Impact of Induction Immunosuppressants on T Lymphocyte Subsets after Kidney Transplantation: A Prospective Observational Study with Focus on Anti-Thymocyte Globulin and Basiliximab Induction Therapies.

Induction immunosuppressive therapy for kidney transplant recipients (KTRs) primarily includes interleukin-2 receptor antagonists, such as basiliximab (BXM) or lymphocyte-depleting agents, and anti-thymocyte globulin (ATG). This study aimed to investigate their effects on T cell dynamics during the early post-transplantation period. This prospective observational study included 157 KTRs. Peripheral blood samples were collected from each patient within 5 days before and 4 and 12 weeks after transplantation. Flow cytometric analysis was performed to assess various T cell subsets whose changes were then analyzed. In the ATG group, CD4+ T cell expression decreased significantly compared with that in the BXM group. However, CD4+CD161+ and CD4+CD25+CD127low T cell expression levels increased significantly. In the CD8+ T cell subset, a decrease in CD8+CD28nullCD57+ and CD8+CCR7+ T cell expression was observed in the ATG group. However, among patients diagnosed with biopsy-proven acute rejection, T cell subset expression did not significantly differ relative to non-rejection cases. In conclusion, ATG induction therapy resulted in more pronounced changes in T lymphocyte subsets than BXM induction, with increased CD4+CD161+ and CD4+CD25+CD127low T cells and an early decrease in CD8+CD28nullCD57+ and CD8+CCR7+ T cells, some of which are associated with acute rejection.

Time-Varying Risk Factors for Incident Fractures in Kidney Transplant Recipients: A Nationwide Cohort Study in South Korea.

Little is known about the time-varying risk factors for fractures in kidney transplant recipients (KTRs). Using the Korea Organ Transplantation Registry, a nationwide cohort study of KTRs, the incidence, locations, and time-varying predictors of fractures were analyzed, including at baseline and post-transplant 6-month variables in KTRs who underwent KT between January 2014 and June 2019. Among 4134 KTRs, with a median follow-up of 2.94 years (12,441.04 person-years), 63 patients developed fractures. The cumulative 5-year incidence was 2.10%. The most frequent locations were leg (25.40%) and foot/ankle (22.22%). In multivariable analysis, older recipient age at baseline (hazard ratio [HR], 1.035; 95% confidence interval [CI], 1.007-1.064; p = 0.013) and higher tacrolimus trough level (HR, 1.112; 95% CI, 1.029-1.202; p = 0.029) were associated with higher risks for fractures. Pretransplant diabetes mellitus had a time-dependent impact on fractures, with increasing risk as time elapses (HR for diabetes mellitus 1.115; 95% CI, 0.439-2.832; HR for diabetes mellitus × time, 1.049; 95% CI, 1.007-1.094; p = 0.022). In conclusion, KTRs had a high risk of peripheral skeletal fractures in the first 5 years. At baseline recipient age, pretransplant diabetes mellitus and tacrolimus trough level after KT were responsible for the fractures in KTRs.

Impact of Low-Level Donor-Specific Anti-HLA Antibody on Posttransplant Clinical Outcomes in Kidney Transplant Recipients.

Background: The clinical significance of low-level donor-specific anti-HLA antibody (low-DSA) remains controversial. We investigated the impact of low-DSA on posttransplant clinical outcomes in kidney transplant (KT) recipients. Methods: We retrospectively reviewed 1,027 KT recipients, namely, 629 living donor KT (LDKT) recipients and 398 deceased donor KT (DDKT) recipients, in Seoul St. Mary's Hospital (Seoul, Korea) between 2010 and 2018. Low-DSA was defined as a positive anti-HLA-DSA result in the Luminex single antigen assay (LABScreen single antigen HLA class I - combi and class II - group 1 kits; One Lambda, Canoga Park, CA, USA) but a negative result in a crossmatch test. We compared the incidence of biopsy-proven allograft rejection (BPAR), changes in allograft function, allograft survival, patient survival, and posttransplant infections between subgroups according to pretransplant low-DSA. Results: The incidence of overall BPAR and T cell-mediated rejection did not differ between the subgroups. However, antibody-mediated rejection (ABMR) developed more frequently in patients with low-DSA than in those without low-DSA in the total cohort and the LDKT and DDKT subgroups. In multivariate analysis, low-DSA was identified as a risk factor for ABMR development. Its impact was more pronounced in DDKT (odds ratio [OR]: 9.60, 95% confidence interval [CI]: 1.79-51.56) than in LDKT (OR: 3.76, 95% CI: 0.99-14.26) recipients. There were no significant differences in other outcomes according to pretransplant low-DSA. Conclusions: Pretransplant low-DSA has a significant impact on the development of ABMR, and more so in DDKT recipients than in LDKT recipients, but not on long-term outcomes.

CRISPR/Cas9-mediated A4GALT suppression rescues Fabry disease phenotypes in a kidney organoid model.

The objective of this study was to investigate whether CRISPR/Cas9-mediated suppression of A4GALT could rescue phenotype of Fabry disease nephropathy (FDN) using human induced pluripotent stem cells (hiPSCs) derived kidney organoid system. We generated FDN patient-derived hiPSC (CMC-Fb-002) and FD-specific hiPSCs (GLA-KO) by knock-out (KO) of GLA in wild-type (WT) hiPSCs using CRISPR/Cas9. We then performed A4GALT KO in both CMC-Fb-002 and GLA-KO to make Fb-002-A4GALT-KO and GLA/A4GALT-KO, respectively. Using these hiPSCs, we generated kidney organoids and compared alpha-galactosidase-A enzyme (α-GalA) activity, globotriaosylceramide (Gb-3) deposition, and zebra body formation under electron microscopy (EM). We also compared mRNA expression levels using RNA-seq and qPCR. Generated hiPSCs showed typical pluripotency markers without chromosomal disruption. Expression levels of GLA in CMC-Fb-002 and GLA-KO and expression levels of A4GALT in Fb-002-A4GALT-KO and GLA/A4GALT-KO were successfully decreased compared to those in WT-hiPSCs, respectively. Generated kidney organoids using these hiPSCs expressed typical nephron markers. In CMC-Fb-002 and GLA-KO organoids, α-GalA activity was significantly decreased along with increased deposition of Gb-3 in comparison with WT organoids. Intralysosomal inclusion body was also detected under EM. However, these disease phenotypes were rescued by KO of A4GALT in both GLA/A4GALT-KO and Fb-002-A4GALT-KO kidney organoids. RNA-seq showed increased expression levels of genes related to FDN progression in both GLA-mutant organoids compared to those in WT. Such increases were rescued in GLA/A4GALT-KO or Fb-002-A4GALT-KO organoids. CRISPR/Cas9 mediated suppression of A4GALT could rescue FDN phenotype. Hence, it can be proposed as a therapeutic approach to treat FDN.

Severity of COVID-19 Pneumonia in Kidney Transplant Recipients According to SARS-CoV-2 Vaccination.

We reviewed 24 kidney transplantat recipients (KTRs) who had radiologically confirmed coronavirus disease 2019 (COVID-19) pneumonia. Enrolled KTRs were divided into a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-vaccination (+) group (n = 18) and a vaccination (-) group (n = 6). Clinical outcomes of the two groups including death, pulmonary outcome, and renal outcome were compared. COVID-19 pneumonia was worse in vaccination (-) KTRs. Two out of six vaccination (-) KTRs needed continuous renal replacement therapy (CRRT) and mechanical ventilator (MV) and expired. In contrast, only one KTR expired and required CRRT and MV out of 18 vaccination (+) KTRs. Our results suggest that SARS-CoV-2 vaccination attenuates severity of COVID-19 pneumonia in KTRs.

Combined impact of the inter and intra-patient variability of tacrolimus blood level on allograft outcomes in kidney transplantation.

Introduction: Tacrolimus (TAC) has been widely used as an immunosuppressant after kidney transplantation (KT); however, the combined effects of intra-patient variability (IPV) and inter-patient variability of TAC-trough level (C0) in blood remain controversial. This study aimed to determine the combined impact of TAC-IPV and TAC inter-patient variability on allograft outcomes of KT. Methods: In total, 1,080 immunologically low-risk patients who were not sensitized to donor human leukocyte antigen (HLA) were enrolled. TAC-IPV was calculated using the time-weighted coefficient variation (TWCV) of TAC-C0, and values > 30% were classified as high IPV. Concentration-to-dose ratio (CDR) was used for calculating TAC inter-patient variability, and CDR < 1.05 ng•mg/mL was classified as rapid metabolizers (RM). TWCV was calculated based on TAC-C0 up to 1 year after KT, and CDR was calculated based on TAC-C0 up to 3 months after KT. Patients were classified into four groups according to TWCV and CDR: low IPV/non-rapid metabolizer (NRM), high IPV/NRM, low IPV/RM, and high IPV/RM. Subgroup analysis was performed for pre-transplant panel reactive antibody (PRA)-positive and -negative patients (presence or absence of non-donor-specific HLA-antibodies). Allograft outcomes, including deathcensored graft loss (DCGL) and biopsy-proven allograft rejection (BPAR), were compared. Results: The incidences of DCGL, BPAR, and overall graft loss were the highest in the high-IPV/RM group. In addition, a high IPV/RM was identified as an independent risk factor for DCGL. The hazard ratio of high IPV/RM for DCGL and the incidence of active antibody-mediated rejection were considerably increased in the PRA-positive subgroup. Discussion: High IPV combined with RM (inter-patient variability) was closely related to adverse allograft outcomes, and hence, more attention must be given to pre-transplant PRA-positive patients.

Combined Analysis of HLA Class II Eplet Mismatch and Tacrolimus Levels for the Prediction of De Novo Donor Specific Antibody Development in Kidney Transplant Recipients.

We investigated whether HLA class II eplet mismatch was related to dnDSA development and analyzed its combined impact with tacrolimus levels for kidney transplantation outcomes. A total of 347 kidney transplants were included. HLA Matchmaker was used for the single molecular eplet, total eplet, antibody (Ab)-verified eplet mismatch analyses, and Ab-verified single molecular analysis to identify HLA-DR/DQ molecular thresholds for the risk of dnDSA development. A time-weighted tacrolimus trough level (TAC-C0) of 5 ng/mL and a TAC-C0 time-weighted coefficient variability (TWCV) of 20% were applied to find the combined effects on dnDSA development. A high level of mismatch for single molecular eplet (DQ ≥ 10), total eplet (DQ ≥ 12), Ab-verified eplet (DQ ≥ 4), and Ab-verified single molecular eplet (DQ ≥ 4) significantly correlated with HLA class II dnDSA development. Class II dnDSA developed mostly in patients with low TAC-C0 and high eplet mismatch. In the multivariable analyses, low TAC-C0 and high eplet mismatch showed the highest hazard ratio for the development of dnDSA. No significant combined effect was observed in dnDSA development according to TWCV. In conclusion, the determination of HLA class II eplet mismatch may improve the risk stratification for dnDSA development, especially in conjunction with tacrolimus trough levels.

Comparison of CT volumetry versus nuclear renography for predicting remaining kidney function after uninephrectomy in living kidney donors.

Computed tomography (CT) and nuclear renography are used to determine kidney procurement in living kidney donors (LKDs). The present study investigated which modality better predicts kidney function after donation. This study included 835 LKDs and they were divided into two subgroups based on whether the left-right dominance of kidney volume was concordant with kidney function (concordant group) or not (discordant group). The predictive value for post-donation kidney function between the two imaging modalities was compared at 1 month, 6 months, and > 1 year in total cohort, concordant, and discordant groups. Split kidney function (SKF) measured by both modalities showed significant correlation with each other at baseline. SKFs of remaining kidney measured using both modalities before donation showed significant correlation with eGFR (estimated glomerular filtration rate) after donation in the total cohort group and two subgroups, respectively. CT volumetry was superior to nuclear renography for predicting post-donation kidney function in the total cohort group and both subgroups. In the discordant subgroup, a higher tendency of kidney function recovery was observed when kidney procurement was determined based on CT volumetry. In conclusion, CT volumetry is preferred when determining procurement strategy especially when discordance is found between the two imaging modalities.

Alterations in the Mineral Bone Metabolism of Living Kidney Donors After Uni-Nephrectomy: Prospective Observational Study.

We investigated the dynamic change of mineral bone metabolism and explored factors associated with the alteration of mineral bone metabolism in the living kidney donors (LKDs) after uni-nephrectomy. One-hundred forty-four prospective LKDs who underwent kidney donation between May 2016 and September 2018 were enrolled. Laboratory evaluation regarding mineral bone metabolism including intact parathyroid hormone (iPTH), renal fractional excretion of phosphate (FEPi), and technetium-99m diethylenetriaminepentaacetate (99mTc-DTPA) scan was performed predonation and 6 months after donation. We divided donors into two groups, the low ΔFEPi and high ΔFEPi groups, according to the change of FEPi after donation, and investigated significant risk factors associated with high ΔFEPi. At 6 months after uni-nephrectomy, estimated glomerular filtration rate (eGFR) significantly declined by 30.95 ml/min/1.73 m2 (p < 0.001), but the measured GFR (mGFR) of the remaining kidney by 99mTc-DTPA scan showed significant increase. Serum phosphorus decreased (p < 0.001), whereas FEPi (13.34-20.23%, p < 0.001) and serum iPTH (38.70-52.20 pg/ml, p < 0.001) showed significant increase. In the high ΔFEPi group, the proportion of preexisting hypertension (HTN) was higher, the baseline FEPi was lower, and the percent decline in eGFR was greater. Moreover, all of these factors were independently associated with high ΔFEPi upon multivariable logistic regression analysis. LKDs showed a significant change in mineral bone metabolism after uni-nephrectomy, especially when the donors had preexisting HTN, lower baseline FEPi, and showed greater loss of kidney function. Hence, strict monitoring of the mineral bone metabolism parameters and bone health may be required for these donors.

Intrapatient Variability in Tacrolimus Trough Levels Over 2 Years Affects Long-Term Allograft Outcomes of Kidney Transplantation.

This study aimed to determine the impact of tacrolimus (TAC) trough level (C0) intrapatient variability (IPV) over a period of 2 years after kidney transplantation (KT) on allograft outcomes. In total, 1,143 patients with low immunologic risk were enrolled. The time-weighted coefficient variability (TWCV) of TAC-C0 was calculated, and patients were divided into tertile groups (T1: < 24.6%, T2: 24.6%-33.7%, T3: ≥ 33.7%) according to TAC-C0-TWCV up to post-transplant 1st year. They were classified into the low/low, low/high, high/low, and high/high groups based on a TAC-C0-TWCV value of 33.7% during post-transplant 0-1st and 1st-2nd years. The allograft outcomes among the three tertile and four TAC-C0-TWCV groups were compared. The T3 group had the highest rate of death-censored allograft loss (DCGL), and T3 was considered an independent risk factor for DCGL. The low/low group had the lowest and the high/high group had the highest risk for DCGL. Moreover, patients with a mean TAC-C0 of ≥5 ng/ml in the high/high group were at the highest risk for DCGL. Thus, TAC-IPV can significantly affect allograft outcomes even with a high mean TAC-C0. Furthermore, to improve allograft outcomes, a low TAC-IPV should be maintained even after the first year of KT.

Post-transplant allograft outcomes according to mismatch between donor kidney volume and body size of recipients with pre-transplant diabetes mellitus.

AIMS: The aim of this study was to investigate allograft outcomes when relatively small kidneys were donated to patients with pre-transplant diabetes mellitus (DM). METHODS: From January 2010 to December 2018, 788 cases of non-sensitized living donor kidney transplant recipient and donor pairs were enrolled. The subjects were divided into four groups according to the relative size of kidney and pre-transplant DM status: non-DM large kidney, non-DM small kidney, DM large kidney, and DM small kidney. We compared allograft outcomes between these four groups. RESULTS: The four groups did not show differences in the development of de novo donor-specific antibody and acute rejection. However, a significantly greater decline of allograft function and increased proteinuria were observed in the DM small kidney group. The highest death-censored graft loss rate (P = 0.008) was also observed in this group and the combination of relatively small kidney size and pre-transplant DM was an independent risk factor for death-censored graft loss. In addition, the relatively small kidney and pre-transplant DM showed significant interaction with each other. CONCLUSIONS: The size mismatch between donated kidney volume and recipient body size should be considered in donor selection of patients with pre-transplant DM.

Impact of delayed graft function on clinical outcomes in highly sensitized patients after deceased-donor kidney transplantation.

Background: We investigated whether the development of delayed graft function (DGF) in pre-sensitized patients affects the clinical outcomes after deceased-donor kidney transplantation (DDKT). Methods: The study included 709 kidney transplant recipients (KTRs) from three transplant centers. We divided KTRs into four subgroups (highly sensitized DGF, highly sensitized non-DGF, low-sensitized DGF, and low-sensitized non-DGF) according to panel reactive antibody level of 50%, or DGF development. We compared post-transplant clinical outcomes among the four subgroups. Results: Incidence of biopsy-proven acute rejection (BPAR) was higher in two highly sensitized subgroups than in low-sensitized subgroups. It tended to be higher in highly sensitized DGF subgroups than in the highly sensitized non-DGF subgroups. In addition, the highly sensitized DGF subgroup showed the highest risk for BPAR (hazard ratio, 3.051; P=0.005) and independently predicted BPAR. Allograft function was lower in the two DGF subgroups than in the non-DGF subgroup until one month after transplantation, but thereafter it was similar. Death-censored graft loss rates and patient mortality tended to be low when DGF developed, but it did not reach statistical significance. Conclusions: DGF development in highly sensitized patients increases the risk for BPAR in DDKT compared with patients without DGF, suggesting the need for strict monitoring and management of such cases.