Significance of Perivascular Aggregates in Kidney Allografts: Evaluation of 1-Year Protocol Biopsies Using Recent Banff Classification.

BACKGROUND: Perivascular aggregates (PVAs) often occur in kidney allografts; however, their significance needs to be re-evaluated in light of changes in the concept and criteria of allograft rejection. METHODS: We reviewed 1-year protocol biopsies in 258 patients with kidney transplants to identify PVAs and concurrent pathology based on the Banff 2017 classification, including revised criteria for chronic active T-cell mediated rejection (CA-TCMR). We investigated the incidence of PVA, concurrent allograft lesions, diagnosis, and graft survival. No prisoners were used in this study, and no participants were coerced or paid. RESULTS: We identified PVA in 81 biopsies (31.4%). The incidence of previous rejection (32.1% vs 12.4%, P= .0003) and total inflammation (1.3 ± 0.8 vs 0.6 ± 0.8, P < .0001), inflammation (0.7 ± 0.8 vs 0.2 ± 0.5, P < .0001), inflammation in the area of interstitial fibrosis and tubular atrophy (1.3 ± 1.2 vs 0.7 ± 0.9, P < .0001), tubulitis (1.4 ± 1.1 vs 0.6 ± 0.9, P < .0001), and interstitial fibrosis scores (1.2 ± 0.9 vs 0.9 ± 0.9, P= .01) were higher in PVA-positive compared with patients with PVA-negative. Diagnoses in the PVA-positive group revealed no rejection in 49.4%, CA-TCMR in 21.0%, borderline changes in 18.5%, and acute TCMR in 6.2%. CA-TCMR was more frequent in patients with PVA-positive (21.0% vs 4.0%, P < .0001). Graft survival was similar in both groups among all patients, no-rejection, any type of rejection, and CA-TCMR subgroups. CONCLUSIONS: PVAs occur heterogeneously and are associated with previous rejection or concurrent CA-TCMR. The prognostic significance of PVAs in kidney transplantation is inconclusive, and further investigations are needed.

Association between microscopic hematuria and albuminuria in patients with chronic kidney disease caused by diabetes and hypertension: the Fukuoka Kidney disease Registry Study.

BACKGROUND: The association between microscopic hematuria (MH) and albuminuria in patients with chronic kidney disease (CKD) caused by diabetes and hypertension remains unclear. METHODS: The Fukuoka Kidney disease Registry Study is a Japanese multicenter prospective cohort study of 4476 patients with non-dialysis-dependent CKD. In this cohort, we conducted a cross-sectional study in 994 patients with diabetic nephropathy and hypertensive nephrosclerosis. Patients were divided into three groups according to erythrocyte count in urine sediment [T1: < 5/high power field (HPF); T2: 5-9/HPF; T3: ≥ 10/HPF]. Macroalbuminuria was defined as urinary albumin-creatinine ratio > 300 mg/g. Associations between the degree of MH (T1-T3) and the prevalence of macroalbuminuria were analyzed using logistic regression. RESULTS: The prevalence of macroalbuminuria was 50.8%, 50.4%, and 67.4% in T1 (n = 725), T2 (n = 226), and T3 (n = 43), respectively. The multivariable-adjusted odds ratios for the presence of macroalbuminuria were 0.95 [95% confidence interval (CI) 0.65-1.39; P = 0.86] and 2.50 (95% CI 1.15-5.47; P = 0.022) for patients in T2 and T3, respectively, compared with patients in T1. CONCLUSIONS: MH with erythrocytes ≥ 10/HPF was significantly associated with increased prevalence of macroalbuminuria in patients with non-dialysis-dependent CKD caused by diabetes and hypertension.

Treatment of chronic active T cell-mediated rejection after kidney transplantation: A retrospective cohort study of 37 transplants.

AIM: Data on the treatment of chronic active T cell-mediated rejection (CA-TCMR) are scarce, and therapeutical strategies for CA-TCMR have not been established. We retrospectively evaluated the outcomes and effects of treatment on pathological and clinical findings in patients with CA-TCMR. METHODS: This study comprised 37 patients who underwent kidney transplantation at our institute who were diagnosed with CA-TCMR between January 2018 and December 2020. Patients were followed until October 2021. RESULTS: A total of 32 of the 37 patients were treated. During the observation period, two patients died (5%), and five patients developed allograft loss (13%). A univariate Cox proportional hazards model showed that indication biopsy, higher spot urine protein/creatinine ratio (UPCR) and Banff ci/ct scores were risk factors for allograft loss. Of the treated patients, 23 underwent follow-up biopsies. The Wilcoxon signed-rank test showed significant improvement in the Baff scores for "ti", "i-IFTA", "t" and "t-IFTA" after treatment. On pathology, 13 (57%) of the patients who underwent follow-up biopsy improved to "no evidence of rejection" or "borderline change." Assuming that improvement in pathology to "borderline change" or "no evidence of rejection" on follow-up biopsy indicates response to treatment, multivariate logistic analysis showed that lower UPCR was a predictive factor for response to treatment. No specific effect of treatment type was observed. CONCLUSIONS: Our results indicate that treatment could improve the pathological findings in CA-TCMR.

Pathologic Diabetic Nephropathy in Autopsied Diabetic Cases With Normoalbuminuria From a Japanese Community-Based Study.

INTRODUCTION: Albuminuria is a clinical hallmark of diabetic nephropathy (DN). Nevertheless, it is controversial whether pathologic DN lesions exist in individuals with diabetes with normoalbuminuria. We investigated the association between albuminuria levels and the frequency of DN lesions in autopsied diabetic cases from a Japanese community. METHODS: A total of 106 autopsied cases with diabetes mellitus (mean age = 76 years, 43.4% male) who died within 6 years after their last health examination were included in the study. Urinary albumin-creatinine ratio (UACR) levels were divided into the following 3 groups: <30.0, 30.0 to 299.9, and ≥300.0 mg/g. The kidney specimens were evaluated with light microscopy. Glomerular DN lesions were categorized into class 0 to I, IIa, IIb, and III glomerular DN lesions according to the criteria of the Renal Pathology Society. A Cochran-Armitage test was used to evaluate the association between the UACR levels and the presence of class IIa or higher glomerular DN lesions. RESULTS: The frequency of class IIa or higher glomerular DN lesions was 63.2% (IIa, 36.8%; IIb, 3.8%; and III, 22.6%) among overall cases. The frequencies increased significantly with higher UACR levels (P for trend = 0.02). The frequency of class IIa or higher glomerular DN lesions was 51.2%, even in individuals with UACR < 30 mg/g. CONCLUSION: This study revealed a positive association of the UACR levels with the presence of class IIa or higher glomerular DN lesions, which were also frequently found even in the normal range of UACR levels, among autopsied diabetic cases from a Japanese community.

Development and validation of a risk score for the prediction of cardiovascular disease in living donor kidney transplant recipients.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of death in kidney transplant (KT) recipients. To improve their long-term survival, it is clinically important to estimate the risk of CVD after living donor KT via adequate pre-transplant CVD screening. METHODS: A derivation cohort containing 331 KT recipients underwent living donor KT at Kyushu University Hospital from January 2006 to December 2012. A prediction model was retrospectively developed and risk scores were investigated via a Cox proportional hazards regression model. The discrimination and calibration capacities of the prediction model were estimated via the c-statistic and the Hosmer-Lemeshow goodness of fit test. External validation was estimated via the same statistical methods by applying the model to a validation cohort of 300 KT recipients who underwent living donor KT at Tokyo Women's Medical University Hospital. RESULTS: In the derivation cohort, 28 patients (8.5%) had CVD events during the observation period. Recipient age, CVD history, diabetic nephropathy, dialysis vintage, serum albumin and proteinuria at 12 months after KT were significant predictors of CVD. A prediction model consisting of integer risk scores demonstrated good discrimination (c-statistic 0.88) and goodness of fit (Hosmer-Lemeshow test P = 0.18). In a validation cohort, the model demonstrated moderate discrimination (c-statistic 0.77) and goodness of fit (Hosmer-Lemeshow test P = 0.15), suggesting external validity. CONCLUSIONS: The above-described simple model for predicting CVD after living donor KT was accurate and useful in clinical situations.

Significance of revised criteria for chronic active T cell-mediated rejection in the 2017 Banff classification: Surveillance by 1-year protocol biopsies for kidney transplantation.

Diagnostic criteria for chronic active T cell-mediated rejection (CA-TCMR) were revised in the Banff 2017 consensus, but it is unknown whether the new criteria predict graft prognosis of kidney transplantation. We enrolled 406 kidney allograft recipients who underwent a 1-year protocol biopsy (PB) and investigated the diagnostic significance of Banff 2017. Interobserver reproducibility of the 3 diagnosticians showed a substantial agreement rate of 0.68 in Fleiss's kappa coefficient. Thirty-three patients (8%) were classified as CA-TCMR according to Banff 2017, and 6 were previously diagnosed as normal, 12 as acute TCMR, 10 with borderline changes, and 5 as CA-TCMR according to Banff 2015 criteria. Determinant factors of CA-TCMR were cyclosporine use (vs tacrolimus), previous acute rejection, and BK polyomavirus-associated nephropathy. In survival analysis, the new diagnosis of CA-TCMR predicted a composite graft endpoint defined as doubling serum creatinine or death-censored graft loss (log-rank test, P < .001). In multivariate analysis, CA-TCMR was associated with the second highest risk of the composite endpoint (hazard ratio: 5.42; 95% confidence interval, 2.02-14.61; P < .001 vs normal) behind antibody-mediated rejection. In conclusion, diagnosis of CA-TCMR in Banff 2017 may facilitate detecting an unfavorable prognosis of kidney allograft recipients who undergo a 1-year PB.

Late renal recovery after treatment over 1 year post-onset in an atypical hemolytic uremic syndrome: a case report.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disease that leads to end-stage kidney disease if only a poor response to plasma exchanges (PEs) or eculizumab therapy is achieved. CASE PRESENTATION: A 58-year-old Japanese man presented with thrombocytopenia, anemia, and kidney failure requiring dialysis without any underlying disease. A kidney biopsy revealed marked mesangiolysis in all glomeruli, compatible with thrombotic microangiopathy (TMA). Based on the positive anti- factor H antibody and negative result for secondary TMA, we diagnosed him as aHUS. Despite eculizumab administration after eight sessions of PE, neither platelet normalization nor kidney recovery was achieved. Eight months later, we discontinued eculizumab therapy due to anaphylactic reaction. At 15 months after the onset of TMA, his platelet count increased gradually from 40 to 150 × 103/µL with a decreased serum creatinine level and increased urine output, eventually allowing the withdrawal of dialysis therapy. A second kidney biopsy showed mesangial widening compatible with the healing of TMA. CONCLUSIONS: This case indicates that aHUS with PEs and eculizumab therapy has the potential for renal recovery even if over 1 year has passed.

Utility of Columbia classification in focal segmental glomerulosclerosis: renal prognosis and treatment response among the pathological variants.

BACKGROUND: The utility of the Columbia classification (Col-class) for focal segmental glomerulosclerosis (FSGS) has not yet been fully proven. METHODS: We extracted 201 FSGS patients from 10 nephrology centers in Japan and investigated the difference of a composite renal endpoint, defined as doubling of serum creatinine and/or development of end-stage renal disease, in pathological variants. Sensitivity analysis was used to prove the utility of the Col-class to predict renal outcomes. Additionally, the renal protective effects of steroids and/or immunosuppression (steroid/IS) were investigated in patients stratified according to the Col-class. RESULTS: The patients were classified into the following variants: not otherwise specified [NOS; n = 121 (60.1%)], perihilar [n = 31 (15.4%)], cellular [n = 19 (9.5%)], tip [n = 17 (8.5%)] and collapsing [n = 13 (6.5%)]. No tip variant patients reached the renal endpoint. The renal outcome in the collapsing variant was significantly poorer than that in the NOS [hazard ratio (HR) 3.71; P = 0.005]. In the sensitivity analysis, the area under the receiver operating characteristic curve for the renal endpoint was increased by adding Col-class to a model including common risk factors (P = 0.021). In a subgroup treated without steroid/IS, the outcome in the cellular variant was worse than that in the NOS (HR 5.10; P = 0.040) but the difference was not observed in the subgroup with steroid/IS (HR 0.54; P = 0.539). CONCLUSIONS: The Col-class is useful to predict renal prognosis in Japanese patients with FSGS. In addition to good prognosis in the tip variant and poor in the collapsing variant, good clinical course in the cellular variant treated with steroid/IS was suggested.

Effect of renin-angiotensin system blockade on graft survival and cardiovascular disease in kidney transplant recipients: retrospective multicenter study in Japan.

BACKGROUND: Renin-angiotensin system blockers (RASBs) reduce end-stage kidney disease and cardiovascular event (CVE) development in chronic kidney disease. However, whether RASBs improve long-term prognosis in kidney transplant (KT) recipients remain unknown. METHOD: We investigated 900 kidney transplant patients in a multicenter retrospective cohort study in Japan and compared death-censored graft survival and CVE (total, cardiac events, stroke) based on RASB use within 12 months after KT. The associations were examined using a Cox hazard model and propensity score-matching analysis. RESULTS: The cohort comprised 375 patients treated with RASBs (RASB group) and 525 patients without RASBs (control group). The median observational period was 82 months, with 68 patients reaching graft loss: 79 total CVE, 36 cardiac events, 26 stroke. In a matching cohort comprising 582 patients, death-censored graft survival, total CVE, and cardiac events were not different between the two groups. Only stroke incidence rate was significantly lower in the RASB group compared with the control group (1.4 vs. 6.4 per 1000 patients/year, log-ranked P = 0.005). In a multivariable analysis, stroke events were also significantly lower in the RASB group compared with the control group (Hazard ratio and 95% confidence interval, 0.20 [0.04-0.62]). CONCLUSION: Thus, RASBs potentially reduce stroke events in KT recipients.

Survival comparison between superficialization of the brachial artery and tunneled central venous catheter placement in hemodialysis patients with heart failure: A retrospective study.

It remains unclear which vascular access provides better survival in hemodialysis patients with heart failure, superficialization of the brachial artery (SBA), or tunneled central venous catheter (TCVC). We retrospectively followed up 60 hemodialysis patients with heart failure who underwent SBA (n = 36) or TCVC placement (n = 24). During the median 2.2-year follow-up period, 36 patients died. The median survival time was significantly longer for the SBA group than for the TCVC group (5.7 vs 1.7 years; P < .05, log-rank test). A multivariate-adjusted Cox regression analysis showed that SBA was associated with a reduced risk of all-cause death (hazard ratio [HR] 0.30; 95% confidence interval [CI] 0.14-0.65). In the cohort of propensity score-matched 15 pairs, patients with SBA experienced fewer all-cause deaths (HR 0.29; 95% CI 0.10-0.77). Our study suggests that SBA is an alternative option in hemodialysis patients with heart failure.

Asymptomatic Brain Edema after Hemodialysis Initiation in a Patient with Severe Uremia.

A 66-year-old man with severe renal insufficiency presented with mild confusion associated with uremia. Cranial magnetic resonance imaging (MRI) showed no remarkable changes. The patient was placed on short-duration hemodialysis (2 hours) with smaller surface area and low blood flow (100 mL/min) to avoid dialysis disequilibrium syndrome (DDS). His consciousness gradually improved and he did not develop apparent DDS symptoms. However, T2-weighted FLAIR MRI showed increased signal intensities bilaterally in the cortical and subcortical areas of the occipital lobe on day 15. In other words, cranial MRI showed cerebral edema, indicating asymptomatic DDS. On day 29, cranial MRI showed a return to findings on admission. In this case, because the patient did not have apparent DDS symptoms despite MRI changes, we diagnosed asymptomatic cerebral edema. The patient was discharged on regular intermittent HD without any neurological deficits. No further neurological disturbances were noted during 1-year follow-up. MRI findings in ESKD patients without DDS symptoms help to clarify the diagnosis of cerebral edema. In this case, the patient did not have apparent DDS symptoms and was therefore diagnosed with asymptomatic cerebral edema.