Long-term prognosis of monoclonal immunoglobulin-associated glomerular diseases with non-organized deposits: A report of 38 cases from a Japanese single center.

Monoclonal immunoglobulin (MIg)-associated glomerular diseases with non-organized deposits are rare disorders. They have recently been categorized into light chain deposit disease (LCDD), light and heavy chain deposit disease (LHCDD), heavy chain deposit disease (HCDD), proliferative glomerulonephritis with MIg deposits (PGNMID) and its light chain only variant (PGNMID-LC), and membranous glomerulopathy with light chain-restricted deposits (MG-LC). In our Japanese cohort of more than 9,500 patients who underwent renal biopsy (1979 - 2020), we evaluated clinicopathological features and long-term outcomes in 38 patients with MIg-associated glomerular diseases with non-organized deposits: LCDD (n = 9), LHCDD (n = 8), HCDD (n = 5), PGNMID-membranoproliferative glomerulonephritis (MPGN) (n = 7), PGNMID-LC (n = 2), and MG-LC (n = 7). In patients with LCDD, a low estimated glomerular filtration rate (eGFR) at biopsy, a high detection rate of urinary MIgs, a high incidence rate of multiple myeloma, and sever tubulointerstitial and vascular lesions were significant clinicopathological characteristics. Median duration of follow-up in each group was 42 - 114 months. Most patients were treated with steroid-based therapy. Patients with LCDD, LHCDD, HCDD, and MG-LC were recently treated with bortezomib-based therapy. Renal survival rate was significantly shorter for LCDD than of PGNMID and MG-LC. Patient survival rate was significantly longer for MG-LC than HCDD and PGNMID. Major causes of death were pulmonary and cardiovascular complications. Among disease groups, significant differences were observed in eGFR at biopsy, detection rates of urinary MIgs, incidence rates of multiple myeloma, severities of tubulointerstitial and vascular lesions, and long-term outcomes.

Evaluation of a newly proposed renal risk score for Japanese patients with ANCA-associated glomerulonephritis.

BACKGROUND: We determined the usefulness and prognostic ability of the renal risk score (RRS), proposed in Europe, for Japanese patients with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN) and high myeloperoxidase (MPO)-ANCA positivity; these aspects remain to be verified. METHODS: This retrospective study was conducted on 86 Japanese patients with new, biopsy-confirmed AAGN. We calculated the RRS and analyzed the relationship between this classification, and clinicopathological features and prognosis. We also compared the predictive values between RRS for endpoints including renal death and conventional prognostic tools for patients with AAGN. RESULTS: There were 33, 37, and 16 patients in the low-, medium-, and high-risk groups, respectively. All patients were MPO-ANCA positive. The median follow-up period was 33 months; 16 (18.6%) patients progressed to end-stage renal disease (ESRD). In the high-risk group, 9/16 (56.3%) patients progressed to ESRD, and renal prognosis was significantly poorer than that in other groups (low-risk group, P < 0.001; medium-risk group, P = 0.004). In Cox multivariate regression analysis, RRS was an independent, poor renal prognostic factor (hazard ratio 5.22; 95% confidence interval 2.20-12.40; P < 0.001). The receiver-operating characteristic curves of the RRS for each endpoint were comparable with those of the 2010 histological classification and those of the severity classification of Japanese rapidly progressive glomerulonephritis. CONCLUSIONS: This is the first study to report the usefulness of the RRS for predicting renal outcomes among Japanese patients with AAGN. Our predictive value of the RRS was comparable with that of conventional prognostic tools.

Adult-onset Still's Disease during Pregnancy Treated with Tocilizumab.

A 28-year-old woman exhibited a spiking fever, arthritis, and liver disfunction when she was 22 weeks pregnant. She was diagnosed with adult-onset Still's disease (AOSD). As her condition was resistant to corticosteroid therapy, tocilizumab (TCZ) was selected. The TCZ treatment was effective, and she delivered a healthy child while receiving TCZ treatment. Cases in which AOSD first arises during pregnancy are rare, and there have been no reports of TCZ treatment for AOSD being initiated during pregnancy. Although the safety of TCZ treatment during pregnancy has not been established, it may be effective against severe AOSD that develops during pregnancy.

Refractory IgG4-related disease complicated with organising pneumonia and hypertrophic pachymeningitis.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) involves multiple organs, including the lungs and central nervous system. Lung lesions are frequently reported as mass lesions or non-specific interstitial pneumonia, whereas organising pneumonia (OP) due to IgG4-RD is rare. Furthermore, limited information is currently available on hypertrophic pachymeningitis (HP). We herein report a case of IgG4-RD complicated with OP and HP. The diagnosis was confirmed based on the serum concentration of IgG4 and the results of salivary gland and transbronchial lung biopsies. HP did not respond to steroid monotherapy and was also resistant to rituximab and intravenous cyclophosphamide; however, the combination therapy of methotrexate and dexamethasone was effective.

Successful Pregnancies in a Patient with Childhood-onset Steroid-dependent Nephrotic Syndrome during Rituximab Maintenance Therapy.

There are an increasing number of reports on the safe use of rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, in pregnant women with hematological malignancies or refractory autoimmune diseases. In 2014, the use of RTX for patients with complicated steroid-dependent nephrotic syndrome (SDNS) was approved in Japan. We herein report a woman with childhood-onset complicated SDNS due to focal and segmental glomerulosclerosis, who had two successful pregnancies while receiving RTX maintenance therapy. No adverse complications were observed during the pregnancies, and she delivered healthy newborns. This case suggested that RTX may be used safely in pregnant women complicated with SDNS.

Clinicopathological features and outcomes of diabetic kidney disease with extracapillary hypercellularity: a Japanese single-center experience.

BACKGROUND: The prognostic significance of glomerular extracapillary hypercellularity (EXHC) in diabetic kidney disease (DKD) is unclear. The aim of this study was to investigate the clinicopathological features and outcomes of DKD patients with EXHC. METHODS: We studied 70 cases of renal biopsy-confirmed type 2 DKD that were diagnosed between 2004 and 2014 and compared the clinicopathological features and outcomes of 22 patients with EXHC (EXHC group) with those of 48 patients without EXHC (control group). All of the patients were Japanese. We assessed the renal biopsy specimens based on the Renal Pathology Society classification system. Clinical and laboratory data were collected at the time of the renal biopsy, and renal outcomes were assessed based on progression to end-stage renal disease (ESRD) requiring renal replacement therapy. The median duration of the observation period was 3 years. RESULTS: In pathological features, nodular sclerosis (Kimmelstiel-Wilson lesions) was observed more frequently in the EXHC group than in the control group (63.6% vs. 35.4%, P = 0.027). There were no significant intergroup differences in clinical features or renal outcomes. Univariate and multivariate Cox regression analyses of all patients showed that a high level of proteinuria, a low initial eGFR, and severe interstitial inflammation were poor prognostic factors. CONCLUSIONS: EXHC is related to nodular sclerosis, which is a known risk factor for ESRD. Careful observation is needed during the follow-up of DKD patients with EXHC, although there were no significant differences in renal outcomes between the EXHC and control groups.

A Pediatric Case of Relapsing Eosinophilic Granulomatosis with Polyangiitis Successfully Treated with Mepolizumab.

We herein report the first pediatric case (a 13-year-old girl) of relapsing eosinophilic granulomatosis with polyangiitis (EGPA) successfully treated with mepolizumab (anti-interleukin-5). She was classified as having EGPA based on the presence of asthma, eosinophilia, pulmonary infiltrates, and extravascular eosinophil infiltration confirmed by a biopsy. She achieved remission after initial oral prednisolone (PSL) therapy, but EGPA relapsed during PSL tapering. Subsequent combined therapy with PSL and tacrolimus did not improve the recurrent disease. Intravenous methylprednisolone pulse therapy was started, followed by oral PSL. During PSL tapering, mepolizumab was added to the treatment, which resulted in sustained remission and successful PSL tapering.

Disappearance of a thrombotic microangiopathy-like glomerular lesion in a patient with a placental site trophoblastic tumor after hysterectomy.

A 32-year-old woman presented with amenorrhea after a normal childbirth and subsequently developed nephrotic syndrome. Renal biopsy showed a thrombotic microangiopathy (TMA)-like glomerular lesion with deposits of immunoglobulins, complements, and fibrinogen. Increased serum levels of the beta subunit of human chorionic gonadotropin, abnormal uterine findings from imaging studies, and endometrial biopsy findings suggested gestational trophoblastic disease. She was diagnosed with a placental site trophoblastic tumor (PSTT) after hysterectomy and, following treatment, her proteinuria disappeared. Follow-up renal biopsy showed the disappearance of the TMA-like lesion. To our knowledge, this is the first case report of the pathological remission of renal disease associated with PSTT.

Strong correlation between cancer progression and anti-transcription intermediary factor 1γ antibodies in dermatomyositis patients.

OBJECTIVES: Transcription intermediary factor 1γ (ΤΙF1γ) protein is known as a tumour suppressor that promotes cellular differentiation. Autoantibodies to ΤΙF1γ have a strong clinical association with cancers associated with dermatomyositis (DM). This study aims to identify the clinical characteristics of cancers in anti-ΤΙF1γ antibody-positive adult patients with DM. METHODS: This retrospective analysis covered 160 adult DM patients who visited Nagoya University Hospital or collaborating medical centres between 2003 and 2016. Anti-TIF1γ antibody and other myositis-specific autoantibodies were detected by ELISA. Based on a review of medical charts, the cancers were staged according to the TNM Classification of Malignant Tumours of the Union for International Cancer Control and were divided into the two groups of "advanced" or "non-advanced" according to the stage classification. RESULTS: Forty-one of the 160 (26%) patients had cancer. The incidence was significantly higher in the anti-TIF1γ-positive patients than in the anti-TIF1γ-negative patients (23/34=68% vs. 18/126=14%, p<1x10-6). Anti-TIF1γ-positive patients with cancer were found more frequently in the "advanced" group than in the "non-advanced" group (21/23=91% vs. 9/18=50%, p<0.0046). The intervals between DM diagnosis and cancer diagnosis were significantly shorter in the anti-TIF1γ-positive patients than in the anti-TIF1γ-negative patients (p=0.047). CONCLUSIONS: Not only did anti-TIF1γ antibodies correlate strongly with malignancy in DM patients, but cancers were also significantly more advanced in anti-TIF1γ-positive DM patients than in anti-TIF1γ-negative patients. Cancers in such cases were very frequently found close to the time of the DM diagnosis.

Clinicopathological and long-term prognostic features of membranous nephropathy with crescents: a Japanese single-center experience.

BACKGROUND: Three recent studies from the United States and China reported the clinicopathological features and short-term prognosis in patients with membranous nephropathy (MN) and crescents in the absence of secondary MN, anti-glomerular basement membrane (GBM) antibodies, and anti-neutrophil cytoplasmic antibodies (ANCA). METHODS: We compared clinicopathological and prognostic features in 16 MN patients with crescents (crescent group) and 38 MN patients without crescents (control group), in the absence of secondary MN, anti-GBM antibodies, and ANCA. Median follow-up periods in the crescent and control groups were 79 and 50 months, respectively. RESULTS: Decreased estimated glomerular filtration rates (<50 mL/min/1.73 m2), glomerulosclerosis, and moderate-to-severe interstitial fibrosis were more frequently observed in the crescent group than in the control group (P = 0.043, P = 0.004, and P = 0.035, respectively). Positive staining rates for glomerular IgG2 and IgG4 were significantly different between the 2 groups (P = 0.032, P = 0.006, respectively). Doubling of serum creatinine during follow-up was more frequently observed in the crescent group than in the control group (P = 0.002), although approximately two-thirds of patients in the crescent group were treated with immunosuppressive therapy. Crescent formation and interstitial fibrosis were risks for doubling of serum creatinine [hazard ratio (HR) = 10.506, P = 0.012; HR = 1.140, P = 0.009, respectively]. CONCLUSIONS: This is the first Japanese study demonstrating significant differences in clinicopathological and prognostic features between the 2 groups. Most patients in the crescent group may develop a long-term decline in renal function despite immunosuppressive therapy.

Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis Complicated by Periaortitis and Cranial Hypertrophic Pachymeningitis: A Report of an Autopsy Case.

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic inflammatory disorder categorized as small-vessel vasculitis. We herein report an elderly Japanese man with AAV (granulomatosis with polyangiitis affecting the eyes, nose, lungs, and kidneys) who also showed periaortitis at the diagnosis and developed cranial hypertrophic pachymeningitis (HP) during steroid maintenance therapy. His consciousness disturbance caused by HP improved after steroid pulse therapy, but he died of aspiration pneumonia. Autopsy findings showed giant cells in the thickened pachymeninges and obsolete inflammatory lesions in the aortic adventitia and renal tubulointerstitium. This is the first case of AAV complicated by periaortitis and cranial HP.

Quantification of Interstitial Fibrosis in Renal Allografts and Clinical Correlates of Long-Term Graft Function.

BACKGROUND: The present study investigated interstitial fibrosis (IF) in 144 kidney recipients 0 h and 1 year post transplantation and assessed relationships with Banff code scores, clinical parameters, and long-term graft function. METHODS: A quantitative analysis of IF was performed using the computer-assisted imaging of Sirius red-stained biopsy samples. Percent IF (%IF) in the cortical region was assessed at 0 h and 1 year, and an increase in the ratio of %IF from 0 h to 1 year was calculated. The relationship between %IF and Banff code scores was analyzed. Demographics and trough concentrations of tacrolimus were tested as risk factors in the top 20 patients with increases in %IF. The influence of increases in the ratio of %IF at 1 year on long-term graft function and survival was also assessed in these 20 patients. RESULTS: Median %IF at 0 h and 1 year were 1.55 and 2.80%, respectively. No correlation was found between %IF and Banff code scores. The mean increase in the ratio of %IF from 0 h to 1 year was 4.31-fold. The increase in %IF in the top 20 patients correlated with diabetes mellitus. Graft function, but not graft survival, was lower in the top 20 patients for 10 years post transplantation. CONCLUSIONS: A correlation was not found between %IF and Banff code scores. Greater increases in %IF within 1 year post transplantation may influence long-term graft survival. Computer-analyzed increases in %IF at 1 year may be a surrogate marker for long-term graft function.

Two Cases of Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis/Renal Failure, and Organomegaly (TAFRO) Syndrome with High Serum Procalcitonin Levels, Including the First Case Complicated with Adrenal Hemorrhaging.

Thrombocytopenia, Anasarca, Fever, Reticulin fibrosis/Renal failure, and Organomegaly (TAFRO) syndrome is a recently described systemic inflammatory disorder characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly. It has an acute or subacute onset of unknown etiology, although some pathological features resemble those of multicentric Castleman disease. We here report two cases of TAFRO syndrome. The symptoms and pathological findings in these cases met the 2015 diagnostic criteria. Our cases showed high serum procalcitonin levels, suggesting bacterial infection as an onset trigger. In addition, Case 1 is the first case complicated with adrenal hemorrhaging. Case 2 is the second case of tocilizumab-resistant TAFRO syndrome successfully treated with rituximab.

Long-term prognosis of AL and AA renal amyloidosis: a Japanese single-center experience.

BACKGROUND: Few studies have been conducted on the long-term prognosis of patients with amyloid light chain (AL) and amyloid A (AA) renal amyloidosis in the same cohort. METHODS: We retrospectively examined 68 patients with biopsy-proven renal amyloidosis (38 AL and 30 AA). Clinicopathological findings at the diagnosis and follow-up data were evaluated in each patient. We analyzed the relationship between clinicopathological parameters and survival data. RESULTS: Significant differences were observed in several clinicopathological features, such as proteinuria levels, between the AL and AA groups. Among all patients, 84.2 % of the AL group and 93.3 % of the AA group received treatments for the underlying diseases of amyloidosis. During the follow-up period (median 18 months in AL and 61 months in AA), 36.8 % of the AL group and 36.7 % of the AA group developed end-stage renal failure requiring dialysis, while 71.1 % of the AL group and 56.7 % of the AA group died. Patient and renal survivals were significantly longer in the AA group than in the AL group. eGFR of >60 mL/min/1.73 m2 at biopsy and an early histological stage of glomerular amyloid deposition were identified as low-risk factors. A multivariate analysis showed that cardiac amyloidosis and steroid therapy significantly influenced patient and renal survivals. CONCLUSIONS: Our results showed that heart involvement was the major predictor of poor outcomes in renal amyloidosis, and that the prognosis of AA renal amyloidosis was markedly better than that in previously reported cohorts. Therapeutic advances in inflammatory diseases are expected to improve the prognosis of AA amyloidosis.

Effects of CYP3A5 polymorphism and the tacrolimus 12 h concentration on tacrolimus-induced acute renal dysfunction in patients with lupus nephritis.

1. The purpose of the present study was to investigate the effect of tacrolimus concentration in blood 12 h after administration (C12h) on acute renal dysfunction in patients with lupus nephritis (LN) taking tacrolimus once daily. 2. Five of the 35 LN patients experienced tacrolimus-induced acute renal dysfunction. 3. The average annual C12h of tacrolimus was higher for patients with events of elevated serum creatinine level than for patients not experiencing these events [6.4 (5.6-8.8) versus 2.8 (2.2-4.6) ng/mL, respectively, p=0.001]. 4. The average annual tacrolimus C12h was higher for patients with CYP3A5*3/*3 (PM) than for patients with the CYP3A5*1 allele (EM) [4.6 (3.2-6.6) versus 2.5 (2.0-3.1) ng/mL, respectively, p=0.002]. 5. The area under the receiver operating characteristic was 0.887, which gave the best sensitivity (80.0%) and specificity (86.7%) at a tacrolimus C12h (average annual C12h or C12h at events) threshold of 5.2 ng/mL. 6. C12h measurements, CYP3A5 genotyping and dose adjustments of tacrolimus should be performed to prevent acute renal dysfunction in LN patients taking tacrolimus once daily.

Effect of CYP3A5 and ABCB1 polymorphisms on the interaction between tacrolimus and itraconazole in patients with connective tissue disease.

PURPOSE: The aim of this study was to investigate the effect of itraconazole (ITCZ), a potent inhibitor of CYP3A4 and P-glycoprotein, on the blood concentration 12 h after tacrolimus administration (C 12h) in relation to CYP3A5 6986A>G and ABCB1 3435C>T genotype status in patients with connective tissue disease (CTD). METHODS: Eighty-one CTD patients taking tacrolimus (Prograf®) once daily at night (2100 hours) were enrolled in this study. Whole blood samples were collected 12 h after tacrolimus administration at steady state. RESULTS: The dose-adjusted tacrolimus C 12h with or without ITCZ co-administration was significantly higher in patients with CYP3A5*3/*3 than in those with the CYP3A5*1 allele [CYP3A5 *1/*1 vs. *1/*3 vs. *3/*3 = 1.67 vs. 2.70 vs. 4.83 ng/mL/mg (P = 0.003) and 0.68 vs. 0.97 vs. 2.20 ng/mL/mg (P < 0.001), respectively], but differences were not observed for ABCB1 genotypes. However, there was no difference in the increase rate of the dose-adjusted C 12h of tacrolimus between CYP3A5 or ABCB1 genotypes (P = 0.378 and 0.259). On the other hand, reduction of the estimated glomerular filtration rate exhibited a correlation with the C 12h of tacrolimus after ITCZ co-administration (r = -0.482, P = 0.009). CONCLUSIONS: In CYP3A5*3/*3 patients, because the metabolic pathway for tacrolimus occurs only through CYP3A4, the combination with ITCZ seems to lead to a higher risk of acute renal dysfunction. Therefore, we suggest that the target blood tacrolimus concentration be set as low as possible through dose-adjustment for patients with the CYP3A5*3/*3 allele.

Relapsing polychondritis with encephalitis: a case report and literature review.

We herein report the case of a 39-year-old man who developed bilateral auricular chondritis, conjunctivitis, and central neurological symptoms. He was diagnosed with encephalitis associated with relapsing polychondritis (RP) based on the findings of an ear cartilage biopsy, cerebrospinal fluid examination and magnetic resonance imaging. Although oral prednisolone (60 mg/day) was administered, the initial steroid therapy did not improve his symptoms. In contrast, methylprednisolone (mPSL) pulse therapy followed by prednisolone gradually ameliorated his condition. There were no episodes of recurrence during the two-year follow-up period. A review of the literature revealed that meningoencephalitis and encephalitis are rare, but important, complications of RP responsive to mPSL pulse therapy.