PLA2R-positive membranous nephropathy in IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory disease that affects multiple organs, including the pancreas, lacrimal glands, salivary glands, periaortic/retroperitoneum, and kidney. Interstitial nephritis is a typical renal disorder associated with IgG4-RD, but membranous nephropathy is also seen in some cases. CASE PRESENTATION: Herein we report on the case of a 77-year-old male patient with nephrotic syndrome and IgG4-related lung disease. His serum phospholipase A2 receptor (PLA2R) antibody was positive. His renal biopsy specimen was also positive for PLA2R. The renal biopsy specimen showed membranous nephropathy with equal IgG3 and IgG4 immunofluorescence staining and no interstitial nephritis, suggesting IgG4-RD manifesting as membranous nephropathy. CONCLUSIONS: Nephrotic syndrome caused by membranous nephropathy is sometimes associated with IgG4-RD. In such cases, even if serum PLA2R antibody is positive, it should be considered that the membranous nephropathy may be secondary to IgG4-RD.

Factors associated with early-onset intracranial aneurysms in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Recently, the importance of attribute-based medicine has been emphasized. The effects of early-onset intracranial aneurysms on patients can be significant and long-lasting. Herein, we compared the factors associated with intracranial aneurysms in patients with autosomal dominant polycystic kidney disease (ADPKD) according to age categories (≥ 50 years, < 50 years). METHODS: We included 519 ADPKD patients, with a median age of 44 years, estimated glomerular filtration rate of 54.5 mL/min/1.73 m2, and total follow-up duration of 3104 patient-years. Logistic regression analyses were performed to determine factors associated with intracranial aneurysms. RESULTS: Regarding the presence of intracranial aneurysm, significant interactions were identified between the age category (age ≥ 50 years), female sex (P = 0.0027 for the interaction) and hypertension (P = 0.0074 for the interaction). Female sex and hypertension were associated with intracranial aneurysm risk factors only in patients aged ≥ 50 years. The presence of intracranial aneurysm was significantly associated with chronic kidney disease (CKD) stages 4-5 (odds ratio [OR] = 3.87, P = 0.0007) and family history of intracranial aneurysm or subarachnoid hemorrhage (OR = 2.30, P = 0.0217) in patients aged < 50 years. For patients aged ≥ 50 years, in addition to the abovementioned factors [OR = 2.38, P = 0.0355 for CKD stages 4-5; OR = 3.49, P = 0.0094 for family history of intracranial aneurysm or subarachnoid hemorrhage], female sex (OR = 4.51, P = 0.0005), and hypertension (OR = 5.89, P = 0.0012) were also associated with intracranial aneurysm. CONCLUSION: Kidney dysfunction and family history of intracranial aneurysm or subarachnoid hemorrhage are risk factors for early-onset intracranial aneurysm. Patients aged < 50 years with a family history of intracranial aneurysm or subarachnoid hemorrhage or with CKD stages 4-5 may be at an increased risk of early-onset intracranial aneurysm.

Citric acid-based bicarbonate dialysate attenuates aortic arch calcification in maintenance hemodialysis patients: a retrospective observational study.

BACKGROUND: Progression of aortic calcification is associated with all-cause and cardiovascular mortality in hemodialysis patients. Blood calciprotein particle (CPP) levels are associated with coronary artery calcification and were reported to be inhibited when using citric acid-based bicarbonate dialysate (CD). Therefore, this study aimed to examine the effect of CD on the progression of the aortic arch calcification score (AoACS) and blood CPP levels in hemodialysis patients. METHODS: A 12-month retrospective observational study of 262 hemodialysis patients was conducted. AoACS was evaluated by calculating the number of calcifications in 16 segments of the aortic arch on chest X-ray (minimum score is 0; maximum score is 16 points). The patients were divided into the following groups according to their baseline AoACS: grade 0, AoACS = 0 points; grade 1, AoACS 1-4 points; grade 2, AoACS 5-8 points; grade 3, AoACS 9 points or higher. Patients on bisphosphonates or warfarin or with AoACS grade 3 were excluded. Progression, defined as ΔAoACS (12-month score - baseline score) > 0 points, was compared between the CD and acetic acid-based bicarbonate dialysate (AD) groups before and after adjusting the background using propensity score matching. RESULTS: The AoACS progression rate was significantly lower in the CD group than in the AD group (before matching: P = 0.020, after matching: P = 0.002). Multivariate logistic regression analysis showed that CD was significantly associated with AoACS progression (odds ratio 0.52, 95% confidence interval 0.29‒0.92, P = 0.025). CONCLUSION: CD may slow the progression of vascular calcification in hemodialysis patients.

First case of a renal cyst infection caused by Desulfovibrio: a case report and literature review.

BACKGROUND: Genus Desulfovibrio species is a sulphate-reducing anaerobic gram-negative rod that resides in the human oral cavity and intestinal tract. It was reported as the causative pathogen of bacteraemia and abdominal infections, but not renal cyst infection, and Desulfovibrio fairfieldensis has higher pathogenicity than other Desulfovibrio species. CASE PRESENTATION: A 63-year-old man was on haemodialysis for end-stage renal failure due to autosomal dominant polycystic kidney disease. On admission, he had a persistent high-grade fever, right lumbar back pain, and elevated C-reactive protein levels. His blood and urine cultures were negative. He received ciprofloxacin and meropenem; however, there was no clinical improvement. Contrast-enhanced computed tomography and plain magnetic resonance imaging revealed a haemorrhagic cyst at the upper pole of the right kidney. The lesion was drained. Although the drainage fluid culture was negative, D. fairfieldensis was detected in a renal cyst using a polymerase chain reaction. After the renal cyst drainage, he was treated with oral metronidazole and improved without any relapse. CONCLUSIONS: To the best of our knowledge, this is the first reported case of a renal cyst infection with Desulfovibrio species. D. fairfieldensis is difficult to detect, and polymerase chain reaction tests can detect this bacterium and ensure better management for a successful recovery.

Grading system utilising the total score of Oxford classification for predicting renal prognosis in IgA nephropathy.

The Oxford classification of IgA nephropathy (IgAN) can evaluate each MEST-C score individually. We analysed a new grading system that utilised the total MEST-C score in predicting renal prognosis. Altogether, 871 IgAN patients were classified into three groups using the new Oxford classification system (O-grade) that utilised the total MEST-C score (O-grade I: 0-1, II: 2-4, and III: 5-7 points), and the 10-year renal prognosis was analysed. The clinical findings became significantly severer with increasing O-grades, and the renal survival rate by the Kaplan-Meier method was 94.1%, 86.9%, and 74.1% for O-grades I, II, and III, respectively. The hazard ratios (HRs) for O-grades II and III with reference to O-grade I were 2.8 (95% confidence interval [CI] 1.3-6.0) and 6.3 (95% CI 2.7-14.5), respectively. In the multivariate analysis, mean arterial pressure and eGFR, proteinuria at the time of biopsy, treatment of corticosteroids/immunosuppressors, and O-grade (HR 1.63; 95% CI 1.11-2.38) were the independent factors predicting renal prognosis. Among the nine groups classified using the O-grade and Japanese clinical-grade, the renal prognosis had an HR of 15.2 (95% CI 3.5-67) in the severest group. The O-grade classified by the total score of the Oxford classification was associated with renal prognosis.

Reduction in flippase activity contributes to surface presentation of phosphatidylserine in human senescent erythrocytes.

Mature human erythrocytes circulate in blood for approximately 120 days, and senescent erythrocytes are removed by splenic macrophages. During this process, the cell membranes of senescent erythrocytes express phosphatidylserine, which is recognized as a signal for phagocytosis by macrophages. However, the mechanisms underlying phosphatidylserine exposure in senescent erythrocytes remain unclear. To clarify these mechanisms, we isolated senescent erythrocytes using density gradient centrifugation and applied fluorescence-labelled lipids to investigate the flippase and scramblase activities. Senescent erythrocytes showed a decrease in flippase activity but not scramblase activity. Intracellular ATP and K+ , the known influential factors on flippase activity, were altered in senescent erythrocytes. Furthermore, quantification by immunoblotting showed that the main flippase molecule in erythrocytes, ATP11C, was partially lost in the senescent cells. Collectively, these results suggest that multiple factors, including altered intracellular substances and reduced ATP11C levels, contribute to decreased flippase activity in senescent erythrocytes in turn to, present phosphatidylserine on their cell membrane. The present study may enable the identification of novel therapeutic approaches for anaemic states, such as those in inflammatory diseases, rheumatoid arthritis, or renal anaemia, resulting from the abnormally shortened lifespan of erythrocytes.

Validation of the revised Oxford classification for IgA nephropathy considering treatment with corticosteroids/immunosuppressors.

The Oxford classification for IgA nephropathy (IgAN) was updated in 2017. We have validated the revised Oxford classification considering treatment with corticosteroids/immunosuppressors. In this retrospective analysis, 871 IgAN patients were enrolled. Patients were divided into two groups, those treated with or without corticosteroids/immunosuppressors. The 20-year renal prognosis up to end-stage renal disease was assessed using the Oxford classification. In all patients, the renal survival rate was 87.5% at 10 years and 72.6% at 20 years. The T score alone was significantly related to renal prognosis in the Kaplan-Meier analysis and multivariate Cox regression analysis. In the non-treatment group (n = 445), E, S, T, and C scores were significantly related to renal survival rates, however, in the treatment group (n = 426), T score alone was significantly related to renal prognosis on Kaplan-Meier analysis, indicating that corticosteroids/immunosuppressors improved renal prognosis in E1, S1, and C1. In patients with E1, S1, or C1, the treatment group showed significantly better renal prognosis than the non-treatment group in univariate and multivariate analysis. The Oxford classification and T score were used to determine renal prognosis in IgAN patients. Corticosteroids/immunosuppressors improved renal prognosis, especially E1, S1, and C1 scores.

Long-Term Beneficial Effects of Tonsillectomy on Patients with Immunoglobulin A Nephropathy.

Background: Tonsillectomy may treat IgA nephropathy (IgAN) by reducing the levels of galactose-deficient IgA1. Therefore, we aimed to analyze the long-term effects of tonsillectomy on patients with IgAN, as an initial treatment and as a treatment at any time in their lives. Methods: In this retrospective cohort analysis, 1147 patients with IgAN were grouped according to whether they had undergone tonsillectomy at any time, >1 year after renal biopsy (study 1), or within 1 year after renal biopsy (study 2). The patients were propensity-score matched or divided into four groups according to their proteinuria and renal function. The 20-year renal survival rates were evaluated until serum creatinine levels doubled (primary end point) and ESKD occurred (secondary end point). Results: Patients in both studies had similar background characteristics after propensity score matching. In study 1, the renal survival rates for the primary and secondary end points were significantly higher for patients who underwent tonsillectomy at any time or >1 year after renal biopsy compared with those who did not. In study 2, the renal survival rates for the primary and secondary end points were significantly higher for patients who underwent tonsillectomy soon after renal biopsy compared with those who did not (primary end point, 98% versus 69%, P=0.001; secondary end point, 100% versus 75%, P=0.0001). A stratified analysis showed that significant treatment efficacy was observed for patients with proteinuria >1.0 g/d. Multivariate Cox regression analyses showed that tonsillectomy was associated with disease progression (hazard ratio, 0.27; P=0.04). Complications associated with tonsillectomy occurred in 8% of patients. Conclusions: Among patients with IgAN, tonsillectomy at any time of life, or soon after renal biopsy, prevents disease progression, and the procedure is relatively safe.

ATP11C T418N, a gene mutation causing congenital hemolytic anemia, reduces flippase activity due to improper membrane trafficking.

Distribution of phosphatidylserine (PS) in the erythrocyte membrane is essential for its activity. Flippase transports phospholipids from the outer to the inner leaflet of the lipid bilayer and maintains asymmetric distribution of phospholipids in the plasma membrane. ATP11C, a flippase, catalyzes PS flipping at the plasma membrane in association with cell cycle control protein 50A (CDC50A). ATP11C T418 N mutation causes 90% decrease in erythrocyte PS-flippase activity. However, the mechanism of the activity reduction remains unknown. To study the endogenous expression of ATP11C in erythrocytes, we produced a monoclonal antibody against human ATP11C. Immunoblotting analyses with this antibody revealed the absence of ATP11C in erythrocyte membranes derived from a patient with the T418 N mutation. Transiently expressed ATP11C wild-type in cultured cells localized in the cell membranes in the presence of CDC50A. Contrastingly, ATP11C T418 N mutants stacked at the endoplasmic reticulum (ER) even in the presence of CDC50A, suggesting improper intracellular trafficking. Expression of the T418 N mutant in cultured cells was lower than that in the wild-type. However, reduced expression of the T418 N mutant was partially restored by treatment with proteasome inhibitors, suggesting ER-associated degradation of the mutant protein. Cells expressing T418 N did not show flippase activity at the plasma membrane. These data show that the loss of PS-flippase activity in erythrocytes carrying ATP11C T418 N mutation is due to impaired enzymatic activity, improper membrane trafficking, and increased proteasome degradation.