Minako Yabuki

Complement‐mediated chronic inflammation is associated with diabetic microvascular complication

Chronic inflammation is characteristic of type 2 diabetes mellitus (T2DM). Obesity‐activated adipocytes release adipocytokines, which induce the secretion of proinflammatory cytokines, resulting in vascular endothelial dysfunction and organ injury. C3a is a candidate to induce tissue inflammation.

Two novel genotypes of the thiazide-sensitive Na-Cl cotransporter (SLC12A3) gene in patients with Gitelman’s syndrome

Gitelman’s syndrome is an autosomal recessive disorder marked by salt wasting and hypokalaemia resulting from loss-of-function mutations in the SLC12A3 gene that codes for the thiazide-sensitive Na-Cl cotransporter. Gitelman’s syndrome is usually distinguished from Bartter’s syndrome by the presence of both hypomagnesaemia and hypocalciuria. Although recent advances in molecular genetics may make it possible to both diagnose and differentiate these diseases, the phenotypes sometimes overlap. Here we report two sporadic cases of Gitelman’s syndrome and two novel genotypes of SLC12A3. Patient 1 was a compound heterozygote with a known missense mutation, L849H, and a novel mutation, R852H in exon 22. Patient 2 was homozygous for the missense mutation L849H. To our knowledge, this is the first report of a patient homozygous for 849H. Interestingly, both patients were affected with autoimmune thyroid disease. Patient 1 was affected with Hashimoto’s disease, and Patient 2 was affected with Graves’ disease. The symptoms of Patient 2 were more serious than those of Patient 1. Although the patients both carried the 849H allele (Patient 1 as a heterozygote and Patient 2 as a homozygous), their clinical symptoms differed. The difference in the clinical features may have been due both to phenotypic differences and the fact that Gitelman’s syndrome is a complicated disorder.

Diminished complement-activating capacity through the classical pathway in sera from type 2 diabetes mellitus

Complement-activating capacity through the classical pathway in type 2 diabetes mellitus (T2DM) was examined in the context of free sialic acid as a potential modulator of complement activation. Complement-activating capacity was investigated in an incubation study of heat-aggregated IgG (HAG) and sera from 42 T2DM patients. The study demonstrated diminished in-vitro complement-activating capacity through the classical pathway in T2DM. Various doses of N-acetyl neuraminic acid (NANA) were incubated with normal serum and HAG. Complement activation product levels decreased in a NANA dose-dependent manner. Isoelectrofocusing analysis in a mixture of NANA and purified C3 indicated that C3 changed pI dose-dependently, resulting in the downregulation of complement activation. The serum levels of free sialic acid were determined by fluorometric assay in the 42 T2DM sera samples, and were significantly increased in patients with diminished complement activation. These data indicate that increased serum sialic acid may become a candidate for decreasing complement-activating capacity in T2DM.

A Case Report of Hemodialysis Intolerance With Eosinophilia

Abstract:  We report the case of a patient who developed eosinophilia during hemodialysis and became intolerant to dialysis therapy. The patient, a 40‐year‐old woman, was initiated on hemodialysis for end‐stage renal failure caused by chronic glomerulonephritis. After starting on dialysis, her eosinophil count gradually increased. During the ninth session, she developed abdominal pain of an unknown cause after approximately 1 h of dialysis. The symptom, which persisted in the following sessions, was considered to be a dialysis‐related complication. We attempted different dialyzers and anticoagulants, but without improvement. The dialysis therapy was discontinued and steroid treatment was given. The hypereosinophilic condition improved rapidly and dialysis therapy was restarted successfully without causing abdominal pain. To investigate the cause of this problem, we measured the leukocyte count and anaphylatoxin C3a level in peripheral blood during dialysis, and compared the results before and after steroid treatment. The results showed that the significant decrease in the leukocyte count observed before steroid treatment was reduced to a mild decrease after steroid treatment. In contrast, C3a did not show a significant difference between the values obtained before and after steroid treatment. These findings suggest that eosinophilia played an important role in the etiology of dialysis intolerance and that C3a was not involved in the decrease in leukocytes under the conditions experienced by the present patient. 

Persistent Complement Activation is Associated with Insulin Resistance and Chronic Inflammation in Overweight Patients with Type 2 Diabetes with Dyslipidemia

Insulin resistance is a major player in the pathogenesis of type 2 diabetes. C3 converts to C3a and acylation stimulating protein (ASP) by complement activation. ASP activates adipose tissue macrophages and accelerates continuous inflammation. Tissuebound C3a is known to induce insulin resistance. We examined the relationship between insulin resistance and complement activation by the in vivo alteration of ASP. The levels of ASP and parameters of insulin resistance and inflammation were measured in plasma from 25 patients with type 2 diabetes. A selective peroxisome proliferator-activated receptor gamma (PPAR) agonist was administered to these 25 patients for three months, and then ASP and the parameters were measured again. The alterations of ASP and the parameters were examined in the pathophysiological state. Plasma levels of ASP and complement activation products were significantly higher in diabetes. Parameters of insulin resistance were also significantly increased. The ASP level significantly improved after PPAR agonist administration. The improvement in ASP level correlated with improvements in parameters of insulin resistance and inflammation. The levels of other relevant adipocytokines by insulin resistance correlated with the degree of inflammation. ASP and complement activation were associated with insulin resistance and chronic inflammation in diabetes.

DPP4 Inhibitor Decreases Urinary Albumin Excretion in Association with the Improvement of Glomerular Endothelial Injury in Patients with Type 2 Diabetes

Background: Glomerular endothelial injury is commonly encountered in diabetic nephropathy, as in type 2 diabetes mellitus (T2DM). Microalbuminuria is associated with endothelial cell dysfunction, and is a significant risk factor for cardiovascular mortality in diabetes. This study was undertaken to study the effect of sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, on microalbuminuria as a mechanism of improving glomerular endothelial injury in patients with T2DM. Methods: Sitagliptin, a DPP4 inhibitor, was administered to twenty patients with T2DM, 50 mg/day, for 8 weeks. Plasma levels of glucose, HbA1c, stromal-cell-derived factor-1 alpha (SDF1α), thrombomodulin (TM), serum creatinine, and urinary albumin/creatinine ratio (ACR) were measured at the start and the end of the study. The alteration patterns were statistically compared and analyzed together with their pathologic states. Another nineteen control patients were enrolled in this study. Results: Sitagliptin treatment resulted in 14% decrease (P=0.0003 vs. control) in HbA1c from 7.2±1.2 to 6.2±1.4%, 74% increase (P<0.0001 vs. control) in SDF1α from 205±70 to 355±80mmol/L, 9% decrease(P=0.0029 vs. control) in TM from 3.2±1.3 to 2.9±1.1FU/mL, 41% decrease (P=0.0095 vs. control) in ACR from 5.5±5.2 to 3.3±4.5mg/mmol. Cr after 8 weeks. Regression analysis revealed a closer relationship between SDF1α and ACR. No remarkable changes were observed in controls. As microalbuminuria represents glomerular endothelial dysfunction, these data suggest the additional effect by DPP4 inhibitor on glomerular endothelial damage. Conclusion: DPP4 inhibitor decreased urinary albumin excretion in association with the improvement of glomerular endothelial injury in patients with T2DM.

A case of ANCA-associated vasculitis with glomerular eosinophilic infiltration : a possible pathogenic implication

We present a 58-year-old male patient with myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis with rapidly progressive glomerulonephritis. He failed to fulfill the common American College of Rheumatology criteria for eosinophilic granulomatosis with polyangiitis and was tentatively diagnosed with microscopic polyangiitis. Kidney biopsy showed pauci-immune crescentic necrotizing glomerulonephritis with neutrophilic and eosinophilic infiltration. Previous reports implicate eosinophils in the pathogenesis of this disease. Therefore, this case suggests that infiltrated eosinophils as well as neutrophils might play roles in the development of tissue injury in systemic vasculitis.