Primary aldosteronism and obstructive sleep apnea: A single-center cross-sectional study of the Japanese population.

ABSTRACT: A recent report demonstrated that the prevalence of obstructive sleep apnea (OSA) is 67.6% among Caucasian and Chinese patients with primary aldosteronism (PA). Moreover, the report showed a significant association between plasma aldosterone concentration (PAC) and the severity of OSA in Caucasian patients. However, no studies have examined the prevalence of OSA with PA or the association of its severity with PAC in the Japanese population. We retrospectively evaluated the prevalence and severity of OSA in 71 newly diagnosed Japanese patients with PA. Thirty-nine (55%) of the 71 patients were diagnosed with OSA, and 69% of PA patients with OSA reported snoring. No correlation was found between the respiratory event index (REI), snoring index, and PAC and plasma renin activity (PRA). In contrast, REI correlated significantly with body mass index (BMI), which was significantly correlated with PRA. In conclusion, although the severity of OSA did not correlate with PAC and PRA, there was a high prevalence of OSA among Japanese patients with PA. Moreover, the severity of OSA was strongly affected by BMI. Thus, the examination of OSA in patients with PA and the proper management of OSA might be important for the Japanese population.

Identification of Clock Genes Related to Hypertension in Kidney From Spontaneously Hypertensive Rats.

BACKGROUND: There is a diurnal variation in the blood pressure fluctuation of hypertension, and blood pressure fluctuation abnormality is considered to be an independent risk factor for organ damage including cardiovascular complications. In the current study, we tried to identify molecules responsible for blood pressure circadian rhythm formation under the control of the kidney biological clock in hypertension. METHODS: DNA microarray analysis was performed in kidneys from 5-week-old spontaneously hypertensive rats (SHRs)/Izm, stroke-prone SHR rats (SHRSP)/Izm, and Wistar Kyoto (WKY)/Izm rats. To detect variation, mouse tubular epithelial cells (TCMK-1) were stimulated with dexamethasone. We performed immunostaining and western blot analysis in the renal medulla of kidney from 5-week-old WKY rats and SHRs. RESULTS: We extracted 1,032 genes with E-box, a binding sequence for BMAL1 and CLOCK using a Gene Set Enrichment Analysis. In a microarray analysis, we identified 12 genes increased as more than 2-fold in the kidneys of SHRs and SHRSP in comparison to WKY rats. In a periodic regression analysis, phosphoribosyl pyrophosphate amidotransferase (Ppat) and fragile X mental retardation, autosomal homolog 1 (Fxr1) showed circadian rhythm. Immunocytochemistry revealed PPAT-positivity in nuclei and cytoplasm in the tubules, and FXR1-positivity in the cytoplasm of TCMK-1. In 5-week-old WKY rat and SHR kidneys, PPAT was localized in the nucleus and cytoplasm of the proximal and distal tubules, and FXR1 was localized to the cytoplasm of the proximal and distal tubules. CONCLUSIONS: PPAT and FXR1 are pivotal molecules in the control of blood pressure circadian rhythm by the kidney in hypertension.

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.

Imbalance of interleukin-18 and interleukin-18 binding protein in patients with IgA nephropathy implicating renal vasculopathy.

BACKGROUND: Interleukin-18 (IL-18) is a proinflammatory cytokine which induces interferon-γ production and plays a crucial role in immune systems. IL-18 binding protein (IL-18BP) is a naturally occurring inhibitor of IL-18. The aim was to investigate the involvement of IL-18 and IL-18BP in IgA nephropathy (IgAN). METHODS: Serum samples from 21 IgAN patients and 16 idiopathic membranous nephropathy (MN) patients and 32 healthy controls were assayed by an enzyme-linked immunosorbent method. RESULTS: Compared to the controls, IgAN patients showed significantly higher levels of IL-18 and the increased IL-18/IL-18BP ratio. Despite IL-18 elevation, the levels of IL-18BP did not parallel the increase of IL-18, which resulted in an increased IL-18/IL-18BP ratio. Furthermore, the ratio in patients with renal vasculopathy was significantly increased compared to those without arteriolar lesions. CONCLUSIONS: These findings provide the first evidence that there is an imbalance of IL-18/IL-18BP ratio in IgAN patients, which may be associated with the pathophysiology of renal vasculopathy.

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.

Development of pyrrole-imidazole polyamide targeting fc receptor common gamma chain for the treatment of immune-complex related renal disease.

Fcγ receptors I and III are thought to be involved in the development of lupus nephritis. Expression of Fc receptor common gamma chain (FcRγ) is necessary for the stable expression of Fcγ receptors I and III. The aim of this study was to develop a novel agent for the treatment of immune complex related renal disease using a gene regulator, pyrrole(Py)-imidazole(Im) (PI) polyamide, targeting the mouse FcRγ gene promoter. Two PI polyamides targeting FcRγ promoters were designed and synthesized. The effect of the PI polyamides on FcRγ mRNA expression was evaluated in J774.A cells by real-time polymerase chain reaction (PCR), and CD16/32 protein expression was determined by immunocytochemical analysis and flow cytometry. The effects of these polyamides on FcRγ gene expression and CD16/32 protein expression were evaluated in mouse peripheral blood mononuclear cells (PBMCs). One milligram per kilogram body weight of PI polyamide was injected via the tail vein every 2 d for 1 week and PBMCs were collected and analyzed. PI polyamide showed a specific binding to the target DNA in a gel mobility shift assay. Treatment of J774.A cells with 1.0 µM PI polyamide 1 significantly reduced FcRγ mRNA expression and CD16/32 surface protein expression in J774.A cells. Similarly, PI polyamide significantly decreased expression of FcRγ mRNA and CD16/32 in the PBMCs of C57B6 mice. PI polyamide designed to bind the FcRγ promoter decreased FcRγ gene and CD16/32 protein expression. PI polyamide targeting the FcRγ gene may be a novel gene regulator for the prevention of lupus nephritis or other immune complex-related disease.

Functional mannose-binding lectin levels in patients with end-stage renal disease on maintenance hemodialysis.

BACKGROUND: Innate immunity is generally impaired in chronic renal failure (CRF). Mannose-binding lectin (MBL) has an important role in first-line host defense against pathogens via the lectin pathway. We recently reported that functional MBL was significantly lower in CRF patients than in healthy subjects. In this study, we aimed to determine whether functional MBL would be improved following hemodialysis (HD) therapy. METHODS: This study included 22 patients with end-stage renal disease (ESRD) on maintenance HD. Functional MBL was measured every 6 months for 1 year after HD using an enzyme-linked immunosorbent assay. RESULTS: Median serum functional MBL levels of ESRD patients were significantly higher after 6 and 12 months than at the start of HD therapy (p < 0.05 and p < 0.01, respectively). Furthermore, median functional MBL levels at 12 months were significantly higher than those at 6 months (p < 0.05). CONCLUSIONS: We found significant increases in serum functional MBL levels in patients on HD. Our results indicated that HD tailored to remove uremic toxins could improve functional MBL levels in these patients.

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.

High circulating levels of interleukin-18 binding protein indicate the severity of glomerular involvement in systemic lupus erythematosus.

In systemic lupus erythematosus (SLE), glomerular involvement often progresses with the activity of the disease. Immune complexes and abnormal secretion of cytokines are thought to be involved in the central mechanism of the development of lupus nephritis. We investigated serum levels of interleukin 18 (IL-18), a proinflammatory cytokine, and its natural antagonist IL-18 binding protein (IL-18 BP) in 45 patients with lupus nephritis. IL-18 levels were significantly increased in patients with Class II, Class III, and Class IV lupus nephritis compared with the level in a healthy control group. However, the levels stayed within the non-significant range in Class V. IL-18 BP levels were significantly increased in patients with Class III and Class IV lupus nephritis, in which histological activity and chronicity are severe. However, IL-18 BP levels stayed within the non-significant range in Class II and Class V, in which histological markers are mild. We also compared the levels of IL-18 and IL-18 BP in patients with and without glomerular infiltration of inflammatory cells. IL-18 was increased regardless of glomerular infiltration. However, IL-18 BP was increased only in patients with glomerular infiltration. These data suggest that IL-18 levels indicate the extent of the offending inflammatory response not only in the bloodstream but also in renal tissue, and that high IL-18 BP levels indicate the severity of existing glomerular injury.

Interleukin-18 contributes more closely to the progression of diabetic nephropathy than other diabetic complications.

Diabetic complication is comprised of a wide variety of pathophysiological factors involving proinflammatory cytokines, adipokines, and oxidative stress, among others. Each of these complications differs in their incidence and the stage of their occurrence. We examined cytokines and stress markers in 48 patients with type 2 diabetes mellitus and compared the difference of their contribution to pathogenesis between nephropathy and other diabetic complications. Hemoglobin A1c correlated with the level of low-density lipoprotein-cholesterol, and significantly elevated in the severe macroangiopathy group. Cystatin C increased in the severe microangiopathy groups but did not increase in the macroangiopathy group. The levels of interleukin 18 (IL-18), high-sensitive CRP (H-CRP), liver-type fatty acid binding protein, and 8-hydroxy-2-deoxyguanosine increased in the severe microangiopathy group. These data suggest the participation of proinflammatory signaling and oxidative stress in the progression of microangiopathy. In particular, IL-18 and H-CRP were significantly elevated only in the severe nephropathy group but did not significantly elevate in other complications. These data suggest another effect of IL-18 on glomerulus in addition to its proinflammatory effect. In conclusion, we propose that IL18 has a specific role that contributes more closely to the progression of diabetic nephropathy than other diabetic complications.

Serum interleukin-18 binding protein increases with behavior different from IL-18 in patients with diabetic nephropathy.

We investigated alterations between serum interleukin 18 (IL-18) and IL-18 binding protein (18BP) in T2DM patients. 18 BP began to increase after IL-18 increased and reached a threshold, in which case kidney dysfunction would have developed. These data indicate that 18BP might express glomerular dysfunction more closely than IL-18.

A case of femoral hemorrhage in a patient with microscopic polyangiitis with low levels of myeloperoxidase-antineutrophil cytoplasmic autoantibody.

We present the case of a 67-year-old female with femoral hemorrhage accompanied by microscopic polyangiitis. She was admitted to our hospital with symptoms of general fatigue, fever, and edema of the lower limbs. She was diagnosed with microscopic polyangiitis on the basis of the cardinal symptoms of the condition, including rapidly progressive glomerulonephritis and the presence of myeloperoxidase-antineutrophil cytoplasmic autoantibody (MPO-ANCA), albeit at a low titer. Renal biopsy demonstrated the presence of fibrocellular crescent-shaped glomeruli with interstitial infiltration. No immune deposits were detected in immunofluorescence studies. The patient was treated with steroids and anti-platelet agents; subsequently, the inflammatory reaction subsided and MPO-ANCA and C-reactive protein titers decreased. However, on day 14, the patient experienced sudden onset of swelling in the left femoral region accompanied by hypotension. Her hemoglobin level dropped from 8.8 to 4.5 g/dl in the subsequent hours. Although computed tomography of the legs revealed an extensive hematoma in the left quadriceps femoris muscle, the patient recovered after receiving a transfusion and supportive therapy with discontinuation of dipyridamole. Thereafter, her renal function improved, and she was discharged. To our knowledge, this is the first report of a case of microscopic polyangiitis accompanied by femoral hemorrhage.

Relationship between oligomer and functional serum mannose-binding lectin in chronic renal failure.

INTRODUCTION: Mannose-binding lectin (MBL) plays an important role in first-line host defence against pathogens via the lectin pathway. The binding affinity for ligands is greatly increased by oligomerization, although the basic triplet does not bind solid phase mannan and cannot activate complement. Besides, MBL is a positive acute-phase protein. In this study, we examined the relationship between oligomer and functional serum MBL in chronic renal failure patients who were either uraemic [Pre-haemodialysis (pre-HD) patients], or who were receiving maintenance haemodialysis treatment (HD patients). MATERIALS AND METHODS: This study included a total of 20 Pre-HD patients, 130 HD patients and 28 healthy subjects. The oligomer and functional serum MBL levels were measured using enzyme-linked immunosorbent assays established previously. RESULTS: The median serum functional MBL levels were significantly reduced in both Pre-HD and HD patients compared with healthy subjects (P<0·05 for both). Furthermore, the median functional MBL level in Pre-HD patients was significantly lower than that in HD patients (P<0·05). The median serum oligomer MBL levels in both Pre-HD and HD patients were significantly higher compared with healthy subjects (P<0·05 for both). Furthermore, the median oligomer MBL level in HD patients was significantly (P<0·05) higher than that in Pre-HD patients. The ratios of median serum functional MBL levels to oligomer MBL levels were significantly reduced in both Pre-HD and HD patients compared with healthy subjects (P<0·05 for both). CONCLUSIONS: We found significant reductions in the ratios of serum functional MBL levels to oligomer MBL levels in HD and Pre-HD patients compared with healthy subjects.

Peritonitis associated with Pasteurella multocida: molecular evidence of zoonotic etiology.

A patient on continuous cyclic peritoneal dialysis for chronic kidney disease due to type 2 diabetes mellitus developed peritoneal dialysis-associated peritonitis induced by Pasteurella multocida that was isolated from a sample of dialysis effluent. The route of infection was unknown for this case; however, P. multocida was also isolated from a culture of a pharyngeal swab obtained from the patient's cat. There was no evidence that the cat had bitten and ruptured the peritoneal dialysis tubing or bags. Pulsed-field gel electrophoresis (PFGE) showed that the P. multocida isolated from the patient was completely identical to the strain isolated from the domestic cat. As there is a rise in the pet-keeping population, an increase in zoonoses is to be expected. It is necessary to be carefully informed of hygiene rules in keeping pets because a pet may transmit zoonoses, even on casual contact.

Alterations of insulin resistance and the serum adiponectin level in patients with type 2 diabetes mellitus under the usual antihypertensive dosage of telmisartan treatment.

BACKGROUND: Insulin resistance plays a central role in the pathophysiology of diabetes complications. Angiotensin II receptor blockers (ARBs) regulate angiotensin II receptor-mediated inhibition of intracellular glucose transporter 4 translocation. Telmisartan, one of the known ARBs, was reported to improve insulin resistance via the increase of peroxisome proliferator-activated receptor gamma activity in the model animal. This study examined whether this effect was observed in diabetes patients under the usual antihypertensive dosage of telmisartan treatment. METHODS: Twenty-seven diabetes patients were chosen for this prospective study. Patient blood pressures were successfully controlled for the most recent 6 months by ARBs other than telmisartan. After informed consent was obtained, we changed to telmisartan from the other ARBs. The parameters of hypertension, hyperlipidemia, glycemic control, and renal function were examined. RESULTS: The values of the homeostasis model assessment of insulin resistance (HOMA-IR) improved from 7.1 +/- 1.5 to 3.8 +/- 3.6 after 3 months. The serum level of adiponectin significantly increased after 6 months. The distributions of other parameters were correlated with that of HOMA-IR or adiponectin. CONCLUSIONS: The data indicate that the usual antihypertensive dosage of telmisartan improves insulin resistance and changes adiponectin effect in patients with diabetes mellitus. Adipokine-related insulin resistance and angiotensin II receptor 1-mediated insulin resistance are improved by telmisartan.

[Longstanding intractable massive ascites caused by chronic lupus peritonitis with nephrotic syndrome: a case report].

A 36-year-old woman with systemic lupus erythematosus (SLE) and nephrotic syndrome showed massive ascites. She was admitted to our hospital because of edema in both legs and a remarkably distended non-tender abdomen. On admission, massive ascites was observed in the abdominal CT scan findings. Laboratory examination of the ascites showed low levels of total protein (1.5 g/dL), albumin (0.5 g/dL) and LDH (89 IU/L), which were characterized as ascites per diapedesis. In addition, she was diagnosed with SLE and nephrotic syndrome from the clinical and laboratory findings. We treated her with steroid therapy, including methylprednisolone plus therapy. Although the serological abnormalities with SLE had normalized and urinary protein almost disappeared on the 51th hospital day, the ascites had not improved at all. These findings indicated that she had suffered from chronic lupus peritonitis, complicated with nephrotic syndrome and we had continued to treat her with prednisolone for a long time. The ascites was remarkably diminished at 220 days after admission. We believe that in addition to nephrotic syndrome, impaired vascular circulation caused by chronic lupus peritonitis might have contributed to accumulation of the massive ascites.