Hepatocellular carcinoma and cancer-related mortality after kidney transplantation with rituximab treatment

Purpose@#There are increased therapeutic usages of rituximab in kidney transplantation (KT). However, few studies have evaluated the effect of rituximab on cancer development following KT. This study aimed to evaluate the effect of rituximab on the cancer occurrence and mortality rate according to each type of cancer. @*Methods@#Five thousand consecutive recipients who underwent KT at our center were divided into era1 (1990–2007) and era2-rit– (2008–2018), and era2-rit+ (2008–2018) groups. The era2-rit+ group included patients who received single-dose rituximab (200–500 mg) as a desensitization treatment 1–2 weeks before KT. @*Results@#The 5-year incidence rates of malignant tumors after KT were 3.1%, 4.3%, and 3.5% in the era1, era2-rit–, and era2-rit+ group, respectively. The overall incidence rate of cancer after transplantation among the 3 study groups showed no significant difference (P = 0.340). The overall cancer-related mortality rate was 17.1% (53 of 310). Hepatocellular carcinoma (HCC) had the highest mortality rate (61.5%) and relative risk of cancer-related death (hazard ratio, 8.29; 95% confidence interval, 2.40–28.69; P = 0.001). However, we found no significant association between rituximab and the incidence of any malignancy. @*Conclusion@#Our results suggest that single-dose rituximab for desensitization may not increase the risk of malignant disease or cancer-related mortality in KT recipients. HCC was associated with the highest risk of cancer-related mortality in an endemic area of HBV infection.

Beneficial effects of posttransplant dipeptidyl peptidase-4 inhibitor administration after pancreas transplantation to improve β cell function

Purpose@#Dipeptidyl peptidase-4 (DPP-4) inhibitors lower blood glucose levels and enhance the function of pancreatic βcells. Yet, it is unknown whether posttransplant administration of DPP4 inhibitors is beneficial for pancreas transplant recipients. @*Methods@#We thus retrospectively analyzed the records of 312 patients who underwent pancreas transplantation between 2000 and 2018 at Asan Medical Center (Seoul, Korea) and compared the metabolic and survival outcomes according to DPP-4 inhibitor treatment. @*Results@#The patients were divided into the no DPP-4 inhibitor group (n = 165; no treatment with DPP-4 inhibitors or treated for <1 month) and the DPP-4 inhibitor group (n = 147; treated with DPP-4 inhibitors for ≥1 month). There were no significant differences in levels of glucose, hemoglobin A1c, and insulin between the 2 groups during 36 months of follow-up. However, the level of C-peptide was significantly higher in the DPP-4 inhibitor group at 1, 6, and 24 months posttransplant (all P < 0.05). Moreover, the DPP-4 inhibitor group had significantly higher rates of overall (log-rank test, P = 0.009) and death-censored (log-rank test, P = 0.036) graft survival during a 15-year follow-up. @*Conclusion@#Posttransplant DPP-4 inhibitor administration may help improve the clinical outcomes including β cell function after pancreas transplantation.

Beneficial effects of posttransplant dipeptidyl peptidase-4 inhibitor administration after pancreas transplantation to improve β cell function

Purpose@#Dipeptidyl peptidase-4 (DPP-4) inhibitors lower blood glucose levels and enhance the function of pancreatic βcells. Yet, it is unknown whether posttransplant administration of DPP4 inhibitors is beneficial for pancreas transplant recipients. @*Methods@#We thus retrospectively analyzed the records of 312 patients who underwent pancreas transplantation between 2000 and 2018 at Asan Medical Center (Seoul, Korea) and compared the metabolic and survival outcomes according to DPP-4 inhibitor treatment. @*Results@#The patients were divided into the no DPP-4 inhibitor group (n = 165; no treatment with DPP-4 inhibitors or treated for <1 month) and the DPP-4 inhibitor group (n = 147; treated with DPP-4 inhibitors for ≥1 month). There were no significant differences in levels of glucose, hemoglobin A1c, and insulin between the 2 groups during 36 months of follow-up. However, the level of C-peptide was significantly higher in the DPP-4 inhibitor group at 1, 6, and 24 months posttransplant (all P < 0.05). Moreover, the DPP-4 inhibitor group had significantly higher rates of overall (log-rank test, P = 0.009) and death-censored (log-rank test, P = 0.036) graft survival during a 15-year follow-up. @*Conclusion@#Posttransplant DPP-4 inhibitor administration may help improve the clinical outcomes including β cell function after pancreas transplantation.

Diagnostic usefulness of the cytomegalovirus (CMV)-specific T cell-based assay for predicting CMV infection after kidney transplant

Background/Aims@#We evaluated the usefulness in kidney transplant (KT) candidates of cytomegalovirus (CMV)-specific enzyme-linked immunospot (ELISPOT) assays for predicting the development of post-transplant CMV infections. @*Methods@#All adult recipients admitted for living-donor KT between March 2014 and March 2015 were prospectively enrolled except donor CMV-seropositive and recipient seronegative (D+/R–) recipients. All the enrolled patients underwent CMV-specific ELISPOT assays before transplant, and a researcher blinded to the results of these assays examined the patients for CMV infection at least 6 months post-transplant. @*Results@#Of 133 KT recipients, 44 (33%) developed CMV infections. When we used the cut-off determined by receiver operator characteristic curve, 16 of the 34 patients (47%) with negative pp65-specific ELISPOT results (< 11 spots/200,000 cells) developed CMV infections, whereas 28 of the 99 patients (39%) with positive pp65-specific ELISPOT results at baseline (≥ 11 spots/200,000 cells) developed CMV infections after KT (p = 0.02). Based on the multivariable Cox regression model, negative pp65-specific ELISPOT assay results was an independent risk factor for CMV infection (adjusted hazard ratio [AHR], 1.87; 95% confidence interval [CI], 1.01 to 3.46; p = 0.047) as well as age (AHR, 1.05; 95% CI, 1.01 to 1.08; p = 0.007). @*Conclusions@#Pre-transplant CMV-specific ELISPOT assay appears to predict the development of CMV infections after KT in recipients at moderate risk such as CMV-seropositive recipients (Clinical Trial Registration Number NCT 02025335).

Urinary transglutaminase 2 as a potent biomarker to predict interstitial fibrosis and tubular atrophy of kidney allograft during early posttransplant period in deceased donor kidney transplantation

PURPOSE: Transglutaminase type 2 (TG2) is an extracellular matrix crosslinking enzyme with a pivotal role in kidney fibrosis. We tested whether quantification of urinary TG2 may represent a noninvasive method to estimate the severity of kidney allograft fibrosis. METHODS: We prospectively collected urine specimens from 18 deceased donor kidney transplant recipients at 1-day, 7-day, 1-month, 3-month, and 6-month posttransplant. In addition, kidney allograft tissue specimens at 0-day and 6-month posttransplant were sampled to analyze the correlation of urinary TG2 and kidney allograft fibrosis. RESULTS: Thirteen recipients had increased interstitial fibrosis and tubular atrophy (IFTA) scores at the 6-month protocol biopsy (IFTA group). The mean level of urinary TG2 in the IFTA group was higher compared to that of 5 other recipients without IFTA (no IFTA group). Conversely, the mean level of urinary syndecan-4 in the IFTA group was lower than levels in patients without IFTA. In the IFTA group, double immunofluorescent staining revealed that TG2 intensity was significantly upregulated and colocalizations of TG2/heparin sulfate proteoglycan and nuclear syndecan-4 were prominent, usually around tubular structures. CONCLUSION: Urinary TG2 in early posttransplant periods is a potent biomarker for kidney allograft inflammation or fibrosis.

Predictors of Avascular Necrosis after Kidney Transplantation / 대한이식학회지

BACKGROUND: Risk factors for bone avascular necrosis (AVN), a common late complication after kidney transplantation (KT), are not well known. METHODS: Patients that underwent living-donor KT at Asan Medical Center between January 2009 and July 2016 were included in this retrospective study to determine the incidence and risk factors for AVN after KT. RESULTS: Among 1,570 patients that underwent living-donor KT, 33 (2.1%) developed AVN during a mean follow-up of 49.8±25.0months. Additionally, AVN was diagnosed at a mean of 13.9±6.6 months after KT. The mean cumulative corticosteroid dose during the last follow-up in patients without AVN (9,108±3,400 mg) was higher than that that in patients with AVN (4,483±1,114 mg) until AVN development (P < 0.01). More patients among those with AVN (n=4, 12.1%) underwent steroid pulse treatment because of biopsy-proven rejections during the first 6 months after KT than patients without AVN (n=68, 4.4%; P=0.04). Female (hazard ratio [HR], 2.29; P=0.04) and steroid pulse treatment during the first 6 months (HR, 2.31; P=0.02) were significant AVN risk factors as revealed by the Cox proportional multivariate analysis. However, no significant differences in rejection-free graft survival rates were observed between the two groups (P=0.67). CONCLUSIONS: Steroid pulse treatment within 6 months of KT and being female were independent risk factors for AVN development.

Differences of cytomegalovirus diseases between kidney and hematopoietic stem cell transplant recipients during preemptive therapy

BACKGROUND/AIMS: Cytomegalovirus (CMV) surveillance and preemptive therapy is a widely-used strategy for preventing CMV disease in transplant recipients. However, there are limited data on the incidence and patterns of CMV disease during the preemptive period. Thus, we investigated the incidence and pattern of tissue-invasive CMV disease in CMV seropositive kidney transplantation (KT) and hematopoietic stem cell transplantation (HCT) recipients during preemptive therapy. METHODS: We prospectively identified patients with tissue-invasive CMV disease among 664 KT (90%) and 496 HCT (96%) recipients who were D+/R+ (both donor and recipient seropositive) during a 4-year period. RESULTS: The incidence rates of CMV disease were 4.1/100 person-years (4%, 27/664) in KT recipients and 5.0/100 person-years (4%, 21/496) in HCT recipients. Twenty-six (96%) of the KT recipients with CMV disease had gastrointestinal CMV, whereas 17 (81%) of the HCT recipients had gastrointestinal CMV and 4 (19%) had CMV retinitis. Thus, CMV retinitis was more common among HCT recipients (p = 0.03). All 27 KT recipients with CMV disease suffered abrupt onset of CMV disease before or during preemptive therapy; 10 (48%) of the 21 HCT recipients with CMV disease were also classified in this way but the other 11 (52%) were classified as CMV disease following successful ganciclovir preemptive therapy (p < 0.001). CONCLUSIONS: The incidence of CMV disease was about 4% in both KT and HCT recipients during preemptive therapy. However, CMV retinitis and CMV disease as a relapsed infection were more frequently found among HCT recipients.

Diagnostic Usefulness of Cytomegalovirus (CMV)-Specific T Cell Immunity in Predicting CMV Infection after Kidney Transplantation: A Pilot Proof-of-Concept Study / 감염과화학요법

BACKGROUND: Cytomegalovirus (CMV) is one of the most important opportunistic infections in transplant recipients. Currently sero-positivity for CMV IgG before solid organ transplantation is the laboratory test of choice for stratifying the risk of CMV reactivation after solid organ transplantation. Theoretically, CMV-specific cell-mediated immune responses before solid organ transplantation should further categorize patients as high or low risk of CMV development. We therefore evaluated the usefulness of the CMV-specific enzyme-linked immunospot (ELISPOT) assay in kidney transplant (KT) candidates for predicting the development of CMV infections after transplantation. MATERIALS AND METHODS: All adult CMV IgG (+) recipients admitted to the KT institute between March 2014 and June 2014 were enrolled, and CMV infections after KT were observed between March 2014 and December 2014. All patients underwent CMV pp65 and IE1-specific ELISPOT assays before transplantation. CMV infection was defined in the presence of CMV antigenemia, CMV syndrome, or tissue-invasive CMV disease. We used the data to select optimal cut-off values for pp65 and IE1, respectively, on ROC curves. RESULTS: A total of 69 transplant recipients involving 54 (78%) living-donor KT, 9 (13%) deceased-donor KT, 3 (4%) kidney-pancreas transplants, and 3 (4%) pancreas transplants were enrolled. Of the 69 patients, 27 (39%) developed CMV infections. There was no association between the IE1-specific ELISPOT assay and CMV infection. However, only 15 (31%) of the 48 patients with positive pp65-specific ELISPOT results (>10 spots/2.0 x 105 cells) developed CMV infections, whereas 12 (57%) of the 21 patients with negative pp65-specific ELISPOT results developed CMV infection (P = 0.04). CONCLUSION: Negative pp65-specific ELISPOT assay results before transplantation appear to predict the subsequent development of CMV infections after transplantation in CMV IgG (+) KT recipients. Therefore, risk stratification of CMV IgG (+) recipients using the CMV-specific ELISPOT, together with preventive strategies, may further reduce CMV development.

Kidney Transplantation from the Deceased Donor Who Need Continuous Renal Replace Therapy / 대한이식학회지

BACKGROUND: Brain death donors may require continuous renal replacement therapy (CRRT) in severe acute renal failure (ARF) during management. To maximize donor organ usage we performed renal transplantation from deceased donors requiring CTTR with informed consent. This single-center study reviewed the clinical outcomes of kidney transplant recipients from extreme marginal donors requiring CRRT. METHODS: Medical records of all patients using a graft from extreme marginal donors who underwent CRRT in Asan Medical Center between June 2007 and September 2014 were reviewed retrospectively. RESULTS: Between June 2007 and September 2014, 27 kidneys were transplanted from 19 CRRT donors. Mean donor age was 35.1 years (range; 16~56), male donors were 14 (74%). The causes of brain death included head trauma in 6, hypoxia in 5, stroke in 4, and others in 4. The main causes of CRRT were anuria in 14, electrolyte imbalance or acidosis in 5, and mean duration of donor CRRT was 3.6 days (range; 1~11). Delayed graft function (DGF) developed in 24 (88.9%), but all recovered renal function; they can be free from dialysis 11 days after transplantation. Mean serum creatinine level at 1 month, 1 year, and 5 years was 1.85, 1.26, and 1.31 mg/dL, respectively. CONCLUSIONS: Five-year follow-up data showed that renal transplantation from severe ARF donor has an excellent outcome. Although CRRT donor kidney transplants have a higher rate of DGF, the presence of DGF, unlike other donation after brain death donor kidney transplants, does not portend a worse prognosis.

ABO Incompatible Living Donor Kidney Transplantation with Rituximab and Plasmapheresis: A Single Center Experience / 대한신장학회지

PURPOSE: ABO incompatibility had long been an obstacle in kidney transplantation. However, recent reports showed excellent outcomes. In this study, we evaluated the outcomes of ABO incompatible kidney transplantation with preconditioning protocol using rituximab and plasmapheresis. METHODS: The recipients who had an ABO-incompatible donor and underwent living donor kidney transplantation were enrolled. Preconditioning protocol was pretransplant single dose rituximab with plasmapheresis at pretransplantation 7-10 days. Immune suppression regimen consisted of tacrolimus, mycophenolate mofetil and steroid. Anti-A or anti-B antibody titer was monitored during preconditioning and post transplantation period. RESULTS: 37 patients underwent living donor ABO incompatible kidney transplantation. Median pre-treatment antibody titer was 1:64 and pre transplant antibody titer after 1-6 times of plasmapheresis was 1:2. Median follow-up duration was 332 days (range 156-681). One episode of acute T cell mediated rejection was observed. Mean serum creatinine at 2 weeks was 1.00+/-0.27 mg/dL and at 24 weeks was 1.21+/-0.37 mg/dL. CONCLUSION: ABO incompatible kidney transplantation with rituximab and plasmapheresis can be safely performed. It is therefore a valuable option for expanding donor pool and should be actively performed in Korea.

Medication Adherence in Patients Taking Immunosuppressants after Kidney Transplantation / 대한이식학회지

BACKGROUND: Kidney transplant recipients inevitably take a life-long immunosuppressive medication to prevent graft rejection. Non-compliance to immunosuppressive medication is one of the main causes leading to acute and chronic rejection and diminished renal function, resulting in a return to dialysis, increased morbidity, or mortality with an additional health care cost and poor quality of life. The purpose of this study was to investigate actual medication compliance and its related factors. METHODS: A total of 222 functioning kidney transplant recipients were surveyed in a single center, and 25 patients were excluded due to incomplete responses. We reviewed medical records retrospectively, and the data were statistically analyzed with SPSS version 13.0. RESULTS: Among 197 patients, 113 (57.4%) were compliant to the immunosuppressive agents, and 84 (42.6%) recipients were non-compliant. Non-compliant patients were significantly younger (P=0.004), highly educated (P=0.004), employed (P=0.005), more likely to live alone (P=0.035), and drank more (P=0.001) than the compliant patients. Regarding psychosocial factors, more barriers (P=0.015), weak beliefs about the necessity of taking medications (P=0.001), strong beliefs about specific concerns related to medications (P=0.038), and low self efficacy (P=0.003) were identified in the non-compliant group compared with the compliant group. CONCLUSIONS: This study revealed that multiple factors affected medication compliance in patients taking immunosuppressants. It would be helpful to identify potential recipients with a risk for non-compliance based on their general characteristics and psychosocial factors, so they can be provided a specialized education program to promote compliance. This strategy may help produce more favorable long-term outcomes among kidney transplant recipients.