Higher Donor Age and Severe Microvascular Inflammation Are Risk Factors for Chronic Rejection After Treatment of Active Antibody-Mediated Rejection.

Recent developments in intensive desensitization protocols have enabled kidney transplantation in human leukocyte antigen (HLA)-sensitized recipients. However, cases of active antibody-mediated rejection (AABMR), when they occur, are difficult to manage, graft failure being the worst-case scenario. We aimed to assess the impact of our desensitization and AABMR treatment regimen and identify risk factors for disease progression. Among 849 patients who underwent living-donor kidney transplantation between 2014 and 2021 at our institution, 59 were diagnosed with AABMR within 1 year after transplantation. All patients received combination therapy consisting of steroid pulse therapy, intravenous immunoglobulin, rituximab, and plasmapheresis. Multivariable analysis revealed unrelated donors and preformed donor-specific antibodies as independent risk factors for AABMR. Five-year death-censored graft survival rate was not significantly different between patients with and without AABMR although 27 of 59 patients with AABMR developed chronic AABMR (CABMR) during the study period. Multivariate Cox proportional hazard regression analysis revealed that a donor age greater than 59 years and microvascular inflammation (MVI) score (g + ptc) ≥4 at AABMR diagnosis were independent risk factors for CABMR. Our combination therapy ameliorated AABMR; however, further treatment options should be considered to prevent CABMR, especially in patients with old donors and severe MVI.

Renal outcome of living kidney donors aged more than 70 years.

BACKGROUND: The number of marginal living kidney donors has increased. Medically complex donors who have hypertension, older age, or low estimated glomerular filtration rate (eGFR) have been more likely to be used. METHODS: We conducted a retrospective cohort study of living kidney donors at a single center. We analyzed 309 living donors and divided them into three groups: group with older donors (aged ≥70 years) (n = 41), middle-aged (aged 46-69 years) (n = 239), and young donors (aged <46 years) (N = 29). Donor factors associated with chronic kidney disease (CKD) stage 3b or worse within 5 years post-donation were investigated. RESULTS: Of the 309 live donors, 86 (27.8%) developed CKD stage3b or worse within 5 years post-donation. The incidence of CKD stage3b or worse within 5 years post-donation was significantly higher in older donor (p < 0.01). Cox regression models revealed that older donor ages and lower eGFR were significantly related to the development of CKD stage3b or worse, independent of comorbidities such as obesity and hypertension [hazard ratio (95% CI); 4.59 (1.02-20.6), p = 047, 0.95 (0.94-0.96), p ≤ 0.01, respectively]. However, recovery of eGFR 4-5 years after donation was noted in the middle-aged and older donor groups, whereas the level of eGFR remained unchanged in the young group. CONCLUSIONS: Older donors tend to develop CKD stage3b within 5 years post-donation but with the potential of recovery. Healthy older people (aged ≥70 years) could be candidates for living donors under careful monitoring of kidney function after donation.

Long-term prolonged-release tacrolimus outcomes in living donor kidney transplantation: The Japan Academic Consortium of Kidney Transplantation study-II.

OBJECTIVES: To evaluate the 10-year efficacy and safety of a prolonged-release tacrolimus-based combination immunosuppressive regimen on longer-term outcomes in living donor kidney transplantation. METHODS: Data from Japanese living donor kidney transplant recipients (n = 410) maintained on continuous prolonged-release tacrolimus-based immunosuppression from 2009-2013 were analyzed with a median follow-up of 9.9 years. RESULTS: A prolonged-release, tacrolimus-based combination regimen provided death-censored graft failure and all-cause death rates at 10 years of 7.0% and 6.8%, respectively. In multivariable analyses, acute and chronic rejection and 'throughout' (new-onset plus preexisting) diabetes mellitus were risk factors for death-censored graft failure. Recipient age ≥ 65 years, throughout diabetes mellitus and malignancy were common risk factors for all-cause death. Throughout diabetes mellitus was the most common risk factor for both death-censored graft failure and all-cause death. Additional analyses showed 10-year cumulative rates of death-censored graft failure were 14.0% and 5.4% for recipients with or without preexisting diabetes mellitus, respectively (log-rank test: p = 0.009). All-cause death rates were 12.7% and 5.4% in the preexisting and non-diabetes mellitus groups, respectively (log-rank test: p = 0.023). CONCLUSIONS: In this real-world, retrospective, living donor kidney transplantation study, a prolonged-release tacrolimus-based immunosuppressive combination regimen provided 10-year death-censored graft failure rates of 14.0% and 5.4% in diabetes mellitus and non-diabetes mellitus patients, respectively; Similarly, 10-year all-cause death rates were 12.7% and 5.4% in diabetes mellitus and non-diabetes mellitus patients, respectively. To our knowledge, the data in this study are the first to provide 10-year transplant outcomes in living donor kidney transplant recipients under prolonged-release tacrolimus-based regimen.

Influence of a low-dose tacrolimus protocol on the appearance of de novo donor-specific antibodies during 7 years of follow-up after renal transplantation.

BACKGROUND: Tacrolimus (TAC) is a key immunosuppressant drug for kidney transplantation (KTx). However, the optimal serum trough level of TAC for good long-term outcomes remains unclear. This study aimed to investigate the relationship between the maintenance TAC trough level and the appearance of de novo donor-specific anti-human leukocyte antigen (HLA) antibodies (dnDSAs). METHODS: A total of 584 KTx recipients were enrolled in this study, of whom 164 developed dnDSAs during the follow-up period and 420 did not. RESULTS: We found no significant relationship between TAC trough level during the follow-up period and dnDSA incidence. Patients who developed dnDSAs had a significantly greater number of HLA-A/B/DR mismatches (3.4 ± 1.3 versus 2.8 ± 1.5; P < 0.001), were more likely to have preformed DSAs (48.2% versus 27.1%; P < 0.001) and showed poor allograft outcome. CONCLUSIONS: There was no clear relationship between TAC trough level and dnDSA incidence for KTx recipients whose TAC trough levels were kept within the narrow range of 4-6 ng/mL during the immunosuppression maintenance period.

Monoclonal immunoglobulin G deposits on tubular basement membrane in renal allograft: is this significant for chronic allograft injury?

BACKGROUND: Tubular basement membrane immune deposits (TBMID) has rarely been observed in renal allografts. It is usually found in BK virus nephropathy and immune complex glomerulonephritis; however, its significance is not well understood. We conducted a retrospective clinicopathological study on monoclonal immunoglobulin G (IgG) TBMID. METHODS: We studied 7177 renal allograft biopsy specimens obtained from Tokyo Women's Medical University from 2007 to 2015 and performed light microscopic, electron microscopic and immunofluorescence studies. RESULTS: Tubular basement membrane (TBM) deposits of IgG were found in 73 biopsies from 61 patients and the IgG subclass was obtained in 31 biopsies. There were no cases of monoclonal IgA or IgM TBMID. In total, 13 biopsies from 10 patients showed monoclonal IgG TBMID. Of these, seven showed monoclonal IgG1κ TBMID and one each showed monoclonal IgG2κ, IgG2λ and IgG3κ TBMID. Conversely, eight patients showed polyclonal IgG TBMID. In electron microscopy, large granular electron-dense deposits (EDDs) in the TBM were detected in all patients with monoclonal IgG1κ TBMID. EDDs were absent in TBM in patients with monoclonal IgG2κ, IgG2λ or IgG3κ TBMID. Progression of interstitial fibrosis and tubular atrophy (IFTA) was significantly higher in patients with monoclonal IgG1κ TBMID than in those with polyclonal IgG TBMID (P < 0.05). There were no significant differences in the other clinical parameters between monoclonal IgG1κ and polyclonal IgG TBMID. CONCLUSIONS: This is the first study of patients with monoclonal IgG TBMID in renal allografts. We found that monoclonal IgG1κ TBMID was associated with EDD formation in TBM and IFTA progression.

The interaction between post-transplant anemia and allograft function in kidney transplantation: The Japan Academic Consortium of Kidney Transplantation-II study.

BACKGROUND: The interaction between post-transplant anemia (PTA) and allograft function in kidney transplantation has not been evaluated directly. PTA, defined by WHO/AST criteria, was investigated in 1307 adult kidney transplant recipients between 2000 and 2015 (median follow-up, 7 years). METHODS: We investigated the impact of hemoglobin (Hb) on graft failure (non-censored for death) and their interactions, time-dependent Cox model, and subgroup analysis were used. RESULTS: PTA prevalence was 43.6% at 7 years and varied according to allograft function, recipient sex, and follow-up period. Decreased Hb considering the time-varying effect was associated with an increased risk of graft failure (hazard ratio = 1.83, 95% CI 1.66-2.02, P < 0.001). In subgroup analysis, allograft function (post-transplant time-averaged estimated glomerular filtration rate and cut point: 45 mL/min/1.73 m2) had significant interaction (P = 0.032). The 7-year graft failure rate in recipients with PTA and high eGFR was 7.7% (HR 1.52, 95% CI 1.25-1.84), whereas in those with PTA and low eGFR was 19.9% (HR 2.00, 95% CI 1.74-2.31). CONCLUSIONS: The unfavorable impact of PTA was significantly enhanced by low allograft function. PTA is likely to be associated with graft failure due to interaction with allograft function. Therefore, we should consider both Hb level and allograft function while determining the treatment strategy.

Post-donation satisfaction in kidney transplantation: a survey of living donors in Japan.

BACKGROUND: No studies using a valid, standardized method to measure post-donation satisfaction levels among living kidney donors (LKDs) have been published. METHODS: Donor satisfaction levels were measured using the Japanese version of the Client Satisfaction Questionnaire-8 (CSQ-8), a validated, self-report questionnaire. To identify factors related to post-donation satisfaction levels, we compared donors' sociodemographic and psychological characteristics and health-related quality of life (HRQoL), using the Short Form-36 Health Survey (SF-36), as well as recipients' clinical characteristics and SF-36 scores between donors with and without low satisfaction. In addition, donors' perceptions of the donation results and transplant procedure were assessed using measures that we developed. RESULTS: The mean (standard deviation [SD]) CSQ-8 score for the 195 participants was 26.9 (3.4). Twenty-nine (14.9%) respondents with total scores < 1 SD below the mean CSQ-8 score were placed into the low satisfaction group. Multiple logistic regression analysis demonstrated that lower perceptions of receiving adequate information prior to transplantation (odds ratio [OR] = 0.17; 95% confidence interval [CI] = 0.079-0.379; p < 0.001), lower optimism according to the Life Orientation Test (OR = 1.24; 95% CI = 1.045-1.470; p = 0.014), and increased serum creatinine levels in the paired recipient (OR = 0.05; 95% CI = 0.250-1.011; p = 0.054) independently increased the odds of having less satisfaction with donation. CONCLUSIONS: Our findings suggest that careful pre-donation education and more detailed informed consent may be needed, especially in LKDs with low constitutional optimism.

Once-daily vs twice-daily tacrolimus for de novo living kidney transplantation patients including ABO/HLA compatible and incompatible: A randomized trial.

Tacrolimus (TAC) is available as a twice-daily capsule (TAC-BID), once-daily capsule (TAC-QD), and once-daily tablet. Recipients with ABO-incompatible/anti-human leukocyte antigen (HLA)-incompatible transplantation were excluded in previous trials and have thus not been evaluated. We conducted a 5-year trial to determine whether TAC-QD is noninferior to TAC-BID for transplant outcomes. Adults who underwent de novo living kidney transplantation were randomly assigned (62 TAC-QD; 63 TAC-BID). We did not exclude ABO-/HLA- incompatible transplantation. TAC was initiated 7 days preoperatively (0.10 mg/kg/d). Mycophenolate mofetil, methylprednisolone, and basiliximab were administered. The primary endpoint was graft failure (non-censored for death). We performed a noninferiority test. The noninferiority margin was 10% in risk difference. Five-year graft failure rates were 6.5% and 9.5% for TAC-QD and TAC-BID, respectively (noninferiority, P = 0.009). The estimated glomerular filtration rates were similar between the groups (noninferiority, P < 0.001). TAC-QD did not have point estimates of risk difference above the inferiority margin in any assessed endpoints. However, a tendency of interaction was observed between biopsy-proven acute rejection and the follow-up period. In a living kidney transplant population with 40% of patients with ABO/HLA incompatibility, the effect of TAC-QD was not appreciably worse on various clinical transplant outcomes than that of TAC-BID over 5 years.

Diabetes mellitus after kidney transplantation in Japanese patients: The Japan Academic Consortium of Kidney Transplantation study.

OBJECTIVES: To clarify the incidence rate of post-transplant diabetes mellitus and associated risk factors in Japanese kidney transplant recipients, and to explore which treatment components are most effective in reducing post-transplant diabetes mellitus. METHODS: We analyzed 849 Japanese non-diabetic adult recipients who had undergone living kidney transplantation and had received tacrolimus-based immunosuppression from 1996 to 2013 with a median follow-up of 5 years. RESULTS: In all, 127 patients developed post-transplant diabetes mellitus during the follow-up period. The incidence rate of post-transplant diabetes mellitus was 15.1% (95% confidence interval 12.7-17.5) at 5 years. Recipient age (hazard ratio 1.05, 95% confidence interval 1.05-1.06, P < 0.001 for every 5-year increase), obesity (hazard ratio 1.70, 95% confidence interval 1.06-2.73, P = 0.028), tacrolimus trough level at 2 weeks post-transplantation (hazard ratio 1.06, 95% confidence interval 1.03-1.09, P < 0.001 for a 1-ng/mL increase) and mycophenolate mofetil use (hazard ratio 0.46, 95% confidence interval 0.28-0.77, P = 0.003) were significant predictors of post-transplant diabetes mellitus. Estimated 5-year predicted incidence rate after adjusting for age and obesity was 9.4% for recipients with a low tacrolimus trough level, and receiving mycophenolate mofetil and 38.4% for recipients with a high tacrolimus trough level and not receiving mycophenolate mofetil. CONCLUSIONS: Post-transplant diabetes mellitus is a common complication in Japan, similar to that in other Western countries. The present results show that an appropriate immunosuppressive regimen with a combination of tacrolimus and mycophenolate mofetil can reduce the likelihood of developing post-transplant diabetes mellitus. Clinical trials are required to confirm these findings.

Interstitial fibrosis is the critical determinant of impaired renal function in transplant glomerulopathy.

AIM: Transplant glomerulopathy (TG) is a feature of chronic antibody-mediated injury in the glomerular capillaries in renal transplant recipients. TG is generally associated with proteinuria; however, renal function at the diagnosis of TG varies. This study aimed to determine which morphological abnormalities are associated with renal function and proteinuria at the diagnosis of TG. METHODS: A total of 871 renal transplantations were performed at Tokyo Women's Medical University between 2005 and 2013. TG was diagnosed in 127 biopsies from 58 (6.7%) recipients. Renal function was evaluated by the estimated glomerular filtration rate (eGFR). Proteinuria was assessed by a dipstick test: positive for +1 and over. RESULTS: At diagnosis, of 127 biopsies, 72, 37, and 18 had mild, moderate, and severe TG (Banff cg). The severity of TG was not associated with decreased eGFR at the time of biopsy (cg1: 36.1 ± 14.8, cg2-3: 38.8 ± 14.5 mL/min per 1.73 m(2) , P = 0.25), whereas the severity of interstitial fibrosis (IF) (Banff ci) was significantly associated with decreased eGFR (ci0-1: 42.75 ± 13.32, ci2-3: 27.69 ± 11.94 mL/min per 1.73 m(2) , P < 0.0001). The multivariate analysis revealed that IF was the only independent risk factors for decreased eGFR (OR = 4.38, P = 0.0006). Meanwhile, TG was identified as the only independent risk factor for the incidence of proteinuria (OR = 2.67, P = 0.014). CONCLUSION: Interstitial fibrosis was a critical determinant of impaired renal function at the diagnosis of TG. The severity of TG was significantly associated with proteinuria, but did not contribute to renal dysfunction.

Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits complicated by immunoglobulin A nephropathy in the renal allograft.

Immunoglobulin (Ig) A nephropathy (IgAN) is a known autoimmune disease due to abnormal glycosylation of IgA1, and occasionally, IgG co-deposition occurs. The prognosis of IgG co-deposition with IgAN is adverse, as shown in the previous studies. However, in the clinical setting, monoclonality of IgG co-deposition with IgAN has not been observed. We describe a case of proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) combined with IgAN in a renal allograft. A-21-year-old man developed end-stage renal failure with unknown aetiology and underwent living-donor kidney transplantation from his mother 2 years after being diagnosed. One year after kidney transplantation, proteinuria 2+ and haematuria 2+ were detected; allograft biopsy revealed mesangial IgA and C3 deposits, indicating a diagnosis of IgAN. After tonsillectomy and steroid pulse therapy, proteinuria and haematuria resolved. However, 4 years after transplantation, pedal oedema, proteinuria (6.89 g/day) and allograft dysfunction (serum creatinine (sCr) 203.3 µmol/L) appeared. A second allograft biopsy showed mesangial expansion and focal segmental proliferative endocapillary lesions with IgA1λ and monoclonal IgG1κ depositions. Electron microscopic analysis revealed a massive amount of deposits, located in the mesangial and subendothelial lesions. A diagnosis of PGNMID complicated with IgAN was made, and rituximab and plasmapheresis were added to steroid pulse therapy. With this treatment, proteinuria was alleviated to 0.5 g/day, and the allograft dysfunction recovered to sCr 132.6 µmol/L. This case suggests a necessity for investigation of PGNMID and IgA nephropathy in renal allografts to detect monoclonal Ig deposition disease.

Clinical and pathological analyses of interstitial fibrosis and tubular atrophy cases after kidney transplantation.

AIM: We carried out a clinicopathological analysis of cases presenting with interstitial fibrosis and tubular atrophy (IF/TA) after renal transplantation in an attempt to clarify the mechanisms underlying the development and prognostic significance of IF/TA. METHODS: IF/TA was diagnosed in 35 renal allograft biopsy specimens (BS) obtained from 35 renal transplant recipients under follow up at the Department of Transplant Surgery, Kidney Center, Toda Chuo General Hospital, between January 2014 and March 2015. RESULTS: IF/TA was diagnosed at a median of 39.9 months after the transplantation. Among the 35 patients with IF/TA, 19 (54%) had a history of acute rejection. Among the 35 BS showing evidence of IF/TA, the IF/TA was grade I in 25, grade II in 9, and grade III in 1. Arteriosclerosis of the middle-sized arteries was observed in 30 BS (86%). We then classified the 35 BS showing evidence of IF/TA according to their overall histopathological features, as follows; IF/TA alone (6 BS; 17%), IF/TA + medullary ray injury (12 BS; 34%), and IF/TA + rejection (12 BS; 34%). Loss of the renal allograft occurred during the observation period in one of the patients (3%). Of the remaining patients with functioning grafts, deterioration of the renal allograft function after the biopsies occurred in 15 patients (43%). CONCLUSIONS: The results of our study suggests that rejection contributes to IF/TA in 30-40% of cases, medullary ray injury in 30-40% of cases, and nonspecific injury in 20% of cases. IF/TA contributes significantly to deterioration of renal allograft function.

Postoperative rebound of antiblood type antibodies and antibody-mediated rejection after ABO-incompatible living-related kidney transplantation.

The purpose of this study is to examine whether postoperative antiblood type antibody rebound is attributed to kidney allograft rejection in ABO blood type-incompatible (ABO-I) living-related kidney transplantation (KTx). A total of 191 ABO-I recipients who received ABO-I living-related KTx between 2001 and 2013 were divided into two groups: Group 1 consisted of low rebound [(≦1:32), N = 170] and Group 2 consisted of high rebound [(≧1:64), N = 21], according to the levels of the rebounded antiblood type antibodies within 1 year after transplantation. No prophylactic treatment for rejection was administered for elevated antiblood type antibodies, regardless of the levels of the rebounded antibodies. Within 1 year after transplantation, T-cell-mediated rejection was observed in 13 of 170 recipients (13/170, 8%) in Group 1 and in 2 of 21 recipients (2/21, 10%) in Group 2 (Groups 1 vs. 2, P = 0.432). Antibody-mediated rejection was observed in 15 of 170 recipients (15/170, 9%) and 2 of 21 recipients (2/21, 10%) in Groups 1 and 2, respectively (P = 0.898). In this study, we found no correlation between the postoperative antiblood type antibody rebound and the incidence of acute rejection. We concluded that no treatment is necessary for rebounded antiblood type antibodies.

Solid-type RCC originating from native kidneys in renal transplant recipients should be monitored cautiously.

Incidental hemodialysis-related renal cell carcinoma (id-RCC) has been reported to have a good prognosis. However, we have observed rapid progression of id-RCC in some renal transplant patients. Operative indications for id-RCC detected via computed tomography (CT) immediately before renal transplantation (RTx) remain unclear. The purpose of this study was to examine the effects of immunosuppression on the progression of solid-type RCC (s-RCC) and cystic-type RCC (c-RCC). We divided 202 patients with id-RCC into four groups as follows: Group 1, s-RCC with RTx (n = 17); Group 2, c-RCC with RTx (n = 27); Group 3, s-RCC without RTx (n = 53); and Group 4, c-RCC without RTx (n = 105). Five-year cancer specific survival (CSS) rates were significantly worse in Group 1 than Group 3 (79.6% and 100%, respectively, P = 0.012), as were non-recurrence rates (NRRs) (59.2 and 100%, respectively, P < 0.001). In contrast, 5-year CSS rates were similar in Group 2 and Group 4 (100% and 95.7%, respectively, P = 0.295) as were NRR (100% and 98.7%, respectively, P = 0.230). Solid-type RCC should be removed immediately after RTx, and more carefully monitored for recurrence during follow-up.

The impact of C4d-negative acute antibody-mediated rejection on short-term prognosis among kidney transplant recipients.

AIM: We aimed to investigate the clinical and pathological features of C4d-negative acute antibody-mediated rejection (aAMR), and examined the impact of C4d-negative aAMR on short-term prognosis. METHODS: From 2005 to 2011, 626 kidney transplantations were performed in our institution and related hospitals. We excluded 174 ABO-incompatible transplantations, and analysed clinical and pathological data from the remaining 452 until December 2013. RESULTS: During the follow-up period, 39 patients underwent aAMR. We divided them into two groups. According to C4d positivity in each patient's first AMR, we divided the cohort into a C4d-positive aAMR group and a C4d-negative aAMR group, using the new Banff 2013 classification. We compared each aAMR patient's features to controls. Clinical and pathological characteristics were similar in both groups and the short-term outcomes of the two groups were similar, but both were worse than control. CONCLUSION: C4d-negative aAMR resembles C4d-positive aAMR in terms of clinical and pathological features, and that C4d positivity has no influence on short-term outcome.

Arteriosclerosis in zero-time biopsy is a risk factor for tacrolimus-induced chronic nephrotoxicity.

AIM: Calcineurin inhibitors reduce the acute rejection rate and greatly improve renal allograft survival. However, they are associated with some adverse events, including nephrotoxicity, a risk factor for allograft failure. Chronic calcineurin inhibitor-induced nephrotoxicity causes irreversible damage to renal components, such as arteriolar hyaline thickening. The aim of this study is to investigate the risk factors for tacrolimus-induced chronic nephrotoxicity using zero-time biopsy specimens. METHODS: Between January 2001 and December 2010, 483 patients who underwent living-related kidney transplantation and had also been placed on a tacrolimus-based regimen were enrolled in this study. There were 1859 specimens evaluated comprising 483 zero-time biopsy specimens and 1376 protocol and for-cause biopsy specimens. De novo arteriolar hyaline thickening due to tacrolimus-induced chronic nephrotoxicity was scored according to the Banff classification aah score. In this study, tacrolimus-induced nephrotoxicity was defined as a positive aah score. RESULTS: Of the 483 patients, 108 patients (22.4%) had biopsy-proven tacrolimus-induced chronic nephrotoxicity. Multivariate analysis showed that interlobular arteriosclerosis proven by zero-time biopsy (OR: 2.23, 95%CI: 1.38-3.58, P < 0.01) and acute rejection episodes (OR: 1.58, 95%CI: 1.00-2.47, P = 0.04) were independent risk factors for tacrolimus-induced chronic nephrotoxicity. However, tacrolimus-induced chronic nephrotoxicity did not affect long-term graft survival. CONCLUSION: This is the first report showing that arteriosclerosis in zero-time biopsy specimens is a risk factor for histological tacrolimus-induced chronic nephrotoxicity.

Clinical and pathological analyses of chronic vascular rejection after kidney transplantation.

AIM: We discuss the clinicopathological analysis of cases of chronic vascular rejection (CVR) cases after renal transplantation and clarify the mechanisms underlying the development and prognostic significance of CVR. PATIENTS: CVR was diagnosed in 46 renal allograft biopsy specimens (BS) obtained from 34 renal transplant patients being followed up at the Department of Urology, Tokyo Women's Medical University, between January 2009 and December 2013. RESULTS: CVR was diagnosed at a median of 47.4 months post-transplant. Among the 36 patients, 23 had a history of acute rejection. Among the 46 BS showing evidence of CVR, the CVR was mild (cv1 in Banff's classification) in 23, moderate (cv2) in 17, and severe (cv3) in 6. Of the 40 samples obtained at the time of the biopsy and assayed with plastic beads coated with HLA antigen, 31 (78%) showed circulating ant-HLA alloantibody, and 15 (38%) showed donor-specific antibodies. We then classified the 46 BS showing evidence of CVR by their overall histopathological features, as follows; cv alone was seen in 16 (35%) BS, cv + antibody-mediated rejection (AMR) in 26 (56%), and cv + T-cell-mediated rejection in 9 (19%). Loss of the renal allograft occurred during the observation period in nine of the patients (26%). Of the remaining patients with functioning grafts, deterioration of the renal allograft function after the biopsies occurred in 11 patients (32%). CONCLUSION: The results of our study suggest that AMR may underlie CVR in many cases, while T cell-mediated rejection may play an important role in some cases.

A case of recurrent focal segmental glomerulosclerosis after kidney transplantation associated with variant conversion in the Columbia classification.

Focal segmental glomerulosclerosis commonly recurs following kidney transplantation. A 33-year-old man underwent living donor kidney transplantation. Proteinuria appeared two months after transplantation, and an episode biopsy on postoperative day 66 revealed recurrent focal segmental glomerulosclerosis lesions of the cellular variant by Columbia classification. We reviewed the native kidney biopsy and confirmed collapsing variant focal segmental glomerulosclerosis. Plasma exchange therapy was performed, and his proteinuria temporarily resolved. A second allograft biopsy performed on postoperative day 200 showed no evidence of focal segmental glomerurosclerosis. He experienced incomplete remission with a proteinuria of 0.5 g/day during the subsequent three years until his urinary protein level rose to 1.3 g/day. A third biopsy performed on postoperative day 1248 showed focal segmental glomerulosclerosis cellular variant lesions. Plasma exchange was resumed in combination with additional rituximab, but his proteinuria persisted. Intermittent plasma exchange was performed 42 times in total. However, his proteinuria continued, and his renal function gradually worsened. A fourth biopsy performed on postoperative day 2540 showed focal segmental glomerulosclerosis collapsing variant lesions with severe interstitial fibrosis and tubular atrophy. He ultimately required hemodialysis seven years after transplantation. Intensive therapy with long-term intermittent plasma exchange and rituximab suppressed proteinuria and preserved graft function for seven years, at which time graft failure occurred. We here present the clinical course and histological findings from consecutive allograft biopsies.

Influence of preoperative anti-HLA antibodies on short- and long-term graft survival in recipients with or without rituximab treatment.

We investigated the relationship between preoperative anti-HLA antibodies (donor-specific antibody, DSA) and the graft survival rate in recipients who had or had not received rituximab (Rit) treatment. The subjects were categorized into four groups as follows: DSA+Rit-, n = 39; DSA-Rit-, n = 121; DSA+Rit+, n = 74; and DSA-Rit+, n = 47. We examined the influence of preoperative DSA on the incidence of graft rejection and the survival rate of recipients who had or who had not received rituximab before transplantation. The 6-month acute rejection rates based on graft biopsies were 39%, 19%, 15%, and 0% for the DSA+Rit-, DSA-Rit-, DSA+Rit+, and DSA-Rit+ groups. The rates of chronic antibody-mediated rejection after more than 6 months were 50%, 22%, 18%, and 0%. The 5-year graft survival rate was significantly lower in the DSA+Rit- group (84%) than in the other groups (95% for DSA-Rit-, 98% for DSA+Rit+, and 91% for DSA-Rit+). The rate of the appearance of de novo anti-HLA antibodies was higher in the groups that did not receive rituximab treatment. The rate of graft loss associated with chronic antibody-mediated rejection was also higher in the DSA+Rit- group than in the other groups (P = 0.01). The presence of DSA and the administration of rituximab had strong impacts on not only short-term graft rejection, but also long-term graft rejection and its association with the graft survival time.

Clinical and pathological analyses of transplant glomerulopathy cases.

AIM: Transplant glomerulopathy (TG) is included as one of the criteria of chronic active antibody-mediated rejection (c-AMR) in Banff 09 classification. In this report, we discuss the clinical and pathological analyses of cases of TG after renal transplantation. PATIENTS: TG was diagnosed in 86 renal allograft biopsy specimens (BS) obtained from 50 renal transplant patients followed up at our institute between January 2006 and October 2012. We retrospectively reviewed the data of these 86 BS and 50 patients. RESULTS: Among the 50 patients, 42 (84%) had a history of acute rejection (AR); of these, 30 (60%) had acute antibody-mediated rejection (a-AMR). Among the 86 BS of TG, the TG was mild in 35 cases (cg1 in Banff classification), moderate in 28 cases (cg2) and severe in 23 cases (cg3). Peritubular capillaritis was present in 74 BS (86%), transplant glomerulitis in 65 (76%), interstitial fibrosis and tubular atrophy (IF/TA) in 71 (83%), thickening of the peritubular capillary (PTC) basement membrane in 72 (84%), and interstitial inflammation in 40 (47%). C4d deposition in the PTC was present in 49 BS (57%); 39 of these 49 BS showed diffuse C4d deposits in the PTC (C4d3), while the remaining 10 BS showed focal deposits (C4d2). Diffuse C4d deposition in the glomerular capillaries (GC) was seen in 70 BS (81%), while focal C4d deposition in the GC was seen in 9 (11%). In the assay using plastic beads coated with HLA antigen performed in 67 serum samples obtained in the peri-biopsy period, circulating ant-HLA alloantibody was detected in 55 (82%); in 33 of the 55 (49%) samples, donor-specific antibodies (DSA) were detected. Among our study, the findings in 22 BS (26%) fully met the criteria for c-AMR in Banff '09 classification, including TG, C4d deposition in the PTC and presence of DSA, while those in 27 BS were suspicious of c-AMR. Deterioration of the renal allograft function after the biopsies was seen in 31 patients (62%), of which 11 lost their graft. CONCLUSIONS: We suggest that histopathological changes of transplant glomerulopathy might be accompanied by inflammation of the microvasculature, such as transplant glomerulitis and peritubular capillaritis, thickening of the peritubular capillary basement membrane, and circulating anti-HLA antibodies. C4d deposition in the PTC is not always present in biopsy specimens of TG. We speculated that C4d deposition in the GC, rather than that in the PTC might be a more characteristic manifestation of TG. Many of the patients with TG had a history of AR. Anti-HLA antibody Class II, particularly when the antibody was DSA Class II, appeared to be associated with the development of TG. The prognosis of grafts exhibiting TG was not too good even under the currently used immunosuppressive protocol.