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Acute rejection (AR) is critical for long-term graft survival in kidney transplant recipients (KTRs). This study aimed to evaluate the efficacy of the integrated risk score of omics-based biomarkers in predicting AR in KTRs. This prospective, randomized, controlled, multicenter, pilot study enrolled 40 patients who recently underwent high-immunologic-risk kidney transplantation (KT). Five omics biomarkers were measured, namely, blood mRNA (three-gene signature), urinary exosomal miRNA (three-gene signature), urinary mRNA (six-gene signature), and two urinary exosomal proteins (hemopexin and tetraspanin-1) at 2 weeks and every 4 weeks after KT for 1 year. An integrated risk score was generated by summing each biomarker up. The biomarker group was informed about the integrated risk scores and used to adjust immunosuppression, but not the control group. The outcomes were graft function and frequency of graft biopsy. Sixteen patients in the biomarker group and nineteen in the control group completed the study. The mean estimated glomerular filtration rate after KT did not differ between the groups. Graft biopsy was performed in two patients (12.5%) and nine (47.4%) in the biomarker and control groups, respectively, with the proportion being significantly lower in the biomarker group (p = 0.027). One patient (6.3%) in the biomarker group and two (10.5%) in the control group were diagnosed with AR, and the AR incidence did not differ between the groups. The tacrolimus trough level was significantly lower in the biomarker group than in the control group at 1 year after KT (p = 0.006). Integrated omics biomarker monitoring may help prevent unnecessary or high-complication-risk biopsy and enables tailored immunosuppression by predicting the risk of AR in KTRs. [ABSTRACT FROM AUTHOR]

The waiting time for deceased donor kidney transplants (DDKT) is increasing. We evaluated DDKT prognosis according to the pretransplant dialysis vintage. A total of 4117 first-time kidney transplant recipients were enrolled from a prospective nationwide cohort in Korea. DDKT recipients were divided into tertiles according to pretransplant dialysis duration. Graft failure, mortality, and composite were compared between DDKT and living donor kidney transplant (LDKT) recipients. Pretransplant dialysis vintage was longer annually in DDKT recipients. In the subdistribution of the hazard model for the competing risk, the first tertile did not show an increased risk of graft failure compared with LDKT recipients; however, the second and third tertile groups had an increased risk of graft failure compared to LDKT recipients (adjusted hazard ratio [aHR] 3.59; 95% confidence interval [CI] 1.69–7.63; P < 0.001; aHR 2.37; 95% CI 1.06–5.33; P = 0.037). All DDKT groups showed a significantly higher risk of patient death than LDKT, with the highest risk in the third tertile group (aHR 11.12; 95% CI 4.94–25.00; P < 0.001). A longer pretransplant dialysis period was associated with a higher risk of the composite of patient death and graft failure in DDKT recipients. DDKT after a short period of dialysis had non-inferior results on graft survival compared with LDKT. [ABSTRACT FROM AUTHOR]

Summary: We evaluated the temporal trend of preemptive kidney transplantation (KT) and the effect of pretransplant dialysis duration on post‐transplant outcomes. This was a nationwide cohort study of the first‐time 3392 living donor KT (LDKT) recipients (2014–2019). The annual changes in proportion of preemptive KT, factors associated with preemptive KT, and post‐transplant outcomes were analyzed. Preemptive KT was performed in 816 (24.1%) patients. Annual trend analysis revealed gradual decrease in preemptive KT over time (P = 0.042). Among the underlying causes of preemptive KT, the proportion of diabetes increased and that of glomerulonephritis decreased during the study period. Glomerulonephritis as the primary renal disease was a predictor of preemptive KT. Patients with pretransplant dialysis >6 months showed increased graft failure risk than preemptive KT in the subdistribution of hazard model for competing risk (adjusted hazard ratio [aHR], 2.53; 95% confidence interval [CI], 1.09–5.87; P = 0.031) and in propensity score‐matched analysis (aHR, 2.45; 95% CI, 1.02–5.92; P = 0.034); however, pretransplant dialysis ≤6 months showed comparable graft survival with preemptive KT in both analyses. Preemptive KT declined over successive years, associated with an increase in diabetes and a decrease in glomerulonephritis as underlying causes of KT. Short period of dialysis less than 6 months does not affect graft survival compared with preemptive KT; however, longer dialysis decreases graft survival. [ABSTRACT FROM AUTHOR]

Summary: The smoking status of kidney transplant recipients and living donors has not been explored concurrently in a prospective study, and the synergistic adverse impact on outcomes remains uncertain. The self‐reported smoking status and frequency were obtained from recipients and donors at the time of kidney transplantation in a prospective multicenter longitudinal cohort study (NCT02042963). Smoking status was categorized as "ever smoker" (current and former smokers collectively) or "never smoker." Among 858 eligible kidney transplant recipients and the 858 living donors, 389 (45.3%) and 241 (28.1%) recipients were considered ever smokers at the time of transplant. During the median follow‐up period of 6 years, the rate of death‐censored graft failure was significantly higher in ever‐smoker recipients than in never‐smoker recipients (adjusted HR, 2.82; 95% CI 1.01–7.87; P = 0.048). A smoking history of >20 pack‐years was associated with a significantly higher rate of death‐censored graft failure than a history of ≤20 pack‐years (adjusted HR, 2.83; 95% CI 1.19–6.78; P = 0.019). No donor smoking effect was found in terms of graft survival. The smoking status of the recipients and donors or both did not affect the rate of biopsy‐proven acute rejection, major adverse cardiac events, all‐cause mortality, or post‐transplant diabetes mellitus. Taken together, the recipient's smoking status before kidney transplantation is dose‐dependently associated with impaired survival. [ABSTRACT FROM AUTHOR]

Donor-recipient age difference (DRAD) is one of the reasons why patients on kidney waiting lists refuse to receive the offered organ. However, its impact on deceased donor kidney transplantation (DDKT) outcomes is still controversial. One hundred fifty-three kidney transplant recipients (KTRs) who received their first-time DDKT were enrolled. The KTRs were divided into groups by DRAD: group 1 (n = 74) (DRAD < 0) and group 2 (n = 79) (DRAD ≥ 0). The KTRs in group 2 were divided into 3 subgroups: DRAD 0 to 10 (n = 35), 10 to 20 (n = 32), and ≥ 20 (n = 12). The outcome measures included estimated glomerular filtration rate (eGFR), delayed graft function (DGF), acute rejection (AR), and graft and patient survival. There were no significant differences in clinical outcomes between group 1 and 2 except eGFR until 5 years after DDKT. Among the subgroups of group 2, DGF, AR, patient survival, and eGFR until 5 years showed no significant differences. However, graft survival was significantly different (P =.015); in addition, in the DRAD ≥ 20 subgroup, graft survival decreased compared with that in the DRAD 10 to 20 subgroup and DRAD 0 to 10 subgroup (P =.020, P =.012, respectively). In a multivariate Cox proportional hazards analysis, the DRAD ≥ 20 subgroup showed a higher risk for graft failure than the DRAD 0 to 10 subgroup. Although donors were of the same age or older than recipients, DDKT showed acceptable graft outcomes. However, because donors over 20 years older than recipients showed a decreased graft survival, it might be important to consider this point in donor-recipient matching of DDKT. • DRAD is one of the major factors in determining organ acceptance in DDKT. • Although donors were of the same age or older than recipients, DDKT showed acceptable graft outcomes. • Donors more than 20 years older than recipients showed a decreased graft survival. [ABSTRACT FROM AUTHOR]

Background: Little is known regarding optimal tacrolimus (TAC) trough levels after 1 year post-transplant in stable kidney transplant recipients (KTRs) who have not experienced renal or cardiovascular outcomes. This study aimed to investigate the effect of 1-year post-transplant TAC trough levels on long-term renal and cardiovascular outcomes and opportunistic infections in stable KTRs. Methods: KTRs receiving TAC with mycophenolate-based immunosuppression who did not experience renal or cardiovascular outcomes within 1 year post-transplant were enrolled from a multicenter observational cohort study. Renal outcome was defined as a composite of biopsy-proven acute rejection, interstitial fibrosis and tubular atrophy, and death-censored graft loss. Cardiovascular outcome was defined as a composite of de novo cardiomegaly, left ventricular hypertrophy, and cardiovascular events. Opportunistic infections were defined as the occurrence of BK virus or cytomegalovirus infections. Results: A total of 603 eligible KTRs were divided into the low-level TAC (LL-TAC) and high-level TAC (HL-TAC) groups based on a median TAC level of 5.9 ng/mL (range 1.3–14.3) at 1 year post-transplant. The HL-TAC group had significantly higher TAC trough levels at 2, 3, 4, and 5 years compared with the levels of the LL-TAC group. During the mean follow-up of 63.7 ± 13.0 months, there were 121 renal outcomes and 224 cardiovascular outcomes. In multivariate Cox regression analysis, LL-TAC and HL-TAC were not independent risk factors for renal and cardiovascular outcomes, respectively. No significant differences in the development of opportunistic infections and de novo donor-specific anti-human leukocyte antigen antibodies and renal allograft function were observed between the two groups. Conclusions: TAC trough levels after 1 year post-transplant remained at a similar level until the fifth year after kidney transplantation and were not directly associated with long-term outcomes in stable Korean KTRs who did not experience renal or cardiovascular outcomes. Therefore, in Asian KTRs with a stable clinical course, TAC trough levels higher than approximately 6 ng/mL might not be required after a year of kidney transplantation. [ABSTRACT FROM AUTHOR]

Background: Prior studies have explored the use of regular reminders to improve adherence among kidney transplant recipients (KTRs), but none have included real-time alarms about drug dosage, frequency, and interval. In the present study, we aimed to evaluate the efficacy and stability of an information and communication technology (ICT)-based centralized monitoring system for increasing medication adherence among Korean KTRs.Methods: In this prospective, multicenter, randomized controlled study, enrolled KTRs were randomized to either the ICT-based centralized monitoring group or control group. The ICT-based centralized monitoring system alerted both patients and medical staff with texts and pill box alarms if there was a missed dose or a dosage/time error. We compared the two groups in terms of medication adherence and transplant outcomes over 6 months, and evaluated patient satisfaction with the ICT-based monitoring system.Results: Among 114 enrolled KTRs, 57 were assigned to the ICT-based centralized monitoring group and 57 to the control group. The two groups did not significantly differ in mean adherence at each follow-up visit. The intrapatient variability of tacrolimus and mycophenolic acid levels, renal function, and adverse transplant outcomes did not differ between the intervention and control groups, or between the intervention group with feedback generation and the intervention group without feedback generation. Patients showed high overall satisfaction with the ICT-based centralized monitoring system, which significantly improved across the study period (p = 0.012).Conclusions: Due to high baseline adherence, the ICT-based centralized monitoring system did not maximize medication adherence or enhance transplant outcomes among Korean KTRs. However, patients were highly satisfied with the system. Our results suggest that the ICT-based centralized monitoring system could be successfully applied in clinical trials.Trial Registration: ClinicalTrials.gov, NCT03136588. Registered 20 April 2017 - Retrospectively registered. [ABSTRACT FROM AUTHOR]

Slow graft function (SGF) is considered to be an intermediate state between immediate graft function (IGF) and delayed graft function (DGF). However, the criteria of SGF is still arbitrary, and the clinical outcomes of SGF are not fully understood. A total of 212 deceased donor kidney transplantation recipients were enrolled. Three schemas were adopted, which classified SGF according to the serum creatinine (Cr) level by a given postoperative day (POD). SGF was defined as Cr ≥ 3.0 mg/dL on POD5, Cr ≥ 2.5 mg/dL on POD7, and Cr ≥ 1.5 mg/dL on POD14 without dialysis in schema I, II, and III, respectively. Estimated glomerular filtration rate (eGFR) after transplantation, acute rejection, and graft survival were compared in each schema. Decreased renal function, defined as eGFR less than 30.0 mL/min/1.73m2, was also compared. In schema I and III, SGF had significantly lower eGFR at 3 months after transplantation compared with IGF (P <. 017), and only schema III maintained the difference until 36 months after transplantation. The incidence of decreased renal function showed significant difference among groups in schema I and III (P <. 05). Graft survival did not show significant difference among groups in all schemas. However, SGF and DGF groups showed a higher probability of decreased renal function than the IGF group (P <. 017) in schema I and III. In deceased donor kidney transplantation, certain definitions of SGF identified significantly worse clinical outcomes compared with IGF, suggesting similar impact with DGF. It is necessary to reach a consensus on a clearer definition of SGF with further studies. [ABSTRACT FROM AUTHOR]

There is a high risk of fracture after kidney transplantation (KT). Recipients of KT are susceptible to persistent hyperparathyroidism and other disorders of bone and mineral metabolism. However, the risk factors for fractures after KT remain uncertain. The aim of the present study was to investigate the risk factors for fracture after KT. A total of 941 recipients of KT were enrolled from a multicenter observational cohort study in Korea from 2012 to 2016. The biochemical markers were measured at the time of KT, then annually for 5 years following KT. All fracture events were recorded. A Cox proportional hazards analysis was performed to calculate hazard ratios (HR) for the association of risk factors with fractures. Twenty-two fractures had occurred in 20 patients during the study period. Baseline and serial changes of mineral and bone biochemical markers were similar between fracture and nonfracture patient groups. Among the total study population, 104 patients were diagnosed with osteoporosis and 422 patients were diagnosed with osteopenia in a pretransplant bone mineral density test. In a multivariate Cox analysis, pretransplant osteoporosis (HR = 11.76; 95% confidence interval [CI], 2.28-60.69; P =. 003) and pretransplant osteopenia (HR = 5.21; 95% CI, 1.15-23.57; P =. 032) were independent risk factors for fracture in recipients of KT. Pretransplant osteoporosis and osteopenia were independent risk factors for fracture after KT. More careful monitoring of bone mineral density before and after KT might be beneficial to predict the risk for fracture after KT. • Twenty out of 941 patients had fractures in the Korean cohort study for Outcome in Patients With Kidney Transplantation. • Pretransplant osteoporosis and osteopenia were risk factors for fracture in kidney transplantation. • Mineral and bone biochemical marker changes were not related to fracture. [ABSTRACT FROM AUTHOR]

Compared to tacrolimus, cyclosporine increases cardiovascular risk. Furthermore, tacrolimus has a negative effect on glucose metabolism compared to cyclosporine. This study investigated the effect of the conversion from cyclosporine to tacrolimus for immunosuppressive therapy on glucose metabolism and cardiovascular risk profiles in long-term stable kidney transplant recipients (KTRs). In this prospective, open-label, single-arm study, 36 KTRs were enrolled; 3 were excluded. Patients were evaluated for glucose metabolism and cardiovascular risk factors at baseline, 3, and 6 months after conversion of medication. Serial changes were analyzed by repeated analysis of variance. The mean duration from transplantation was 12.6 ± 4.0 years and baseline serum creatinine levels were 1.10 ±.23 mg/dL. After conversion, fasting plasma glucose levels increased sequentially from 101.7 ± 18.5 to 107.4 ± 21.3 mg/dL (P =. 007), and glycated hemoglobin levels increased from 5.7 ±.8 to 6.0 ± 1.2% (P =. 016). Among cardiovascular risk factors, fibrinogen levels were decreased (P =. 015), but other factors, including blood pressure and lipid profile, did not change (all P >. 05). There was no change in renal function, including serum creatinine (P =. 611) and urine protein-to-creatinine ratio (P =. 092). Body mass index levels were decreased (P =. 037) and body weight tended to decrease (P =. 063). Switching immunosuppressant therapy to tacrolimus has an apparent negative effect on glucose metabolism and imparts an unclear advantage on cardiovascular risk profiles for long-term stable KTRs. • The conversion effect of calcineurin inhibitors in long-term stable KTRs was prospectively evaluated. • Conversion cyclosporine to tacrolimus was detrimental for glucose metabolism. • No clear benefits on cardiovascular risk profiles and graft function. [ABSTRACT FROM AUTHOR]

Introduction: HLA-incompatible (HLAi) and ABO-incompatible (ABOi) kidney transplantation (KT) has been on the increase over the last decade. However, there are wide variations in outcomes from these procedures. In this study we evaluated the graft and patient outcomes in incompatible KT and non-sensitized KT. Methods: Patients who underwent KT between January 2012 and April 2018 were enrolled and reviewed. We divided kidney transplant recipients (KTRs) into five groups as follows: HLAi (n = 50); ABOi (n = 65); HLAi+ABOi (n = 5); control (n = 428); and living-donor control (LD control, n = 218). We compared the risk of rejection, graft function, graft survival, and patient survival between incompatible KTRs and control/LD control KTRs. Results: Although the incidence of active antibody-mediated rejection in HLAi group tends to be higher than in control and LD control groups (6.0% vs. 2.8%, P = 0.20; 6.0% vs. 3.7%, P = 0.44, respectively), the rejection-free survival, graft survival, and patient survival were not significantly different from those of the control and LD control groups in all three incompatible KT groups (all P>0.05). Graft function during the study period was also not different between incompatible KTRs and control/LD control groups (both P>0.05). Using Cox regression analysis, neither HLAi nor ABOi were risk factors for graft failure. Some infectious diseases such as urinary tract infection and cytomegalovirus infection were more common in the HLAi group than in the control/LD control group (both P<0.05), but only one infection-related death occurred in HLAi KTRs. Infection risks were similar in the ABOi and HLAi+ABOi groups compared to controls. Conclusion: Our results showed favorable outcomes for incompatible KT after desensitization. Although desensitization therapy for incompatible KT has improved access to transplantation for KT candidates with high immunological risk, more clinical data are clearly needed. [ABSTRACT FROM AUTHOR]

Background: Immunosuppression non-adherence in kidney transplant recipients (KTRs) not only increases the risk of medical intervention due to acute rejection and graft loss but burdens the socioeconomic system in the form of increased healthcare costs. An aggressive preemptive effort by healthcare professionals, geared to ensure adherence to immunosuppressants in KTRs, is significant and imperative.Methods/design: This study was designed as a prospective, open-label, multicenter, randomized controlled study aimed at evaluating the efficacy and stability of an information and communication technology (ICT)-based centralized monitoring system in boosting medication adherence in KTRs. One hundred fourteen KTRs registered throughout the year 2017 to 2018 are randomized into either the ICT-based centralized home monitoring system or to ambulatory follow-up. The planned follow-up duration is 6 months. The ICT-based centralized home monitoring system described consists of a smart pill box equipped with personal identification system, a home monitoring system, an electronic Case Report Form (eCRF) system, and a comprehensive clinical trial management system (CTMS). It alerts both patients and medical staff with texts and pill box alarms if there is a dosage/dosing time error or a missed dose. Medication adherence and transplant outcomes for the follow-up period are compared between the two groups, while patient satisfaction as well as the stability and cost-effectiveness of the ICT-based monitoring system are to be evaluated.Discussion: This on-going study is expected to determine if consistent use of the ICT-based centralized monitoring system described could maximize mediation adherence and subsequently enhance transplant outcomes in KTRs. Further, it would lay the foundation for successful implementation of this ICT-based monitoring system for effective management of medication adherence in KTRs.Trials Registration: ClinicalTrials.gov, Identifier: NCT03136588 . Registered on 20 April 2017. [ABSTRACT FROM AUTHOR]

BackgroundTherapeutic drug monitoring of mycophenolic acid (MPA) is required to optimize the immunosuppressive effect and minimize toxicity. We validated a new particle-enhanced turbidimetric inhibition immunoassay (PETINIA) for the determination of MPA levels and evaluated the relationship of MPA trough level with drug-related adverse events.MethodsPETENIA and liquid chromatography-mass spectrometry (LC-MS) were used to determine MPA concentrations from 54 kidney transplant recipients (KTRs). Agreement between PETINIA and LC-MS results was assessed by Passing-Bablok regression and the Bland-Altman plot method. The association of adverse events with MPA trough level obtained by PETINIA was analyzed.ResultsPETINIA revealed a good agreement with the LC-MS; Regression analysis gave an equation of y = 1.27x − 0.12 (r2 = 0.975,p < 0.001). PETINIA showed a systemic positive bias with a mean difference of 0.66 mg/L compared to LC-MS. However, the magnitude of the positive bias decreased to 0.44 mg/L within the therapeutic range of MPA. Multiple logistic regression showed that MPA trough level determined by PETINIA was an independent risk factor for adverse events (odds ratio 2.28, 95% CI 1.25–4.16,p = 0.007). MPA trough level predicted adverse events with a sensitivity of 77.8% and a specificity of 86.7% using a cut-off level of 5.25 mg/L.ConclusionsGood correlation between the two methods indicates that PETINIA is an acceptable method for the monitoring of MPA therapeutic levels. Furthermore, MPA trough level obtained by PETINIA is a useful monitoring tool to minimize toxicity in KTRs. [ABSTRACT FROM PUBLISHER]

Recurrence of focal segmental glomerulosclerosis (FSGS) is a major therapeutic challenge in kidney transplantation (KT). Although intensive plasmapheresis and high-dose rituximab have been introduced to treat recurrent FSGS, the most effective dosage and regimen of rituximab have not been determined. Herein we reported the first case of successful treatment of recurrent FSGS with a low-dose rituximab. The patient showed marked proteinuria (3.5 g/d) and oliguria 2 d after KT. Two courses of plasmapheresis and immunoglobulin were applied to the patient, however, nephrotic range proteinuria persisted and creatinine level increased to 3.56 mg/dL. Five months post-transplant, the patient received injection with only one dose of rituximab 100 mg, without further plasmapheresis, which resulted in immediate reduction of serum creatinine and full remission of proteinuria during the following 18 months. This case suggested that recurrent FSGS, which frequently relapses after plasmapheresis, could be treated successfully with a low-dose rituximab even without plasmapheresis. [ABSTRACT FROM AUTHOR]

• A proteomic approach was employed to measure urinary extracellular vesicle changes in KTRs. • CAMR and two controls (LGS and rejection-free matched control) were included. • Six proteins that were distinguishable between CAMR and LGS were selected and validated. • AZGP1 was found to be a CAMR-specific proteomic biomarker that was distinguishable from the rejection-free matched control. The aim of this study was to identify potential proteomic biomarkers for chronic active antibody-mediated rejection (CAMR) in kidney transplant recipients (KTRs). Among 385 KTRs enrolled in a cross-sectional multicenter study, 26 KTRs with biopsy-proven CAMR, 57 KTRs with long-term graft survival (LGS), and 10 rejection-free matched KTRs were included. A proteomic approach was employed to measure urinary extracellular vesicle (EV) changes in the KTRs. The urinary EVs were trypsin-digested using a gel-assisted protocol and quantified by label-free liquid chromatography with tandem mass spectrometry, using a data-dependent acquisition (DDA) mode. Western blot analysis was performed to confirm the protein levels for each candidate biomarker. Analysis of the isolated EV proteins revealed 93 and 97 proteins in the CAMR and LGS patients, respectively. Proteins that were identical in both groups were excluded and only high-significance proteins with a fold change of at least 1.5 were selected as candidate biomarkers. Six proteins (APOA1, TTR, PIGR, HPX, AZGP1, and CP) that were distinguishable between CAMR and LGS were selected. The proteins were confirmed by immunoblot analyses using independently acquired urinary EV samples. AZGP1 in particular was found to be a CAMR-specific proteomic biomarker that was distinguishable from the rejection-free control group with matching kidney function, duration of transplantation, and age. We identified and validated six proteomic biomarkers for CAMR and clarified one CAMR-specific proteomic biomarker in KTRs. Further clinical trials are needed before these rejection-specific biomarkers can be applied for the early prediction, diagnosis, and monitoring of the clinical response of KTRs to the treatment of CAMR. [ABSTRACT FROM AUTHOR]