Electrocardiography-based Artificial Intelligence Algorithms Aid in Prediction of Long-term Mortality After Kidney Transplantation.

BACKGROUND: Predicting long-term mortality postkidney transplantation (KT) using baseline clinical data presents significant challenges. This study aims to evaluate the predictive power of artificial intelligence (AI)-enabled analysis of preoperative electrocardiograms (ECGs) in forecasting long-term mortality following KT. METHODS: We analyzed preoperative ECGs from KT recipients at three Mayo Clinic sites (Minnesota, Florida, and Arizona) between January 1, 2006, and July 30, 2021. The study involved 6 validated AI algorithms, each trained to predict future development of atrial fibrillation, aortic stenosis, low ejection fraction, hypertrophic cardiomyopathy, amyloid heart disease, and biological age. These algorithms' outputs based on a single preoperative ECG were correlated with patient mortality data. RESULTS: Among 6504 KT recipients included in the study, 1764 (27.1%) died within a median follow-up of 5.7 y (interquartile range: 3.00-9.29 y). All AI-ECG algorithms were independently associated with long-term all-cause mortality (P < 0.001). Notably, few patients had a clinical cardiac diagnosis at the time of transplant, indicating that AI-ECG scores were predictive even in asymptomatic patients. When adjusted for multiple clinical factors such as recipient age, diabetes, and pretransplant dialysis, AI algorithms for atrial fibrillation and aortic stenosis remained independently associated with long-term mortality. These algorithms also improved the C-statistic for predicting overall (C = 0.74) and cardiac-related deaths (C = 0.751). CONCLUSIONS: The findings suggest that AI-enabled preoperative ECG analysis can be a valuable tool in predicting long-term mortality following KT and could aid in identifying patients who may benefit from enhanced cardiac monitoring because of increased risk.

Direct Correlation of Soluble HLA and HLA-Containing Exosomes and Inverse Correlation of Tolerance Marker-Containing Exosomes With Antibody-Mediated Rejection After Simultaneous Liver-Kidney Transplantation: A Case Study.

There is a lower incidence of antibody-mediated rejection (AMR) after simultaneous liver-kidney transplantation (SLKT) than after kidney-only transplantation. It has been suggested that soluble human leukocyte antigen (sHLA) produced by the liver protects the kidney from AMR. However, this hypothesis has not been tested after SLKT. We present a case of SLKT with 2 donor-specific antibodies (DSAs) (DR53, 12,364 mean fluorescence intensity [MFI]; DQ7, 1253 MFI) that displayed a decrease by day 7 (DR53, 2747 MFI; DQ7, 107 MFI). On day 351, the patient was diagnosed with kidney AMR associated with high levels of DSA (DR53, 18,542 MFI; DQ7, 22,007 MFI) that persisted until day 531. High levels of sHLA-DR/DQ and HLA-DR/DQ-containing exosomes were also detected on day 398. Consequently, the patient underwent treatment with plasmapheresis, intravenous immunoglobulin, prednisone, and rituximab. On day 752, biopsy results were negative for AMR. Moderate levels of DSA (DR53, 9798 MFI; DQ7, 1271 MFI), and baseline levels of sHLA-DR/DQ and HLA-DR/DQ-containing exosomes were observed. Increases in CD4+CD25+FOXP3+ regulatory T cell marker-containing exosomes (CD73, programmed death-ligand 1) were observed on day 752 compared to day 398. These data show a direct correlation between sHLA and HLA-containing exosomes and an inverse correlation between tolerance marker-containing exosomes and kidney AMR after SLKT.

Impact of Pregnancy on GFR Decline and Kidney Histology in Kidney Transplant Recipients.

INTRODUCTION: Women with advanced kidney disease are advised to wait until after transplant to pursue pregnancy, but the impact of pregnancy on estimated glomerular filtration rate (eGFR) decline and kidney histology is unclear. METHODS: We identified a cohort of women aged 18 to 44 years at transplant from 1996 to 2014 at our 3-site program (N = 816) and determined whether they had a pregnancy >20 weeks gestation post-transplant by chart review. Outcomes included rate of change in eGFR after pregnancy, changes in kidney histology before and after pregnancy, graft failure, and 50% reduction in eGFR. RESULTS: There were 37 women with one or more pregnancies lasting longer than 20 weeks gestation post-transplant. Comparing women with and without pregnancy post-transplant, there was a significant increase in the rate of eGFR decline after pregnancy (-2.4 ml/min per 1.73 m2 per year vs. -1.9 ml/min per 1.73 m2 per year in women with no pregnancy, P < 0.001). Pregnancy did not affect the risk of graft failure, death-censored graft failure, or 50% reduction in eGFR. CONCLUSION: Pregnancy affects the rate of eGFR decline in the allograft. Postpregnancy biopsy findings revealed an increase in vascular injury, which could be a potential mechanism. We did not find a significant increase in risk of graft failure or reduction in eGFR by 50% owing to pregnancy.

Successful outcomes with transplanting kidneys from deceased donors with acute kidney injuryon temporary renal replacement therapy.

BACKGROUND AND OBJECTIVES: We aimed to determine outcomes with transplanting kidneys from deceased donors with severe acute kidney injury requiring acute renal replacement therapy (RRT). MATERIALS AND METHODS: A total of 172 recipients received a kidney from donors with acute kidney injury stage 3 (AKIN3) requiring RRT. We compared the study group to 528 recipients who received a kidney from donors with AKIN stage 3 not on RRT and 463 recipients who received < 85% Kidney Donor Profile Index (KDPI) AKIN stage 0 kidney. RESULTS: The study group donors were younger compared to the 2 control groups. Despite higher DGF in the study group, the length of hospital stay and acute rejection were similar. Death censored graft survival (96% AKIN3-RRT vs. 97%AKIN3 no RRT vs. 96% KDPI < 85% AKIN0, P = 0.26) and patient survival with functioning graft at 1 year (95% across all groups, P = 0.402) were similar. The estimated glomerular filtration rate were similar across the 3 groups after first month. Interstitial fibrosis and tubular atrophy score ≥ 2 on protocol biopsy at time 0, 4 and 12 months were similar. Primary nonfunction was rare and associated with high KDPI. CONCLUSIONS: Transplanting selected kidneys from deceased donors with AKIN3 requiring RRT is safe and has good outcomes.

Overcoming Mismatch Concerns for Adult Recipients of Small Pediatric Deceased Donor Kidneys.

BACKGROUND: Kidneys from very young pediatric donors continue to be underutilized. To reduce discard, the Organ Procurement and Transplantation Network (OPTN) policy was recently updated to allow kidneys from donors weighing <18 kg to be recovered en bloc. METHODS: We reviewed our center's experience with kidney transplantation in adult recipients of <18 kg pediatric donor kidneys to assess renal function outcomes specific to solitary vs en bloc usage. RESULTS: The majority of <18 kg donors were used en bloc (n = 39, 72.2% vs n = 15, 27.8%). Donor weight (kg) was similar between the 2 groups (12.3 ± 3.2 vs 14.1 ± 2.5, P = .05). Recipient weight was lower in the solitary kidney group (P = .01). Both groups had a similar donor-to-recipient body weight ratio (0.24 ± 0.3 vs 0.18 ± 0.3, P = .51). The solitary kidney group had a lower estimated glomerular filtration rate at 1 (56.9 ± 24.3 vs 81.8 ± 24.8, P = .01) and 2 years (72 ± 18.6 vs 93.7 ± 21.6, P = .03). By 2 years, both groups had an average estimated glomerular filtration rate >60 mL/min. Kidney allograft growth occurred in both groups, with the largest increase occurring the first month posttransplant (11.9%, 18.6%, P < .0001). CONCLUSION: For pediatric donors weighing <18 kg, improvements in renal function continue beyond the first posttransplant year. Risk for hyperfiltration injury appears low and renal mass-recipient mass matching is useful in guiding decision-making for solitary vs en bloc utilization.

Ten Years of Kidney Paired Donation at Mayo Clinic: The Benefits of Incorporating ABO/HLA Compatible Pairs.

BACKGROUND: We examined the 10-year experience of Mayo Clinic's kidney paired donation (KPD).We aimed to determine the benefits for the recipients of enrolled ABO/HLA compatible pairs and determine the factors associated with prolonged KPD waiting time. METHODS: We performed a retrospective study of 332 kidney transplants facilitated by the Mayo 3-site KPD program from September 2007 to June 2018. RESULTS: The median (interquartile range) time from KPD entry to transplantation was 89 days (42-187 days). The factors independently associated with receiving a transplant >3 months after KPD entry included recipient blood type O and calculated panel reactive antibodies ≥98%. Fifty-four ABO/HLA compatible pairs participated in KPD for the following reasons: cytomegalovirus mismatch (18.5% [10/54]), Epstein-Barr virus (EBV) mismatch (EBV) (9.3% [5/54]), age/size mismatch (51.9% [28/54]), or altruistic reasons (20.3% [11/54]). Cytomegalovirus and EBV mismatch were avoided in 90% (9/10) and 100% (5/5) of cases. Recipients who entered KPD for age/size mismatch and altruistic reasons received kidneys from donors with lower Living Kidney Donor Profile Index scores than their actual donor (median [interquartile range] 31.5 [12.3-47]; P < 0.001 and 26 (-1 to 46); P = 0.01 points lower, respectively). Median time to transplant from KPD entry for compatible pair recipients was 70 days (41-163 days), and 44.4% (24/54) of these transplants were preemptive. All chains/swaps incorporating compatible pairs included ABO/HLA incompatible pairs. CONCLUSIONS: KPD should be considered for all living donor/recipient pairs because the recipients of these pairs can derive personal benefit from KPD while increasing the donor pool for difficult to match pairs.

Transplanting kidneys from donation after cardiac death donors with acute kidney injury.

Donation after cardiac death (DCD) and acute kidney injury (AKI) donors have historically been considered independent risk factors for delayed graft function (DGF), allograft failure, and inferior outcomes. With growing experience, updated analyses have shown good outcomes. There continues to be limited data, however, on outcomes specific to DCD donors who have AKI. Primary outcomes for this study were post-kidney transplant patient and allograft survival comparing two donor groups: DCD AKIN stage 2-3 and DBD AKIN stage 2-3. In comparing these groups, there were no short- or long-term differences in patient (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.54-1.93, P = .83) or allograft survival (HR 1.47, 95% CI 0.64-2.97, P = .32). In multivariate models, the DCD/DBD status had no significant impact on the estimated GFR (eGFR) at 1 (P = .38), 2 (P = .60), and 3 years (P = .52). DGF (57.9% vs 67.9%, P = .09), rejection (12.1% vs 13.9%, P = .12), and progression of interstitial fibrosis/tubular atrophy (IFTA) on protocol biopsy (P = .16) were similar between the two groups. With careful selection, good outcomes can be achieved utilizing severe AKI DCD kidneys. Historic concerns regarding primary nonfunction, DGF resulting in interstitial fibrosis and rejection, and inferior outcomes were not observed. Given the ongoing organ shortage, increased effort should be undertaken to further utilize these donors.

Managing highly sensitized renal transplant candidates in the era of kidney paired donation and the new kidney allocation system: Is there still a role for desensitization?

Kidney paired donation (KPD) and the new kidney allocation system (KAS) in the United States have led to improved transplantation rates for highly sensitized candidates. We aimed to assess the potential need for other approaches to improve the transplantation rate of highly sensitized candidates such as desensitization. Using the UNOS STAR file, we analyzed transplant rates in a prevalent active waiting-list cohort as of June 1, 2016, followed for 1 year. The overall transplantation rate was 18.9% (11 129/58769). However, only 9.7% (213/2204) of candidates with a calculated panel reactive antibody ≥99.9% received a transplant, and highly sensitized candidates were less likely to receive a living donor transplant. Among candidates with a CPRA ≥ 99.5% (ie. 100%), only 2.5% of transplants were from living donors (13 total, 7 from KPD). Nearly 4 years after KAS (6/30/2018), 1791 actively wait-listed candidates had a CPRA of ≥99.9% and 34.6% (620/1791) of these had ≥5 years of waiting time. Thus, despite KPD and KAS, many sensitized candidates have not been transplanted even with prolonged waiting time. We conclude that candidates with a CPRA ≥ 99.9% and sensitized candidates with an incompatible living donor and prolonged waiting time may benefit from desensitization to improve their ability to receive a transplant.

Long-term Outcomes Following Kidney Transplantation From Donors With Acute Kidney Injury.

BACKGROUND: Kidneys from deceased donors with acute kidney injury (AKI) are more likely to be discarded because of concerns for poor outcomes after transplantation. The aim of this study was to determine the long-term outcomes of a large cohort of patients transplanted utilizing kidneys from deceased donors with AKI. METHODS: All patients receiving a deceased donor kidney transplant during a recent 10-year period were included. Acute Kidney Injury Network (AKIN) criteria were used to classify the donors. Donor kidneys with >10% cortical necrosis or more than mild chronic changes were discarded. The primary outcome is the combined endpoint of death or graft loss. RESULTS: The cohort included 1313 kidneys from 974 donors, AKIN stage 0 (no AKI) in 319 (24.3%), stage 1 in 370 (28.2%), stage 2 in 177 (13.5), and stage 3 in 447 (34.0%). Estimated 5-year graft survival (95% confidence interval) was 78.5% (72.5-84.5), 77.8% (72.8-82.1), 83.8% (76.8-88.9), and 84.6% (79.5-88.7) for AKIN donor stage 0 to 3, respectively (log-rank P = 0.10). After adjusting for baseline differences, the hazard ratio (95% confidence interval) for the combined endpoint for the AKIN stage 3 group (relative to AKIN 0 group) was 0.70 (0.45-1.10). Delayed graft function occurred in 44.6% and 75.4% of AKIN 2 and 3 groups, as compared to 33.9% and 33.5% in AKIN 0 and 1 (P < 0.001). CONCLUSION: We conclude that transplanting selected kidneys from deceased donors with AKI with preimplantation biopsy showing <10% cortical necrosis and no more than mild chronic changes have excellent long-term graft survival.

Cardiorespiratory Fitness (Peak Oxygen Uptake): Safe and Effective Measure for Cardiovascular Screening Before Kidney Transplant.

BACKGROUND: Significant heterogeneity exists in practice patterns and algorithms used for cardiac screening before kidney transplant. Cardiorespiratory fitness, as measured by peak oxygen uptake (VO2peak), is an established validated predictor of future cardiovascular morbidity and mortality in both healthy and diseased populations. The literature supports its use among asymptomatic patients in abrogating the need for further cardiac testing. METHODS AND RESULTS: We outlined a pre-renal transplant screening algorithm to incorporate VO2peak testing among a population of asymptomatic high-risk patients (with diabetes mellitus and/or >50 years of age). Only those with VO2peak <17 mL/kg per minute (equivalent to <5 metabolic equivalents) underwent further noninvasive cardiac screening tests. We conducted a retrospective study of the a priori dichotomization of the VO2peak <17 versus ≥17 mL/kg per minute to determine negative and positive predictive value of future cardiac events and all-cause mortality. We report a high (>90%) negative predictive value, indicating that VO2peak ≥17 mL/kg per minute is effective to rule out future cardiac events and all-cause mortality. However, lower VO2peak had low positive predictive value and should not be used as a reliable metric to predict future cardiac events and/or mortality. In addition, a simple mathematical calculation documented a cost savings of ≈$272 600 in the cardiac screening among our study cohort of 637 patients undergoing evaluation for kidney and/or pancreas transplant. CONCLUSIONS: We conclude that incorporating an objective measure of cardiorespiratory fitness with VO2peak is safe and allows for a cost savings in the cardiovascular screening protocol among higher-risk phenotype (with diabetes mellitus and >50 years of age) being evaluated for kidney transplant.

Glucose homeostasis after simultaneous pancreas and kidney transplantation: a comparison of subjects with C-peptide-positive non-type 1 diabetes mellitus and type 1 diabetes mellitus.

BACKGROUND: While simultaneous pancreas kidney transplant (SPKTx) is a therapeutic option for patients with type 1 diabetes (T1DM) and renal failure, few centers offer SPKTx to "select" non-T1DM patients. To address concerns that existing insulin resistance may limit the benefits of the pancreas allograft among non-T1DM, we compared several indices of glucose homeostasis, in "select" non-T1DM and T1DM patients who received SPKTx. METHODS: Criteria for "select" non-T1DM included the following: positive C-peptide, BMI <30 kg/m(2) , treatment with oral agents before insulin initiation, and insulin at <1 unit/kg/d. We compared several indices of glucose homeostasis within 1 yr post-SPKTx among seven "select" patients with non-T1DM and nine patients with T1DM with similar age, BMI, and immunosuppression. Measurements of insulin resistance included the following: homeostatic model, insulin sensitivity index, and insulin-glucose ratio; insulin secretion measures included the following: corrected insulin response. RESULTS: Non-T1DM had similar pre-transplant metabolic (fasting glucose, HbA1c, blood pressure, and lipid) parameters to the T1DM cohort. There were no significant differences in the various measures of insulin resistance and secretion between T1DM and "select" non-T1DM patients. CONCLUSION: Our results suggest SPKTx should be considered in the therapeutic armamentarium among carefully select non-T1DM with features of minimal insulin resistance; however, a larger cohort with longer follow-up is needed to confirm our results.

Assessing the efficacy of kidney paired donation--performance of an integrated three-site program.

BACKGROUND: Kidney paired donation (KPD) has emerged as a viable option for renal transplant candidates with incompatible living donors. The aim of this study was to assess the "performance" of a three-site KPD program that allowed screening of multiple donors per recipient. METHODS: We reviewed retrospectively the activity of our KPD program involving three centers under the same institutional umbrella. The primary goal was to achieve a transplant that was both ABO compatible and had a negative or low-positive flow cytometric crossmatch (+XM). RESULTS: During the 40-month study period, 114 kidney transplant candidates were enrolled-57% resulting from a +XM and 39% resulting from ABO incompatible (ABOi) donors. Important outcomes were as follows: (1) 81 (71%) candidates received a transplant and 33 (29%) were still waiting; (2) 368 donors were evaluated, including 10 nondirected donors; (3) 82% (37/45) of ABOi candidates underwent transplantation; (4) 56% (36/65) of +XM candidates underwent transplantation (however, all but four of these had a cPRA less than 95%); (5) at the end of the study period, 97% (28/29) of +XM candidates still waiting had a cPRA greater than 95%. CONCLUSIONS: These data suggest evaluating large numbers of donors increases the chances of KPD. Patients with a cPRA greater than 95% are unlikely to receive a negative or low-positive +XM, suggesting the need for desensitization protocols in KPD.

Kidney Transplant Program at the Mayo Clinic in Arizona.

Since 1999, we have performed 2,302 kidney transplants at the Mayo Clinic in Arizona. Transplant volume has increased by 45% since 2010. Our center performed 269 kidney transplants in 2013. Our growth is related to multiple factors, including an experienced, committed team and strong support from our institution and referring nephrologists. Areas of program innovation at our center include: transplanting deceased donors with acute kidney injury, outcomes in older kidney transplant recipients, alemtuzumab induction with steroid avoidance, living donor paired kidney exchange-3 site experience, and other non-traditional deceased donor kidney transplants. Of the 162 acute kidney injury (AKI) donor transplants done at our program, 71% had severe AKI. The AKI donor kidneys had more delayed graft function; but graft survival, estimated glomerular filtration rate, and biopsy findings at 1 year were not different form the control group. We have transplanted 188 patients ≥ 70 years old at the time of transplantation. Graft survival at 1, 3, and 5 years was similar to that of patients < 70. Since 2008, 778 (37%) patients received alemtuzumab induction, therapy with excellent patient and graft survival. We have used steroid avoidance immunosuppression with excellent outcomes since 2003. Since starting kidney paired donation in 2009, it has resulted in 54 kidney transplants, including 4 compatible pairs. More than half of the deceased donor transplants done at our center are from non-traditional donors such as Public Health Service increased risk, donation after cardiac death, extended criteria donors/high kidney donor profile index, and pediatric en-bloc donors. One- and 3-year graft survival of the non-traditional deceased donor kidney transplants are not different than the traditional deceased donor kidney transplants.

Delayed allograft inflammation following alemtuzumab induction for kidney transplantation.

BACKGROUND: In a recent clinical trial in kidney transplant recipients, induction with alemtuzumab and rabbit-antithymocyte globulin (r-ATG) was equally effective in preventing rejection during the first post-transplant year; however, this study did not include protocol biopsies. METHODS: The aim of this study was to analyze the impact of alemtuzumab induction on rejection and subclinical inflammation during the first post-transplant year compared with a historic control group receiving induction with r-ATG. All patients received tacrolimus and mycophenolate mofetil (MMF). RESULTS: There were 361 in the alemtuzumab group and 478 in the r-ATG groups. Rejection (excluding Banff borderline), during the first year, occurred in 14% of the alemtuzumab group and 9% of the r-ATG group (p = 0.03). Estimated glomerular filtration rate (GFR) (chronic kidney disease (CKD)-EPI formula) at one yr and graft survival at three yr were similar. On the protocol biopsies, interstitial inflammation (Banff i scores) and tubulitis (Banff t scores) were more likely in the r-ATG group at one month, but at four and 12 months, both inflammation and tubulitis were more likely in the alemtuzumab group. CONCLUSIONS: We conclude that alemtuzumab induction is associated with delayed inflammation at four and 12 months, but this inflammation did not appear to negatively impact the GFR or graft survival.

Desensitization in the era of kidney paired donation: the Mayo Foundation 3-site experience.

Sensitized renal allograft candidates face significant barriers to transplantation. While several options exist, including: kidney paired donation (KPD), desensitization, or pursuing a deceased donor kidney transplant, it is unclear from existing data what is the appropriate protocol for an individual patient. In this study, we seek to devise a balance between waiting for a paired donor and combining desensitization with KPD.

Transplant tourism: a modern iteration of an ancient problem.

PURPOSE OF REVIEW: To explore the scope and implications of emerging global problem of transplant tourism, a practice in which patients seek transplant services (most commonly kidney allografts) in countries other than their permanent residence. Potential remedies that must be implemented if abuses are to be curbed are also offered. RECENT FINDINGS: Although traveling abroad for medical services may not be problematic from a number of perspectives, what makes transplant tourism so troubling is its link with organ trafficking and transplant commercialism. Unlike many illegal markets, however, this one is driven by the need of patients with irreversible kidney failure, who, along with kidney vendors, are the most vulnerable participants in the process in terms of medical and financial outcomes. SUMMARY: This review explores the scope and implications of transplant tourism, and offers potential remedies that must be implemented if abuses are to be curbed.