Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells.

The complexity of organogenesis hinders in vitro generation of organs derived from a patient's pluripotent stem cells (PSCs), an ultimate goal of regenerative medicine. Mouse wild-type PSCs injected into Pdx1(-/-) (pancreatogenesis-disabled) mouse blastocysts developmentally compensated vacancy of the pancreatic "developmental niche," generating almost entirely PSC-derived pancreas. To examine the potential for xenogenic approaches in blastocyst complementation, we injected mouse or rat PSCs into rat or mouse blastocysts, respectively, generating interspecific chimeras and thus confirming that PSCs can contribute to xenogenic development between mouse and rat. The development of these mouse/rat chimeras was primarily influenced by host blastocyst and/or foster mother, evident by body size and species-specific organogenesis. We further injected rat wild-type PSCs into Pdx1(-/-) mouse blastocysts, generating normally functioning rat pancreas in Pdx1(-/-) mice. These data constitute proof of principle for interspecific blastocyst complementation and for generation in vivo of organs derived from donor PSCs using a xenogenic environment.

Survey of Japanese nephrologists' use of clinical practice guidelines for rapidly progressive glomerulonephritis.

BACKGROUND: The guidelines in Japan for the treatment of rapidly progressive glomerulonephritis (RPGN) have been revised; the latest update was released in 2020. We investigated the actual usage of the new guidelines in Japan. METHODS: We distributed a survey electronically to board-certified nephrologists throughout Japan from December 15, 2021 to January 31, 2022. The survey focused on anti-neutrophil cytoplasmic antibody (ANCA)-associated RPGN and anti-glomerular basement membrane (GBM)-antibody RPGN, plus the treatment strategies and infection-prevention measures used. RESULTS: The survey was completed by 155 certified nephrologists from medical facilities across Japan. Their responses regarding treatment procedures revealed that ANCA-associated RPGN was treated with immunosuppressants and/or biologics by 58.1% of the survey respondents, and with plasma exchange (PE) in combination with corticosteroids by 21.3%. Regarding anti-GBM-antibody RPGN, 78.1% of the respondents used corticosteroids in combination with PE (63.2%), cyclophosphamide (CY) (23.9%), or rituximab (RTX) (8.4%), suggesting a discrepancy between clinical practice and the actual use of the guidelines. Trimethoprim-sulfamethoxazole was prescribed as prophylaxis by 94.8% of the respondents, reflecting the widespread recognition of the need to prevent infectious disease in patients with RPGN. CONCLUSIONS: The survey responses revealed how Japan's new RPGN guidelines are used in actual clinical practice. Our findings will contribute to the guidelines' dissemination and implementation.

NT-pro BNP level at dialysis initiation is a useful biomarker for predicting hospitalization for ischemic heart disease.

BACKGROUND: Patients with end-stage kidney disease (ESKD) are at high risk of cardiovascular disease including stroke, heart failure, and ischemic heart disease (IHD). To prevent the occurrence and progression of CVD, a reliable prognostic cardiac biomarker is essential. We investigated the prognostic value of NT-proBNP for each incident type of CVD. METHODS: Male patients from the Ibaraki Dialysis Initiation Cohort (iDIC) study with preserved serum samples from dialysis initiation day (n = 212) were analyzed. Patients were classified into four groups according to quartiles of baseline NT-pro BNP levels. The relationship between NT-proBNP levels at the initiation of dialysis and the subsequent incidence of hospitalization events due to IHD, heart failure, and stroke was analyzed. RESULTS: The incidence rate for hospitalization due to IHD was significantly higher in the highest NT-proBNP category (Log rank p = 0.008); those of stroke and heart failure showed no significant differences among quartiles. Cox proportional hazards regression analysis revealed that serum NT-proBNT was the only prognostic factor for hospitalization for IHD after adjustment by major known IHD risk factors. (HR, 1.008; 95% confidence interval, 1.002-1.014; p = 0.01) The ROC curve analysis for the incidence of hospitalization due to IHD showed that NT-proBNP had an area under the curve (AUC) of 0.759 (95% CI 0.622-0.897; p = 0.004) at a cut-off value of 956.6 pg/mL. CONCLUSION: NT-proBNP measurement at the initiation of dialysis therapy is useful to predict later hospitalization for IHD. TRIAL REGISTRATION: UMIN000010806.

Aberrant splicing caused by exonic single nucleotide variants positioned 2nd or 3rd to the last nucleotide in the COL4A5 gene.

BACKGROUND AND OBJECTIVES: The evident genotype-phenotype correlation shown by the X-linked Alport syndrome warrants the assessment of the impact of identified gene variants on aberrant splicing. We previously reported that single nucleotide variants (SNVs) in the last nucleotide of exons in COL4A5 cause aberrant splicing. It is known that the nucleotides located 2nd and 3rd to the last nucleotides of exons can also play an essential role in the first step of the splicing process. In this study, we aimed to investigate whether SNVs positioned 2nd or 3rd to the last nucleotide of exons in COL4A5 resulted in aberrant splicing. METHODS: We selected eight candidate variants: six from the Human Gene Variant Database Professional and two from our cohort. We performed an in-vitro splicing assay and reverse transcription-polymerase chain reaction (RT-PCR) for messenger RNA obtained from patients, if available. RESULTS: The candidate variants were initially classified into the following groups: three nonsense, two missense, and three synonymous variants. Splicing assays and RT-PCR for messenger RNA revealed that six of the eight variants caused aberrant splicing. Four variants, initially classified as non-truncating variants, were found to be truncating ones, which usually show relatively more severe phenotypes. CONCLUSION: We revealed that exonic SNVs positioned 2nd or 3rd to the last nucleotide of exons in the COL4A5 were responsible for aberrant splicing. The results of our study suggest that attention should be paid when interpreting the pathogenicity of exonic SNVs near the 5' splice site.

All reported non-canonical splice site variants in GLA cause aberrant splicing.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by insufficient α-galactosidase A (GLA) activity resulting from variants in the GLA gene, which leads to glycosphingolipid accumulation and life-threatening, multi-organ complications. Approximately 50 variants have been reported that cause splicing abnormalities in GLA. Most were found within canonical splice sites, which are highly conserved GT and AG splice acceptor and donor dinucleotides, whereas one-third were located outside canonical splice sites, making it difficult to interpret their pathogenicity. In this study, we aimed to investigate the genetic pathogenicity of variants located in non-canonical splice sites within the GLA gene. METHODS: 13 variants, including four deep intronic variants, were selected from the Human Gene Variant Database Professional. We performed an in vitro splicing assay to identify splicing abnormalities in the variants. RESULTS: All candidate non-canonical splice site variants in GLA caused aberrant splicing. Additionally, all but one variant was protein-truncating. The four deep intronic variants generated abnormal transcripts, including a cryptic exon, as well as normal transcripts, with the proportion of each differing in a cell-specific manner. CONCLUSIONS: Validation of splicing effects using an in vitro splicing assay is useful for confirming pathogenicity and determining associations with clinical phenotypes.

Histamine receptor agonist alleviates severe cardiorenal damages by eliciting anti-inflammatory programming.

Heart failure and chronic kidney disease are major causes of morbidity and mortality internationally. Although these dysfunctions are common and frequently coexist, the factors involved in their relationship in cardiorenal regulation are still largely unknown, mainly due to a lack of detailed molecular targets. Here, we found the increased plasma histamine in a preclinical mouse model of severe cardiac dysfunction, that had been cotreated with angiotensin II (Ang II), nephrectomy, and salt (ANS). The ANS mice exhibited impaired renal function accompanied with heart failure, and histamine depletion, by the genetic inactivation of histidine decarboxylase in mice, exacerbated the ANS-induced cardiac and renal abnormalities, including the reduction of left ventricular fractional shortening and renal glomerular and tubular injuries. Interestingly, while the pharmacological inhibition of the histamine receptor H3 facilitated heart failure and kidney injury in ANS mice, administration of the H3 agonist immethridine (Imm) was protective against cardiorenal damages. Transcriptome analysis of the kidney and biochemical examinations using blood samples illustrated that the increased inflammation in ANS mice was alleviated by Imm. Our results extend the pharmacological use of H3 agonists beyond the initial purposes of its drug development for neurogenerative diseases and have implications for therapeutic potential of H3 agonists that invoke the anti-inflammatory gene expression programming against cardiorenal damages.

Increased intrarenal post-glomerular blood flow is a key condition for the development of calcineurin inhibitor-induced renal tubular acidosis in kidney transplant recipients.

BACKGROUND: Hyperchloremic metabolic acidosis (HCMA) from renal tubular acidosis (RTA) is common in kidney transplant (KT) recipients. Calcineurin inhibitors (CNIs) are a potential cause of RTA, and whether HCMA is a determinant of poor graft prognosis is controversial. METHODS: The subjects were living-donor KT recipients (LDKTRs, n = 47) and matched donors (n = 43). All cases of rejection, extrarenal causes, and respiratory disorders were excluded. HCMA was defined as having a [Na+]-[Cl- ] value of ≤34 or starting alkalization. We determined the potential causes of HCMA in LDKTRs at 3 months (m) and 1 year (y) post-KT. We examined renal hemodynamic parameters in 26 LDKTRs at 1 y post-KT: namely, glomerular filtration rate (GFR), renal plasma flow (RPF), filtration fraction (FF; GFR/RPF) and pre-/post-glomerular vascular resistance (pre-/postVR). RESULTS: The HCMA incidence in the 3-m post-KT LDKTR group was higher than that of the donors (51.0% vs. 6.9%, p < 0.001, adjusted odds ratio: 6.7-15.7). Among adjusted factors, the most dominant HCMA contributor was low hemoglobin concentration (Hb ≤ 12 g/dl). Compared to non-HCMA cases, HCMA patients had low FF and low post-VR (p = 0.008, 0.003, respectively) suggesting increased intrarenal post-glomerular blood flow. The high pathological score of alternative arteriolar hyalinosis (aah) ≥2 was a significant HCMA risk. The tacrolimus trough level was not high in HCMA but was significantly high in HCMA in the low post-VR setting (p = 0.002). CONCLUSION: Among LDKTRs, low hemoglobin level is an important contributor to the manifestation of HCMA in the induction period, and increased intrarenal post-glomerular blood flow is a key condition for the development of CNI-induced RTA.

Epidemiology and temporal changes in the prognosis of rapidly progressive glomerulonephritis in Japan: a nationwide 1989-2015 survey.

BACKGROUND: Rapidly progressive glomerulonephritis (RPGN) can progress to end-stage kidney disease within a short period. This study is a continuation of the chronological nationwide survey conducted by the Japan-RPGN working group. METHODS: We examined a total of 2793 RPGN cases registered during four periods (1989-1998, 1999-2001, 2002-2008, 2009-2011) plus 1386 cases in 2012-2015. As potential prognostic determinants, we investigated the onset period, the clinical severity (CS) grade [classified according to age, serum creatinine (sCr) and C-reactive protein levels, and presence/absence of lung lesions], and causative disease. RESULTS: The cumulative overall RPGN patient survival at 24 months kept improving over the five periods (72.0%, 72.9%, 77.7%, 83.0%, 84.9%, p < 0.001 for trend). The cumulative renal survival also improved in the latest period (68.7%, 75.4%, 76.7%, 73.4%, 78.2%, p < 0.001 for trend). The CS grade was well stratified to predict both life and renal prognoses. Anti-glomerular basement membrane disease (aGBMD)-RPGN had a poorer renal prognosis than other diseases. In anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV-RPGN, accounting for > 70% of the overall RPGN), the prognostic results were similar to that for overall RPGN. There was a much better renal prognosis for the latest period under the condition of sCr < 3 mg/dL (the 24-month cumulative renal survival: 97.9%), but not for sCr ≥ 3 mg/dL (61.5%). CONCLUSIONS: In overall RPGN as well as AAV-RPGN, both life and renal prognoses tended to improve, but the favorable renal result was substantially limited to mild cases. There was no improvement of the renal prognosis in aGBMD-RPGN.

The efficacy and safety of mizoribine for maintenance therapy in patients with myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis: the usefulness of serum mizoribine monitoring.

BACKGROUND: The life prognosis of elderly patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies-associated vasculitis (MPO-AAV) has been improved by reducing the corticosteroid or cyclophosphamide dose to avoid opportunistic infection. However, many elderly MPO-AAV patients experience recurrence and renal death. An effective and safer maintenance treatment method is necessary to improve the renal prognosis of MPO-AAV. METHODS: Patients with MPO-AAV who reached complete or incomplete remission after induction therapy were prospectively and randomly divided into mizoribine (MZR; n = 25) and control (n = 28) groups. The primary endpoint was relapse of MPO-AAV. The patients' serum MZR concentration was measured before (C0) and 3 h after taking the MZR. The maximum drug concentration (Cmax) and the serum MZR concentration curves were determined using population pharmacokinetics parameters. We also assessed the relationship between the MZR concentrations and adverse events. The observation period was 12 months. RESULTS: Fifty-eight MPO-AAV patients from 16 hospitals in Japan were enrolled. Ten patients relapsed (MZR group, n = 6; control group, n = 4; a nonsignificant between-group difference). Changes in the serum MZR concentration could be estimated for 22 of the 25 MZR-treated patients: 2 of the 11 patients who reached a Cmax of 3 µg/mL relapsed, whereas 4 of the 11 patients who did not reach this Cmax relapsed. The treatment of one patient with C0 > 1 µg/mL was discontinued due to adverse events. No serious adverse events occurred. CONCLUSION: There was no significant difference in the recurrence rate of MPO-AAV between treatment with versus without MZR.

Study protocol and baseline characteristics of newly induced dialysis patients: a prospective multi-center cohort study with a biological sample bank, the Ibaraki Dialysis Initiation Cohort (iDIC) study.

BACKGROUND: Patients with end-stage kidney disease (ESKD) face higher risks of life-threatening events including cardiovascular disease. Various risk factors are identified as agents influencing the life prognosis of ESKD patients. Herein, we evaluated the risk factors related to the outcomes of Japanese patients with dialysis induction. We present the study protocol, the patients' baseline characteristics, and their outcomes. METHODS: The Ibaraki Dialysis Initiation Cohort (iDIC) Study is a prospective multi-center cohort study in collaboration with 60 tertiary-care facilities in Ibaraki Prefecture, Japan. We collected baseline data from clinical records and analyzed blood and urine samples of these facilities' patients with diabetic nephropathy, hypertensive nephrosclerosis, and chronic glomerulonephritis (CGN). The study's primary outcome was the survival rate at 24 months after dialysis induction. We performed a Kaplan-Meier analysis for cumulative survival and a Cox proportional hazards analysis for all-cause mortality and hospitalization. RESULTS: We analyzed 636 patients' cases (424 males, 212 females, age 67.4 ± 13.1 yrs. [mean ± SD]). We compared the patients' baseline data with those of similar cohort studies. As the primary kidney disease, 327 cases (51.4%) were diagnosed as diabetic nephropathy, 101 (15.9%) as hypertensive nephrosclerosis, and 114 (17.9%) as CGN. The mean serum creatinine value was 9.1 ± 2.9 mg/dL. The mean estimated glomerular filtration rate was 5.6 ± 1.8 mL/min/1.73m2. The cumulative survival rates at 6 months and 24 months after dialysis induction were 95.2 and 87.7%, respectively. The cumulative survival rate was significantly lower with increasing age. A Cox proportional hazards regression analysis demonstrated that high age was significantly associated with all-cause mortality. CONCLUSIONS: Regarding the clinical characteristics of these newly induced dialysis patients, the same trend as in other cohort studies was observed. Another study is underway to explore prognostic factors based on the iDIC Study's findings.

Clinical impact of urinary CD11b and CD163 on the renal outcomes of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

BACKGROUND: The detection of leukocyte-derived CD11b (α subunit of integrin Mac-1) and CD163 (scavenger receptor) in urine may reflect renal inflammation in antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN). The objective of this study was to evaluate the clinical significance of urinary CD11b (U-CD11b) and CD163 (U-CD163) in ANCA-GN. METHODS: U-CD11b and U-CD163 were examined using enzyme-linked immunosorbent assay in ANCA-GN urine samples from our institutional cohort (n = 88) and a nationwide cohort (n = 138), and their association with renal histology was subsequently analyzed. Logistic regression analyses were performed on a nationwide ANCA cohort to determine the associations of the two urinary molecules with renal remission failure at 6 months or with yearly estimated glomerular filtration rate (eGFR) slope over a 24-month observation period. RESULTS: U-CD11b and U-CD163 were significantly associated with cellular crescent formation and leukocyte accumulation in glomerular crescents. With regard to interstitial inflammation, both levels of U-CD11b and U-CD163 at diagnosis remarkably increased in ANCA-GN compared with the levels observed in nonglomerular kidney disorders including nephrosclerosis, immunoglobulin G4-related disease and tubulointerstitial nephritis; however, the presence of U-CD11b alone was significantly correlated with tubulointerstitial leukocyte infiltrates. Although neither U-CD11b nor U-CD163 at diagnosis was associated with remission failure at 6 months, multivariate analysis demonstrated that the baseline U-CD11b levels were significantly associated with the increase in eGFR following immunosuppressive therapy. CONCLUSIONS: Although both U-CD11b and U-CD163 reflect renal leukocyte accumulation, U-CD11b at diagnosis provides additional clinical value by predicting the recovery rate after the treatment of ANCA-GN.

Literature review of allograft adenovirus nephritis and a case presenting as mass lesions in a transplanted kidney without symptoms of urinary tract infection or acute kidney injury.

Adenovirus (AdV) infection is a common complication in bone marrow/hematopoietic stem cell transplant and solid organ transplant recipients. AdV infection usually presents as hemorrhagic cystitis, but sometimes it can progress to acute kidney injury showing AdV nephritis (AdVN). We present the case of a 52-year-old Japanese female who had received a living kidney transplantation (KT) from her husband. At 21 months post-KT, the patient presented with a fever, but no renal dysfunction and no abnormal urine findings. A contrast-enhanced computed tomography (CT) scan revealed a few mass lesions with hypoperfusion in the transplanted kidney. An enhanced CT-guided biopsy targeting one of these lesions revealed a necrotizing tubulointerstitial nephritis suggesting AdVN. The polymerase chain reaction tests for ADV were negative in a urine sample but positive in the sera and the frozen kidney biopsy samples. AdVN can manifest as an unusual pattern of acute lobar nephritis/acute focal bacterial nephritis-like localization without symptoms of acute kidney injury or urinary tract infection. Enhanced CT can provide clues for clinical diagnosis.

Unusual ischemic kidney injury presenting as slowly declining graft function and successful use of oral desmopressin in a kidney transplant recipient with subclinical central diabetes insipidus.

Polyuria in post-kidney transplant (KT) patients is a common condition generally attributed to delayed tubular function, fluid administration, and solute diuresis. Since excessive water intake post-KT physiologically suppresses arginine vasopressin (AVP) secretion, central diabetes insipidus (CDI) caused by deficient primary AVP release can be overlooked. Although DDAVP (desmopressin) - a selective AVP V2 receptor agonist - has been used to treat massive polyuria, CDI rarely progresses to kidney injury due to the preservation of fluid balance by thirst-dependent osmoregulation. Administration of DDAVP in post-KT recipients with mild polyuria and subclinical CDI is difficult to assess, and whether long-term use of DDAVP is beneficial for the transplanted kidney has not been established. We present the case of a 36-year-old Japanese female who was diagnosed with subclinical/partial CDI post KT. CDI was caused by a sequela of suprasellar germinoma. Graft function gradually declined without evidence of hypovolemia or hypernatremia, and a kidney biopsy revealed advanced ischemic kidney injury. Although daily oral DDAVP administration did not increase extracellular fluid volume, treatment resulted in a gradual improvement of graft function, and a follow-up transplanted kidney biopsy indicated substantial recovery.

Ratio of serum creatinine to cystatin C is related to leg strength in predialysis CKD patients.

BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) patients have lower levels of physical function. Especially, leg strength is important for daily living and preventing falls. However, physical function screenings are difficult to perform at clinical sites. To find clinically useful method to evaluate physical function in predialysis CKD patients, we tried to evaluate the relationship between the ratio of serum creatinine to serum cystatin C (Cre/CysC), and knee extensor muscle strength/body weight (KEMS) which reflects their leg strength. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: We recruited 147 outpatients with CKD (87 men; mean age, 61.6 ± 9.8 years; mean eGFRcreat, 40.7 ± 12.9 mL/min/1.73m2) in this cross-sectional study. KEMS was assessed using a wire strain gauge dynamometer. Skeletal muscle mass and body fat mass were assessed by bioelectrical impedance analysis. RESULTS: The mean value of Cre/CysC was 1.01 ± 0.18. The mean value of KEMS was 1.60 ± 0.47 Nm/kg. In multivariate linear regression analysis, skeletal muscle mass (p < 0.01), body fat mass (p < 0.01), hemoglobin (p = 0.01), and Cre/CysC (p < 0.01) was independently related to KEMS. The correlation between Cre/CysC and KEMS is stronger in high quantile of Cre/CysC. CONCLUSIONS: In predialysis CKD patients, KEMS showed lower as CKD stage advanced. Cre/CysC is significantly related to KEMS independently. Cre/CysC may be an alternative marker for leg strength in CKD patients and even more valuable to utilize in cases with high Cre/CysC.

Transcription factor MafB in podocytes protects against the development of focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a common cause of steroid-resistant nephrotic syndrome. Spontaneous remission of FSGS is rare and steroid-resistant FSGS frequently progresses to renal failure. Many inheritable forms of FSGS have been described, caused by mutations in proteins that are important for podocyte function. Here, we show that a basic leucine zipper transcription factor, MafB, protects against FSGS. MAFB expression was found to be decreased in the podocytes of patients with FSGS. Moreover, conditional podocyte-specific MafB-knockout mice developed FSGS with massive proteinuria accompanied by depletion of the slit diaphragm-related proteins (Nphs1 and Magi2), and the podocyte-specific transcription factor Tcf21. These findings indicate that MafB plays a crucial role in the pathogenesis of FSGS. Consistent with this, adriamycin-induced FSGS and attendant proteinuria were ameliorated by MafB overexpression in the podocytes of MafB podocyte-specific transgenic mice. Thus, MafB could be a new therapeutic target for FSGS.

Correction to: Temporal change in life and renal prognosis of rapidly progressive glomerulonephritis in Japan via nationwide questionnaire survey.

In the Original publication of the article, the text in the horizontal axis in Fig. 1a and b appears incorrectly as "Time from treatment start (Months)".

Chest High-Resolution CT Findings of Microscopic Polyangiitis: A Japanese First Nationwide Prospective Cohort Study.

OBJECTIVE. The lung is one of the organs possibly involved in microscopic polyangiitis (MPA), and myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA) is commonly found in patients with MPA. The aim of this study was to assess pulmonary lesions in Japanese patients with MPA. SUBJECTS AND METHODS. This prospective study was based on 144 patients with MPA who were enrolled in the Remission Induction Therapy in Japanese Patients With ANCA-Associated Vasculitis and Rapidly Progressive Glomerulonephritis Study and who underwent chest high-resolution CT (HRCT) imaging at the time of diagnosis during 2011-2014. We reviewed the electronic case report forms of patients with MPA who did and did not have interstitial pneumonia (IP), and the clinical features and laboratory findings of these groups were compared. RESULTS. Abnormal HRCT findings were noted in 134 of the 144 patients (93%). Chest HRCT findings included ground-glass opacity (n = 72; 50%), reticulation (n = 69; 48%), traction bronchiectasis (n = 57; 42%), honeycombing (n = 44; 31%), and emphysema (n = 32; 22%). IP was diagnosed radiologically in 74 patients (51%), 38% of whom had the usual IP (UIP) pattern. Ground-glass opacity, reticulation, traction bronchiectasis, honeycombing, and interlobular septal thickening were frequent in patients with IP (p < 0.05). Patients with MPA with the UIP or possible UIP pattern also had minor findings, such as bronchial wall thickening, consolidation, increased attenuation around honeycombing, and traction bronchiectasis. CONCLUSION. IP (51%) was most commonly observed in Japanese patients with MPA, and 38% of these patients exhibited a UIP pattern. Increased attenuation around honeycombing or traction bronchiectasis was also found.

Association between renal outcome and the number of steroid pulse therapies after tonsillectomy in patients with IgA nephropathy.

BACKGROUND: Tonsillectomy performed on patients with Immunoglobulin A glomerulonephritis (IgAN) improved the clinical remission rate as defined by urinary protein. But the number of times steroid pulse therapies (SP) should be administered remained poorly understood. METHOD: Multicenter, observational, retrospective cohort study at four hospitals in the Tokyo metropolitan area between March 1981 and December 2013. We divided patients into two groups: those treated with SP three times and those treated without SP or with SP only once or twice, and we analyzed standard Cox proportional hazard model unadjusted and adjusted the confounding covariates to estimate the hazard ratio for the primary outcome, the 30% estimated decline in glomerular filtration rate, in four models: model 1, unadjusted; model 2, adjusted for age, sex, body mass index, estimated glomerular filtration rate, biopsy year, proteinuria, hematuria, Japanese historical grade, systolic blood pressure, smoking history, and diabetes as a comorbidity; model 3, adjusted for propensity score, which was estimated by multiple logistic regressions; model 4, multilevel mixed-effects parametric survival models, whose facilities comprise the second level. RESULTS: Patients that received three times SP therapy were significantly associated with better renal outcome compared with patients with less number of SP therapy (HR 0.66; 95% CI 0.37-1.17 in model 1, 0.40 (0.20-0.78) in model 2, 0.46 (0.25-0.88) in model 3, 0.36 (0.18-0.71) in model 4). CONCLUSIONS: For treatment of IgAN, SP administered three times after tonsillectomy was associated with better renal prognosis compared with SP administered only once or twice.

Histopathological classification of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis in a nationwide Japanese prospective 2-year follow-up cohort study.

BACKGROUND: The prognostic value of the EUVAS-proposed histopathological classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis has been evaluated throughout the world. Here, we performed a Japanese nationwide biopsy survey to assess the association between this histopathological classification and renal prognosis after 2-year follow-up in ANCA-associated glomerulonephritis. METHODS: We collected 67 renal biopsy materials of the 321 entries in the RemIT-JAV-RPGN cohort study, and assessed their histologies. Based on the EUVAS-proposed histopathological classification and some histological parameters, we statistically evaluated renal survival and the comparison of renal function for 2 years. RESULTS: Based on the histopathological classification, the largest number of biopsy samples belonged to the Focal class, followed by the Mixed, Crescentic, and Sclerotic classes (n = 30, 19, 10, 8, respectively). Although the number of events might be too low (four patients with renal death) to make this conclusion, the Focal and Mixed classes had higher renal-survival rates compared to the others in the renal-survival curve. Comparing renal function among all classes, the estimated glomerular filtration rate (eGFR) throughout 2-year follow-up period was significantly higher in the Focal class compared to the other 3 classes. The eGFR-values in the Crescentic, Mixed, and Sclerotic classes increased with time. Based on both combined results, the Focal class could be the best prognosis. CONCLUSION: This histopathological classification was valuable for both the stratification of renal function and the estimation of partial renal survival during 2-year follow-up in ANCA-associated glomerulonephritis.

2017 Clinical practice guidelines of the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis for the management of ANCA-associated vasculitis.

OBJECTIVE: The Japan Research Committee for Intractable Vasculitis has fully revised the clinical practice guidelines (CPG) for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) to improve and standardize the medical treatment of the disease in Japan. METHODS: The previous CPG was published in a classical review style in Japanese in 2011 and 2014. We adopted the Grading of Recommendations Assessment, Development and Evaluation system for this revision, and various stakeholders, including patients, participated in it. The expected users of this CPG are AAV patients in Japan and their families and healthcare professionals, including both AAV specialists and non-specialists. We set clinical questions concerning the three important clinical topics of remission induction therapy, plasma exchange, remission maintenance therapy, and developed eight recommendation statements. RESULTS: For remission induction therapy for newly developed AAV, we weakly recommend glucocorticoid (GC) plus intravenous cyclophosphamide pulse (IVCY) or oral cyclophosphamide (POCY) rather than GC alone, and IVCY rather than POCY. We also weakly recommend CY rather than rituximab. In the case of AAV with severe renal impairment, we weakly recommend plasma exchange as a conjunction therapy. We weakly recommend azathioprine for remission maintenance therapy. CONCLUSION: The revised CPG has demonstrated evidence-based treatment recommendations for AAV.