KNOW-KT (KoreaN cohort study for outcome in patients with kidney transplantation: a 9-year longitudinal cohort study): study rationale and methodology

BACKGROUND: Asian patients undergoing kidney transplantation (KT) generally have better renal allograft survival and a lower burden of cardiovascular disease than those of other racial groups. The KNOW-KT aims to explore allograft survival rate, cardiovascular events, and metabolic profiles and to elucidate the risk factors in Korean KT patients. METHODS: KNOW-KT is a multicenter, observational cohort study encompassing 8 transplant centers in the Republic of Korea. KNOW-KT will enroll 1,000 KT recipients between 2012 and 2015 and follow them up to 9 years. At the time of KT and at pre-specified intervals, clinical information, laboratory test results, and functional and imaging studies on cardiovascular disease and metabolic complications will be recorded. Comorbid status will be assessed by the age-adjusted Charlson co-morbidity index. Medication adherence and information on quality of life (QoL) will be monitored periodically. The QoL will be assessed by the Kidney Disease Quality of Life Short Form. Donors will include both living donors and deceased donors whose status will be assessed by the Kidney Donor Risk Index. Primary endpoints include graft loss and patient mortality. Secondary endpoints include renal functional deterioration (a decrease in eGFR to <30 mL/min/1.73 m(2)), acute rejection, cardiovascular event, albuminuria, new-onset diabetes after transplant, and QoL. Data on other adverse outcomes including episodes of infection, malignancy, recurrence of original renal disease, fracture, and hospitalization will also be collected. A bio-bank has been established for the acquisition of DNA, RNA, and protein from serum and urine samples of recipients at regular intervals. Bio-samples from donors will also be collected at the time of KT. KNOW-KT was registered in an international clinical trial registry (NCT02042963 at http://www.clinicaltrials.gov) on January 20(th), 2014. CONCLUSION: The KNOW-KT, the first large-scale cohort study in Asian KT patients, is expected to represent the Asian KT population and provide information on their natural course, complications, and risk factors for complications

Non-Invasive Diagnosis for Acute Rejection Using Urinary mRNA Signature Reflecting Allograft Status in Kidney Transplantation

Urine has been regarded as a good resource based on the assumption that urine can directly reflect the state of the allograft or ongoing injury in kidney transplantation. Previous studies, suggesting the usefulness of urinary mRNA as a biomarker of acute rejection, imply that urinary mRNA mirrors the transcriptional activity of the kidneys. We selected 14 data-driven candidate genes through a meta-analysis and measured the candidate genes using quantitative PCR without pre-amplification in the cross-sectional specimens from Korean kidney transplant patients. Expression of 9/14 genes (CXCL9, CD3ϵ, IP-10, LCK, C1QB, PSMB9, Tim-3, Foxp3, and FAM26F) was significantly different between acute rejection and stable graft function with normal pathology and long-term graft survival in 103 training samples. CXCL9 was also distinctly expressed in allografts with acute rejection in in situ hybridization analysis. This result, consistent with the qPCR result, implies that urinary mRNA could reflect the magnitude of allograft injury. We developed an AR prediction model with the urinary mRNAs by a binary logistic regression and the AUC of the model was 0.89 in the training set. The model was validated in 391 independent samples, and the AUC value yielded 0.84 with a fixed manner. In addition, the decision curve analysis indicated a range of reasonable threshold probabilities for biopsy. Therefore, we suggest the urine mRNA signature could be used as a non-invasive monitoring tool of acute rejection for clinical application and could help determine whether to perform a biopsy in a recipient with increased creatinine

Ipsilateral dual kidney transplantation in an elderly patient with severe atherosclerosis: a case report

Dual Kidney Transplantation (DKT) has been developed to improve outcomes from transplantation based on extended criteria of donors (ECD) and demonstrated excellent short-term outcomes. We performed DKT at Samsung Medical Center in March 2021. The donor was a 74-year-old male with no history of known underlying diseases but died from traumatic subarachnoid hemorrhage. The recipient was a 72-year-old male who had been undergoing nephrological observation for 4 years prior to the kidney transplant. The patient had been on hemodialysis since July 2017 and had been suffering from type 2 diabetes since 2003. On non-contrast computed tomography, diffuse calcific atherosclerosis was observed in the abdominal aorta and left iliac artery. As a result, ipsilateral DKT was performed. Because of this diffuse calcific atherosclerosis, we planned ipsilateral DKT on the right side. Postoperative healing was uneventful without complications. In conclusion, DKT is an option for improving survival in the ECD pool, and ipsilateral DKT can be helpful option for preventing organ discard in ECDs

Infectious Risks and Optimal Strength of Maintenance Immunosuppressants in Rituximab-Treated Kidney Transplantation

Background: Rituximab, an anti-CD20 antibody, effectively depletes B lymphocytes. It is not clear whether the use of conventional doses of mycophenolate mofetil (MMF), methylprednisolone and tacrolimus as maintenance immunosuppression in rituximab-treated kidney transplantation is associated with increased risk. Methods: We retrospectively evaluated 67 patients who underwent HLA-sensitized or ABO-incompatible living donor kidney transplantation after one dose of rituximab (200 or 500 mg) (group 1). Eighty-seven kidney transplant recipients who did not require rituximab served as a control (group 2). Results: Cytomegalovirus infection (16.4 vs. 5.7%, p = 0.031) and pneumonia (9.0 vs. 1.1%, p = 0.043) occurred more often in group 1, and 2 patients of group 1 died of infection. The doses of methylprednisolone and tacrolimus levels of the two groups were not different. MMF dose was reduced when serious infection occurred. The doses of MMF (in grams/day) at the following times postoperatively were lower in group 1 than in group 2: 1 month: 1.26 ± 0.42 vs. 1.40 ± 0.39, p = 0.033; 3 months: 1.14 ± 0.51 vs. 1.36 ± 0.39, p = 0.011; 6 months: 1.07 ± 0.50 vs. 1.30 ± 0.42, p = 0.012; 1 year: 0.88 ± 0.52 vs. 1.19 ± 0.44, p = 0.009; 2 years: 0.69 ± 0.55 vs. 1.25 ± 0.49, p = 0.059, but the reduction of MMF doses did not increase the incidence of acute rejection in group 1 (4.5% in group 1 vs. 9.2% in group 2, p = 0.351). If patients who died with functioning graft were excluded, graft survival was 98.5% in group 1 and 100% in group 2. Conclusions: Serious infectious complications were increased in rituximab-treated kidney transplant recipients and it might be adequate to reduce the MMF dose from the early postoperative period

Establishment of a Novel PDX Mouse Model and Evaluation of the Tumor Suppression Efficacy of Bortezomib Against Liposarcoma

The patient-derived xenograft (PDX) model has been adopted as a major tool for studying tumorigenesis and differentiation in various carcinomas. In addition, it has been used in the development of anticancer agents. PDX models have been among the most meaningful tools used to understand the role of stromal cells and vascular cells in the body, which are major factors in cancer development and the application of therapeutic agents. Also, the establishment of PDX models from liposarcoma patients is considered to be important for understanding lipomagenesis and following drugs development. For these reasons, we developed patient-derived cell (PDC) and PDX models derived from 20 liposarcoma patients. The tissues of these patients were obtained in accordance with the principles of the Samsung Medical Center's ethics policy, and cell culture and xenografting onto the mice were performed under these principles. High-throughput drug screening (HTS) was carried out using established PDCs to select candidate drugs. Among the different candidate anticancer drugs, we tested the effect of bortezomib, which was expected to inhibit MDM2 amplification. First, we confirmed that the PDCs maintained the characteristics of liposarcoma cells by assessing MDM2 amplification and CDK4 overexpression using fluorescence in situ hybridization. Analysis of short tandem repeats and an array using comparative genomic hybridization confirmed that the PDX model exhibited the same genomic profile as that of the patient. Immunohistochemistry for MDM2 and CDK4 showed that the overexpression patterns of both proteins were similar in the PDX models and the PDCs. Specifically, MDM2 amplification was observed to be significantly correlated with the successful establishment of PDX mouse models. However, CDK4 expression did not show such a correlation. Of the anticancer drugs selected through HTS, bortezomib showed a strong anticancer effect against PDC. In addition, we observed that bortezomib suppressed MDM2 expression in a dose-dependent manner. In contrast, p21 tended to elicit an increase in PDC expression. Treatment of the PDX model with bortezomib resulted in an anticancer effect similar to that seen in the PDCs. These results support that PDCs and PDX models are among the most powerful tools for the development and clinical application of anticancer drugs for the treatment of liposarcoma patients

Factors to consider during anesthesia in patients undergoing preemptive kidney transplantation: a propensity-score matched analysis

Abstract Background International guidelines have recommended preemptive kidney transplantation (KT) as the preferred approach, advocating for transplantation before the initiation of dialysis. This approach is advantageous for graft and patient survival by avoiding dialysis-related complications. However, recipients of preemptive KT may undergo anesthesia without the opportunity to optimize volume status or correct metabolic disturbances associated with end-stage renal disease. In these regard, we aimed to investigate the anesthetic events that occur more frequently during preemptive KT compared to nonpreemptive KT. Methods This is a single-center retrospective study. Of the 672 patients who underwent Living donor KT (LDKT), 388 of 519 who underwent nonpreemptive KT were matched with 153 of 153 who underwent preemptive KT using propensity score based on preoperative covariates. The primary outcome was intraoperative hypotension defined as area under the threshold (AUT), with a threshold set at a mean arterial blood pressure below 70 mmHg. The secondary outcomes were intraoperative metabolic acidosis estimated by base excess and serum bicarbonate, electrolyte imbalance, the use of inotropes or vasopressors, intraoperative transfusion, immediate graft function evaluated by the nadir creatinine, and re-operation due to bleeding. Results After propensity score matching, we analyzed 388 and 153 patients in non-preemptive and preemptive groups. The multivariable analysis revealed the AUT of the preemptive group to be significantly greater than that of the nonpreemptive group (mean ± standard deviation, 29.7 ± 61.5 and 14.5 ± 37.7, respectively, P = 0.007). Metabolic acidosis was more severe in the preemptive group compared to the nonpreemptive group. The differences in the nadir creatinine value and times to nadir creatinine were statistically significant, but clinically insignificant. Conclusion Intraoperative hypotension and metabolic acidosis occurred more frequently in the preemptive group during LDKT. These findings highlight the need for anesthesiologists to be prepared and vigilant in managing these events during surgery

The effect of alkaline phosphatase and intrahepatic metastases in large hepatocellular carcinoma

BACKGROUND: Hepatectomy is the standard treatment for HCC. However, large HCC poses a difficult challenge because of the technical complexity of surgical resection and the fear of postoperative hepatic decompensation. We analyzed the outcome and prognostic factors in patients with large hepatocellular carcinoma (HCC ≥10 cm) after surgery. METHODS: We retrospectively investigated the medical records of 91 patients who had undergone hepatectomy between January 2006 and June 2010. A survival analysis was performed utilizing the Kaplan-Meier method and prognostic factors were evaluated using Cox regression analysis. RESULTS: Of the 91 patients evaluated, most tumors were associated with hepatitis B virus (HBV). The median tumor size was 12.3 cm (range, 10 to 21 cm), with microvascular invasion present in most patients. The postoperative mortality rate was 2.2%. The median disease-free survival and overall survival were six months and 41 months. The one-year, two-year, and three-year disease-free survival rates were 33.5%, 29.3%, and 18.8%, respectively. The one-year, two-year, and three-year overall survival rates were 73.9%, 63.7%, and 54.8%, respectively. Of the 89 surviving patients, 69 patients (77.5%) developed HCC recurrence during the mean follow-up period of 23.4 ± 15.9 months. On multivariate analysis, the statistically significant factors that predicted HCC recurrence were ALP ≥ 80 IU/mL (P = 0.009) and intrahepatic metastases (P = 0.013). CONCLUSIONS: Our study suggests that preoperative ALP levels (≥ 80 IU/L) and intrahepatic metastases could be utilized to monitor and predict recurrence in HCC patients

Comparison of clinical outcomes of deceased donor kidney transplantations, with a focus on three induction therapies

Background : Graft survival rate of kidney transplantation recipients improves after induction therapy. However, there is no conclusive evidence on which regimen is superior for deceased donor kidney transplantation (DDKT). This study aims at discussing effective induction therapy in DDKT. Methods : Between 2003 and 2016, 395 DDKT recipients were divided into three groups following induction therapy. Recipients of the basiliximab group (n=184) received basiliximab (20 mg/kg) on days 0 and 4. Recipients of the low-dose rabbit anti-thymocyte globulin (rATG) group (n=113) received rATG (1.5 mg/kg) on days 0, 1, and 2, while those of the high-dose rATG group (n=98) received it for more than 4 days. We retrospectively reviewed and analyzed the clinical outcomes and adverse effects of induction therapy.Results : Compared to other groups, the low-dose rATG group donors were older (P<0.001); rATG group donors had higher serum creatinine levels (P<0.001), and the basiliximab group showed a lower delayed graft function rate (P=0.004). In graft failure, the low-dose rATG group did not differ significantly from the basiliximab group (P=0.080), but was significantly different from the high-dose rATG group (P=0.004).Conclusion : s: The low-dose rATG group had the best graft survival rate, although it had older donors and higher serum creatinine levels. Therefore, low-dose rATG may be considered an effective induction therapy in DDKT