Long-term Outcome Of Kidney Transplantation Research Articles

Immune monitoring in pediatric kidney transplant.

Long-term outcomes in pediatric kidney transplantation remain suboptimal, largely related to chronic rejection. Creatinine is a late marker of renal injury, and more sensitive, early markers of allograft injury are an active area of current research. This is an educational review summarizing existing strategies for monitoring for rejection in kidney transplant recipients. We summarize supporting currently available clinical tests, including surveillance biopsy, donor specific antibodies, and donor-derived cell free DNA, as well as the potential limitations of these studies. In addition, we review the current avenues of active research, including transcriptomics, proteomics, metabolomics, and torque tenovirus levels. Advancing the use of noninvasive immune monitoring will depend on well-designed multicenter trials that include patients with stable graft function, include biopsy results on all patients, and can demonstrate both association with a patient-relevant clinical endpoint such as graft survival or change in glomerular filtration rate and a potential timepoint for intervention.

Maximizing matching, equity and survival in kidney transplantation using molecular HLA immunogenicity quantitation

HLA matching improves long-term outcomes of kidney transplantation, yet implementation challenges persist, particularly within the African American (Black) patient demographic due to donor scarcity. Consequently, kidney survival rates among Black patients significantly lag behind those of other racial groups. A refined matching scheme holds promise for improving kidney survival, with prioritized matching for Black patients potentially bolstering rates of HLA-matched transplants.To facilitate quantity, quality and equity in kidney transplants, we propose two matching algorithms based on quantification of HLA immunogenicity using the hydrophobic mismatch score (HMS) for prospective transplants. We mined the national transplant patient database (SRTR) for a diverse group of donors and recipients with known racial backgrounds. Additionally, we use novel methods to infer survival assessment in the simulated transplants generated by our matching algorithms, in the absence of actual target outcomes, utilizing modified unsupervised clustering techniques.Our allocation algorithms demonstrated the ability to match 87.7% of Black and 86.1% of White recipients under the HLA immunogenicity threshold of 10. Notably, at the lowest HMS threshold of 0, 4.4% of Black and 12.1% of White recipients were matched, a marked increase from the 1.8% and 6.6% matched under the prevailing allocation scheme. Furthermore, our allocation algorithms yielded similar or improved survival rates, as illustrated by Kaplan–Meier (KM) curves, and enhanced survival prediction accuracy, evidenced by C-indices and Integrated Brier Scores.

Outcome of ABO-incompatible living-donor kidney transplants : Aplea for crossover living-donor kidney transplantation

The lack of postmortem donated organs is the background to varyingly high rates of living-donor kidney transplants worldwide. ABO blood group-incompatible living-donor kidney transplants have also been established for at least 20years. The equivalence of the results of ABO-incompatible and ABO-compatible transplants has recently been questioned. In the sense of acritical reflection of our own kidney transplant program, we were interested in comparing ABO-incompatible with ABO-compatible living-donor kidney transplants. Aretrospective analysis of the long-term outcomes of all living-donor kidney transplants performed at our center since the first ABO-incompatible transplants were performed in 2005 up to and including 2022 was performed. Between 2005 and 2022, 1099 living kidney transplants were performed at the authors' center. Among them were 241ABO-incompatible transplants. Transplant survival was significantly lower after ABO-incompatible donation than after ABO-compatible donation. This effect consisted of an increased mortality of the recipients, especially in the early phase, and areduced longevity of the grafts. Including ABO-incompatible pairs for living-donor kidney transplants in crossover programs can improve medical outcomes and reduce costs.

Peri-operative and long-term outcomes of kidney transplantation in patients with cystic fibrosis.

There is a lack of data regarding the peri-operative and long-term outcomes of kidney transplantation in cystic fibrosis (CF) patients. Herein, we report the peri-operative and long-term outcomes of kidney transplantation in CF patients. All CF patients who received a kidney transplant at the national kidney transplant center between 1993 and 2022 were identified. Recipients of the contralateral donor kidney were selected as a control group. Primary outcomes included 1-, 5-, and 10- year death-censored graft survival and overall survival. Secondary outcomes included peri-operative morbidity, acute graft rejection, delayed graft function (DGF), and length of stay (LOS). Fourteen patients received a kidney transplant over the study period. Median age at transplantation was 35 (IQR 31, 40) years. The 1-, 5-, and 10-year death-censored graft survival was 92, 74, and 74% in the CF group compared to 100, 92, and 92% in the control group (p=.44). The 1-, 5-, and 10-year overall survival in the CF group was 85, 66, and 57% compared to 100, 92, and 82% in the control group (p=.036). There was no significant difference in peri-operative outcomes including LOS (10vs. 11 days, p=.84), ICU admission (1vs. 0 patients, p>.99), acute rejection episodes (2vs. 1 patients, p>.99), and DGF (1vs. 2 patients, p=.60). CF patients have good long-term graft survival, however, overall survival was worse compared to a matched cohort. These data provide important information for transplant surgeons when considering suitable donor allografts in this unique patient population.

Effect of delayed graft function on immediate and long-term kidney transplant outcomes

Objective: to analyze the immediate and long-term outcomes of kidney transplantation (KT) depending on the duration of delayed graft function (DGF). Materials and methods. The study conducted a retrospective analysis of KT outcomes in 312 patients operated on at Botkin Hospital from June 2018 to December 2022. Exclusion criteria were primary non-function, severe surgical complications that required emergency transplantectomy in the first week after KT and cases where a comprehensive approach to DGF prevention was applied. DGF was defined as the need for dialysis within the first 7 days of KT. The severity of this complication was assessed by the time it took the transplanted kidney function to normalize from mild DGF to severe. We analyzed the immediate and long-term outcomes of KT depending on the presence of initial function and the severity of DGF. Results. DGF developed in 25.3% of cases. The mean time for graft function normalization was 16.5 ± 6.8 days. Mild DGF occurred in 68% of cases, severe DGF was determined in the remaining cases (32%). The incidence of complications was statistically significantly higher in the severe DGF group: 14/25 (56%) vs. 15/54 (27.8%) (p = 0.047). There were also no significant differences in the rate of complications between recipients with immediate and mild DGF: 43/233 (18.4%) vs. 15/54 (27.8%) (p > 0.05). Severe DGF lasting for more than 2 weeks had a statistically significant association with postoperative complications (p = 0.047) and with decreased long-term graft survival (log-rank p = 0.021). Conclusion. Development of severe DGF mainly depends on donor characteristics, timing and peculiarities of graft preservation. Nevertheless, other factors, such as acute calcineurin inhibitor nephrotoxicity, should not be ignored. Therefore, prevention of all potentially modifiable risk factors for DGF should go hand in hand with the expansion of the indications for donation.

Predicting long-term outcomes of kidney transplantation in the era of artificial intelligence

The ability to accurately predict long-term kidney transplant survival can assist nephrologists in making therapeutic decisions. However, predicting kidney transplantation (KT) outcomes is challenging due to the complexity of the factors involved. Artificial intelligence (AI) has become an increasingly important tool in the prediction of medical outcomes. Our goal was to utilize both conventional and AI-based methods to predict long-term kidney transplant survival. Our study included 407 KTs divided into two groups (group A: with a graft lifespan greater than 5 years and group B: with poor graft survival). We first performed a traditional statistical analysis and then developed predictive models using machine learning (ML) techniques. Donors in group A were significantly younger. The use of Mycophenolate Mofetil (MMF) was the only immunosuppressive drug that was significantly associated with improved graft survival. The average estimated glomerular filtration rate (eGFR) in the 3rd month post-KT was significantly higher in group A. The number of hospital readmissions during the 1st year post-KT was a predictor of graft survival. In terms of early post-transplant complications, delayed graft function (DGF), acute kidney injury (AKI), and acute rejection (AR) were significantly associated with poor graft survival. Among the 35 AI models developed, the best model had an AUC of 89.7% (Se: 91.9%; Sp: 87.5%). It was based on ten variables selected by an ML algorithm, with the most important being hypertension and a history of red-blood-cell transfusion. The use of AI provided us with a robust model enabling fast and precise prediction of 5-year graft survival using early and easily collectible variables. Our model can be used as a decision-support tool to early detect graft status.

Impact of acute kidney injury and renal recovery status in deceased donor to kidney transplant outcome: results from the Thai national transplant registry

The influence of acute kidney injury (AKI) and renal recovery in deceased donor (DD) on long-term kidney transplant (KT) outcome has not previously been elucidated in large registry study. Our retrospective cohort study included all DDKT performed in Thailand between 2001 and 2018. Donor data was reviewed case by case. AKI was diagnosed according to the KDIGO criteria. Renal recovery was defined if DD had an improvement in AKI to the normal or lower stage. All outcomes were determined until the end of 2020. This study enrolled 4234 KT recipients from 2198 DD. The KDIGO staging of AKI was as follows: stage 1 for 710 donors (32.3%), stage 2 for 490 donors (22.3%) and stage 3 for 342 donors (15.6%). AKI was partial and complete recovery in 265 (17.2%) and 287 (18.6%) before procurement, respectively. Persistent AKI was revealed in 1906 KT of 990 (45%) DD. The ongoing AKI in DD significantly increases the risk of DGF development in the adjusted model (HR 1.69; 95% CI 1.44–1.99; p < 0.001). KT from DD with AKI and partial/complete recovery was associated with a lower risk of transplant loss (log-rank P = 0.04) and recipient mortality (log-rank P = 0.042) than ongoing AKI. KT from a donor with ongoing stage 3 AKI was associated with a higher risk of all-cause graft loss (HR 1.8; 95% CI 1.12–2.88; p = 0.02) and mortality (HR 2.19; 95% CI 1.09–4.41; p = 0.03) than stage 3 AKI with renal recovery. Persistent AKI, but not recovered AKI, significantly increases the risk of DGF. Utilizing kidneys from donors with improving AKI is generally safe. KT from donors with persistent AKI stage 3 results in a higher risk of transplant failure and recipient mortality. Therefore, meticulous pretransplant evaluation of such kidneys and intensive surveillance after KT is recommended.

Association of high intra-patient variability in tacrolimus exposure with calcineurin inhibitor nephrotoxicity in kidney transplantation

Tacrolimus intra-patient variability (IPV) is a novel predictive marker for long-term kidney transplantation outcomes. We examined the association between IPV and calcineurin inhibitor (CNI) nephrotoxicity and the impact of pharmacogenes on CNI nephrotoxicity and IPV. Among kidney transplant recipients at our hospital between January 2013 and December 2015, the records of 80 patients who underwent 1-year protocol renal allograft biopsy and agreed to donate blood samples for genetic analysis were retrospectively reviewed. The cohort was divided into the low and high IPV groups based on a coefficient variability cutoff value (26.5%). In multivariate analysis, the IPV group was involved in determining CNI nephrotoxicity (HR 4.55; 95% CI 0.05–0.95; p = 0.043). The 5-year graft survival was superior in the low IPV group than in the high IPV group (100% vs 92.4% respectively, p = 0.044). Analysis of the time above therapeutic range (TATR) showed higher CNI nephrotoxicity in the high IPV with high TATR group than in the low IPV with low TATR group (35.7% versus 6.7%, p = 0.003). Genetic analysis discovered that CYP3A4 polymorphism (rs2837159) was associated with CNI nephrotoxicity (HR 28.23; 95% CI 2.2–355.9; p = 0.01). In conclusion, high IPV and CYP3A4 polymorphisms (rs2837159) are associated with CNI nephrotoxicity.

Qualifying a Novel Clinical Trial Endpoint (iBOX) Predictive of Long-Term Kidney Transplant Outcomes.

New immunosuppressive therapies that improve long-term graft survival are needed in kidney transplant. Critical Path Institute's Transplant Therapeutics Consortium received a qualification opinion for the iBOX Scoring System as a novel secondary efficacy endpoint for kidney transplant clinical trials through European Medicines Agency's qualification of novel methodologies for drug development. This is the first qualified endpoint for any transplant indication and is now available for use in kidney transplant clinical trials. Although the current efficacy failure endpoint has typically shown the noninferiority of therapeutic regimens, the iBOX Scoring System can be used to demonstrate the superiority of a new immunosuppressive therapy compared to the standard of care from 6months to 24months posttransplant in pivotal or exploratory drug therapeutic studies.

The Long-Term Outcome of Kidney Transplant Recipients in the Eighth Decade Compared With Recipients in the Seventh Decade of Life

With the aging of the population, more older patients are being considered for kidney transplantation; therefore, it is crucial to evaluate the risks and benefits of transplantation in this population. This study aimed to assess long-term outcomes of kidney transplantation in a cohort of patients who underwent kidney transplantation at age >70 years, compared with patients aged 60 to 69 years at transplantation. Included in the study were 261 consecutive kidney transplant recipients: 52 were aged >70 years, and 209 were aged 60 to 69 years at transplantation. Data were collected retrospectively and analyzed using multivariate logistic regression to identify potential outcome risk factors. The number of transplants in both groups increased during the study period. Mortality after transplantation was strongly correlated to age (hazard ratio [HR]=1.11; 95% CI, 1.05-1.18; P < .001), deceased donor (HR=2.0; 95% CI, 1.1-3.8; P=.034), and pretransplant diabetes (HR=2.9; 95% CI, 1.7-4.9; P=.001). Recipients aged >70 years had an increased risk of death censored graft failure (HR=2.98; 95% CI, 1.56-5.74; P=.001). In living donor transplants, 3-year survival was 80% in recipients age >70 years, compared with 98% in the 60- to 69-year group. Five-year survival was 71% and 92%, respectively. In deceased donor transplants, 3-year survival was 63% and 78%, and 5-year survival was 58% and 72%, respectively. The risk of malignancy (excluding nonmelanotic skin cancer) was nearly triple in the age >70 years group (HR=2.96; 95% CI, 1.3-6.8; P=.01). Patient and graft survival in kidney recipients in the eighth decade is worse compared with recipients in the seventh decade of life. However, it is improved with living kidney donation.

Qualifying a novel clinical trial endpoint (iBOX) predictive of long-term kidney transplant outcomes

New immunosuppressive therapies that improve long-term graft survival are needed in kidney transplant. Critical Path Institute’s Transplant Therapeutics Consortium received a qualification opinion for the iBOX Scoring System as a novel secondary efficacy endpoint for kidney transplant clinical trials through European Medicines Agency’s qualification of novel methodologies for drug development. This is the first qualified endpoint for any transplant indication and is now available for use in kidney transplant clinical trials. Although the current efficacy failure endpoint has typically shown the noninferiority of therapeutic regimens, the iBOX Scoring System can be used to demonstrate the superiority of a new immunosuppressive therapy compared to the standard of care from 6 months to 24 months posttransplant in pivotal or exploratory drug therapeutic studies.

Molecular immune monitoring in kidney transplant rejection: a state-of-the-art review.

Although current regimens of immunosuppressive drugs are effective in renal transplant recipients, long-term renal allograft outcomes remain suboptimal. For many years, the diagnosis of renal allograft rejection and of several causes of renal allograft dysfunction, such as chronic subclinical inflammation and infection, was mostly based on renal allograft biopsy, which is not only invasive but also possibly performed too late for proper management. In addition, certain allograft dysfunctions are difficult to differentiate from renal histology due to their similar pathogenesis and immune responses. As such, non-invasive assays and biomarkers may be more beneficial than conventional renal biopsy for enhancing graft survival and optimizing immunosuppressive drug regimens during long-term care. This paper discusses recent biomarker candidates, including donor-derived cell-free DNA, transcriptomics, microRNAs, exosomes (or other extracellular vesicles), urine chemokines, and nucleosomes, that show high potential for clinical use in determining the prognosis of long-term outcomes of kidney transplantation, along with their limitations.

Long-Term Results in Recipients of Late Conversion to a Calcineurin Inhibitor-Free Regimen with Everolimus After Kidney Transplantation

Conversion to a calcineurin inhibitor (CNI)-free regimen in cases of CNI nephrotoxicity (CNIT) is a strategy to improve the long-term outcomes of kidney transplantation. However, the long-term results of late conversion to a CNI-free regimen using everolimus (EVR) remain uncertain. Nine kidney transplant recipients with biopsy-confirmed CNIT were enrolled. The median time of CNIT diagnosis was 9.0 years. All recipients underwent a conversion from CNI to EVR. We evaluated the clinical outcomes, development of donor-specific antibody (DSA), the incidence of rejection, alternativearteriolar hyalinosis (aah) scores, renal function changes, and T cell responses by mixed lymphocyte reaction (MLR) assay after conversion. The median follow-up after conversion was 5.4 years. Currently, 7 of 9 recipients have received a CNI-free regimen for 1.6 to 9.5 years. In the other 2 recipients, one experienced graft loss due to CNIT 3.8 years after conversion, and the other had to resume CNI due to acute T cell-mediated rejection (ATMR) a year after conversion. None of the recipients developed DSA. No rejection was observed in the kidney allograft histology except for the ATMR case. Moreover, improvement in aah scores was noted in one patient. Furthermore, serum creatinine levels were stable in recipients without proteinuria before the EVR add-on. In the MLR analysis, low responses against donors were observed in stable patients. Late conversion to an EVR-based regimen without CNI may be a promising therapeutic strategy against CNIT, particularly for recipients without proteinuria before the EVR add-on.

Long-term results of kidney transplantation in patients with familial mediterranean fever.

Long-term kidney transplantation (KT) results in patients with familial Mediterranean fever (FMF)-related amyloidosis are not well studied. This study reviewed the long-term survival outcomes of FMF patients who underwent KT. We compared the outcomes of 31 patients who underwent (KT) for biopsy-proven amyloidosis secondary to FMF with 31 control patients (five with diabetes mellitus and 26 with nondiabetic kidney disease) undergoing KT between 1994 and 2021 at Başkent University Hospital. All data were recorded retrospectively from patients' files. THE MEDIAN AGE (QUARTILE DEVIATION: QD) at the time of KT in the FMF and control group were 31 (6.7) and 33 (11), respectively. The median follow-up period (QD) after KT was 108 (57) months in the FMF and 132 (72) months in the control group. In the FMF group, graft and patient survivals were 71% and 84% at 5 years and 45% and 48% at 10 years, respectively. In the control group, graft and patient survivals were 79% and 100% at 5 years and 63% and 71% at 10 years, respectively. Patient survival in the FMF group at 5 years was significantly lower than in the control group (p=.045). There was no statistically significant difference between the FMF and control groups in terms of graft and patient survival, and serum creatinine levels at 10 years. All patients were given triple immunosuppressive treatment with cyclosporine, mycophenolate mofetil, and prednisolone. Three patients received anakinra and one received canakinumab in addition to colchicine treatment. One FMF patient also underwent heart transplantation due to AA amyloidosis. Of the FMF patients, 11 died during follow-up. We have found that the long-term outcome of KT in patients with FMF amyloidosis is numerically worse but not statistically different from the control group. However, short- and long-term complications still need to be resolved.

Excellent Clinical Long-Term Outcomes of Kidney Transplantation From Small Pediatric Donors (Age ≤ 5 Years) Despite Early Hyperfiltration Injury

The use of small pediatric donors (age ≤ 5 years and body weight < 20kg) for adult transplant recipients is still regarded controversially in terms of early complications, long-term outcomes, and development of hyperfiltration injury due to body size mismatch. To investigate long-term outcomes of adult renal allograft recipients receiving a kidney from small pediatric donor (SPD) in terms of kidney function and early features of hyperfiltration injury such as histological changes and proteinuria. Retrospective, single center study. Transplant center of the University Hospital of Basel, Switzerland. Adult renal allograft recipients receiving a kidney from a small pediatric donor at our center between 2005 and 2017. The outcome of 47 transplants from SPD were compared with 153 kidney transplants from deceased-standard criteria donors (SCD) occurring during the same time period. Incidence of clinical signs of hyperfiltration injury (eg, proteinuria) was investigated. According to our policy, surveillance biopsies were taken at 3 and 6 months post-transplant and were evaluated in terms of signs of hyperfiltration injury. At a median follow-up of 2.3 years post-transplant, death-censored graft survival of SPD was comparable to transplants from SCD (94% vs 93%; P = .54). Furthermore, allograft function at last follow-up (estimated glomerular filtration rate-Modification of Diet in Renal Disease) was significantly higher in pediatric transplant (80 vs 55 ml/min/1.73 m2, P = .002). We found histological signs of early hyperfiltration injury in 55% of SPD. There was an equally low proteinuria in both groups during follow-up. It is a single center and retrospective observational study with small sample size. The outcomes were investigated in a well-selected population of recipients with low body mass index, low immunological risk, and well-controlled hypertension and was not compared with equal selected group of recipients. Early histological and clinical signs of hyperfiltration injury in SPD is frequent. Despite the hyperfiltration injury, there is an equal allograft survival and even superior allograft function in SPD compared with SCD during follow-up. This observation supports the concept of high adaptive capacity of pediatric donor kidneys.

Long-term outcomes of kidney transplantation from deceased donors with terminal acute kidney injury: Single center experience and literature review.

Long-term outcomes of kidney transplantation from deceased donors (DDKTs) with terminal acute kidney injury (AKI) are not well defined. Single center retrospective review of DDKTs from 1/31/07-12/31/19. AKI kidneys were defined by a doubling of the donor's admission serum creatinine (SCr) level AND a terminal SCr ≥2.0mg/dl. A total of 188 AKI DDKTs were performed, including 154 from brain-dead standard criteria donors (SCD). Mean donor age was 36 years and mean Kidney Donor Profile Index was 50%; mean admission and terminal SCr levels were 1.3 and 3.1mg/dl, respectively. With a mean follow-up of 94 months (median 89 months), overall patient (both 71.3%) and graft survival (54% AKI vs. 57% non-AKI) rates were comparable to concurrent DDKTs from brain-dead non-AKI SCDs (n=769). Delayed graft function (DGF) was higher in AKI kidney recipients (47%vs. 20% non-AKI DDKTs, p<.0001). DGF was associated with lower graft survival in recipients of both AKI and non-AKI SCD kidneys but the impact was earlier and more pronounced in non-AKI recipients. Despite having more than twice the incidence of DGF, kidneys from deceased donors with terminal AKI have long-term outcomes comparable to non-AKI SCD kidneys and represent a safe and effective method to expand the donor pool.

From the Wright Brothers to the A380: Developing Transplantation Takes Teams of Teams.

From the Wright Brothers to the A380: Developing Transplantation Takes Teams of Teams.

Long-term clinical outcomes of ABO incompatible kidney transplantation in patients with high baseline anti-A/B antibody titer

Long-term clinical outcomes of ABO incompatible kidney transplantation in patients with high baseline anti-A/B antibody titer

Comparison of Tacrolimus Intra-Patient Variability during 6-12 Months after Kidney Transplantation between CYP3A5 Expressers and Nonexpressers.

A high intra-patient variability (IPV) of tacrolimus exposure is associated with poor long-term kidney transplantation outcomes. To assess the influence of cytochrome P450 (CYP)&amp;nbsp;3A5 genetic polymorphisms on tacrolimus IPV, 188 clinically stable kidney transplant recipients, who had received an immediate-release tacrolimus-based immunosuppressive regimen, were enrolled in this retrospective cohort study. Genotyping of CYP3A5*3 (rs776746) was performed and 110 (58.5%) were identified as CYP3A5 expressers and 78 (41.5%) as nonexpressers. Whole blood tacrolimus concentrations were analyzed by chemiluminescent microparticle immunoassay. Dose-adjusted trough tacrolimus concentrations (C0/D) measured at months 6, 9, and 12 were used to determine IPV. There were no significant differences in the IPV estimated by the coefficient of variation, the IPV calculated by mean absolute deviation method, and the proportions of recipients with the IPV estimated by the coefficient of variation of 30% or more between CYP3A5 expressers and nonexpressers (p = 0.613, 0.686, and 0.954, respectively). Tacrolimus C0/D in CYP3A5 expressers was approximately half of those in nonexpressers, overall (p &lt; 0.001). In both CYP3A5 expressers and nonexpressers, tacrolimus C0/D increased gradually from month 6 to month 12 (p = 0.021). There was no evidence that the CYP3A5 polymorphisms significantly influence tacrolimus IPV during the 6 to 12 months after kidney transplantation.

The cellular landscape of the normal kidney allograft: Main players balancing the alloimmune response

Despite recent advances made in short-term outcomes; minimal improvements have been observed in long-term kidney transplantation outcomes. Due to an imbalance between organ transplant availability and patient waiting list, expanding kidney allograft longevity is a critical need in the field. Prior studies have either focused on early ischemic and immunological conditions affecting kidney allografts (e.g., delayed graft function, acute rejection) or late stage chronic injury when interventions are no longer feasible. However, studies characterizing kidney allografts with normal function by its cellular distribution, cell-cell interactions, and associated molecular pathways are lacking. Herein, we used single nuclei RNA-sequencing to uncover the cellular landscape and transcriptome of the normal kidney allograft. We profiled 40,950 nuclei from seven human kidney biopsies (normal native, N = 3; normal allograft, N = 4); normal allograft protocol biopsies were collected ≥15-months post-transplant. A total of 17 distinct cell clusters were identified with proximal tubules (25.70 and 21.01%), distal tubules (15.22 and 18.20%), and endothelial cells (EC) (4.26 and 9.94%) constituting the major cell populations of normal native and normal allograft kidneys, respectively. A large proportion of cycling cells from normal native kidneys were in G1-phase (43.96%) whereas cells from normal allograft were predominantly in S-phase (32.69%). This result suggests that transcriptional differences between normal native and normal allograft biopsies are dependent on the new host environment, immunosuppression, and injury-affliction. In the normal allograft, EC-specific genes upregulated metabolism, the immune response, and cellular growth, emphasizing their role in maintaining homeostasis during the ongoing alloreactive stress response. Immune cells, including B (2.81%), macrophages (24.96%), monocytes (15.29%), natural killer (NK) (12.83%), neutrophils (8.44%), and T cells (14.41%, were increased in normal allografts despite lack of histological or clinical evidence of acute rejection. Phenotypic characterization of immune cell markers supported lymphocyte activation and proinflammatory cytokines signaling pathways (i.e., IL-15, IL-32). The activation of B, NK, and T cells reveals potential immune cells underlying subclinical inflammation and repair. These single nuclei analyses provide novel insights into kidney and immune cell associated signaling pathways that portray kidney grafts with normal allograft function beyond 2-years post-transplant, revealing a novel perspective in understanding long-term allograft graft survival.