Jong Cheol Jeong

Outcomes of combination therapy for chronic antibody-mediated rejection in renal transplantation

Chronic antibody‐mediated rejection (CAMR) in renal transplant patients has poor allograft outcomes. However, treatment strategy has not been established yet. Herein, we present short‐term outcomes of combination therapy for CAMR.

Association of complement 5 genetic polymorphism with renal allograft outcomes in Korea

BACKGROUNDnComplements play important roles in both rejection and ischemia-reperfusion injury after transplantation. Complement 5 (C5) is a pivotal complement, which initiates the assembly of the membrane attack complex, and mediates chemotaxis of various immune cells. We investigated the impacts of genetic variations in C5 and its receptor (C5aR) of both recipients and donors on renal allograft outcomes.nnnMETHODSnSeven single-nucleotide polymorphisms (SNPs) in C5 (rs12237774, rs2159776, rs17611, rs25681, rs2241004, rs10985126 and rs10818500) and one SNP (rs10404456) in the C5aR gene were genotyped in 191 recipient-donor pairs. The association of the polymorphisms with allograft outcomes was determined.nnnRESULTSnThree C5 SNPs (rs2159776, rs17611 and rs25681) in recipients had a tendency toward a reduced glomerular filtration rate at 1 year after transplantation. There were four haplotypes in the H2 linkage disequilibrium block, which was formed by four SNPs (rs2159776, rs17611, rs25681 and rs2241004). The GGCG haplotype in both recipients and donors was associated with lower glomerular filtration rate at 1 year (60.9 ± 15.9 versus 66.4 ± 15.5 mL/min/1.73 m(2), P = 0.020; 60.6 ± 15.3 versus 66.2 ± 15.8 mL/min/1.73 m(2), P = 0.017). The association was sustained over 7 years after transplantation (P = 0.015 in recipients; P = 0.039 in donors). The presence of the GGCG haplotype in recipients was associated with poorer graft survival (logrank test, P = 0.024). However, C5 polymorphisms were not correlated with serum C5 level. C5aR polymorphism had no significant impact on the allograft outcomes.nnnCONCLUSIONSnThe GGCG haplotype of C5 in both recipients and donors was associated with lower renal allograft function.

Utility of QuantiFERON-TB Assay for Prediction of Tuberculosis Development in Kidney Transplant Patients in an Intermediate- Tuberculosis-Burden Country: Lack of Evidence for Enhanced Prediction for Short-Term Tuberculosis Development

INTRODUCTIONnAlthough a latent tuberculosis (TB) infection is a risk factor for active TB, the diagnosis of latent TB infection is difficult in end-stage renal disease patients.nnnPATIENTS AND METHODSnWe retrospectively compared the results of the QuantiFERON-TB (QFT) test and the tuberculin skin test in patients on the waiting list for kidney transplantation (KT), and investigated whether the QFT test can predict TB development in KT recipients in an intermediate-TB-burden country.nnnRESULTSnThe incidence of post-KT TB was 283 cases/100,000 patient-years among 1274 KT recipients at the Seoul National University Hospital. The overall standardized incidence ratio of TB was 4.358 compared with the general population. A past history of TB infection, smoking history, myocardial infarction after KT, and pneumocystis infection were significant predictors of subsequent TB development (adjusted odds ratios were 3.618, 2.959, 9.993, and 5.708, respectively). Among the 129 recipients who had the QFT test, 42 patients (32.5%) had positive a QFT. At a median follow-up of 8.4 ± 6.8 months, 1 patient with positive QFT results developed TB after KT, and 1 of the 87 patients with negative QFT results developed TB after KT. In both of these 2 cases, active TB developed despite isoniazid prophylaxis. Among 272 patients on the waiting list for KT, the tuberculin skin test and QFT were positive in 22.8% and 35.3%, respectively. The degree of agreement between the 2 tests was poor (κ = 0.352).nnnCONCLUSIONSnThe QFT test did not predict subsequent short-term TB development. Furthermore, a long-term and larger-scale study is needed to confirm our results.

Kidney Transplantation Using Expanded Criteria Donors in Korea

BACKGROUNDnUse of expanded criteria donor (ECD) grafts seeks to solve the organ shortage. We investigated the current status of donor selection and transplantation outcomes.nnnMETHODSnWe retrospectively analyzed 791 kidney transplantations performed between 1997 and 2009. An expanded criteria deceased donor (ECDD) was defined as an individual who fulfilled the United Network for Organ Sharing criteria or, the Nyberg criteria. An expanded criteria living donor (ECLD) was determined by fulfillment of 1 or more of 5 criteria.nnnRESULTSnDeceased and living donor kidney transplantations were performed in 228 (28.8%) and 563 (71.2%) cases, respectively. Forty-three cases (18.9%) belonged to the ECDDs. The ECDD group showed a lower posttransplantation 1-year estimated glomerular filtration rate (eGFR) than that of the standard criteria deceased donor (SCDD) group (70.7 ± 19.2 vs 48.6 ± 11.5; P < .001). The ECDDs were allocated to older recipients or recipients with more HLA mismatches than SCDDs. The number of ECLD cases was 173 (30.7%). The proportions of each medical abnormality of living donors were as follows: age older than 60 years (0.5%), hypertension (2.5%), obesity (2.1%), low eGFR (25.9%), proteinuria (0%), and microscopic hematuria (1.4%). The ECLD group showed a lower posttransplantation 1-year eGFR than that of the standard criteria living donor (SCLD) group (66.9 ± 16.0 vs 58.3 ± 11.2; P < .001). Graft survival was not different among the donor types (P = .518).nnnCONCLUSIONSneCDs were 27.3% of the total kidney donors. Posttransplantation 1-year eGFR was lower in the ECD group. However, there was no difference in the graft survival among the different donor types.

Human thrombomodulin regulates complement activation as well as the coagulation cascade in xeno-immune response.

With the introduction of the α1, 3‐galactosyltransferase gene‐knockout (GT‐KO) pig and its pivotal role in preventing hyperacute rejection (HAR), coagulation remains a considerable obstacle yet to be overcome in order to provide long‐term xenograft survival. Thrombomodulin (TBM) plays a critical anticoagulant and anti‐inflammatory role in its part of the protein C pathway. Many studies have demonstrated the strong anticoagulant effects of TBM in xenotransplantation, but its complement regulatory effects have not been appropriately examined. Here, we investigate whether TBM can regulate complement activation as well as coagulation in response to xenogeneic stimuli.

Beneficial effects of the transgenic expression of human sTNF-αR-Fc and HO-1 on pig-to-mouse islet xenograft survival

Both human soluble tumor necrosis factor-α receptor-Fc (sTNF-αR-Fc) and heme oxygenase-1 (HO-1) transgenic pigs have been generated previously for xenotransplantation. Here, we investigated whether overexpression of sTNF-αR-Fc or HO-1 in pig islets prolongs islet xenograft survival. Adult porcine islets were isolated from human sTNF-αR-Fc or HO-1 transgenic and wild type pigs, and were transplanted into diabetic nude mice. Effects of the expression of both genes on islet apoptosis, chemokine expression, cellular infiltration, antibody production, and islet xenograft survival were analyzed. Human sTNF-αR-Fc transgenic pigs successfully expressed sTNF-αR-Fc in the islets; human HO-1 transgenic pigs expressed significant levels of HO-1 in the islets. Pig-to-mouse islet xenograft survival was significantly prolonged in both the sTNF-αR-Fc and HO-1 groups compared with that in the wild type group. Both the sTNF-αR-Fc and HO-1 groups exhibited suppressed intragraft expression of monocyte chemoattractant protein-1 (MCP-1) and decreased perigraft infiltration of immune cells. However, there was no difference in the anti-pig antibody levels between the groups. Apoptosis of islet cells during the early engraftment was suppressed only in the HO-1 group. Porcine islets from both sTNF-αR-Fc and HO-1 transgenic pigs prolonged xenograft survival by suppressing islet cell apoptosis or secondary inflammatory responses following islet death, indicating that these transgenic pigs might have applications in successful islet xenotransplantation.

Impact of Vitamin D, Bisphosphonate, and Combination Therapy on Bone Mineral Density in Kidney Transplant Patients

BACKGROUNDnOsteoporosis can develop and become aggravated in kidney transplant patients; however, the best preventive options for post-transplantation osteoporosis remain controversial.nnnMETHODSnWe retrospectively analyzed cohort of 182 renal transplant recipients of mean age 46.7 ± 12.1 years including 47.3% women. Seventy-three patients received neither vitamin D nor bisphosphonate after transplantation (group 1). The other patients were classified into the following 3 groups: calcium plus vitamin D (group 2; nxa0= 40); bisphosphonate (group 3; nxa0= 18); and both regimens (group 4; nxa0= 51). Bone mineral density (BMD) was evaluated by dual-energy X-ray absorptiometry at baseline and at 1xa0year after transplantation.nnnRESULTSnAt 1 year after transplantation, T-scores of the femoral neck and entire femur were significantly decreased in group 1 (-0.23 ± 0.65 [Pxa0= .004] andxa0-0.21 ± 0.74 [Pxa0= .018], respectively), whereas the lumbar spine was significantly increased in group 4 (0.27 ± 0.79; Pxa0= .020). Post hoc analysis demonstrated that the delta T-score was significantly lower in group 1 than in group 4 (Pxa0= .009, 0.035, and 0.031 for lumbar spine, femoral neck, and entire femur, respectively). In a multivariate analysis adjusted by age, sex, body mass index, dialysis duration, diabetes, calcineurin inhibitors, estimated glomerular filtration rate, and persistent hyperparathyroidism, both group 2 and group 4 showed protective effects on BMD reduction (odds ratio [OR], 0.165; 95% confidence interval [CI] 0.032-0.845 [Pxa0= .031]; and OR, 0.169; 95% CI, 0.045-0.626 [Pxa0= .008]; respectively). However, group 3 did not show a protective effect (OR, 0.777; 95% CI, 0.198-3.054; Pxa0= .718), because their incidence of persistent hyperparathyroidism after transplantation was significantly higher (50.0%) than the other groups (Pxa0< .001). The incidence of bone fractures did not differ among the groups.nnnCONCLUSIONSnCombination therapy with vitamin D and bisphosphonate was the most effective regimen to improve BMD among kidney recipients.

Clinical Manifestations of Hypercalcemia and Hypophosphatemia After Kidney Transplantation

INTRODUCTIONnAbnormalities of calcium and phosphorus metabolism in end-stage renal disease patients can persist after transplantation. We investigated their natural courses after transplantation, their risk factors for posttransplantation hypercalcemia and hypophosphatemia, and their impacts on allograft outcomes.nnnMETHODSnWe retrospectively analyzed a total of 490 adult patients who underwent kidney transplantations between 2000 and 2009.nnnRESULTSnThe serum calcium continued to increase, and reaching a plateau at around 3 months after transplantation. Thereafter it decreased, reaching a stable level by 2 years. Forty-four patients (9.0%) displayed hypercalcemia within 1 year; it persisted longer than that in 23 subjects (4.7%). Both longer dialysis duration (odds ratio [OR] 1.423; 95% confidence interval [CI], 1.192-1.699) and high intact serum parathyroid hormone (iPTH) level before transplantation (OR 1.002; 95% CI, 1.000-1.003) increased the risk for posttransplantation hypercalcemia. After a significant decrease during the first week, the serum phosphorus level increased, becoming stable between 1 and 6 months after transplantation. Hypophsphatemia occurred in 379 patients (77.3%) with 336 patients displaying hypophosphatemia without hypercalcemia. However, neither hypercalcemia nor hypophosphatemia influenced graft outcomes. Eight patients underwent pretransplantation parathyroidectomy, whereas 4 patients underwent posttransplantation parathyroidectomy. Neither group of patients experienced posttransplantation hypercalcemia.nnnCONCLUSIONSnBoth hypercalcemia and hypophosphatemia are common after renal transplantation, especially among patients with a long history of dialysis before transplantation. Strict control of hyperparathyroidism including parathyroidectomy before transplantation may be the appropriate approach to these abnormalities.

Outcomes of Management for Potential Deceased Donors

BACKGROUNDSnPotential deceased donor management optimization is important for organ recovery maximization. Before optimization, the current state of donor management and predictors for organ recovery require analysis.nnnMETHODSnWe retrospectively analyzed organ procurement activity and medical management for 2005 to 2010 potential brain death donors at Seoul National University Hospital.nnnRESULTSnOf 316 contacts for potential brain-dead donors, 129 (39.7%) patients were transferred to the donor management team. Among the causes of transfer failure, issues related to proper donor management affected 33%. Expanded criteria donors were 17.9% of transferred donors. Organ recovery was successful in 111 (90.2%) donors. A total of 360 organs were recovered, corresponding to a mean of 2.92 ± 1.37 organs per donor. The absence of organ demand was an important cause of recovery failure among less transplanted organs. Brain death-related complications were identified as follows: acute kidney injury (AKI), defined by AKI network criteria, occurred in 19 (15.4%); cardiopulmonary resuscitation in 5 (3.1%); bacteremia in 12 (9.7%); thrombocytopenia in 24 (19.5%); and diabetes insipidus in 42 (34.1%). AKI was a significant independent risk factor for organ recovery failure in both the liver and kidney (odds ratio [OR] 0.147, 95% confidence interval [0.045, 0.473], P = .001; OR 0.096, 95% confidence interval [0.023, 0.392], P = .001, for kidney and liver, respectively).nnnCONCLUSIONSnBoth the transfer success rate and rate of organs transplanted per donor of potential deceased donors remained low in Korea. AKI during potential donor management was a risk factor for kidney and liver recovery failure.

Impact of Combined Acute Rejection on BK Virus-Associated Nephropathy in Kidney Transplantation

BK virus-associated nephropathy (BKVAN) is one of the major causes of allograft dysfunction in kidney transplant (KT) patients. We compared BKVAN combined with acute rejection (BKVAN/AR) with BKVAN alone in KT patients. We retrospectively analyzed biopsy-proven BKVAN in KT patients from 2000 to 2011 at Seoul National University Hospital. Among 414 biopsies from 951 patients, biopsy-proven BKVAN was found in 14 patients. Nine patients had BKVAN alone, while 5 patients had both BKVAN and acute cellular rejection. BKVAN in the BKVAN alone group was detected later than in BKVAN/AR group (21.77 vs 6.39 months after transplantation, P=0.03). Serum creatinine at diagnosis was similar (2.09 vs 2.00 mg/dL). Histological grade was more advanced in the BKVAN/AR group (P=0.034). Serum load of BKV, dose of immunosuppressants, and tacrolimus level showed a higher tendency in the BKVAN alone group; however it was not statistically significant. After anti-rejection therapy, immunosuppression was reduced in the BKVAN/AR group. Renal functional deterioration over 1 yr after BKVAN diagnosis was similar between the two groups (P=0.665). These findings suggest that the prognosis of BKVAN/AR after anti-rejection therapy followed by anti-BKV therapy might be similar to that of BKVAN alone after anti-BKV therapy.