Leukocyte transcriptome indicators of development of infection in kidney transplant recipients.

After kidney transplantation, infection and death are important clinical complications, especially for the growing numbers of older patients with limited resilience to withstand adverse events. Evaluation of changes in gene expression in immune cells can reveal the underlying mechanisms behind vulnerability to infection. A cohort of 60 kidney transplant recipients was evaluated. Gene expression in peripheral blood mononuclear cells 3 months after kidney transplantation was analyzed to compare differences between patients with infection and those who were infection-free in the first-year post-transplant. Pro-inflammatory genes such as IL1B, CCL4, and TNF were found to be downregulated in post-transplant PBMC from patients who developed infection. In contrast, genes involved in metabolism, HLA genes, and transcripts involved in type I interferon innate antiviral responses were found to be upregulated. Promoter-based bioinformatic analyses implicated increased activity of interferon regulatory factors, erythroid nuclear factor (E2), and CCAAT-enhancer-binding protein (C/EBP) in patients who developed infections. Differential patterns of gene expression were observed in patients who developed infection after kidney transplantation, with patterns distinct from changes associated with patient age, suggesting possible mechanisms behind vulnerability to infection. Assessment of gene expression in blood may offer an approach for patient risk stratification and monitoring after transplantation.

PD 1 checkpoint inhibition in solid organ transplants: 2 sides of a coin - case report.

BACKGROUND: The management of malignancy post kidney transplantation includes reduction in immunosuppression and referral to an oncologist management of their malignancy. Recent advances in oncology have resulted in the approval of several classes of drugs with immune-modulatory activity. However, activation of the immune system against malignant cells may precipitate allograft rejection in solid organ transplant recipients. CASE PRESENTATION: Herein we present a case of acute kidney allograft rejection in a 50 year old man following administration of the novel immune-modulatory agent nivolumab for the treatment of metastatic squamous cell carcinoma. CONCLUSION: The management of malignancy in solid organ transplant recipients requires a heightened awareness of the potential for allograft rejection in this new era of cancer therapeutics.

Cell-free DNA for the detection of kidney allograft rejection.

Donor-derived cell-free DNA (dd-cfDNA) is an emerging noninvasive biomarker that has the potential to detect allograft injury. The capacity of dd-cfDNA to detect kidney allograft rejection and its added clinical value beyond standard of care patient monitoring is unclear. We enrolled 2,882 kidney allograft recipients from 14 transplantation centers in Europe and the United States in an observational population-based study. The primary analysis included 1,134 patients. Donor-derived cell-free DNA levels strongly correlated with allograft rejection, including antibody-mediated rejection (P < 0.0001), T cell-mediated rejection (P < 0.0001) and mixed rejection (P < 0.0001). In multivariable analysis, circulating dd-cfDNA was significantly associated with allograft rejection (odds ratio 2.275; 95% confidence interval (CI) 1.902-2.739; P < 0.0001) independently of standard of care patient monitoring parameters. The inclusion of dd-cfDNA to a standard of care prediction model showed improved discrimination (area under the curve 0.777 (95% CI 0.741-0.811) to 0.821 (95% CI 0.784-0.852); P = 0.0011) and calibration. These results were confirmed in the external validation cohorts (n = 1,748) including a cohort of African American patients (n = 439). Finally, dd-cfDNA showed high predictive value to detect subclinical rejection in stable patients. Our study provides insights on the potential value of assessing dd-cfDNA, in addition to standard of care monitoring, to improve the detection of allograft rejection. ClinicalTrials.gov registration: NCT05995379 .

Cold Ischemia Time, Kidney Donor Profile Index, and Kidney Transplant Outcomes: A Cohort Study.

Rationale & Objective: An average of 3,280 recovered deceased donor kidneys are discarded annually in the United States. Increased cold ischemia time is associated with an increased rate of organ decline and subsequent discard. Here we examined the effect of prolonged cold ischemia time on kidney transplant outcomes. Study Design: Retrospective observational study. Setting & Participants: Recipients of deceased donor kidney transplants in the United States from 2000 to 2018. Exposure: Recipients of deceased donor kidneys were divided based on documented cold ischemia time: ≤16, 16-24, 24-32, 32-40, and >40 hours. Outcomes: The incidence of delayed graft function, primary nonfunction, and 10-year death-censored graft survival. Analytical Approach: The Kaplan-Meier method was used to generate survival curves, and the log rank test was used to compare graft survival. Results: The rate of observed delayed graft function increased with cold ischemia time (20.9%, 28.1%, 32.4%, 37.5%, and 35.8%). Primary nonfunction also showed a similar increase with cold ischemia time (0.6%, 0.9%, 1.3%, 2.1%, and 2.3%), During a median follow-up time of 4.6 years, 37,301 recipients experienced death-censored graft failure. Analysis based on kidney donor profile index (KDPI) demonstrated significant differences in 10-year death-censored graft survival, with a death-censored graft survival in recipients of a kidney with a KDPI <85% of 71.0% (95% CI, 70.5%-71.5%), 70.5% (95% CI, 69.9%-71.0%), 69.6% (95% CI, 68.7%-70.4%), 65.5% (95% CI, 63.7%-67.3%), and 67.2% (95% CI, 64.6%-69.6%), compared to 53.5% (95% CI, 51.1%-55.8%), 50.7% (95% CI, 48.3%-53.1%), 50.3% (95% CI, 46.6%-53.8%), 50.7% (95% CI, 45.1%-56.1%), and 48.3% (95% CI, 40.0%-56.1%), for recipients of a kidney with a KDPI >85%. Limitations: Heterogeneity of acceptance patterns among transplant centers, presence of confounding variables leading to acceptance of kidneys with prolonged cold ischemia times. Conclusions: Cold ischemia time was associated with an increased risk of delayed graft function and primary nonfunction. However, the effect of increased cold ischemia time is modest and has less impact than the KDPI. Transplant programs should not consider prolonged cold ischemia time alone as a predominant reason to decline an organ, especially with a KDPI <85%.

Frailty and Age-Associated Assessments Associated with Chronic Kidney Disease and Transplantation Outcomes.

Background: Frailty is often defined as a decrease in physiological reserve and has been shown to be correlated with adverse health outcomes and mortality in the general population. This condition is highly prevalent in the chronic kidney disease (CKD) patient population as well as in kidney transplant (KT) recipients. Other age-associated changes include sarcopenia, nutrition, cognition, and depression. In assessing the contributions of these components to patient outcomes and their prevalence in the CKD and KT patient population, it can be determined how such variables may be associated with frailty and the extent to which they may impact the adverse outcomes an individual may experience. Objectives: We sought to perform a systematic literature review to review published data on frailty and associated age-associated syndromes in CKD and KT patients. Results: Over 80 references pertinent to frailty, sarcopenia, nutrition, cognition, or depression in patients with CKD or KT were identified. Systematic review was performed to evaluate the data supporting the use of the following approaches: Fried Frailty, Short Physical Performance Battery, Frailty Index, Sarcopenia Index, CT scan quantification of muscle mass, health-related quality of life, and assessment tools for nutrition, cognition, and depression. Conclusion: This report represents a comprehensive review of previously published research articles on this topic. The intersectionality between all these components in contributing to the patient's clinical status suggests a need for a multifaceted approach to developing comprehensive care and treatment for the CKD and KT population to improve outcomes before and after transplantation.

Evaluation of the Modified Oxford Score in Recurrent IgA Nephropathy in North American Kidney Transplant Recipients: The Banff Recurrent Glomerulonephritis Working Group Report.

BACKGROUND: The modified Oxford classification mesangial and endocapillary hypercellularity, segmental sclerosis, interstitial fibrosis/tubular atrophy, and the presence of crescents (MEST-C) of immunoglobulin A nephropathy (IgAN) was recently shown to be a predictor of graft failure in Asians with recurrent IgAN. We aimed to validate these findings in a cohort from North American centers participating in the Banff Recurrent Glomerulopathies Working Group. METHODS: We examined 171 transplant recipients with end-stage kidney disease because of IgAN; 100 of them with biopsy-proven recurrent IgAN (57 of them had complete MEST-C scores) and 71 with no recurrence. RESULTS: IgAN recurrence, which was associated with younger age at transplantation ( P = 0.012), strongly increased the risk of death-censored graft failure (adjusted hazard ratio, 5.10 [95% confidence interval (CI), 2.26-11.51]; P < 0.001). Higher MEST-C score sum was associated with death-censored graft failure (adjusted hazard ratio, 8.57 [95% CI, 1.23-59.85; P = 0.03] and 61.32 [95% CI, 4.82-779.89; P = 0.002] for score sums 2-3 and 4-5 versus 0, respectively), and so were the single components endocapillary hypercellularity, interstitial fibrosis/tubular atrophy, and crescents ( P < 0.05 each). Overall, most of the pooled adjusted hazard ratio estimates associated with each MEST-C component were consistent with those from the Asian cohort (heterogeneity I2 close to 0%, and P > 0.05). CONCLUSIONS: Our findings may validate the prognostic usefulness of the Oxford classification for recurrent IgAN and support the inclusion of the MEST-C score in allograft biopsies diagnostic reports.

Physical Frailty Predicts Outcomes in Patients Undergoing Evaluation for Kidney Transplantation.

INTRODUCTION: An increasing number of older patients are undergoing evaluation for kidney transplantation; however, older patients experience increased rates of complications compared with younger patients, leading to the study of frailty assessments. Although many centers have evaluated the Fried Frailty Phenotype (FFP), less is known about the ability of the Short Performance Physical Battery (SPPB) to predict outcomes. METHODS: Frailty assessment by FFP and SPPB was introduced into routine outpatient evaluation for patients aged 55 years and older referred for transplantation. Transplant rate, length of stay, readmission up to 3 months posttransplant, and death were reviewed. Patients were evaluated in an initial cohort followed by a validation cohort by FFP and SPPB. Multivariate analysis correcting for demographic characteristics was applied. RESULTS: Patient cohorts reflected the racial and ethnic diversity of our population, including approximately 40% Hispanic patients. The first cohort of 514 patients demonstrated a significant association between frailty as measured by SPPB and transplantation (odds ratio [OR], 2.27; 95% CI, 1.38-3.83; p = .002). The second cohort of 1408 patients validated the association between frailty measured by SPPB and transplantation (OR, 2.81; 95% CI, 1.83-4.48; p < .001). In addition, there was a significant association between nonfrail status measured by SPPB and death (OR, 0.16; 95% CI, 0.04-0.62; p = .006). CONCLUSIONS: Frailty assessment is a potentially useful approach for the assessment of transplant candidates. Our real-world study examined the performance of 2 methods of frailty evaluation methods in a diverse population, demonstrating that SPPB but not FFP was predictive of clinical outcomes. Incorporation of frailty assessments into transplant evaluation may improve risk stratification and optimize outcomes for older patients.

Comparison of artificial intelligence and human-based prediction and stratification of the risk of long-term kidney allograft failure.

BACKGROUND: Clinical decisions are mainly driven by the ability of physicians to apply risk stratification to patients. However, this task is difficult as it requires complex integration of numerous parameters and is impacted by patient heterogeneity. We sought to evaluate the ability of transplant physicians to predict the risk of long-term allograft failure and compare them to a validated artificial intelligence (AI) prediction algorithm. METHODS: We randomly selected 400 kidney transplant recipients from a qualified dataset of 4000 patients. For each patient, 44 features routinely collected during the first-year post-transplant were compiled in an electronic health record (EHR). We enrolled 9 transplant physicians at various career stages. At 1-year post-transplant, they blindly predicted the long-term graft survival with probabilities for each patient. Their predictions were compared with those of a validated prediction system (iBox). We assessed the determinants of each physician's prediction using a random forest survival model. RESULTS: Among the 400 patients included, 84 graft failures occurred at 7 years post-evaluation. The iBox system demonstrates the best predictive performance with a discrimination of 0.79 and a median calibration error of 5.79%, while physicians tend to overestimate the risk of graft failure. Physicians' risk predictions show wide heterogeneity with a moderate intraclass correlation of 0.58. The determinants of physicians' prediction are disparate, with poor agreement regardless of their clinical experience. CONCLUSIONS: This study shows the overall limited performance and consistency of physicians to predict the risk of long-term graft failure, demonstrated by the superior performances of the iBox. This study supports the use of a companion tool to help physicians in their prognostic judgement and decision-making in clinical care.

The ability to predict the risk of a particular event is key to clinical decision-making, for example when predicting the risk of a poor outcome to help decide which patients should receive an organ transplant. Computer-based systems may help to improve risk prediction, particularly with the increasing volume and complexity of patient data available to clinicians. Here, we compare predictions of the risk of long-term kidney transplant failure made by clinicians with those made by our computer-based system (the iBox system). We observe that clinicians' overall performance in predicting individual long-term outcomes is limited compared to the iBox system, and demonstrate wide variability in clinicians' predictions, regardless of level of experience. Our findings support the use of the iBox system in the clinic to help clinicians predict outcomes and make decisions surrounding kidney transplants.

KidneyCare Guided Immuno-Optimization in Renal Allografts: The KIRA Protocol.

Immunosuppressant agents are essential in every transplant recipient's care yet walking the fine line of over- or under-immunosuppression is a constant struggle for both patients and transplant providers alike. Optimization and personalization of immunosuppression has been limited by the need for non-invasive graft surveillance methods that are specific enough to identify organ injury in real time. With this in mind, we propose a pilot study protocol utilizing both donor derived cell free DNA (dd-cfDNA, gene expression profiling (GEP), and machine learning (iBox), called KidneyCare, to assess the feasibility and safety in reducing immunosuppressant exposure without increasing the risk of clinical rejection, graft injury, or allograft loss. Patients randomized to the immunominimization arm will be enrolled in one of two protocols designed to eliminate one immunosuppressant and optimize the dose of the Calcineurin Inhibitors (CNIs) using the KidneyCare platform. All patients will be maintained on dual therapy of either steroids and a low dose CNI, or mycophenolate mofetil (MMF) and low dose CNI. Their outcomes will be compared to patients who have their immunosuppressants managed using standard clinical assessment and treatment protocols to determine the impact of immuno-optimization on graft function, complications, and patient reported outcomes.

DNA Methylation Age Is More Closely Associated With Infection Risk Than Chronological Age in Kidney Transplant Recipients.

Older kidney transplant recipients demonstrate increased rates of infection but decreased rates of rejection compared with younger recipients, suggesting that older transplant patients are functionally overimmunosuppressed. We hypothesized that this is a consequence of reduction in immunological activity due to biological aging and that an immune biological age, as determined by DNA methylation (DNAm), would be associated more strongly with incidence of infection than chronological age. METHODS: DNAm analysis was performed on peripheral blood mononuclear cell collected from 60 kidney transplant recipients representing older (≥age 60 y) and younger (aged 30-59 y) patients 3 months after transplantation. DNAm age was calculated based on methylation status of a panel of CpG sites, which have been previously identified as indicative of biological age. RESULTS: Correlation was seen between chronological and DNAm age; however, there were many patients with significant differences (either acceleration or slowing) between DNAm age and chronological age. A statistically significant association was seen between increased DNAm age and incidence of infection in the first year after kidney transplantation, whereas no significant association was seen between chronological age and infection. CONCLUSIONS: Assessment of DNAm age holds promise as an approach for patient evaluation and individualization of immune suppression regimens. This analysis may provide insights into the immunological mechanism behind increased incidence of infection observed in older transplant patients. The ability to measure biological age would allow for patient risk stratification and individualization of immunosuppression, improving outcomes for the growing numbers of older patients undergoing kidney transplantation.

Spectrum of Coronavirus Disease 2019 Outcomes in Kidney Transplant Recipients: A Single-Center Experience.

PURPOSE: We reviewed the clinical experience of kidney transplant recipients diagnosed with severe acute respiratory syndrome coronavirus 2 infection in order to understand the impact of the current coronavirus disease 2019 (COVID-19) pandemic infection on transplant recipients. Given that early reports from heavily affected areas demonstrated a very high mortality rate amongst kidney transplant recipients, ranging between 30% and 40%, we sought to evaluate outcomes at a center with a high burden of cases but not experiencing acute crisis due to COVID-19. PROCEDURES: In this single center retrospective observational study, medical records of all kidney transplant recipients at the UCLA Medical Center were reviewed for a diagnosis of COVID-19 by polymerase chain reaction, followed by chart review to determine kidney transplant characteristics and clinical course. MAIN FINDINGS: A total of 41 kidney transplant recipients were identified with COVID-19 positive polymerase chain reaction. Recipients had been transplanted for a median of 47 months before diagnosis. The large proportion of infected individuals were minorities (Hispanic 65.9%, black 14.6%), on prednisone, tacrolimus, and mycophenolate mofetil (95.1%, 87.8%, and 87.8%, respectively), and had excellent allograft function (median 1.25 mg/dL). The most common presenting symptoms were fever, dyspnea, or cough. Most patients were hospitalized (63.4%); mortality was 9.8% and occurred only in patients in the intensive care unit. The most common treatment was reduction or removal of antimetabolite (77.8%). Approximately 26.9% presented with AKI. CONCLUSIONS: COVID-19 infection in kidney transplant recipients results in a higher rate of hospitalization and mortality than in the general population. In an area with a high number of infections, the mortality rate was lower compared with earlier reports from areas experiencing early surge and strain on the medical system. Minorities were disproportionately affected. Future studies are needed to determine optimal approach to treatment and management of immunosuppression in kidney transplant recipients with COVID-19 infection.

The Frailty Risk Score predicts length of stay and need for rehospitalization after kidney transplantation in a retrospective cohort: a pilot study.

BACKGROUND: Frailty is a widely used measure in older patients as a predictor of poor outcomes after hospitalization and surgery. There is a growing body of data in kidney transplantation suggesting frailty can predict adverse outcomes. There is interest in using chart review measures of frailty and multimorbidity, as they may be equally predictive as physical measurement. This approach holds promise for patient evaluation, identifying candidates for prehabilitation, and targeting resources towards those anticipated to have an increased rate of clinical challenges after kidney transplantation. Frail patients who are often older may place a large resource and economic burden on transplant programs. METHODS: We applied a previously published chart review-based approach in a retrospective, pilot study to calculate the Frailty Risk Score (FRS) utilizing a cohort of kidney transplant patients. We reviewed concurrent comorbidities using the Charlson comorbidity (CM) score to determine the feasibility and utility of applying this approach in transplant patients to predict post-transplant outcomes such as length of hospitalization and the need for rehospitalization. RESULTS: Sixty kidney transplant recipients were evaluated by chart review, 23 characterized as older (> = 60) and 37 younger (ages 30-59). Median FRS score was 3 (range 1-7). Higher FRS was significantly associated with increased patient age (high FRS 19% in younger patients, 43% in older patients). Increased CM score was also associated with increased patient age. Patients with a high FRS stayed in the hospital for an average of 8 days, compared with 5.7 days for a low FRS. Patients with high FRS were readmitted an average of 2.9 times compared with an average of 1.1 for those with a low FRS. FRS score remained significant for predicting outcomes after adjustment for patient age. CONCLUSION: Elevated FRS prior to transplantation was associated with increased hospital stay and the need for readmission in kidney transplant recipients. This analysis demonstrates the potential strength of chart review in evaluating frailty prior to transplantation, permitting risk stratification and targeting of resources for rehabilitation and close post-transplant monitoring. Frail patients may benefit from targeted "prehabilitation" to attenuate the associated adverse clinical outcomes.

Differences in Gene Expression in Older Compared With Younger Kidney Transplant Recipients.

BACKGROUND: For the growing numbers of older transplant patients, increased incidence of infection and death compared with younger patients may limit the many benefits provided by transplantation. However, little is known about age-associated immune dysfunction in the older transplant recipient. METHODS: A cohort of 60 kidney transplant recipients, 23 older (≥ 60y) and 37 younger (30-59y), matched on antithymocyte induction and donor type (living vs deceased) was evaluated. Gene expression in peripheral blood mononuclear cells 3 months after kidney transplantation was analyzed to compare differences between older and younger patients. RESULTS: Proinflammatory genes were upregulated in older kidney transplant patients, including cytokines IL1-ß and IL-6. Downregulated genes were associated with B-cell and T-cell function, including CCR7 and CD27. Analysis of predicted transcription factor binding suggested an increase in proinflammatory transcription factor CCAAT/enhancer binding protein ß-binding sites in older patients, whereas interferon regulatory factor 2 transcription factor binding sites were less prevalent. CONCLUSIONS: Older kidney transplant recipients exhibited multiple differences in gene expression compared with younger patients, with upregulation of proinflammatory genes and downregulation of adaptive immune response genes. These findings may explain the mechanism of increased vulnerability to infection and malignancy observed in older transplant patients.

Differences in Proinflammatory Cytokines and Monocyte Subtypes in Older as Compared With Younger Kidney Transplant Recipients.

BACKGROUND: The number of elderly patients with end-stage kidney disease requiring kidney transplantation continues to grow. Evaluation of healthy older adults has revealed proinflammatory changes in the immune system, which are posited to contribute to age-associated illnesses via "inflamm-aging." Immunologic dysfunction is also associated with impaired control of infections. Whether these immunologic changes are found in older kidney transplant recipients is not currently known, but may have important implications for risk for adverse clinical outcomes. METHODS: Three months after transplant, innate immune phenotype was evaluated by flow cytometry from 60 kidney transplant recipients (22 older [≥60 years] and 38 younger [<60 years old]). Multiplex cytokine testing was used to evaluate plasma cytokine levels. Younger patients were matched to older patients based on transplant type and induction immune suppression. RESULTS: Older kidney transplant recipients demonstrated decreased frequency of intermediate monocytes (CD14++CD16+) compared with younger patients (1.2% vs 3.3%, P = 0.007), and a trend toward increased frequency of proinflammatory classical monocytes (CD14++CD16-) (94.5% vs 92.1%) (P = 0.065). Increased levels of interferon-gamma (IFN-γ) were seen in older patients. CONCLUSIONS: In this pilot study of kidney transplant recipients, we identified differences in the innate immune system in older as compared with younger patients, including increased levels of IFN-γ. This suggests that age-associated nonspecific inflammation persists despite immune suppression. The ability to apply noninvasive testing to transplant recipients will provide tools for patient risk stratification and individualization of immune suppression regimens to improve outcomes after transplantation.