OBJECTIVES:Herpes zoster is a frequent complication after kidney transplantation. This study aimed to assess its incidence and associated risk factors in adult kidney transplant recipients. METHODS:We retrospectively reviewed cases of herpes zoster that occurred between April 2013 and March 2023 among 714 adult patients who had previously undergone kidney transplantation. Incidence rates were calculated per 1000 person-years. Patient characteristics were compared between those with and without herpes zoster. Multivariable logistic regression was used to identify independent risk factors. Patients with herpes zoster were categorized into disseminated and localized groups, and their clinical backgrounds were compared. RESULTS:Herpes zoster occurred in 112 patients (15.7%), with an incidence of 22.1 per 1000 person-years. The median age at onset was 51 years, and the median time from transplantation to onset was 7.8 years. Age-specific incidence rates per 1000 person-years were 12.2 (twenties), 24.0 (thirties), 21.7 (forties), 23.9 (fifties), 25.8 (sixties), and 25.3 (≥ seventies). Notably, elevated incidence was evident from the third decade onwards. Independent risk factors included reduced estimated glomerular filtration rate and administration of rabbit anti-lymphocyte antibodies. Among affected patients, 13 cases were disseminated, 94 were localized, and 5 were unclassified. Disseminated cases showed more frequent anti-lymphocyte antibody use. CONCLUSIONS:Herpes zoster was relatively common, even among younger adult kidney transplant recipients. Strong immunosuppression and impaired renal function may increase the risk of herpes zoster and its dissemination.

A man in 50s with type 2 diabetes and stage 3a chronic kidney disease (CKD) developed metformin-associated lactic acidosis (MALA), even with control of metformin dosage based on renal function. He presented with vomiting, severe lactic acidosis, and acute kidney injury. Continuous hemodiafiltration (CHDF) was initiated after conservative therapy failed, resulting in rapid improvement of acidosis and renal recovery. The serum metformin concentration was in the toxic range, confirming MALA. After stopping CHDF, serum metformin concentration was not detected. This case highlights that MALA can occur even when metformin dosing is appropriately adjusted based on renal function in chronic kidney disease. Previous studies have suggested that metformin concentrations generally remain within the therapeutic range and lactate levels do not increase substantially when the dose is adjusted appropriately in patients with CKD. Therefore, metformin is considered relatively safe in this population. However, several reports have described MALA occurring despite dose adjustment according to renal function. Our review of literature showed several MALA cases with control of metformin dose based on the renal function in CKD patients. Therefore, clinicians should be aware that MALA can occur even when metformin dose was appropriately adjusted based on the renal function in CKD patients. In addition, discontinuation of metformin should be required with unexpected illness. Treatment with CHDF may be a useful therapeutic option for hemodynamically unstable patients with MALA.

Neuroleptic malignant syndrome (NMS) can be complicated by rhabdomyolysis, a known cause of acute kidney injury (AKI) that typically resolves within a short period. However, some cases of NMS-associated rhabdomyolysis require hemodialysis. We report a woman in her fifties who developed AKI secondary to NMS-associated rhabdomyolysis and required prolonged renal replacement therapy (RRT). She experienced sepsis and contrast exposure, and dialysis independence was achieved only after 2 months, the longest reported duration. This case highlights that NMS-associated rhabdomyolysis-induced AKI may lead to prolonged dialysis, particularly in the presence of additional risk factors for renal injury.

Exercise therapy is important for exercise tolerance, for the prevention of frailty or sarcopenia, and to improve quality of life (QOL). Previous studies, including systematic reviews, have shown the efficacy of exercise therapy for kidney transplant recipients (KTRs), but the optimal types of exercise remain unclear. Therefore, we aimed to synthesize the published evidence and compare the efficacy of types of exercise. We systematically searched for randomized controlled trials of the efficacy of exercise therapy in KTRs on PubMed and Ichushi, then performed a meta-analysis. Exercise was categorized as aerobic training (AT), resistance training (RT), or AT + RT. The risk of bias was assessed using ROB2 and the certainty of the evidence was evaluated using the GRADE approach. Twenty-five studies were included in the study and 18 in the meta-analysis. Exercise was associated with significant improvements in QOL (SF-36 physical functioning score), cardiorespiratory function (VO2peak), physical function (performance in the 6-min walk test (6MWT) and sit/stand test (STS)), and a metabolic index (triglyceride concentration). Kidney function tended to be superior in the exercise group, but the difference was not significant. Other indices of glucose and lipid metabolism and the incidence of hospitalization did not differ between the Exercise and Control groups. AT + RT significantly improved VO2peak, 6MWT performance, and the triglyceride concentration, whereas AT alone did not improve VO2peak and RT alone did not improve 6MWT performance or the triglyceride concentration. The certainty of the evidence was generally “low” or “very low”. Exercise therapy improved the QOL, cardiorespiratory function, physical function, and triglyceride concentration of KTRs. The AT + RT combination may be the most effective exercise therapy for such patients.

Introduction: Atrophy of smooth muscle cells (SMCs) in the media of small arteries is occasionally observed, especially in long-term kidney allograft biopsies. The intima-media ratio is used as an index of arteriosclerosis in native kidneys, and medial SMC atrophy suggests severe arteriosclerosis. We aimed to investigate the clinicopathological significance of medial SMC atrophy in small arteries in biopsies from long-term kidney transplants. Methods: Samples were obtained from kidney allograft biopsies carried out from January 2016 to December 2019, and biopsies obtained 10 years after transplantation were included in the study. The distal small arteries with the most atrophic SMCs in longitudinal sections in each biopsy specimen were selected (outer diameter <150 µm and ≥60 µm). The outer diameter, and width of the media, intima, and lumen of each artery were measured. SMC atrophy was evaluated as the media-outer diameter ratio. Results: Fifty biopsies were eligible. The mean media-outer diameter ratio was 0.27±0.11. Donor age and allograft age were significantly inversely correlated with media-outer diameter ratio (rank correlation coefficient −0.3522, p=0.0141 and −0.3700, p=0.0096, respectively). After separation into two groups according to the media-outer diameter ratio, donor age and allograft age were both significantly higher and more focal segmental glomerular sclerosis (FSGS) lesions were observed in the low media-outer diameter ratio group. Multivariate analysis revealed that media-outer diameter ratio was significantly related to donor age, allograft age, and FSGS. Conclusions: Medial SMC atrophy appears to be related to donor age, allograft age, and FSGS in kidney allografts. Disruption of vascular contraction as a result of medial SMC atrophy in aging allografts may lead to the development of FSGS.

A man in his forties experienced foamy urine after COVID-19 infection and received a kidney biopsy. He received tacrolimus for myasthenia gravis; no kidney disease was noted before COVID-19 infection, and he had no family history of kidney disease. The biopsy showed minimal change disease, characterized by IgG deposition in the podocyte and mesangial areas. Prednisone was started at 70 mg, but he required hemodialysis three months after COVID-19 infection. A second biopsy 15 months after the COVID-19 infection showed collapsing focal segmental glomerulosclerosis (FSGS) with IgG deposition in the podocytes and mesangium. Immunofluorescence imaging of the second biopsy using structure illumination microscopy showed decreased nephrin expression and punctuate IgG deposition colocalized with nephrin. Thereafter, his serum was positive for anti-nephrin antibodies (367 IU/ml, cut-off 226 U/ml). To the best of our knowledge, no other reports of collapsing FSGS or minimal change disease with anti-nephrin antibodies triggered by COVID-19 infection have been published. This case summarizes a novel case of collapsing FSGS with IgG-positive podocytes associated with anti-nephrin antibodies following minimal change disease, possibly triggered by COVID-19 infection. Further study is needed to clarify the mechanism by which anti-nephrin antibodies are produced by COVID-19 infection.

INTRODUCTION:There is limited evidence regarding collapsing focal segmental glomerulosclerosis (cFSGS) after kidney transplantation. The aim of this study was to clarify the clinicopathological character of cFSGS. METHODS:Forty-two biopsies from 35 patients with cFSGS were included in the study. The cFSGS variant was determined according to the Colombia classification. The scoring of arteriosclerosis was evaluated as a score of 0-3 on the basis of the intimal fibrous thickening divided by the media, and other histological scoring was evaluated using the Banff score. Biopsies with a sclerosis score ≥3/4 were excluded from the study. Multivariate analysis was performed by a forward selection method using covariates significantly associated with cFSGS biopsies. RESULTS:Of 42 biopsies diagnosed with FSGS, 19 (45.2%) biopsies were cFSGS and 23 (54.8%) were non-collapsing FSGS (ncFSGS). The cFSGS group had a longer time after transplantation, lower eGFR, higher urine protein levels, and higher systolic blood pressure (all statistically significant) compared with the ncFSGS group. The Banff aah, ci, and arteriosclerosis scores were significantly higher in the cFSGS group compared with the ncFSGS group. There were no significant differences in the donor age or arteriosclerosis in 1-h biopsies between groups. Multivariate analysis showed that the arteriosclerosis score and Banff ci score were significantly associated with cFSGS using covariates that were statistically significant-related factors including systolic blood pressure, eGFR, proteinuria, ci score, aah score, and arteriosclerosis score. Graft survival after the time of biopsy was significantly worse in the cFSGS group compared with the ncFSGS group. CONCLUSION:Collapsing FSGS was poor prognostic factor for allograft survival. Arteriosclerosis and chronic interstitial fibrosis may be related to cFSGS after kidney transplantation.

AIM:The aim of the study was to elucidate the clinical and histological significance of glomerular capillary C4d (GC-C4d) deposition in allograft biopsies with microvascular inflammation (MVI), indicating antibody-mediated rejection (AMR). METHODS:The study included MVI biopsies defined as Banff g score ≥1 and/or peritubular capillary (ptc) score ≥1, with available HLA class I and/or class II single antigen test results. Biopsies with ABO-incompatible transplantation and diagnosis of T-cell-mediated rejection without AMR were excluded. We analyzed 84 allograft MVI biopsies obtained from January 2017 to May 2023. GC-C4d positivity was evaluated by immunofluorescence. RESULTS:GC-C4d positivity was determined in 46 of 84 (54.8%) MVI biopsies. Multivariate logistic analysis identified Banff g score and ptc-C4d score as factors significantly related to GC-C4d positivity in MVI biopsies with Banff cg score 0-3, and ptc score and ptc-C4d score as significantly related to GC-C4d positivity in MVI biopsies with cg0. Multivariate linear regression analysis identified Banff cg score and ptc-C4d score as factors significantly related to GC-C4d score in MVI biopsies with Banff cg0-3, and cadaver and Banff ptc-C4d score were significantly related to GC-C4d score in MVI biopsies with cg0. In MVI biopsies with cg0-3, evaluation of GC-C4d and/or ptc-C4d positivity decreased the specificity from 100.0% to 76.9% but increased the sensitivity from 67.2% to 84.5%, compared with the evaluation of ptc-C4d positivity alone for the diagnosis of Banff 2022 AMR. Ten of 19 biopsies (52.6%) with ptc-C4d-negative AMR showed ptc-C4d-negative but GC-C4d-positive AMR. CONCLUSION:GC-C4d-positive findings in MVI biopsies may reflect active lesions as well as ptc-C4d scoring, while a high GC-C4d score may reflect advanced cg lesions in MVI biopsies with cg0-3. The combined evaluation of GC-C4d and ptc-C4d in MVI biopsies may increase the diagnostic sensitivity for Banff 2022 AMR by reducing the diagnosis of "C4d-negative AMR."

Aims: The clinicopathological significance of IgG subclass staining is unclear in IgG immunofluorescence (IF)positive IgA nephropathy (IgAN). This study investigated IgG subclass distribution in IgG IF -positive IgAN by IF staining and examined their clinicopathological significance. Materials and methods: From January 2015 to December 2020, 27 biopsies from 26 patients with IgG IF -positive IgAN who were IF -positive for any IgG subclass staining were collected. We compared the clinicopathological findings between cases with and without IF positivity for each IgG subclass. Results: Of the 27 biopsies with IgG IF -positive IgAN, 20 (74.1%) were IF -positive for IgG1, 10 (37.0%) were positive for IgG2, 7 (25.9%) were positive for IgG3, and none were positive for IgG4. Oxford E and C scores were significantly higher in cases of IgG IFpositive IgAN than IgG IF -negative IgAN. The age at biopsy had a negative correlation with IgG1 IF intensity (gamma = -0.604, p = 0.001). The levels of proteinuria and microscopic hematuria as well as Oxford classification score were not significantly different between cases with or without positive staining for each IgG subclass. IgG IF intensity had a positive correlation with IgG1 IF intensity (gamma = 0.741, p < 0.001). Conclusion: IgG1-positive IF staining intensity was highest among each IgG subclass in IgG IF -positive IgAN biopsies. A negative correlation was revealed between the age at biopsy and IgG1 IF intensity. Oxford E and C scores were higher in patients with IgG IF -positive IgAN than in those with IgG IF -negative IgAN. The Oxford score was not significantly different between the IgG subclasses, but the IF intensity of IgG had a positive correlation with the IF intensity of IgG1 in IgG IF -positive IgAN biopsies. Further studies should assess relationships between IgG subclass IF deposition and examine the pathogenesis of IgAN.

Membranous nephropathy (MN) recurs in some kidney allograft patients, and recurrence increases graft failure rates. We present a unique case of recurrent MN in first and second allografts showing glomerular capillary wall-positivity for complement receptor 1 (CR1) consistent with immunoglobulin G (IgG). A man in his late 20s developed MN and started hemodialysis. MN recurred and caused graft loss after the first transplantation and recurred again soon after the second transplantation. The IgG subclass staining was almost consistently negative for IgG4 and phospholipase A2 receptor (PLA2R)-staining was negative. Recurrent MN of unknown etiology was considered. Mass spectrometry demonstrated that CR1 had increased in the transplanted kidney biopsies. Immunohistochemistry and immunofluorescence studies demonstrated CR1 colocalized with IgG along glomerular capillaries in this case, whereas CR1 was localized in podocytes with no colocalization of IgG in a control case of PLA2R-associated MN. Correlative light and immunoelectron microscopy showed localization of CR1 at the interface between electron-dense deposits and podocytes. Collectively, this case demonstrated a unique enhancement and localization of CR1. MN with enhancement of CR1 has not been reported to date. CR1 may be a candidate causative antigen in this case of recurrent MN, although further study is needed to investigate the pathogenesis of CR1.

A man who was an inactive hepatitis B virus (HBV) carrier with positive hepatitis B surface antigen (HBs antigen) and undetectable HBV-DNA under anti-viral treatment developed nephrotic syndrome at 52 years old, and a renal biopsy revealed advanced membranous nephropathy (MN) with focal cellular crescents, interstitial hemorrhaging, and peritubular capillaritis. Immunofluorescence studies demonstrated granular IgG deposition and HBs antigen-positivity along the capillaries. Glomeruli were negative for phospholipase A2 receptor 1. There were no clinical findings of systemic vasculitis. We considered MN combined with small-vessel vasculitis due to HBV infection. These results suggest that HBV-related kidney disease should be considered even in patients with an inactive HBV carrier status under treatment.

Introduction: At present, there is limited evidence of the histological impact of vesicoureteral reflux (VUR) on pediatric kidney allografts. In this study, we aimed to investigate the relationship between VUR diagnosed by voiding cystourethrography (VCUG) and 1-year protocol biopsy results. Methods: One hundred thirty-eight pediatric kidney transplantations were performed in Toho University Omori Medical Center between 2009 and 2019. We included 87 pediatric transplant recipients who were evaluated for VUR by VCUG prior to or at the time of the 1-year protocol biopsy and underwent a 1-year protocol biopsy after transplantation. We evaluated the clinicopathological findings of the VUR and non-VUR groups, and histological scores were evaluated using the Banff score. Tamm-Horsfall protein (THP) within the interstitium was identified by light microscopy. Results: Of the 87 transplant recipients, 18 cases (20.7%) were diagnosed with VUR by VCUG. The clinical background and findings were not significantly different between the VUR and non-VUR groups. The pathological findings revealed a significantly higher Banff total interstitial inflammation (ti) score in the VUR group than in the non-VUR group. Multivariate analysis indicated a significant relationship between the Banff ti score and THP within the interstitium, and VUR. The 3-year protocol biopsy results (n = 68) revealed a significantly higher Banff interstitial fibrosis (ci) score in the VUR group than in the non-VUR group. Conclusion: VUR caused interstitial fibrosis in the 1-year pediatric protocol biopsies, and interstitial inflammation at the 1-year protocol biopsy may affect interstitial fibrosis at the 3-year protocol biopsy.

The aim of the present study was to clarify the relationship between the Banff score of the 7-year protocol biopsy and the allograft outcome.One-hundred-and-eighty-four patients received kidney transplantation from 2002 to 2008. We excluded patients aged <20 years at transplantation (n = 24), those who did not undergo a 7-year protocol biopsy (n = 66), and those who underwent for-cause biopsy (n = 5). Consequently, 89 patients who underwent a 7-year protocol biopsy were enrolled. We analyzed the relationship between the clinicopathological findings 7 years after transplantation and the estimated glomerular filtration rate (eGFR) change per year and allograft survival. Histological evaluation was performed using the Banff 2015 classification.Among the clinicopathological findings, each Banff mesangial matrix increase (mm) score ≥1 and proteinuria ≥1+ was independently associated with the eGFR decline per year during a median follow-up of 73 months. Furthermore, in the model of the clinicopathological findings including the presence of mm with proteinuria, mm ≥1 alone and mm ≥1 with proteinuria were each independently associated with the eGFR decline. The graft survival was significantly worse for those with mm ≥1 with proteinuria than those with mm ≥1 without proteinuria.Among the 7-year protocol biopsy findings, the presence of mm alone and mm with proteinuria were each significant predictors of eGFR decline. The presence of both proteinuria and mm had a negative impact on graft survival. These results underscore the significance of the Banff mm score and proteinuria at the time of the 7-year protocol biopsy to predict the allograft outcome.

Introduction: This study aimed to determine if immune or non-immune and acute or chronic lesions associated with mesangiolysis (MGLS) occurred in biopsy-proven pathological chronic active antibody-mediated rejection (P-CAABMR) in kidney transplant biopsies. Methods: We evaluated MGLS in 41 patients with biopsy findings of P-CAABMR from January 2016 to December 2019. Histological scoring was evaluated by Banff classification. Multivariate logistic regression analysis was performed using a forward selection method. Results: Fifteen of the 41 P-CAABMR biopsies (36.6%) cases showed MGLS. The estimated glomerular filtration rate (eGFR) was significantly lower in the MGLS-positive compared with the MGLS-negative group, and proteinuria was significantly higher in the MGLS-positive compared with the MGLS-negative group. In the clinical model, multivariate analysis was performed using covariates of eGFR and duration after transplantation significantly correlated with MGLS by simple analysis, in addition to type of calcineurin inhibitor use (tacrolimus or cyclosporine), donor-specific antibodies, diabetes, and hypertension grade defined by use of antihypertensive therapy or/and blood pressure level. Only hypertension grade was significantly correlated with MGLS. In the pathological model, multivariate analysis was performed using the presence of FSGS and the aah and cg scores significantly correlated with MGLS by simple analysis, in addition to g and ptc scores. The cg score was significantly correlated with hypertension grade, duration after transplantation, g, ah and aah. Conclusion: Lower graft function and higher proteinuria was observed in MGLS of P-CAABMR. The Banff cg score was independently related to MGLS in multivariate analysis. Sustained glomerulitis, calcineurin inhibitor nephrotoxicity, and hypertension may cause Banff cg lesions, leading to MGLS in P-CAABMR.

Few previous studies have reported immune-complex nephropathy that has not been classified as a specific phenotype in kidney allografts. We report a case of a de novo subclinical "full-house" pattern of deposition in a pediatric transplantation recipient with possible donor-derived IgA deposition. A five-year-old boy underwent living kidney transplantation due to congenital kidney and urinary tract anomalies. A one-hour implantation biopsy revealed IgA deposition. A four-month protocol biopsy finding showed less intense IgA deposition, in contrast with the one-hour biopsy, and trace para-mesangial deposits. A one-year protocol biopsy demonstrated a full-house deposition pattern and massive electron-dense deposits with minor glomerular changes. At the time of the one-year biopsy, kidney function was stable, with no urinalysis abnormalities. No evidence of systemic lupus erythematosus was observed in clinical and serologic examinations. Mesangial IgG, IgM, C3, and C1q deposition was codominant, and IgA deposition was weaker. We diagnosed this case as C1q nephropathy combined with remaining donor-derived IgA deposition. Few studies have reported C1q nephropathy in kidney allograft; further accumulation of cases is required. To distinguish between donor-derived and de novo glomerular lesions, it is important to assess the serial histologic findings of immunofluorescence and electron microscopy. Here, we report a rare case of subclinical C1q nephropathy with possible donor-derived IgA nephropathy.

Introduction: Multinucleated polyploidization (MNP) of tubular epithelial cells is occasionally observed in kidney allografts. The present study aimed to clarify the clinical and pathological significance of MNP of tubular epithelial cells in kidney allografts. Methods: Fifty-eight 1-year biopsies from 58 patients who underwent kidney transplantation at our hospital from January 2016 to December 2017 were included. MNP was counted in each specimen, and the specimens were divided into two groups by the median value. The differences in clinical and pathological characteristics were compared. Ki67-positive cells were counted among tubular epithelial cells to explore the association between cell cycle and MNP. In an additional cohort, MNP was compared between biopsies after precedent T-cell-mediated rejection and precedent medullary ray injury. Results: The 58 cases were divided into two groups by the median total amount of MNP: group A (MNP > 3) and group B (MNP ≤ 3). Maximum t-score before the 1-year biopsy was significantly higher in group A compared with group B. Other clinical or histological characteristics did not differ significantly. Total amount of Ki67-positive tubular epithelial cells was significantly correlated with total amount of MNP. Significantly higher amount of MNP was observed in cases with precedent T-cell-mediated rejection compared with precedent medullary ray injury. On receiver operating characteristic curve analysis, the cut-off value of MNP to predict precedent T-cell-mediated rejection was 8.5. Conclusions: MNP in tubular epithelial cells reflects prior tubular inflammation in kidney allografts. High amount of MNP indicates precedent T-cell-mediated rejection rather than precedent medullary ray injury caused by nonimmune etiologies.