Search

Background: Chronic active antibody-mediated rejection is a major etiology of graft loss in renal transplant recipients. However, there is no consensus on the optimal treatment strategies., Methods: Computerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of chronic active antibody-mediated rejection. The patients were divided into two groups according to treatment strategy: Group 1 received aggressive treatment (double filtration plasmapheresis and one of the followings: rituximab, intravenous immunoglobulin, antithymogycte globulin, bortezomib, or methylprednisolone pulse therapy); and group 2 received supportive treatment., Results: From February 2009 to December 2017, a total of 82 patients with biopsy-proven chronic antibody mediated rejection were identified. Kaplan-Meier analysis of death-censored graft survival showed a worse survival in group 2 (P = 0.015 by log-rank test). Adverse event-free survival was lower in group 1, whereas patient survival was not significantly different. Proteinuria and supportive treatment were independent risk factors for graft loss in multivariate analysis., Conclusions: Aggressive treatment was associated with better graft outcome. However, higher incidence of adverse events merit personalized treatment, especially for those with higher risk of infection. Appropriate prophylactic antibiotics are recommended for patients undergoing aggressive treatment.

Chronic antibody-mediated rejection is the most common cause of late graft loss in renal transplant recipients. Visfatin is a pre-B cell colony-enhancing factor secreted by activated lymphocytes. We hypothesize that visfatin may play a role in the augmentation of B cell colonies and facilitate antibody-mediated rejection. Renal transplant recipients were randomly selected for the study. Fasting blood samples were obtained for the assay of visfatin. The participants were prospectively followed up for 3 years. A total of 146 patients were recruited for the study and were divided into 3 groups according to tertile of serum visfatin level. At the end of follow-up, 6 patients had graft loss, including 1 graft loss in tertile 1, 3 in tertile 2, and 2 in tertile 3 (P = .60). Fourteen patients experienced at least 1 episode of acute rejection, while 21 patients were diagnosed as having chronic rejection. The distribution of acute rejection was 10.2% in tertile 1, 10.2% in tertile 2, and 8.3% in tertile 3 (P = .94); chronic rejection occurred in 10.2%, 16.3%, and 16.7%, respectively (P = .59). We conclude that serum visfatin level was not correlated with either graft failure or patient mortality in a 3-year observation period., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Tacrolimus is the most commonly prescribed immunosuppressive drug after kidney transplantation (KTx). The trough level of tacrolimus (T0) is currently used for routine monitoring after KTx. The purpose of this study was to examine the association between the variability of T0 and acute rejection., Methods: All kidney transplant recipients (KTR) with tacrolimus-based regimen and episode of biopsy-proven acute rejection (BPAR) between January 2012 and October 2014 were enrolled in the acute rejection (AR) group. KTR with tacrolimus-based regimen and without episode of AR were enrolled in the control group. All of the results of T0 within 6 months before episode of acute rejection were used for the calculation of within-patient variability of T0. The percent coefficient of variation, which is calculated as (standard deviation of mean/mean) × 100%, was used to represent the concentration variability of tacrolimus., Results: In all, 25 KTR with AR and another 136 KTR without BPAR were enrolled in the study. The mean age of all 161 patients was 50.1 ± 10.4 years, and the mean duration after KTx was 4.3 ± 4.7 years. The average daily dose of tacrolimus was 5.7 ± 2.6 mg, and T0 was 5.4 ± 1.8 ng/mL. Age, sex, duration after KTx, daily dose of tacrolimus, and T0 were similar in both groups. Compared with the control group, the percent coefficient of variation of T0 was significantly higher in patients with BPAR 12.1% ± 7.9% vs 39% ± 15.6%, P<.001., Conclusions: The study results suggest that, in KTR, higher variability of tacrolimus trough level is associated with higher risk of acute rejection., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Decoy receptor 3 (DcR3) expression in kidneys has been shown to predict progression of chronic kidney disease. We prospectively investigated a cohort comprising 96 renal transplant recipients (RTRs) undergoing graft kidney biopsies. Computer-assisted quantitative immunohistochemical staining value of DcR3 in renal tubular epithelial cells (RTECs) was used to determine the predictive role of DcR3 in kidney disease progression. The primary end point was doubling of serum creatinine and/or graft failure. A multivariate Cox proportional hazards model was used to assess the risk of DcR3 expression in rejected kidney grafts toward the renal end point. In total, RTRs with kidney allograft rejection were evaluated and the median follow-up was 30.9 months. The greater expression of DcR3 immunoreactivity in RTECs was correlated with a higher rate of the histopathological concordance of acute T cell-mediated rejection. Compared with 65 non-progressors, 31 progressors had higher DcR3 expression (HDE) regardless of the traditional risk factors. Cox regression analysis showed HDE was significantly associated with the risk of renal end point with a hazard ratio of 3.19 (95% confidence interval, 1.40 to 7.27; P = 0.006) after adjusting for other variables. In repetitive biopsies, HDE in tissue showed rapid kidney disease progression due to persistent inflammation.

Background: Cytomegalovirus (CMV) remains the most critical viral pathogen after kidney transplantation (KTx). The universal prophylaxis, but not pre-emptive therapy, could avoid the wide range of indirect effects induced by CMV infection. This study aims to examine the effect of universal prophylaxis with oral valganciclovir for the first year of CMV disease after KTx., Methods: The universal prophylaxis therapy was started in May 2008. Patients who received KTx between January 2006 and September 2010 were included in the study. Oral valganciclovir (Valcyte) was used for 3 months with dosage adjusted by eGFR. CMV disease was defined by typical CMV syndrome with positive viremia or tissue proven. The study end points are episode of CMV disease and first-year biopsy-proven acute rejection., Results: In total, 68 KTx patients who received universal prophylaxis for 3 months (study group) and another 50 KTx recipients without universal prophylaxis (control group) were enrolled. The incidence of CMV disease was 8.0% (4 of 50) in the control group. The universal prophylaxis significantly reduced the first-year episodes of CMV disease to 0% (0 of 68). There were 8 episodes of biopsy-proven acute rejection (8 of 50, 16%) within 1 year after KTx in the control group, but only 2 episodes of biopsy-proven acute rejection (2 of 68, 2.9%) in the treatment group (P < .05)., Conclusions: Universal prophylaxis with oral valganciclovir for 3 months significantly reduced episodes of first-year CMV disease and biopsy-proven acute rejection in kidney transplant recipients., (Copyright © 2014. Published by Elsevier Inc.)

Background Doubling of serum creatinine (DSC) in transplantation has been seen as the end-point of renal function without pathological evidence. We conducted this study to elucidate the relationship between DSC and pathological findings. Material and Methods We conducted a retrospective cohort study to illustrate pathologic changes in patients receiving a kidney biopsy in the previous 5 years with clinicopathological correlations to DSC and proteinuria. Results Of a total of 99 kidney recipients (146 biopsies), results of graft biopsy were as follows: calcineurin inhibitor toxicity (CNI) (38.7%) and rejection (36.9%). Compared to males, females had higher proportions of class I (p=0.003) and class II PRA (p<0.001), and a higher rejection rate (p=0.042), but had the same clinical outcomes as males, like eGFR at follow-up (p=0.882), DSC (p=0.703), and proteinuria (p=0.745).                         Pathological diagnoses and findings were related to proteinuria: glomerulopathy (HR=4.9, p=0.01), AMR (HR=2.5, p=0.025), especially acute AMR (HR=2.9, p=0.008), chronic glomerular change (HR=10.2, p=0.002), arteriolar hyaline (HR=2.3, p=0.026), and mesangial matrix change (HR=6.3, p=0.002).                         BK nephropathy and rejection were the only 2 risk factors. Pathological findings favoring AMR (PTC infiltration and glomerulitis) showed a greater risk of DSC compared with those favoring CMR (interstitial inflammation, intimal arteritis, and tubulitis). DSC was correlated with clinical manifestation (rejection) and provided strong pathological evidence. Conclusions There was more acute rejection and chronic pathological change in women, but outcomes were the same due to less activity of renin-angiotensin-aldosterone and hyperfiltration in females. DSC as an end-point of graft function can be used to identify recipients, especially AMR or mixed AMR and CMR. 1. All forms of support received by each author: None of the authors received support. 2. Any potential conflict of interest for each author: No conflict of interest for any of the authors.

This study was conducted to delineate the frequency of recurrent lupus nephritis in a Chinese kidney transplant cohort and to estimate its impact on long-term transplant outcomes. A total of 32 lupus transplant patients were enrolled in this study, and the medical records were retrospectively reviewed. Patients with unexplained graft abnormalities were subjected to allograft biopsy. Recurrent lupus nephritis was diagnosed by light microscopy, immunofluorescence, and electron microscopy. In addition, to determine the clinical manifestations of recurrent lupus GN in these patients, serum original systemic lupus erythematosus disease activity index (SLEDAI) scores while undergoing allograft biopsy were evaluated. In total, six out of 32 patients (18.8%; mean age, 40.5 ± 9.1 years) were diagnosed as having recurrent lupus nephritis and the mean time at diagnosis was 5.1 ± 4.9 years post-transplantation. According to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 criteria, three of the six cases (50%) were defined as class I, one was class II, one was class IV, and one was class III + V. The graft and patient survival rates of recurrent lupus nephritis (n = 6) were not different from those of patients with other diagnostic entities. Although recurrent lupus nephritis was not uncommon, it did not appear to have a strong negative impact on long-term outcome in Chinese kidney transplant patients. The recurrence was potentially treatable and should not be precluded for receiving transplantation.

Induction therapy with interleukin-2 receptor antagonist (IL2RA) is widely used for renal transplant recipients and this study aimed to examine the impact of IL2RA among Chinese renal transplant recipients. Two hundred and thirty-eight Chinese renal transplant recipients aged 18-65 years at the Taichung Veterans General Hospital from January 2004 to July 2009 were retrospectively studied to assess the influence of IL2RA on biopsy-proven acute rejection (BPAR) within 1 year. Secondary outcomes included acute rejection rate in the first 3 months, delayed graft function, post-transplant diabetes mellitus, and malignancy. Cox proportional hazard analysis was used for multivariate analysis. Of all the patients, 116 received IL2RA (basiliximab, n = 44; daclizumab, n = 72) and 122 had no induction therapy. The mean follow-up duration was 43.3 months (range, 1-79 months). Overall, 227 (95.4%) patients completed the 12-month follow-up period with a functioning graft. No difference of BPAR was observed between the two groups and the secondary outcomes were also similar. After adjusting potential covariates with Cox regression, IL2RA use still provided no benefit on BPAR. In conclusion, there is no benefit of IL2RA in decreasing BPAR was observed in our study. Routine use of IL2RA for adult Chinese kidney transplant recipients may not be as effective as we thought before. More research is still needed to elucidate the effect of IL2RA among Chinese kidney transplant recipients.

Trends in maintenance immunosuppressive drugs used among Taiwanese kidney transplant recipients have not been reported before. We examined the National Health Insurance Research Database to analyze trends in maintenance immunosuppressive drugs used in Taiwanese kidney transplant recipients for the years 2002-2009. The new case number of kidney transplant recipients ranged from 302 to 673 per year. In 2009, 5276 kidney transplant recipients received immunosuppressive therapy. The 5-year renal graft survival rate of kidney transplant recipients was 93%. In 2009, the most common immunosuppressive therapy among Taiwanese kidney transplant recipients was a triple regimen that included tacrolimus, mycophenolate mofetil, and corticosteroid. There was a significant increase in the use of a tacrolimus-based regimen from 35.1%-58.2%, while the use of cyclosporine decreased from 62.2%-24.8% (P < .05). The percentage of calcineurin inhibitor-free regimen increased from 2.7%-17%. Moreover, the use of Rapamune dramatically increased from 8.2%-22.6% in 2002-2004. However, the percentage of kidney transplant recipients using Rapamune maintained 23 ± 1.6% in 2004-2009. The use of mycophenolic acid remained stable at about 74.9 ± 3.2% in 2002-2009. As predicted, the use of Imuran decreased from 6.9%-3.5%. In summary, although calcineurin inhibitors remained the mainstay of immunosuppressive drugs, these findings suggest a general trends toward individualized regimens and the use of calcineurin inhibitor-free and mammalian target of rapamycin inhibitors-based regimens in Taiwanese kidney transplant recipients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

A 55-year-old female received a cadaveric renal transplant in 2003. Sixteen months later, multiple liver nodules were found in a routine abdominal sonogram follow-up. Serial studies were all negative for malignancy. She was placed on a quadruple immunosuppressive regimen, including prednisolone, cyclosporine, mycophenolate mofetil and sirolimus. Her graft function was stable with serum creatinine of 1.0 mg/dl and there had been no rejection since transplantation. Liver function and lipid profile were within normal limits. Serum ferritin level was 1,466 ng/ml. Two liver biopsies, 4 months apart, showed fatty metamorphosis of the liver and no tumor. She was closely watched and no malignancy was found in the subsequent 3 years. Cyclosporine and sirolimus were tapered and corticosteroid withdrawn gradually. Serum ferritin level gradually declined to 600 - 800 ng/ml in subsequent years. Interestingly, the liver nodules gradually disappeared and there were only a few left on the last follow-up in April, 2008.

Background: Chronic allograft nephropathy (CAN) is characterized by a progressive deterioration of renal function with various degrees ofproteinuria. Currently, there is no effective treatment despite the introduction of new generations of immunosuppressants. Pentoxifylline (PTX) is a phosphodiesterase inhibitor that possesses antiproteinuric effect and has been proved to be effective in treating several glomerular diseases. The purpose of the current study was to examine the effect of PTX on renal transplant patients with established CAN., Materials and Methods: Renal transplant recipients with biopsyproven CAN were recruited for the study. All the patients had been on angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for more than 1 year and were on a triple immunosuppressive regimen including corticosteroid, calcineurine inhibitor and mycophenolate mofetil. PTX in a dose of 1,200 mg/day was administered for at least 6 months. The following parameters were assessed at baseline, the 3rd and the 6th month post treatment: systolic and diastolic blood pressure, number of anti-hypertension drugs, serum creatinine (sCr),estimated glomerular filtration rate (eGFR), 24-hour urinary protein excretion (U/P), urinary N-acetylglucosaminidase (NAG) and intracytoplasmic Thl/Th2 cytokines production of peripheral blood CD4+ cells., Results: A total of 17 (11 male and 6 female) patients were enrolled in the study. The mean duration of follow-up post transplant was 10.6+/- 4.4 years. The baseline data of sCr, eGFR and U/P were 1.83+/-0.46 mg/dl, 38+/-8 ml/min and 2.65+/-2.15 g/day, respectively. Corresponding values at the 3rd and 6th month post treatment were 1.90+/-0.43 mg/dl (p = NS), 33+/-7 ml/min (p=NS), 2.13 +/-1.13 g/day (p < 0.05) and 2.03+/-0.64 mg/dl (p < 0.05), 32+/-10 ml/min (p < 0.05), 2.74 +/-0.93 g/day (p = NS), respectively. When individual data were analyzed, five cases (29.4%) showed a U/P significant reduction of more than 50% of baseline value, while in 10 cases (58.8%) the graft function remained either stable (9 cases) or improved (1 case) at the end of treatment. Urinary NAG was elevated at the 3rd month, but stabilized thereafter. The Thl/Th2 intracytoplasmic cytokine pattern of peripheral blood CD4+ cells showed a significant decrease of cells bearing TNF-alpha (15.0+/-14.4% vs 14.2+/-17.0%, p < 0.05) and cells bearing IL-10 (1.60 +/-1.23% vs 0.90+/-0.66%, p < 0.05) at the 3rd month., Conclusion: In this pilot study, PTX seemed to be temporarily effective in reducing proteinuria. The graft function was stabilized in more than half of patients at the end of follow-up.

Chronic allograft nephropathy (CAN) is the most common cause of late renal transplant loss. Calcineurin inhibitor (CNI) nephrotoxicity is known to contribute to CAN. A sirolimus-based regimen way allow for early CNI reduction or elimination. The aim of the present study was to determine the efficacy and safety of a sirolimus-based regimen for CAN. From December 2001 to August 2003, kidney transplant (KTx) recipients with CAN were enrolled for treatment with sirolimus. Among 32 studied patients, 24 (75%) underwent graft biopsy before the initiation of sirolimus. Baseline maintenance immunosuppression consisted of cyclosporine/tacrolimus and prednisone with or without mycophenolate mofetil. The follow-up duration on sirolimus therapy was 8.5 +/- 5.9 months (range: 1 to 22 months). The average dosage of sirolimus was 1.8 +/- 0.5 mg/d at the end of follow-up. The mean trough level of sirolimus was 5.1 +/- 2.1 ng/mL. Sirolimus was effective in 16 (50%) patients while 3 (9.4%) patients improved (serum creatinine [Cr] decrease > 10%) and 13 (40.6%) maintained stable (change of serum Cr within 10%). Sirolimus was effective in 5 (35.7%) patients whose serum Cr was over 3.0 mg/dL but failed to rescue all four patients whose serum Cr was over 4.0 mg/dL. Eleven (68.8%) of 16 responders showed a reduction (29.8% +/- 13.8%) in CNI dosage. The most common adverse events were hyperlipidemia (37.5%), anemia (25%), and diarrhea (21.8%). Twelve patients discontinued sirolimus due to graft failure (4), severe infection (3), stroke related mortality (1), anemia (2), diarrhea (1), and edema (1). In conclusion, sirolimus is effective in 50% of KTx recipients with CAN, especially when the serum Cr is less than 3.0 mg/dL. However, the increased incidence of infection, diarrhea, and hyperlipidemia are of major concern.

A renal allograft transplant patient with high serum creatinine presented clinical symptoms of rejection. Sections of renal biopsy tissue showed mononuclear leukocyte infiltration in the tubulointerstitium and nuclear enlargement with inclusions in the tubular epithelium. The morphological characteristics resembled polyomavirus-induced interstitial nephritis. Electron microscopy of the nuclear inclusions showed paracrystalline arrays of naked viral particles with a diameter of 45 nm. Molecular studies revealed that a new variant of BK virus (BKV) with rearrangement at the regulatory region was involved in the nephritis. The BKV regulatory region contained a tandem repeat from the P-block to the Q-block causing duplication of several important transcriptional elements or transcriptional factor binding motifs. This is the first report to show a naturally occurring BKV variant with regulatory region rearrangement associated with tubulointerstitial nephritis., (Copyright 2001 Wiley-Liss, Inc.)

It is important to differentiate between cell-mediated (acute) and humoral (chronic) rejection in renal transplantation in order to initiate appropriate therapy. Since effective renal plasma flow (ERPF) provides a sensitive method of analyzing renal function, this test was undertaken to evaluate the possibility of differentiating acute and chronic rejections by ERPF. A total of 90 patients (no rejection: 33, acute rejection: 45, chronic rejection: 12) were retrospectively included in this study. ERPF was determined by performing comprehensive renal function test (Tauxe et al., 1980) and Student's unpaired t-test was used to evaluate the statistical difference (no rejection vs chronic rejection, no rejection vs acute rejection, acute rejection vs chronic rejection). The ERPF value of the no rejection group (228.9 +/- 119.2 ml/min) was significantly higher than the ERPF value of the acute rejection group (167.5 +/- 86.9 ml/min) and the chronic rejection group (137.2 +/- 60.2 ml/min) (P < 0.05). By in contrast, there was no significant difference between the acute rejection group and the chronic rejection group (P > 0.05). We concluded that ERPF value alone could not differentiate between acute rejection and chronic rejection in renal transplantation.