs. 8.1, p =.015). Overall, 33.82% of trough measurements resulted in a dose change. There was no difference in the number of tacrolimus trough measurements between PMs and EM/IMs. The total daily tacrolimus dose requirements were higher in EMs and IMs compared to PMs (<.001). TTR was ∼50% in the PMs and EMs/IMs groups. CYP3A5 EM/IM metabolizers have more tacrolimus dose changes and higher dose requirements which increases clinical management complexity. Larger studies are needed to assess the cost and benefits of including genotyping data to improve clinical management. [ABSTRACT FROM AUTHOR]

Dr John S Najarian (1927–2020), chairman of the Department of Surgery at the University of Minnesota from 1967 to 1993, was a pioneer in surgery, clinical immunology and transplantation. A Covid‐delayed Festschrift was held in his honor on May 20, 2022. The speakers reflected on his myriad contributions to surgery, transplantation, and resident/fellow training, as well as current areas of ongoing research to improve clinical outcomes. Of note, Dr Najarian was a founder of the journal Clinical Transplantation. [ABSTRACT FROM AUTHOR]

We asked whether pediatric renal transplant recipients, subgrouped by age, differed in the percentage and number of hospital readmissions and in the incidence of infectious complications post transplant. Between 1 August 1985 and 31 October 1993, a total of 164 patients <18 years of age underwent primary transplants, with cyclosporine-based immunosuppression, at the University of Minnesota. The percentage of readmissions (P = NS), the mean number of readmissions (P = NS), and the length of hospital stay during readmission (P = NS) did not differ significantly among age groups. The overall incidence of acute rejection was greater in those ≥2 years than those <2 years (P = 0.002), and in living donor recipients ≥2 years versus those <2 years (P = 0.02). The incidence of bacterial infection (<2 years, 87%; 2-5 years, 72%; 6-12 years, 51%; 13-17 years, 40%) was greater in younger recipients (P = 0.0001). The most common bacterial infection in recipients ≤5 years was Clostridium difficile-associated diarrhea; in those >5 years, urinary tract infection. The overall incidence of viral infection did not differ among groups (P = NS). The most common viral infection in recipients ≤5 years was varicella and those >5 years, cytomegalovirus infection. Risk factors for infection in the first 6 months post transplant included age <2 years and Solu-Medrol treatment for acute rejection. In conclusion, young recipients <2 years of age at the time of transplant are at a higher risk for bacterial infection post transplant. [ABSTRACT FROM AUTHOR]

Genetic variation in the CYP3A4 and CYP3A5 (CYP3A4/5) genes, which encode the key enzymes in tacrolimus metabolism, is associated with tacrolimus clearance and dose requirements. Tacrolimus has a narrow therapeutic index with high intra‐ and intersubject variability, in part because of genetic variation. High tacrolimus clearance and low trough concentration are associated with a greater risk for rejection, whereas high troughs are associated with calcineurin‐induced toxicity. The objective of this study was to develop a model of tacrolimus clearance with a dosing equation accounting for genotypes and clinical factors in adult kidney transplant recipients of European ancestry that could preemptively guide dosing. Recipients receiving immediate‐release tacrolimus for maintenance immunosuppression from 2 multicenter studies were included. Participants in the GEN03 study were used for tacrolimus model development (n = 608 recipients) and was validated by prediction performance in the DeKAF Genomics study (n = 1361 recipients). Nonlinear mixed‐effects modeling was used to develop the apparent oral tacrolimus clearance (CL/F) model. CYP3A4/5 genotypes and clinical covariates were tested for their influence on CL/F. The predictive performance of the model was determined by assessing the bias (median prediction error [ME] and median percentage error [MPE]) and the precision (root median squared error [RMSE]) of the model. CYP3A5*3, CYP3A4*22, corticosteroids, calcium channel blocker and antiviral drug use, age, and diabetes significantly contributed to the interindividual variability of oral tacrolimus apparent clearance. The bias (ME, MPE) and precision (RMSE) of the final model was good, 0.49 ng/mL, 6.5%, and 3.09 ng/mL, respectively. Prospective testing of this equation is warranted. [ABSTRACT FROM AUTHOR]

What is known and objective: Pharmacogenomic biomarkers are now used in many clinical care settings and represent one of the successes of precision medicine. Genetic variants are associated with pharmacokinetic and pharmacodynamic changes leading to medication adverse effects and changes in clinical response. Actionable pharmacogenomic variants are common in transplant recipients and have implications for medications used in transplant, but yet are not broadly incorporated into practice. Methods: From the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group guidelines, and PharmGKB databases, 12 pharmacogenomic genes with 30 variants were selected and used to create diplotypes and actionable pharmacogenomic phenotypes. A total of 853 kidney allograft recipients who had genomic information available from a genome‐wide association study were included. Results: Each recipient had at least one actionable pharmacogenomic diplotype/phenotype, whereas the majority (58%) had three or four actionable diplotypes/phenotypes and 17.4% had five or more among the 12 genes. The participants carried actionable diplotypes/phenotypes for multiple medications, including tacrolimus, azathioprine, clopidogrel, warfarin, simvastatin, voriconazole, antidepressants and proton‐pump inhibitors. What is new and conclusion: Pharmacogenomic variants are common in transplant recipients, and transplant recipients receive medications that have actionable variants. Clinical trial: Genomics of Transplantation, clinicaltrials.gov (NCT01714440). [ABSTRACT FROM AUTHOR]

Few prognostic models have been created in children that receive liver retransplantation (rLT). We examined the SRTR database of 731 children that underwent second liver transplant between 2002 and 2018. Proportional hazards models using backward variable selection were used to identify recipient, donor, and surgical characteristics associated with survival. A simple prognostic scoring system or nomogram (ie, each risk factor was weighted on a five-point scale) was constructed based on the fitted model. Recipient age (P < .001), MELD/PELD (P < .001), recipient ventilated (P = .003), donor cause of death (P = .024), graft type (P = .045), first graft loss due to biliary tract complications (P = .048), and survival time of the first graft (P = .006) were significant predictors of retransplant survival. The bias-corrected Harrell's C-index for the multivariable model was 0.63. Survival was significantly different (P < .001) for those at low risk (0-4 points), medium risk (5-7 points), and high risk (8+ points). Survival was equivalent between low risk pediatric second transplant recipients and pediatric primary liver transplant recipients (P = .67) but significantly worse for medium- (P < .001) and high-risk (P < .001) recipients. With simple clinical characteristics, this scoring tool can modestly discriminate between those children at high risk and those children at low risk of poor outcomes after second liver transplant. [ABSTRACT FROM AUTHOR]

Background: Little data exist on re‐hospitalization rates in pediatric kidney recipients (KTx) particularly with the evolution of transplant immunosuppression. Methods: In a single‐center, retrospective study of pediatric KTx between 2006 and 2016, we assessed re‐hospitalization after KTx admission, stratified by whether the re‐admit was early (<30 days post‐KTx discharge) or late (>30 days), and compared two different immunosuppression eras (one with and one without steroids). Results: Of 197 KTx, 156 (79%) patients were re‐hospitalized in 1st year, 85 (56%) within 30 days of discharge (total 490 1st year re‐hospitalizations). Younger age was associated with early and late re‐hospitalizations. African American race was associated with early re‐hospitalizations. Of the 123 and 74 discharged on steroid‐avoidance (maintenance immunosuppression included MMF in 95%; FK in 50%; CSA in 50%) and steroid‐inclusive (AZA in 66%; MMF in 34%; FK in 30%; CSA in 70%), re‐hospitalization rates, timing post‐transplant, length, and number were not significantly different (P.38;.1;.56;.11). Admission diagnoses analysis demonstrated that steroid‐avoidance recipients had anemia/leucopenia/thrombocytopenia, significantly more often, as one of their admission diagnoses (16% vs 4%; P <.001) and had a rejection diagnosis significantly less often (6% vs 18%; P <.001). Infection diagnoses were not statistically different between groups. Re‐hospitalization, early or late, did not predict worse graft/ patient survival but predicted further hospitalizations. Conclusions: Re‐hospitalization is common after pediatric transplant discharge and predicts further hospitalization regardless of discharge on or off steroids. [ABSTRACT FROM AUTHOR]

Abstract: In the general population, obesity is associated with an increased risk of developing hypertension (HTN), type 2 diabetes mellitus (DM), and end‐stage renal disease (ESRD). Therefore, most transplant centers have a body mass index (BMI) threshold for accepting living kidney donors. But there have been no studies of postdonation weight gain trends and any associated risks. We tracked serial BMIs in 940 donors for a median (IQ range) follow‐up of 22.3 (15.4‐35.8) years. We studied the impact of postdonation weight gain in a model adjusted for family history of HTN or DM. Donor characteristics included age, sex, smoking, fasting blood glucose, eGFR, systolic and diastolic BP, and BMI at time of donation and time postdonation. Postdonation weight gain was associated with a significant increase in the relative risk of developing HTN RR 1.93 (95% CI 1.51‐2.46) (P < 0.001) and/or DM RR 4.18 (95% CI 2.05‐8.5) (P < 0.0001), but not (to date) cardiovascular disease (CVD), reduced eGFR or death. Like the general population, donors gained weight as they aged; a higher BMI was associated with higher incidence of DM and HTN. Postdonation care should include ongoing counseling on the risks of substantial weight gain. [ABSTRACT FROM AUTHOR]

Abstract: With increasing organ demand, living kidney donation from older donors (>60‐years‐old) has become more common. Between 1975 and 2014, 3752 donor nephrectomies (DN) were performed at University of Minnesota; 167 (4.5%) were >60‐years‐old Short‐ and long‐term outcomes were compared between contemporaneous >60‐years‐old and <60‐years‐old donors. On univariate analysis, >60‐years‐old were more likely to have had prior abdominal surgery and hypertension; and less likely to smoke. Baseline estimated glomerular filtration rate (eGFR) was lower in >60‐years‐old (80 ± 16 vs 101 ± 26 mL/min/1.73 m2; P < .001). Intraoperative and postoperative complications were similar, except a higher prevalence of <30 day ileus (3% vs 7%; P = .021) and longer postoperative length of stay (LOS) (4.2 vs 4.6 days; P = .005). On multivariate analysis, <30 day ileus and LOS continued to be significantly greater for >60‐years‐old After >20 years post‐DN, systolic blood pressure was significantly higher among >60‐years‐old (142 vs 125 mm Hg; P < .001) and HTN was diagnosed earlier (9 vs 14 years). After donation, eGFR was significantly lower for >60‐years‐old but slope of eGFR and rates of end‐stage renal disease (ESRD) were not significantly different >20 years post‐DN. Thus, kidney donation among carefully selected >60‐years‐old poses minimal perioperative risks and no added risk of long‐term ESRD. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus ( EBV) poses a significant threat to patient and graft survival post-transplant. We hypothesized that recipients who shed EBV at transplant had less immunologic control of the virus and hence were more likely to have active EBV infection and disease post-transplant. To test this hypothesis, we conducted a 5-year prospective study in primary solid organ transplant recipients. We measured EBV DNA in oral washes and blood samples by quantitative PCR before transplant and periodically thereafter for up to 4 years. Pre-transplant samples were available from 98 subjects. EBV DNA was detected pre-transplant in 32 of 95 (34%) and 5 of 93 subjects (5%) in oral wash and blood, respectively. Recipients with and without detectable pre-transplant EBV DNA were not significantly different demographically and had no significant difference in patient and graft survival ( P = .6 for both comparisons) or post-transplant EBV viremia-free survival ( P = .8). There were no cases of EBV-related disease or post-transplant lymphoproliferative disorder ( PTLD) in any of the patients with detectable EBV DNA pre-transplant. In conclusion, detectable EBV DNA pre-transplant was not associated with differences in patient/graft survival, post-transplant EBV viremia, or EBV-related diseases including PTLD. [ABSTRACT FROM AUTHOR]

Background: Post-transplant malignancy (PTM) remains a concern among pediatric kidney transplant (PKT) recipients.Study Design: Between 1963 and 2015, 884 pediatric (age 0 to 17 years old) patients received 1,055 PKTs at our institution. Cox proportional hazards models were constructed to identify risk factors for PTM after PKT with time-to-first-PTM as a primary outcome. Secondly, the hazard of death or graft loss was calculated in patients who developed PTM.Results: Median patient survival was 33 years (interquartile range [IQR] 18.7 to 47 years); 260 patients died during the study period and 47 had been diagnosed with PTM. There were 235 PTMs that occurred in 136 (15.4%) recipients at a median age of 29 years (IQR 17.8 to 37 years). The percentages of patients with PTM were 13% at 20 years post-PKT and 26% at 30 years post-PKT. Of PTM patients who died, 63.8% died of PTM. Among those who developed PTM, there was a higher hazard of death or graft loss (hazard ratio [HR] 1.62; 95% CI 1.11 to 2.38). In multivariable proportional hazards models, factors associated with PTM were increasing age at PKT (adjusted HR [AHR] 3.14; 95% CI 1.80 to 5.48 for 14 to 17 year-olds compared with children less than 3 years), having a living unrelated donor (LURD; AHR 3.25; 95% CI 1.27 to 8.35 compared with a living related donor), or implanting an Epstein-Barr virus (EBV)-positive allograft in an EBV-negative recipient (AHR 5.66; 95% CI 1.11 to 29.0). Compared with the general population, the cancer rate for PKT recipients was 6 times higher (126 vs 21 per 100,000 person-years).Conclusions: Pediatric kidney transplant recipients are at increased risk of PTM, which adversely affects survival. Children receiving transplants at an older age, from a LURD, or who receive an EBV-positive organ, should be monitored closely for the development of PTM. [ABSTRACT FROM AUTHOR]

Transplant programs inform potential donors that they should be able to return to normal activities within ~2 weeks and to work by 6 weeks after laparoscopic nephrectomy. We studied actual time. Between 10/2004 and 9/2014, 911 donors having laparoscopic nephrectomy were surveyed 6 months post-donation. Surveys asked questions specific to their recovery experience, including time to return to normal activities and work and a description of their recovery time relative to pre-donation expectations. Of the 911, 646 (71%) responded: mean age at donation was 43.5±10.6 years; 65% were female, 95% were white, 51% were biologically related to their recipient, and 83% reported education beyond high school. Of the 646 respondents, a total of 35% returned to normal activities by 2 weeks post-donation; 79% by 4 weeks post-donation; 94% by 5-6 weeks; however, 6% took >6 weeks. Of the 646, 551 (85%) were working for pay; of these, mean time to return to work was 5.3±2.8 weeks; median, 5 weeks. Of the 551, a total of 14% returned to work in 1-2 weeks, 46% by 3-4 weeks, and 76% by 5-6 weeks. Importantly, 24% required >6 weeks before returning to work with the highest rates for donors in manual labor or a skilled trade. Significantly longer return to work was reported by females (vs males; P=.01), those without (vs those with) post-high school education ( P=.010, those with longer hospital stay ( P=.01), and those with a postoperative complication ( P=.02). Of respondents, 37% described their recovery time as longer than expected. During the donor informed consent process, additional emphasis on realistic expectations around recovery to baseline activities and return to work is warranted. [ABSTRACT FROM AUTHOR]

Post-transplant lymphoproliferative disease ( PTLD) is an uncommon but serious complication of solid organ transplantation. Reduction in immunosuppression is the mainstay of PTLD treatment, but it may precipitate graft loss. Retransplantation remains controversial, as immunosuppression resumption may trigger PTLD relapse. Herein, we describe the experience of eight patients who underwent kidney retransplantation after successful PTLD treatment. Epstein-Barr virus ( EBV) serology was not known before the first transplantation. PTLD was diagnosed 62.5 months (range 5-323 months) after transplantation and was confined to the renal allograft (n = 1), lymph nodes (n = 2), gastrointestinal tract (n = 4), or central nervous system (n = 1). Immunosuppression tapering (8/8), chemotherapy (6/8), oral cavity lymphoma excision (1/8), and allograft nephrectomy (1/8) led to hematological remission in all patients. Retransplantation was performed at a median of 55.5 months (range 29-95 months) after PTLD diagnosis. After a median follow-up of 62.5 months (range 2-125 months) allograft survival was 87.5% (seven functioning grafts, one failed graft from chronic rejection), with no recurrence of PTLD. In all, five patients remain alive; the other three died from causes other than PTLD. In conclusion, kidney retransplantation appears to be safe in patients with prior PTLD and without major risk of hematological recurrence provided that PTLD has remitted. [ABSTRACT FROM AUTHOR]

We performed RNA sequencing (RNAseq) on peripheral blood mononuclear cells (PBMCs) to identify differentially expressed gene transcripts (DEGs) after kidney transplantation and after the start of immunosuppressive drugs. RNAseq is superior to microarray to determine DEGs because it’s not limited to available probes, has increased sensitivity, and detects alternative and previously unknown transcripts. DEGs were determined in 32 adult kidney recipients, without clinical acute rejection (AR), treated with antibody induction, calcineurin inhibitor, mycophenolate, with and without steroids. Blood was obtained pre-transplant (baseline), week 1, months 3 and 6 post-transplant. PBMCs were isolated, RNA extracted and gene expression measured using RNAseq. Principal components (PCs) were computed using a surrogate variable approach. DEGs post-transplant were identified by controlling false discovery rate (FDR) at < 0.01 with at least a 2 fold change in expression from pre-transplant. The top 5 DEGs with higher levels of transcripts in blood at week 1 were TOMM40L, TMEM205, OLFM4, MMP8, and OSBPL9 compared to baseline. The top 5 DEGs with lower levels at week 1 post-transplant were IL7R, KLRC3, CD3E, CD3D, and KLRC2 (Striking Image) compared to baseline. The top pathways from genes with lower levels at 1 week post-transplant compared to baseline, were T cell receptor signaling and iCOS-iCOSL signaling while the top pathways from genes with higher levels than baseline were axonal guidance signaling and LXR/RXR activation. Gene expression signatures at month 3 were similar to week 1. DEGs at 6 months post-transplant create a different gene signature than week 1 or month 3 post-transplant. RNAseq analysis identified more DEGs with lower than higher levels in blood compared to baseline at week 1 and month 3. The number of DEGs decreased with time post-transplant. Further investigations to determine the specific lymphocyte(s) responsible for differential gene expression may be important in selecting and personalizing immune suppressant drugs and may lead to targeted therapies. [ABSTRACT FROM AUTHOR]

Objectives To evaluate quality of life (QOL) in kidney transplant recipients aged 65 and older, identify predictors of impaired physical and mental QOL cross-sectionally and compare QOL over time with that of younger transplant recipients and general population controls. Design Comparison of serial Medical Outcomes Study 36-item Short-Form Survey ( SF-36) QOL scores in transplant recipients aged 65 and older with those of transplant recipients younger than 65 and with those of general population controls from the National Health Measurement Study ( NHMS). Setting University of Minnesota. Participants Individuals aged 65 and older (n = 150) and younger than 65 (n = 1,544) who received a primary kidney transplant between 1963 and 2009. Measurements Two-sample t-tests and logistic regression were used to assess the risk of significant impairment in physical and mental QOL, defined as 1 standard deviation below the general population norms (<40 points) for the SF-36 Physical ( PCS) and Mental Component Subscale ( MCS) scores. Results PCS scores were 39.3 for transplant recipients aged 65 and older, 43.5 for recipients younger than 65, and 49.2 for NHMS controls ( P < .005 for each pairwise comparison). MCS scores were 54.6 for transplant recipients aged 65 and older, 51.0 for recipients younger than 65, and 53.8 for NHMS controls ( P < .005 for ≥65 vs <65 and NHMS vs <65). These scores did not change significantly from the first (3.6 years after transplant) to the last (6.2 years after transplant) survey. Longer time since transplantation in elderly participants was associated with having significantly impaired physical QOL, but no predictors were associated with significantly impaired mental QOL. In younger recipients, rejection, diabetes mellitus, delayed graft function, coronary artery disease, and longer time on dialysis were associated with impaired physical QOL. Rejection, smoking, diabetes mellitus, and longer time on dialysis were predictors of impaired mental QOL. Conclusion Physical QOL is lower in elderly recipients but mental QOL is maintained and is higher than in younger recipients. [ABSTRACT FROM AUTHOR]