Outcomes of COVID-19 in kidney transplant recipients in the vaccination Era: A national multicenter cohort from Thailand.

Introduction: The mortality rate of coronavirus disease 2019 (COVID-19) in kidney transplant recipients (KTR) has significantly decreased with the implementation of vaccination programs. However, the real-world information on the impact of vaccinations, particularly in resource limited settings in Asia, is still limited. Methods: The Thai Transplant Society conducted a prospective multicenter cohort registry, including KTR diagnosed with COVID-19. Cox proportional hazards regression was used to examine factors associated with poor COVID-19 outcomes and complications, including death, COVID-19 pneumonia, and superimposed bacterial infection. Results: A total of 413 patients from 17 transplant centers who developed COVID-19 were analyzed. The COVID-19 mortality rate was 5.6 % and the incidence of pneumonia was 18.8 %. With each 10-year increase in age, the risk of death, pneumonia, and bacterial infection increased by 61 %, 32 %, and 43 %, respectively. A total of 11.4 % of KTR received one dose of COVID vaccination (incomplete vaccination), 25.7 % received two doses (complete primary vaccination), 42.6 % received three doses (first booster dose), and 10.4 % received four doses of vaccination (second booster dose). Even a single dose of vaccination significantly decreased the risk of death, pneumonia, and superimposed bacterial infection among KTR compared to those who remained unvaccinated. Completing the primary vaccination (2-dose) reduced the risk of death by 89 %, pneumonia by 88 %, and bacterial infection by 83 % compared to unvaccinated KTR. Receiving a booster dose (third or fourth dose) further reduced the risk of death by 94 %, pneumonia by 95 %, and bacterial infection by 96 % compared to unvaccinated individuals. Conclusions: This Asian cohort demonstrated that the mortality and complications of COVID-19 significantly decreased in KTR after the national immunization. Our study suggests that any type of COVID-19 vaccine can be beneficial in preventing adverse outcomes. Administering booster vaccinations is strongly recommended.

Clinicopathological Correlation of Polyomavirus Nephropathy in Renal Allograft Recipients According to the Banff 2018 Classification.

BACKGROUND: Polyomavirus nephropathy (PVN) is a rare kidney disease caused by the BK virus, a strain of polyomavirus. The disease primarily affects transplant recipients, which is related to intensive immunosuppression protocol and can lead to kidney allograft failure. OBJECTIVES: The objective of this study is to analyze histopathological features of PVN using the Banff 2018 PVN classification and to determine clinical features and outcomes of patients with PVN in each histologic class. MATERIALS AND METHODS: The study included 44 patients who had been diagnosed with PVN by renal allograft biopsy in a large tertiary care hospital in Thailand from January 2011 to January 2020. The kidney biopsy slides were reviewed for Banff 2018 PVN classification and other histologic features. Patient demographic information, clinical data, and laboratory results were retrospectively collected. RESULTS: Nine (20.45%), 27 (61.36%), and eight (18.18%) cases of PVN were Class I, Class II, and Class III, respectively. The time from transplant to PVN diagnosis for Classes I, II, and III was four, 19, and 33.5 months, respectively. Class III had the worst clinical outcomes in terms of deterioration of allograft function, the lowest rate of resolution, and the highest rate of graft failure. CONCLUSIONS: PVN classification provides prognostic information in renal allograft biopsy. Our study confirmed the validity of the three-tier histologic PVN classification put forward by the Banff Working Group in 2018.

The effect of the very low dosage diltiazem on tacrolimus exposure very early after kidney transplantation: a randomized controlled trial.

The objective of this study was to assess the effect of the very low dosage of diltiazem on tacrolimus exposure during the first week post-kidney transplantation, among cytochrome P450 (CYP) 3A5 expressers who did not receive diltiazem (EXplb), CYP3A5 expressers who received the very low dose diltiazem (EXdtz), CYP3A5 nonexpressers who did not receive diltiazem (NEplb), and CYP3A5 nonexpressers who received the very low dose diltiazem (NEdtz). Forty kidney recipients who receive tacrolimus-based immunosuppressive regimen were randomly assigned, with stratification on the CYP3A5 genotypes, to receive either diltiazem 30 mg every 12 h or a matched placebo. The observed median dose-adjusted area under the 12-h curve of tacrolimus concentration (AUC/D) at day 7 post-transplantation was lowest in the EXplb group followed by EXdtz, NEplb, and NEdtz at 34.9, 43.6, 49.4, and 71.1 ng*h/mL per mg, respectively. A Kruskal-Wallis test showed a significant difference in the mean ranks of AUC/D among groups. Significant differences between EXplb and NEplb, and between EXplb and NEdtz were demonstrated, whereas no sufficient evidence of significant differences was detected between the other pairs. In conclusion, coadministration of diltiazem 30 mg twice daily may be advantageous for increasing tacrolimus exposure early after kidney transplantation among CYP3A5 expressers.

Preemptive Living-Related Kidney Transplantation Is a Cost-Saving Strategy Compared With Post-dialysis Kidney Transplantation in Thailand.

Background: Compared with other kidney replacement therapies, preemptive kidney transplantation (KT) provides better clinical outcomes, reduces mortality, and improves the quality of life of patients with end-stage kidney disease (ESKD). However, evidence related to the cost-effectiveness of preemptive living-related KT (LRKT) is limited, especially in low- and middle-income countries, such as Thailand. This study compared the cost-effectiveness of LRKT with those of non-preemptive KT strategies. Methods: Cost and clinical data were obtained from adult patients who underwent KT at Siriraj Hospital, Mahidol University, Thailand. A decision tree and Markov model were used to evaluate and compare the lifetime costs and health-related outcomes of LRKT with those of 2 KT strategies: non-preemptive LRKT and non-preemptive deceased donor KT (DDKT). The model's input parameters were sourced from the hospital's database and a systematic review. The primary outcome was incremental cost-effectiveness ratios (ICERs). Costs are reported in 2020 United States dollars (USD). One-way and probabilistic sensitivity analyses were performed. Results: Of 140 enrolled KT patients, 40 were preemptive LRKT recipients, 50 were non-preemptive LRKT recipients, and the rest were DDKT recipients. There were no significant differences in the baseline demographic data, complications, or rejection rates of the three groups of patients. The average costs per life year gained were $10,647 (preemptive LRKT), $11,708 (non-preemptive LRKT), and $11,486 (DDKT). The QALY gained of the preemptive option was 0.47 compared with the non-preemptive strategies. Preemptive LRKT was the best-buy strategy. The sensitivity analyses indicated that the model was robust. Within all varied ranges of parameters, preemptive LRKT remained cost-saving. The probability of preemptive LRKT being cost-saving was 79.4%. Compared with non-preemptive DDKT, non-preemptive LRKT was not cost-effective at the current Thai willingness-to-pay threshold of $5113/QALY gained. Conclusions: Preemptive LRKT is a cost-saving strategy compared with non-preemptive KT strategies. Our findings should be considered during evidence-based policy development to promote preemptive LRKT among adults with ESKD in Thailand.

QuantiFERON-Cytomegalovirus Assay for Prediction of Cytomegalovirus Viremia in Kidney Transplant Recipients: Study From High Cytomegalovirus Seroprevalence Country.

Background: Early studies showed the utility of pretransplant QuantiFERON-Cytomegalovirus (QF-CMV) assays for CMV-disease prediction post kidney transplant (KT). However, recent data are conflicting. Methods: This prospective cohort study enrolled adult patients undergoing KT between July 2017 and May 2019. Patients with antithymocyte globulin therapy or negative pretransplant CMV IgG were excluded. QF-CMV assays were performed on transplantation day and one month thereafter, and CMV viral loads were obtained 1, 3, and 6 months posttransplantation. The primary outcome was CMV viremia within 6 months. The QF-CMV assay-posttransplant CMV viremia association was analyzed. Results: Fifty-five patients were enrolled (male, 58.2%; mean (SD) age, 46.5 (10.2) years). Fifty-two (94.5%) received CMV-seropositive donor kidneys. Over 6 months, 29 patients developed CMV viremia (52.7%), with 14 (25.5%) having significant viremia requiring antiviral therapy. The CMV-viremia incidence of patients with nonreactive and reactive baseline QF-CMV assays did not differ significantly (55.3% and 47.1%; p = 0.573). Among patients with reactive pretransplant QF-CMV assays, there was a trend toward a lower incidence of CMV viremia for those who were persistently reactive at 1 month after KTs, although there was no statistically significant difference (50% vs 83%; p = 0.132). Conclusions: Our study could not support the use of single-timepoint pretransplant or 1-month posttransplant QF-CMV assays as a predictor for posttransplant CMV viremia in CMV seropositive KT recipients. Investigation of the association between dynamic QF-CMV-status changes and CMV-viremia incidence are needed.

Long-term outcome of percutaneous transluminal renal angioplasty (PTRA) versus PTRA with stenting (PTRAS) in transplant renal artery stenosis.

BACKGROUND: Endovascular treatment is standard of care for transplant renal artery stenosis (TRAS). No study has evaluated long-term outcomes compared between percutaneous transluminal renal angioplasty (PTRA) and PTRA with stenting (PTRAS). Accordingly, this study aimed to investigate the 1-year clinical success, and short- and long-term event-free survival between PTRA and PTRAS in patients diagnosed with TRAS at Thailand's largest national tertiary referral center. METHODS: This single-center retrospective study included kidney transplant patients treated for TRAS during January 2001 to June 2019. Clinical success was defined as (1) increase in estimated glomerular filtration rate (eGFR) > 15%, or (2) reduction in mean arterial pressure (MAP) > 15% with no decrease in antihypertensive medication, or no reduction in MAP or reduction in MAP < 15% with decrease in antihypertensive medication. Incidence of kidney transplant graft failure and transplant renal artery stenosis were also collected. RESULTS: Sixty-five cases of TRAS were identified from 1072 patients who underwent kidney transplantation. The majority (98.5%) had end-to-side anastomosis technique. Thirty-four patients had PTRA, while 31 patients had PTRAS. One-year clinical success according to renal outcome and BP reduction was 78.5% and 49.2%, respectively. Both renal outcome (79.4% vs. 77.4%, p = 0.845) and BP reduction (40.6% vs. 58.1%, p = 0.166) at 1 year were similar between the PTRA and PTRAS groups. Compared between PTRA and PTRAS, event-free survival for composite of kidney transplant graft failure or transplant renal artery restenosis was significantly higher for PTRAS at 1 year (82.4% vs. 100%, p = 0.025), but not significantly different at 10 years (73.5% vs. 71%, p = 0.818). CONCLUSIONS: We demonstrated the 1-year clinical success, and short- and long-term event-free survival between PTRA and PTRAS in TRAS patients. One-year clinical success was found to be similar between groups. Event-free survival for composite of kidney transplant graft failure or transplant renal artery restenosis was significantly higher in PTRAS at 1 year, but similar between groups at 10 years. Trial registration Thai Clinical Trials Registry, TCTR20200626002. Registered 26 June 2020-Retrospectively registered, http://www.clinicaltrials.in.th/index.php?tp=regtrials&menu=trial search&smenu = fulltext&task = search&task2 = view1&id = 6441.

High Intrapatient Variability in Tacrolimus Exposure Calculated Over a Long Period Is Associated With De Novo Donor-Specific Antibody Development and/or Late Rejection in Thai Kidney Transplant Patients Receiving Concomitant CYP3A4/5 Inhibitors.

BACKGROUND: High intrapatient variability in tacrolimus trough levels (Tac IPV) is associated with poor allograft outcomes. Tac IPV was previously calculated using trough levels 6-12 months after kidney transplantation (KT). Data on the accuracy of Tac IPV calculation over a longer period, the association between high Tac IPV and donor-specific antibody (DSA) development after KT in Asian patients, and the role of IPV in patients receiving concomitant cytochrome P450 (CYP)3A4/5 inhibitors (CYPinh) are limited. METHODS: A retrospective review of patients who underwent KT at our center in 2005-2015, and who received Tac with mycophenolate during the first 2 years after KT was performed. IPV was calculated using Tac levels adjusted by dosage. DSA was monitored annually after KT using a Luminex microbead assay. RESULTS: In total, 236 patients were enrolled. CYPinh were prescribed to 189 patients (80.1%): 145 (61.4%), 31 (13.1%), and 13 (5.5%) received diltiazem, fluconazole, and ketoconazole, respectively. Mean IPV calculated from adjusted Tac levels for 6-12 months (IPV6-12) and 6-24 months (IPV6-24) after KT were 20.64% ± 11.68% and 23.53% ± 10.39%, respectively. Twenty-six patients (11%) showed late rejection and/or DSA occurrence, and had significantly higher IPV6-24 (29.42% ± 13.78%) than others (22.77% ± 9.64%; P = 0.02). There was no difference in IPV6-12 (24.31% ± 14.98% versus 20.17% ± 10.90%; P = 0.18). IPV6-12 and IPV6-24 were comparable in patients who did and did not receive CYPinh. When using mean IPV6-24 as a cutoff, patients with higher IPV6-24 had a higher probability of developing DSA and/or late rejection (P = 0.048). CONCLUSIONS: Tac IPV6-24 was higher and more significantly associated with DSA development and/or late rejection than Tac IPV6-12, independent of Tac trough level. This is the first study to demonstrate the impact of high IPV on DSA development in Asian patients, and that Tac IPV is comparable between patients with and without CYPinh.

Efficacy of Bortezomib as an Adjunctive Therapy for Refractory Chronic Active Antibody-Mediated Rejection in Kidney Transplant Patients: A Single-Center Experience.

BACKGROUND: Chronic active antibody-mediated rejection (CAMR) has unsatisfactory prognosis in spite of intensive standard antihumoral treatment. Efficacy of additional bortezomib in CAMR remains uncertain. METHODS: A retrospective chart review was conducted among kidney transplant patients with biopsy-proven CAMR. Our standard CAMR protocol included plasma exchange, intravenous immunoglobulin, and rituximab. Repeated treatment was provided for refractory cases. Patients receiving at least 1 course of bortezomib were enrolled as the bortezomib group. Allograft outcome was compared among patients receiving repeated standard protocol alone and the bortezomib group. RESULTS: Thirteen and 15 patients were assigned to the bortezomib and control groups, respectively. Repeated bortezomib protocol was given for 1, 2, 3, and 4 courses in 6, 4, 1, and 2 patients, respectively. With a median follow-up time after treatment of 41.8 (18.3-47.4) months, the bortezomib group had a lower rate of glomerular filtration rate declination (-4.20 ± 4.89 mL/min/y vs -12.33 ± 10.44 mL/min/y; P = .014), a higher rate of disappearance of donor specific antibodies (69.2% vs 25%; P = .03), a lower rate of allograft loss (15.4% vs 66.7%; P = .006), and better allograft survival (P = .006). CONCLUSION: In CAMR, additional bortezomib treatment was more effective in eliminating donor specific antibodies and improving allograft survival than standard protocol treatment.

A Study of the Pharmacokinetic Comparison between the Generic and Original Form of Mycophenolate Mofetil Among Thai Renal Transplant Patients.

BACKGROUND: Mycophenolic acid (MPA) is one of the main immunosuppressive regimens used after kidney transplantation (KT). The less expensive, generic form of mycophenolate mofetil (MMF) (Immucept®) is recently available in Thailand. Comparisons of the pharmacokinetic profiles between the original and generic forms of MMF among post-KT patients are limited. METHODS: This prospective cohort study recruited KT patients receiving stable doses of MMF 1000 mg daily along with tacrolimus and steroids. All participants were prescribed CellCept® 500 mg every 12 hours for at least 2 weeks before measuring the MPA area under the curve from 0 to 12 hours (AUC0-12). CellCept® was switched to Immucept® 500 mg every 12 hours for 2 weeks and MPA AUC0-12 was remeasured. RESULTS: Twenty patients with a median follow-up time of 35.4 (11.13-198.83) months were enrolled. Mean MPA AUC0-12 of Immucept® was higher than CellCept® without statistical significance (48.27 ± 2.31 µg⋅hr/mL vs 42.19±15.20 µg⋅hr/mL; P value = .59). No difference was revealed regarding the minimum measured concentration, maximum measured concentration, and time point with maximum concentration between both drugs. While on CellCept®, 5 patients (25%) had an MPA AUC0-12 < 30.0 µg⋅hr/mL, but 3 patients (15%) had MPA AUC0-12 < 30.0 µg⋅hr/mL when receiving Immucept®. However, 3 (15%) and 6 (30%) patients had MPA AUC0-12 > 60.0 µg⋅hr./mL when treated with CellCept® and Immucept®, respectively. CONCLUSION: Generic MMF exhibited a comparable pharmacodynamic profile as the original formulation. MPA AUC0-12 was more than 30.0 µg⋅hr/mL among most patients receiving MMF 1000 mg/day.

Effect on Dosage Change and Intrapatient Variability After Conversion From Twice-Daily to Once-Daily Tacrolimus Among Thai Kidney Transplant Patients With and Without CYP3A4/5 Inhibitors.

BACKGROUND: Converting to once-daily tacrolimus (Advagraf [Adv]) among renal transplant patients results in better drug adherence. Data regarding dosage and intrapatient variability changes after conversion among patients with CYP3A4/5 inhibitors (CYPinh) is lacking. METHOD: A retrospective chart review among all kidney transplant recipients at Siriraj Hospital was performed. Patients were enrolled who had been on standard release twice-daily tacrolimus and subsequently replaced it with Adv for at least 6 months with no change in CYPinh type or dosage. RESULTS: Fifty-three patients were eligible. Conversion occurred at a mean time after transplant of 51.25 (SD, 40.30) months. Ten patients (18.9%) did not receive CYPinh, while 19 (35.8%), 21 (39.6%), and 3 (5.7%) received diltiazem, ketoconazole or fluconazole, and both diltiazem and ketoconazole, respectively. After conversion, median increment of tacrolimus dosage was 14.29% (-50% to 167%), while no significant change in IPV was demonstrated (17.46% [SD, 11.25%] vs 14.83% [SD, 6.78]; P = .11). Patients receiving azole had less dosage increment than those not receiving CYPinh (P = .02). After conversion, 14 of 22 patients with IPV > 17% (63.6%) had reduced IPV to ≤ 17%, while 25.8% of patients with lower IPV had an increase in IPV > 17%. CONCLUSION: Conversion to Adv required a dosage increment of 30% to achieve the same trough level. Concomitant use of CYPinh significantly reduced tacrolimus dose increment. A trend was noted toward improved IPV after conversion. Conversion to Adv resulted in better IPV among patients with high IPV while receiving twice-daily tacrolimus.

Metabolic Syndrome in Thai Renal Transplant Recipients: A Multicenter Study.

BACKGROUND Many renal transplant recipients develop complications such as obesity, posttransplantation diabetes mellitus, and dyslipidemia. There have been few studies of metabolic syndrome (MS) in Asian renal transplant recipients. MATERIAL AND METHODS This cross-sectional study was performed in 303 patients in 5 transplant centers in Bangkok, Thailand. The diagnosis of MS was based on the criteria of the modified NCEP-ATPIII, and chronic allograft dysfunction was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m^2. RESULTS Of 303 recipients, MS was diagnosed in 94 cases (31.0%) and the prevalence of MS in the first 3 years and after 3 years posttransplantation were 21.4% and 34.7% (P=0.042), respectively. There was an association between advanced age and chronic allograft dysfunction and higher prevalence of MS. Regarding non-anti-hypertensive and non-hypoglycemic medications, m-TOR inhibitor (odds ratio [OR], 2.14; 95% CI, 1.02-4.5) was associated with the prevalence of MS. Multivariate analysis revealed MS was associated with the use of beta-blockers (OR, 3.17; 95% CI, 1.88-5.32). Patients with no MS components had 26.9% prevalence of chronic allograft dysfunction and patients with higher numbers of MS components had 87.5% prevalence of chronic allograft dysfunction, which was significantly different (P=0.022). CONCLUSIONS Our study revealed that the prevalence of MS was higher in patients with higher numbers of MS components, especially after 3 years posttransplantation. Presence of more components of MS was associated with worse renal function in renal transplant recipients.

Mycophenolic acid AUC in Thai kidney transplant recipients receiving low dose mycophenolate and its association with UGT2B7 polymorphisms.

BACKGROUND: Despite use of a lower mycophenolate dose in Thai kidney transplant patients, acceptable graft and patient outcomes can be achieved. We therefore examined the pharmacokinetics of mycophenolic acid (MPA) by area under the curve (AUC) and investigated genetic contribution in mycophenolate metabolism in this population. METHODS: Kidney transplant recipients with stable graft function who were receiving mycophenolate mofetil 1,000 mg/d in combination with either cyclosporine or tacrolimus, and prednisolone were studied. The MPA concentration was measured by fluorescence polarization immunoassay (FPIA), at predose and 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after dosing. Genetic polymorphisms in UGT1A8, UGT1A9, and UGT2B7 were examined by denaturing high-performance liquid chromatography (DHPLC)-based single-base extension (SBE) analysis. RESULTS: A total 138 patients were included in study. The mean AUC was 39.49 mg-h/L (28.39-89.58 mg-h/L), which was in the therapeutic range. The correlation between the predose MPA concentration and AUC was poor. The mean AUC in the tacrolimus group was higher than that in the cyclosporine group. Polymorphisms in UGT2B7 showed significant association with AUC. CONCLUSION: Most of our patients with reduced mycophenolate dose had the AUC within the therapeutic range. Genetic polymorphisms in UGT2B7 may play a role in MPA metabolism in Thai kidney transplant patients.

Prognostic value of normal dobutamine stress echocardiography in renal transplant candidates.

BACKGROUND: Renal transplant candidates are at high-risk for cardiovascular events. No definite screening tool has been recommended for the pre-operative evaluation. OBJECTIVE: The authors studied the prognostic value of normal dobutamine stress echocardiography in this population. MATERIAL AND METHOD: Dobutamine stress echocardiography was performed for the pre-operative assessment in 107 renal transplant candidates (age 53.2 +/- 6.2 years, 66.4% male). The mean follow-up time was 2.8 +/- 1.7 years. The primary endpoint was total mortality. RESULTS: During follow-up, 16 (15.0%) died and 26 (24.3%) patients underwent kidney transplantation. The overall survival probabilities at 1, 3 and 5 years were 87, 83 and 79%, respectively. Among those who underwent renal transplantation, the survival probabilities at 1, 3 and 5 years were 100, 100 and 89%, respectively CONCLUSION: In renal transplant candidates, normal dobutamine stress echocardiography portends a good long-term prognosis.

Nephrotic syndrome in elderly patients: three years experience at Siriraj Hospital.

BACKGROUND: The population age is being high and nephotic syndrome is a common renal disease. OBJECTIVE: To find the etiology and clinical manifestations of nephrotic syndrome in the elderly patients who underwent renal biopsy at Siriraj hospital including management and outcome. MATERIAL AND METHOD: Retrospective study in 76 nephrotic patients whose age > or =50 years and underwent renal biopsy between 2005-2007. RESULTS: Seventy six nephrotic patients with age ranged from 50-84 years were analysed. Primary glomerulonephritis diseases were found more than secondary causes (5:2). The two most common glomerulonephritis were membranous GN and focal/segmental glomerulosclerosis. The etiology of common secondary GN was lupus nephtitis 11.84% following by diabetic nephropathy and amyloidosis. The patients received immunosuppressive drugs and complete response was found in 51%, partial response 10.2%, no response was 2% and no immunosuppressive therapy 36.7%. There was 1 patient died of septicaemia. CONCLUSION: Nephrotic syndrome in the elderly patients were not uncommon. The causes should be identified for prompt management and excellent outcome.

An analysis of 3,555 cases of renal biopsy in Thailand.

BACKGROUND: The knowledge of the epidemiology of biopsied renal diseases provides useful information in clinical practice. There are several epidemiologic population-based studies of biopsy-proven nephropathies with detailed clinicopathologic correlations that could be different according to the country analyzed. OBJECTIVE: To identify the prevalence of primary and secondary glomerular diseases and to study the trend of the pattern changes of the glomerulopathy in Thailand. MATERIAL AND METHOD: A retrospective study of percutaneous renal biopsies during a 23-year period of 1982 to 2005 was performed. A total of 3,555 consecutive native kidney biopsies in adult patients between 12 and 84 years of age were analyzed for the prevalence and changes in the 5-year interval over the two decades. RESULTS: From the clinical trial of 3,275 patients, the ratio between primary and secondary glomerular diseases was 2:1 (2154:1121). The most common primary glomerular disease (2154 patients) were IgM nephropathy (n = 986, 45.8%) followed by IgA nephropathy (n = 386, 17.9%); membranous nephropathy (n = 341, 15.8%); diffuse endocapillary proliferative glomerulonephritis (n = 114, 5.3%) and diffuse crescentic glomerulonephritis (n = 71, 3.3%). Lupus nephritis was the most prevalent cause of secondary glomerulonephritis in the present study (n = 992, 88.5%). Examination of the 5-year interval along the study period revealed a significant increase in the prevalence of IgA nephropathy and diabetic nephropathy. Prevalence of focal and segmental glomerulosclerosis rose by five times over the last two decades in contrast to IgM nephropathy, which prevalence is decreasing. CONCLUSION: There is high prevalence of IgM nephropathy, IgA nephropathy, and lupus nephritis in Thailand which is different from other countries. It could be due to various races and altered environments. The information obtained from these results is an important contribution for the understanding of the prevalence in renal diseases in Thailand. It can be used as the baseline data for making efficient research into the appropriate and beneficial way of management in the future.

Epithelial to mesenchymal transition during late deterioration of human kidney transplants: the role of tubular cells in fibrogenesis.

The hallmark of failing renal transplants is tubular atrophy and interstitial fibrosis (TA/IF). Injury to tubular epithelial cells (TEC) could contribute to fibrogenesis via epithelial-mesenchymal transition (EMT). We examined the features of EMT in renal transplants that developed TA/IF. Biopsies from 10 allograft kidneys with impaired function and TA/IF and 10 biopsies from transplants with stable function were compared to their implantation biopsies. Relative to implantation biopsies, TEC in TA/IF kidneys showed loss of epithelial markers (E-cadherin, cytokeratin) with altered distribution. Some TEC also showed new cytoplasmic expression of mesenchymal markers vimentin, S100A4, and alpha smooth muscle actin (alpha-SMA) and collagen synthesis marker heat shock protein (HSP-47), both in deteriorating and atrophic tubules. Double immunostaining showed coexpression of cytokeratin and vimentin, S100A4 and HSP-47, indicating intermediate stages of EMT in TA/IF. These changes were absent or much less in transplants with stable function. EMT features in the TA/IF group correlated with serum creatinine (vimentin, S100A4, HSP-47), history of T-cell-mediated rejection (cytokeratin, S100A4) and proteinuria (cytokeratin). These findings support a model in which the TEC damage induces loss of epithelial features and expression of fibroblast features, as a common pathway of deterioration by either immunologic or nonimmunologic processes.

Increased expression of senescence-associated cell cycle inhibitor p16INK4a in deteriorating renal transplants and diseased native kidney.

Some features of kidney transplants with dysfunction overlap the lesions of aging, such as tubular atrophy and interstitial fibrosis (TA/IF) without major glomerular abnormalities. Somatic cell limitations could contribute to deterioration in aging and disease states. Since expression of p16(INK4a), a cell cycle inhibitor associated with somatic cell senescence in vitro, is induced in aged kidney, we studied whether kidneys with dysfunction and TA/IF manifested increased p16(INK4a) expression. We performed p16(INK4a) immunostaining on transplanted kidneys and native kidneys with chronic renal diseases. At implantation, transplants manifested little TA/IF, and nuclear p16(INK4a) immunostaining was consistent with age. However, transplants biopsied for abnormal function displaying TA/IF showed strong nuclear and cytoplasmic p16(INK4a) staining, beyond the amount predicted for age. Both atrophic and non-atrophic nephrons displayed increased p16(INK4a), suggesting that it was not simply a feature of atrophy. Epithelial p16(INK4a) staining was not increased in transplants with good function, but was increased in diseased native kidneys. The finding of increased p16(INK4a) expression in renal transplants and diseased kidneys with TA/IF and impaired function supports the concept that some cell senescence changes that accompany aging are also induced by injury and disease stresses. Thus, aging, injury and disease may share common pathways involving somatic cell senescence.

Peritubular capillary changes and C4d deposits are associated with transplant glomerulopathy but not IgA nephropathy.

We examined our renal transplant population for glomerular diseases demonstrated on biopsy between January 1993 and April 2002, focusing on transplant glomerulopathy (TGP). Of 1156 patients followed in our clinics during this period, glomerular disease was diagnosed in 132 cases (11.4%). Glomerulonephritis was diagnosed in 86 transplants (7.4%), with IgA nephropathy (IgAN) being the commonest diagnosis [32 cases (2.8%)]. Thirty-one cases (2.7%) of biopsy-proven TGP were analyzed for associated factors compared with 27 cases (2.3%) of recurrent IgAN. Transplant glomerulopathy was less frequent with mycophenolate mofetil (MMF) and/or tacrolimus, whereas recurrent IgAN showed no such tendency (P= 0.02). Peritubular capillary (PTC) C4d deposition was observed in six of 24 cases (25%) with TGP but none with recurrent IgAN (P= 0.02). Peritubular capillary basement membrane (BM) multilayering was significantly greater in TGP (4.92 +/- 2.94) than in recurrent IgAN (1.86 +/- 1.04) (P < 0.001). The graft survival of TGP was worse than recurrent IgAN (P= 0.05). The association of TGP with BM multilayering and C4d deposits in PTC suggests a generalized disorder of the graft microcirculation and its BM, owing to antibody-mediated rejection in at least some cases. Transplant glomerulopathy has a serious prognosis but is less frequent in patients on newer immunosuppression, unlike recurrent IgAN.

The role of B cells and alloantibody in the host response to human organ allografts.

Some human organ transplants deteriorate slowly over a period of years, often developing characteristic syndromes: transplant glomerulopathy (TG) in kidneys, bronchiolitis obliterans in lungs, and coronary artery disease in hearts. In the past, we attributed late graft deterioration to "chronic rejection", a distinct but mysterious immunologic process different from conventional rejection. However, it is likely that much of chronic rejection is explained by conventional T-cell-mediated rejection (TMR), antibody-mediated rejection (AMR), and other insults. Recently, criteria have emerged to now permit us to diagnose AMR in kidney transplants, particularly C4d deposition in peritubular capillaries and circulating antibody against donor human leukocyte antigens (HLA). Some cases with AMR develop TG, although the relationship of TG to AMR is complex. Thus, a specific diagnosis of AMR in kidney can now be made, based on graft damage, C4d deposition, and donor-specific alloantibodies. Criteria for AMR in other organs must be defined. Not all late rejections are AMR; some deteriorating organs probably have smoldering TMR. The diagnosis of late ongoing AMR raises the possibility of treatment to suppress the alloantibody, but efficacy of the available treatments requires further study.