Serum IgA/C3 ratio: a useful marker of disease activity in patients with IgA nephropathy.

OBJECTIVE: High serum IgA and low serum C3 levels resulting from lectin and alternative pathway activation might be related to IgA nephropathy (IgAN) progression and exacerbation. This study examined whether the serum IgA/C3 ratio can serve as an IgAN progression marker. METHODS: (1) This nationwide multicenter retrospective study in Japan included 718 patients with biopsy-confirmed IgAN. The patients whose serum creatinine levels at the time of renal biopsy had doubled were defined as having disease progression. (2) Furthermore, to investigate the pathological significance of a reduction in serum IgA/C3 ratio, we reviewed 63 patients whose serum IgA and C3 data at the end of the observation period were obtained. RESULTS: (1) A Kaplan-Meier analysis of the patients with IgAN revealed that the group with a high serum IgA/C3 (≥ 3.3) had a significantly worse renal outcome. In a multivariate analysis of eGFR ≥ 60 mL/min per 1.73m2 at the time of biopsy, poor renal outcome was significantly predicted by a serum IgA/C3 ratio of ≥ 3.3. (2) A 15% reduction in the change of serum IgA/C3 ratio was associated with a significantly higher percentage of complete remission of proteinuria. Among the four groups divided by treatment, both the serum IgA/C3 ratio and proteinuria were reduced only in the tonsillectomy and steroid pulse group. CONCLUSION: The serum IgA/C3 level might reflect the disease activity and be a potent surrogate marker of therapeutic efficacy in patients with IgAN.

Validation of a new technique using 4-0 nylon thread as a guide for tube insertion of the Ahmed glaucoma valve into the ciliary sulcus.

ABSTRACT: In this study, we validated the new technique for inserting the tube of the Ahmed glaucoma valve (AGV) into the ciliary sulcus. AGV tube insertion was performed by introducing a 4-0 nylon thread into the anterior chamber from the corneal incision on the opposite side of the AGV. The thread was placed in the lumen of a 23-G needle that was inserted into the sclera and ciliary sulcus from the AGV side. Withdrawing the 23-G needle, the thread was led out of the eye from the scleral wound, passing through the ciliary sulcus. The thread was then placed in the AGV tube lumen, and the tube was inserted through the scleral wound into the ciliary sulcus by using the thread as a guide, as per the Seldinger technique. In all seven eyes, the tube was precisely inserted into the ciliary sulcus without serious intraoperative complications such as vitreous straying of the tube.

A case of novel NFKB2 variant with hypertensive emergency and nephrotic syndrome leading to CKD 5D.

Nuclear factor kappa B (NF-κB) family plays a central role in the human immune system. Heterozygous variants in NFKB2 typically cause immunodeficiency with various degrees of central adrenal insufficiency, autoimmunity, and ectodermal dysplasia. No reported case has presented kidney failure as an initial symptom. Moreover, documentation of kidney involvement of this disease is limited. CASE DIAGNOSIS: A 2-year-old female who presented with dyspnea and hypertensive emergency in the setting of new-onset nephrotic syndrome with acute-on chronic kidney injury with resultant chronic kidney disease (CKD) was found to have a novel heterozygous N-terminal variant in NFKB2 (c.880del: p. Tyr294Ilefs*4) with mild hypogammaglobulinemia, but no adrenal insufficiency or ectodermal dysplasia. She became dialysis-dependent during her initial hospitalization and developed CKD stage 5D, requiring continued peritoneal dialysis. She is currently awaiting kidney transplantation. CONCLUSIONS: Whether nephrotic syndrome or kidney injury or failure is the primary symptom of this variant or secondary to some event remains unknown. Further case accumulation is warranted.

Correlation between bradykinin concentration and blood pressure during Rheocarna therapy: A single-center case series.

INTRODUCTION: A novel LDL (low-density lipoprotein) apheresis therapeutic option, Rheocarna, has garnered attention as an alternative therapy for chronic limb-threating ischemia (CLTI). Bradykinin-mediated vasodilation is involved in the effects of LDL apheresis and a decrease in blood pressure (BP), but the changes in bradykinin concentration during Rheocarna therapy are unknown. METHODS: The study involved patients with CLTI treated with Rheocarna at our hospital, from April 2022 to August 2023. RESULTS: After Rheocarna therapy, skin ulcers improved in 80% of the patients. Circuit coagulation was observed in two patients with high fibrinogen levels. A decrease in BP was observed at approximately the same time when the bradykinin concentration peaked. The peak bradykinin concentration in a patient undergoing hemodialysis at the same time was considerably lower than that in the other patients. CONCLUSION: This is the first report on the changes in bradykinin concentration under Rheocarna therapy.

Effectiveness and safety of plasma exchange for anti-MDA5 antibody-positive clinically amyopathic dermatomyositis with rapidly progressive interstitial lung disease refractory to intensive immune suppression therapy: A case series.

INTRODUCTION: Clinically amyopathic dermatomyositis (CADM) with anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab) with rapidly progressive interstitial lung disease (RP-ILD) is often refractory for intensive immunosuppression. In this study, we verified the effectiveness and safety of plasma exchange (PEx) for this lethal disease. METHODS: We retrospectively examined the clinical course and adverse effect (AE) of 12 patients with anti-MDA5 Ab-positive CADM between January 2017 and December 2021 in our hospital. RESULTS: Five out of six patients treated with simple PEx using fresh frozen plasma or 5% albumin survived with or without home oxygen therapy. Multiple PEx (15-20 times) were required to achieve satisfactory improvement as well as remission of CADM. The AEs caused by PEx were resolved using conventional methods. CONCLUSION: PEx might be a promising option for controlling the disease activity of anti-MDA5 Ab-positive CADM with severe RP-ILD and may contribute to better survival.

Nephrotic "full-house" glomerulonephritis successfully treated with antibiotics alone in secondary syphilis: a case report.

A Japanese female in her twenties developed general edema with heavy proteinuria, and was referred to our hospital. She exhibited the common clinical manifestation of idiopathic nephrotic syndrome with massive proteinuria (20.37 g/day), hypoalbuminemia (1.8 g/dL), and hypercholesterolemia (300 mg/dL). Routine admission tests were positive results for both the rapid plasma reagin latex agglutination test for syphilis (RPR) and the Treponema pallidum particle agglutination assay (TPHA). As such, we made her a diagnosis of nephrotic syndrome due to secondary syphilis. Renal biopsy revealed "full-house" nephropathy. Following the commencement of penicillin treatment, she developed skin rash, indicating the Jarisch-Herxheimer reaction (JHR). Her nephrotic syndrome responded rapidly and she achieved complete remission with antibiotic therapy alone after 4 weeks. In light of the increasing incidence of syphilis in Japan, clinicians should consider syphilis as a reversible cause of nephrotic syndrome.

Nation-wide cohort study of remission induction therapy using rituximab in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis: Effectiveness and safety in the first 6 months.

OBJECTIVES: The aim of this article is to evaluate the effectiveness and safety of rituximab (RTX) for microscopic polyangiitis and granulomatosis with polyangiitis in Japan. METHODS: In this prospective observational study, all patients with microscopic polyangiitis and granulomatosis with polyangiitis administered RTX were enrolled at each institution. During the observation period of 2 years, data up to 6 months were analysed. Cox proportional hazards analysis was used to assess the factors associated with an outcome. RESULTS: Of the 75 patients who received RTX for remission induction therapy, 53 achieved remission by the sixth month and 50 were in remission at the sixth month. During therapy, 38 serious adverse events were observed in 24 patients, 21 serious infections in 16 patients, and 9 patients died. No factors were associated with remission; however, there was a significant difference between patients with and without remission in serious adverse events (22.6% vs. 54.5%), serious infections (11.3% vs. 45.4%), and death (1.9% vs. 36.4%). The hazard ratio (95% confidence interval) for serious infection was 3.49 (1.29-9.74) for patients aged ≥ 75 years and 3.53 (1.31-9.53) for pulmonary complications. Four patients maintained remission for 6 months. CONCLUSIONS: The effectiveness and safety of RTX for microscopic polyangiitis and granulomatosis with polyangiitis for up to 6 months was demonstrated.

Polycystic liver disease with lethal abdominal wall rupture: a case report.

BACKGROUND: Polycystic liver disease is a clinical feature of autosomal dominant polycystic kidney disease, and it can sometimes cause health damage more serious than polycystic kidney. Dialysis therapy can be used for renal failure, but liver transplantation is the only method available for liver failure. Thus, giant and multiple hepatic cysts may affect mortality. However, liver transplantation is not indicated in many cases because of the preserved liver function. CASE PRESENTATION: A 54-year-old Japanese woman with polycystic liver disease was transferred back to our hospital for abdominal pain caused by liver cyst infection with abdominal wall herniation. She had been diagnosed with polycystic liver disease associated with sporadic autosomal dominant polycystic kidney disease 25 years earlier. Although she had several surgical interventions to reduce her liver volume, including right hepatic lobectomy and fenestration for liver cysts in another hospital, she needed further repair of the recurrent incisional herniation with patch graft surgery using fascia lata to cover the herniation site. However, new herniation sites reemerged in the fragile abdominal wall area around the patch, and therefore, she reduced the recurrent abdominal wall herniation by herself. Recurrent intestinal obstructions were luckily released by fasting with decompression treatment via nasogastric tube insertion, but multiple skin ulcers around the enlarged hernia sac gradually developed, and ascites was extremely difficult to control with any medication. At final admission, her abdominal wall was even more prominent, causing shortness of breath, and it spontaneously ruptured many times, which was accompanied by discharge of around 5 liters of ascites each time. She died from sepsis caused by drug-resistant Enterococcus. CONCLUSIONS: We report a case of autosomal dominant polycystic kidney disease with ruptured abdominal wall resulting from a hepatic cyst enlargement despite multiple laparotomy operations. Throughout the entire disease course, her liver volume increased rapidly, and her quality of life was severely impaired, but she could not undergo liver transplantation after readmission to our hospital. We will discuss the therapeutic strategy for this patient, including the timing and indication for liver transplantation.

Graphomotor memory in Exner's area enhances word learning in the blind.

Handwriting is thought to impede vocabulary learning in sighted adults because the motor execution of writing interferes with efficient audiovisual processing during encoding. However, the motor memory of writing may facilitate adult word learning when visual sensory inputs are severely restricted. Using functional MRI, we show that late-blind participants, but not sighted participants, learned novel words by recruiting the left dorsal premotor cortex known as Exner's writing area and its functional coupling with the left hippocampus. During later recall, the phonological and semantic contents of these words are represented in the activation patterns of the left hippocampus as well as in those of left frontotemporal language areas. These findings suggest that motor codes of handwriting help blind participants maintain word-form representations during learning and retrieval. We propose that such reliance on the motor system reflects a broad architecture of the cerebral language network which encompasses the limb motor system as a hardwired component.

Borderline Case of TAFRO Syndrome and POEMS Syndrome.

TAFRO syndrome and POEMS syndrome are lymphoproliferative disorders with elevated interleukin-6 and vascular endothelial growth factor (VEGF) levels; however, their underlying pathogenic mechanisms remain unclear. Similarities have been reported in the pathological findings of the lymph nodes of TAFRO syndrome, Multicentric Castleman disease (MCD), and some cases of POEMS syndrome. However, there is no consensus on the relationship among them. We encountered a case of lymphoproliferative disorder that presented with manifestations of both TAFRO syndrome and POEMS syndrome. This case may be a subtype of idiopathic MCD and will be very important for establishing the disease concept of TAFRO syndrome and POEMS syndrome.

Impaired HVJ-stimulated Interferon producing capacity in MPO-ANCA-associated vasculitis with rapidly progressive glomerulonephritis lead to susceptibility to infection.

ANCA-associated RPGN leads to renal failure through systemic vasculitis and diffuse crescentic glomerulonephritis. MPO-ANCA-RPGN patients are highly susceptible to infections. Our aim in this study was to uncover reasons why these patients were susceptible to infections. We analyzed various aspects of type I interferon system including HVJ-stimulated IFN-α producing capacity and plasmacytoid dendritic cell (pDC) number in whole blood in MPO-ANCA-RPGN patients. Compared with healthy subjects, MPO-ANCA-RPGN patients showed impaired HVJ-stimulated IFN-α producing capacity and lower pDC number with or without glucocorticoid treatment. Immuno-histological staining of MPO-ANCA-RPGN kidney samples revealed a few but apparent pDC in T cell infiltrating regions even in patients with low pDC number in their peripheral blood. Patients' low HVJ-stimulated IFN-α producing capacity and pDC numbers persisted even after patients underwent several years of treatment. Former infection was determined using patients' serum BPI, Lamp-2 and Calprotectin, since they are reflective of a history of infection. These markers were higher in MPO-ANCA-RPGN patients than in healthy subjects. These results indicate that impaired HVJ-stimulated IFN-α production as well as dysfunction of the IFN system might have resulted from a previous bout of infection and can be partially implicated in patients' long-term susceptibility and vulnerability to infection.

The Motor Network Reduces Multisensory Illusory Perception.

Observing mouth movements has strikingly effects on the perception of speech. Any mismatch between sound and mouth movements will result in listeners perceiving illusory consonants (McGurk effect), whereas matching mouth movements assist with the correct recognition of speech sounds. Recent neuroimaging studies have yielded evidence that the motor areas are involved in speech processing, yet their contributions to multisensory illusion remain unclear. Using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) in an event-related design, we aimed to identify the functional roles of the motor network in the occurrence of multisensory illusion in female and male brains. fMRI showed bilateral activation of the inferior frontal gyrus (IFG) in audiovisually incongruent trials. Activity in the left IFG was negatively correlated with occurrence of the McGurk effect. The effective connectivity between the left IFG and the bilateral precentral gyri was stronger in incongruent than in congruent trials. The McGurk effect was reduced in incongruent trials by applying single-pulse TMS to motor cortex (M1) lip areas, indicating that TMS facilitates the left IFG-precentral motor network to reduce the McGurk effect. TMS of the M1 lip areas was effective in reducing the McGurk effect within the specific temporal range from 100 ms before to 200 ms after the auditory onset, and TMS of the M1 foot area did not influence the McGurk effect, suggesting topographical specificity. These results provide direct evidence that the motor network makes specific temporal and topographical contributions to the processing of multisensory integration of speech to avoid illusion.SIGNIFICANCE STATEMENT The human motor network, including the inferior frontal gyrus and primary motor cortex lip area, appears to be involved in speech perception, but the functional contribution to the McGurk effect is unknown. Functional magnetic resonance imaging revealed that activity in these areas of the motor network increased when the audiovisual stimuli were incongruent, and that the increased activity was negatively correlated with perception of the McGurk effect. Furthermore, applying transcranial magnetic stimulation to the motor areas reduced the McGurk effect. These two observations provide evidence that the motor network contributes to the avoidance of multisensory illusory perception.

The features in IgA-dominant infection-related glomerulonephritis distinct from IgA nephropathy: a single-center study.

BACKGROUND: IgA-dominant infection-related glomerulonephritis (IgA-IRGN) is a unique form of IRGN, which needs to be distinguished from IgA nephropathy (IgAN). METHODS: Thirteen patients with IgA-IRGN (IgA-IRGN group) and 122 with IgAN (IgAN group) were selected from 1788 patients who underwent kidney biopsy between 2000 and 2015 in Kitano Hospital. Data selected included clinical and serological parameters; light and electron microscope findings; immunofluorescence findings; and prognostic parameters like renal and overall survival and creatinine increase by > 50%. In addition, a 26-patient IgAN cohort (matching-IgAN), matching with IgA-IRGN group with respect to age, sex, estimated glomerular filtration rate (eGFR), and proteinuria was segregated for comparison. RESULTS: Compared to IgAN group, IgA-IRGN group were older, had lower hemoglobin, higher CRP, lower eGFR, heavier proteinuria, lower serum albumin, and higher serum IgG and IgA levels (p < 0.05). Endocapillary hypercellularity, deposition of immune complexes along the glomerular capillary wall, and subendothelial and subepithelial electron dense deposits were more frequently observed (p < 0.05); and they were more susceptible to renal dysfunction and poorer prognosis. After propensity score-matching, serum albumin was significantly lower in the IgA-IRGN group. Significantly subendothelial and subepithelial deposits were frequently observed in this group. Matching-IgAN group showed relatively advanced sclerotic lesions with more global sclerosis and fibrous crescent. CONCLUSION: Local inflammation involved glomerular capillary wall in IgA-IRGN, in contrast to relatively chronic and sclerotic renal lesion in IgAN, might result in poorer prognosis in former, even under indistinguishable condition of deteriorated renal function and proteinuria.

Neural capacity limits during unconscious semantic processing.

A growing body of neuroimaging data suggests that direct measurements of brain activity can reveal subliminal effects that remain invisible with behavior measures alone. We examined whether sentence comprehension processes could be triggered by a sequence of masked words. On each trial, participants viewed a rapid sequence of masked or unmasked words, including a subject noun, three adverbs and followed by a visible target verb. To probe the capacity limits of unconscious processing, we measured event-related potentials associated with the semantic congruency between the noun and the verb, while varying the subject position in each sentence. Unmasked sentences produced significant behavioral effects of congruency, paralleled by robust N400 effects, independently of subject-verb distance. By contrast, masked sentences produced no behavioral effect and elicited N400 effects only when subjects and verbs were separated by 0 or 1 word. The present results suggest that semantic integration of multiple words can occur unconsciously only if the distance between the words to be integrated does not exceed two words. Although the possibility remains that even longer sequence of invisible words may produce similar neural effects in different experimental settings, our ERP data show that only conscious perception gives access to a buffer that enables robust sentence-level processing independently of temporal distance.

Increase of Total Nephron Albumin Filtration and Reabsorption in Diabetic Nephropathy.

The amount of albumin filtered through the glomeruli and reabsorbed at the proximal tubules in normal and in diabetic kidneys is debated. The megalin/cubilin complex mediates protein reabsorption, but genetic knockout of megalin is perinatally lethal. To overcome current technical problems, we generated a drug-inducible megalin-knockout mouse line, megalin(lox/lox);Ndrg1-CreERT2 (iMegKO), in which megalin expression can be shut off at any time by administration of tamoxifen (Tam). Tam administration in adult iMegKO mice decreased the expression of renal megalin protein by 92% compared with that in wild-type C57BL/6J mice and almost completely abrogated renal reabsorption of intravenously injected retinol-binding protein. Furthermore, urinary albumin excretion increased to 175 µg/d (0.46 mg albumin/mg creatinine) in Tam-treated iMegKO mice, suggesting that this was the amount of total nephron albumin filtration. By comparing Tam-treated, streptozotocin-induced diabetic iMegKO mice with Tam-treated nondiabetic iMegKO mice, we estimated that the development of diabetes led to a 1.9-fold increase in total nephron albumin filtration, a 1.8-fold increase in reabsorption, and a significant reduction in reabsorption efficiency (86% efficiency versus 96% efficiency in nondiabetic mice). Insulin treatment normalized these abnormalities. Akita;iMegKO mice, another model of type 1 diabetes, showed equivalent results. Finally, nondiabetic iMegKO mice had a glomerular sieving coefficient of albumin of 1.7×10-5, which approximately doubled in diabetic iMegKO mice. This study reveals actual values and changes of albumin filtration and reabsorption in early diabetic nephropathy in mice, bringing new insights to our understanding of renal albumin dynamics associated with the hyperfiltration status of diabetic nephropathy.

Exploring the origin and limitations of kidney regeneration.

Epidemiological findings indicate that acute kidney injury (AKI) increases the risk for chronic kidney disease (CKD), although the molecular mechanism remains unclear. Genetic fate mapping demonstrated that nephrons, functional units in the kidney, are repaired by surviving nephrons after AKI. However, the cell population that repairs damaged nephrons and their repair capacity limitations remain controversial. To answer these questions, we generated a new transgenic mouse strain in which mature proximal tubules, the segment predominantly damaged during AKI, could be genetically labelled at desired time points. Using this strain, massive proliferation of mature proximal tubules is observed during repair, with no dilution of the genetic label after the repair process, demonstrating that proximal tubules are repaired mainly by their own proliferation. Furthermore, acute tubular injury caused significant shortening of proximal tubules associated with interstitial fibrosis, suggesting that proximal tubules have a limited capacity to repair. Understanding the mechanism of this limitation might clarify the mechanism of the AKI-to-CKD continuum.

Comparison of phenotype and outcome in microscopic polyangiitis between Europe and Japan.

OBJECTIVE: There are differences between Europe and Japan in the incidence and antineutrophil cytoplasmic antibody (ANCA) serotype of patients with microscopic polyangiitis (MPA). However, differences in phenotype or outcome have not been explored. We aimed to identify differences in phenotype and outcome of MPA between Europe and Japan. METHODS: Sequential cohorts of patients with MPA and renal limited vasculitis were collected from European and Japanese centers (n = 147 and n = 312, respectively). Trial databases from the European Vasculitis Society and the Japanese patients with Myeloperoxidase (MPO)-ANCA-Associated Vasculitis (JMAAV) trial were studied (n = 254 and n = 48, respectively). We evaluated baseline characteristics including ANCA status and organ involvement, treatment, survival, and renal survival. Differences in survival and renal survival were studied using multivariate analysis. RESULTS: The non-trial cohorts showed patients with MPA in Japan had a higher age at onset, more frequent MPO-ANCA positivity, lower serum creatinine, and more frequent interstitial pneumonitis than those in Europe (all p < 0.01). Comparisons between the trial databases demonstrated similar results. Cumulative patient survival and renal survival rates were not different between Europe and Japan (p = 0.71 and p = 0.38, respectively). Multivariate analysis identified age at onset, serum creatinine, gastrointestinal, and respiratory involvement as factors with higher risk of death. For endstage renal failure, serum creatinine and use of plasma exchange were identified as factors with higher risk, and immunosuppressant use as lower risk factors. CONCLUSION: Phenotypes in patients with MPA were different between Europe and Japan. However, the outcomes of patient survival and renal survival were similar.