Plasma C1q/TNF-related protein 9: a promising biomarker for diabetic renal vascular injury.

BACKGROUND: Adipocytokines are associated with the pathophysiology of type 2 diabetes (T2DM). METHODS: We analyzed the relationship between levels of the plasma C1q/tumor necrosis factor-related protein 9 (CTRP9) and other adipocytokines or the endothelial function in patients with T2DM, and analyzed their trending manner. RESULTS: CTRP9 was detected in plasma from 14 out of a total of 28 patients. The values were not normally distributed. In comparing between groups in which CTRP9 was or was not detected, there were statistically significant differences in the high molecular weight adiponectin (HAN) and the urinary albumin/creatinine ratio (ACR). This indicates that both CTRP9 and HAN reflect the pathophysiology of renal involvement in T2DM. HAN correlated with Body Mass Index, ACR, and homeostasis model assessment of insulin resistance. However, CTRP9 did not correlate with HAN or any other parameters. CONCLUSIONS: CTRP9 independently trends in a different manner from HAN, and may reflect diabetic renal vascular risk in association with atherosclerosis and abnormal glucose metabolism besides of impaired vaso-relaxation in patients with T2DM.

Secondary focal segmental glomerulosclerosis in an adolescent born with a very low birth weight.

A 17-year-old man presented with a decreased renal function (creatinine clearance 66.0 ml/min/1.73 m2) and proteinuria (1.25 g/24 hrs). He was born weighing 1,065 g 26 weeks of pregnancy. He was mildly overweight (BMI 26.9 kg/m2) due to an increased weight gain (10 kg) over the past year. Renal biopsy showed perihilar sclerosing lesions in three of eleven glomeruli, low glomerular density, enlarged glomeruli, and limited fusions of foot processes, thus indicating secondary focal segmental glomerulosclerosis (FSGS). We speculated that the patient's overweight status may have caused a worsening of glomerular hyperfiltration due to the fewer number of nephrons leading to the development of secondary FSGS.

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.

Complement-mediated chronic inflammation is associated with diabetic microvascular complication.

BACKGROUND: 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. METHODS: We investigated the association between diabetic microangiopathy and complement-mediated inflammation in 32 obese T2DM patients and 32 normal donors. Plasma levels of complement components and their activation intermediates were examined and related to the level of complication. An incubation study of post-prandial serum was carried out to measure the in vitro production of acylation stimulating protein (ASP/C3a desArg) by chylomicron. RESULTS: Plasma levels of C3, C4, factor B, iC3b, Bb, and ASP were significantly increased in T2DM patients. Levels of C4d and membrane attack complex (C5b-9) were not significantly elevated. The activation rate of these factors indicated that only the early phase of alternative complement pathway was excessively activated. A statistical study revealed close correlation between ASP, body mass index, and highly sensitive C-reactive protein. Plasma ASP was significantly increased in the macroalbuminuric and proliferative retinopathy patient groups. An incubation study revealed that ASP was produced after the in vitro incubation of post-prandial serum from a T2DM patient with hyperchylomicronaemia. CONCLUSIONS: Activation of the alternative complement pathway occurs in obese T2DM patients and is enhanced in the post-prandial hyperchylomicronic condition, which induces overproduction of ASP and C3a-mediated tissue inflammation. Therefore, complement-mediated inflammation may contribute to the acceleration of diabetic microangiopathy in addition to the development of macroangiopathy.

Effects of cyclosporine on bone mineral density in patients with glucocorticoid-dependent nephrotic syndrome in remission.

PURPOSE: Cyclosporine (CsA) is often prescribed to patients with glucocorticoid (GC)-dependent nephrotic syndrome. Although it is well known that long-term administration of GC causes osteoporosis, the effects of CsA on bone metabolism are not fully established. Therefore, we examined the effects of CsA on bone metabolism in patients with GC-dependent nephrotic syndrome in remission. METHODS: We followed 23 patients treated with prednisolone alone (GC alone group) and 17 patients treated with CsA in combination with prednisolone (GC + CsA group). Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry, and biochemical markers of bone metabolism were simultaneously measured in serum and urine samples. RESULTS: BMD decreased significantly in the GC group from 752 to 623 mg/cm(2) but non-significantly in the GC + CsA group from 751 to 684 mg/cm(2). Although the cumulative dose of GC increased in both groups, there were no significant differences in biochemical markers at either the start or the end of the study. Vertebrate bone fracture and other side effects associated with CsA treatment did not occur in our study. CONCLUSIONS: Our results indicate that CsA does not accelerate GC-induced osteoporosis in patients with nephrotic syndrome. We conclude that CsA is appropriate for the treatment of GC-dependent nephrotic syndrome, because it does not adversely affect bone metabolism and has favorable glomerular effects.

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.

Oligomeganephronia in an adult without end stage renal failure.

A 23 year-old male was investigated for hypertension, moderate renal insufficiency, persistent proteinuria and bilateral small kidneys. The renal pathological features were diagnostic with greatly enlarged glomeruli (the mean diameter was 325 µm, which was approximately two times larger than normal glomeruli), indicating oligomeganephronia (OMN). He also showed malrotated kidneys, expanded extrarenal pelvis, and hearing loss. Thus, these clinical and pathological features aided in diagnosing the renal disorder as OMN. This is a very rare case of OMN, which did not advance to end-stage renal failure as an adult. We believe that multiple anomalies might be suggestive findings of OMN in patients, such as renal insufficiency, persistent proteinuria, and bilateral small kidneys.

Molecular and functional characterization of choline transporter in rat renal tubule epithelial NRK-52E cells.

Homeostatic regulation of the plasma choline concentration depends on the effective functioning of a choline transporter in the kidney. However, the nature of the choline transport system in the kidney is poorly understood. In this study, we examined the molecular and functional characterization of choline uptake in the rat renal tubule epithelial cell line NRK-52E. Choline uptake was saturable and mediated by a single transport system, with an apparent Michaelis-Menten constant (K(m)) of 16.5 microM and a maximal velocity (V(max)) of 133.9 pmol/mg protein/min. The V(max) value of choline uptake was strongly enhanced in the absence of Na(+) without any change in K(m) values. The increase in choline uptake under Na(+)-free conditions was inhibited by Na(+)/H(+) exchanger (NHE) inhibitors. Choline uptake was inhibited by the choline uptake inhibitor hemicholinium-3 (HC-3) and organic cations, and was decreased by acidification of the extracellular medium and by intracellular alkalinization. Collapse of the plasma membrane H(+) electrochemical gradient by a protonophore inhibited choline uptake. NRK-52E cells mainly express mRNA for choline transporter-like proteins (CTL1 and CTL2), and NHE1 and NHE8. CTL1 protein was recognized in both plasma membrane and mitochondria. CTL2 protein was mainly expressed in mitochondria. The biochemical and pharmacological data indicated that CTL1 is functionally expressed in NRK-52E cells and is responsible for choline uptake. This choline transport system uses a directed H(+) gradient as a driving force, and its transport functions in co-operation with NHE8. Furthermore, the presence of CTL2 in mitochondria provides a potential site for the control of choline oxidation.

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.

A case report of hemodialysis intolerance with eosinophilia.

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.