Long-term study of the association of adipokines and glucose variability with diabetic complications

BACKGROUND/AIMS: Recent studies have suggested an important role of adipokines in the development of insulin resistance and diabetes mellitus. The clinical relevance of adipokines on long-term outcomes in patients with diabetes and chronic kidney disease is uncertain. The purpose of this study was to identify a predictable factor in patients with long-term diabetic complications. METHODS: A total of 161 diabetic individuals were followed-up from 2002 to 2013. Circulating plasma levels of adiponectin, glypican-4, irisin, visfatin, and visit-to-visit glucose variability were measured in diabetic patients. Associations among adipokines and variable metabolic parameters and microvascular, and macrovascular complications were evaluated. RESULTS: Plasma adiponectin and glypican-4 levels were significantly increased in patients with renal insufficiency. These adipokines were negatively associated with estimated glomerular filtration rate and positively associated with urinary albumin excretion. The relative risk of renal progression to dialysis increased independently with increasing level of adiponectin. Glypican-4 and visfatin were not predictive of any microvascular or macrovascular complications. Glucose variability increased the risk of diabetic nephropathy and cerebrovascular complications. CONCLUSIONS: Adiponectin and glypican-4 were associated with renal function and might be able to predict renal progression. Glucose variability was a predictable factor for diabetic nephropathy and cerebrovascular complications.

Renoprotective Effects of a Highly Selective A3 Adenosine Receptor Antagonist in a Mouse Model of Adriamycin-induced Nephropathy

The concentration of adenosine in the normal kidney increases markedly during renal hypoxia, ischemia, and inflammation. A recent study reported that an A3 adenosine receptor (A3AR) antagonist attenuated the progression of renal fibrosis. The adriamycin (ADX)-induced nephropathy model induces podocyte injury, which results in severe proteinuria and progressive glomerulosclerosis. In this study, we investigated the preventive effect of a highly selective A3AR antagonist (LJ1888) in ADX-induced nephropathy. Three groups of six-week-old Balb/c mice were treated with ADX (11 mg/kg) for four weeks and LJ1888 (10 mg/kg) for two weeks as following: 1) control; 2) ADX; and 3) ADX + LJ1888. ADX treatment decreased body weight without a change in water and food intake, but this was ameliorated by LJ1888 treatment. Interestingly, LJ1888 lowered plasma creatinine level, proteinuria, and albuminuria, which had increased during ADX treatment. Furthermore, LJ1888 inhibited urinary nephrin excretion as a podocyte injury marker, and urine 8-isoprostane and kidney lipid peroxide concentration, which are markers of oxidative stress, increased after injection of ADX. ADX also induced the activation of proinflammatory and profibrotic molecules such as TGF-β1, MCP-1, PAI-1, type IV collagen, NF-κB, NOX4, TLR4, TNFα, IL-1β, and IFN-γ, but they were remarkably suppressed after LJ1888 treatment. In conclusion, our results suggest that LJ1888 has a renoprotective effect in ADX-induced nephropathy, which might be associated with podocyte injury through oxidative stress. Therefore, LJ1888, a selective A3AR antagonist, could be considered as a potential therapeutic agent in renal glomerular diseases which include podocyte injury and proteinuria.

Corrigendum: Effects of Toll-like receptor antagonist 4,5-dihydro-3-phenyl-5-isoxasole acetic acid on the progression of kidney disease in mice on a high-fat diet Volume 33, Issue 1, March 2014, Pages 33-44

The authors apologize for a wrong unit in the table 1.

IgG4-related Disease Controlled by a Low-dose Steroid and Mycophenolic Acid / 대한내과학회지

IgG4-related disease (IgG4-RD) is a group of fibro-inflammatory diseases affecting multiple organ systems, pathologically characterized by tissue infiltration with abundant IgG4-positive cells. We here report a case of IgG4-RD that was successfully controlled by mycophenolic acid (MPA). A 62-year-old male visited complaining of dizziness and loss of appetite. He had a clinical history of autoimmune pancreatitis treated with steroids and cyclophosphamide 5 years prior, and had also been diagnosed with Hashimoto's thyroiditis at the age of 55 years. We initially prescribed prednisolone (1 mg/kg), tapered to 5 mg/day over 8 months. However, his eosinophilia gradually deteriorated, and we added cyclophosphamide (1 mg/kg daily) for the next 7 months. His laboratory data fluctuated when he was on low-dose predinisolone and cyclophosphamide, and we thus changed his medication to prednisolone combined with MPA for the following 63 months. Currently, his laboratory findings are stable.

Effects of Toll-like receptor antagonist 4,5-dihydro-3-phenyl-5-isoxasole acetic acid on the progression of kidney disease in mice on a high-fat diet

BACKGROUND: Obesity-related metabolic disorders are closely associated with inflammation induced by innate immunity. Toll-like receptors (TLRs) play a pivotal role in the innate immune system by activating proinflammatory signaling pathways. GIT27 (4,5-dihydro-3-phenyl-5-isoxasole acetic acid) is an active immunomodulatory agent that primarily targets macrophages and inhibits secretion of tumor necrosis factor alpha [as well as interleukin (IL)-1beta, IL-10, and interferon gamma]. However, the effect of TLR antagonist on kidney diseases has rarely been reported. We investigated whether the TLR antagonist GIT27 has beneficial effects on the progression of kidney disease in obese mice on a high-fat diet (HFD). METHODS: Six-week-old male C57BL/6 mice were divided into three groups: mice fed with normal chow diet (N=4); mice fed with a HFD (60% of total calories from fat, 5.5% from soybean oil, and 54.5% from lard, N=4); and GIT27-treated mice fed with a HFD (N=7). RESULTS: Glucose intolerance, oxidative stress, and lipid abnormalities in HFD mice were improved by GIT27 treatment. In addition, GIT27 treatment decreased the urinary excretion of albumin and protein in obesity-related kidney disease, urinary oxidative stress markers, and inflammatory cytokine levels. This treatment inhibited the expression of proinflammatory cytokines in the kidneys and adipose tissue, and improved extracellular matrix expansion and tubulointerstitial fibrosis in obesity-related kidney disease. CONCLUSION: TLR inhibition by administering GIT27 improved metabolic parameters. GIT27 ameliorates abnormalities of lipid metabolism and may have renoprotective effects on obesity-related kidney disease through its anti-inflammatory properties.

Pseudomyxoma Peritonei: A Rare Cause of Oliguric Acute Kidney Injury / 전남의대학술지

Pseudomyxoma peritonei is a rare clinical condition that causes the accumulation of mucinous ascites, which gradually results in the compression of intra-abdominal organs. Most published reports of pseudomyxoma peritonei concern the mass effect of the resulting ascites, which presents as abdominal pain or intestinal ileus in severe cases. However, few reports of renal complications of the disease have been published. Here, we present a case of oliguric acute kidney injury caused by external compression by pseudomyxoma peritonei. After decompression with external drainage, the patient's renal function rapidly improved.

Pseudomyxoma Peritonei: A Rare Cause of Oliguric Acute Kidney Injury / 전남의대학술지

Pseudomyxoma peritonei is a rare clinical condition that causes the accumulation of mucinous ascites, which gradually results in the compression of intra-abdominal organs. Most published reports of pseudomyxoma peritonei concern the mass effect of the resulting ascites, which presents as abdominal pain or intestinal ileus in severe cases. However, few reports of renal complications of the disease have been published. Here, we present a case of oliguric acute kidney injury caused by external compression by pseudomyxoma peritonei. After decompression with external drainage, the patient's renal function rapidly improved.

Plasma leptin concentrations are greater in type II diabetic patients and stimulate monocyte chemotactic peptide-1 synthesis via the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway

BACKGROUND: Leptin is an adipokine that is recently reported to be a biomarker of systemic inflammation. Although atherosclerosis causes cardiovascular diseases, it is not clear whether leptin contributes to the acceleration of this process. In this study, we investigated whether alterations of plasma leptin levels were related to diabetic nephropathy and systemic inflammation. In addition, we examined the physiologic action of leptin in cultured vascular smooth muscle cells (VSMCs). METHODS: A total of 126 type 2 diabetic participants and 37 healthy controls were studied. The diabetic participants were divided into three groups according to stage of nephropathy. We investigated whether leptin induced monocyte chemotactic peptide-1 (MCP-1) synthesis through the mitogen-activated protein kinase (MAPK) pathway using cultured VSMCs. RESULTS: Plasma leptin concentrations were significantly higher in the diabetic group than in the controls. Plasma leptin levels were positively correlated with body mass index, fasting and postprandial blood glucose, hemoglobin A1c, total cholesterol, urinary albumin excretion, high-sensitivity C-reactive protein (hsCRP), and MCP-1 plasma levels, and negatively correlated with creatinine clearance values. In cultured VSMCs, leptin increased MCP-1 production in a dose-dependent manner, and this stimulating effect of leptin on MCP-1 expression was reversed by the MAPK (MEK) inhibitor PD98059. In addition, leptin stimulated the phosphorylation of MEK, extracellular signal-regulated kinase, and E26-like transcription factor, which are components of the MAPK pathway. CONCLUSION: Overall, these findings suggest that activation of leptin synthesis may promote MCP-1 activation in a diabetic environment via the MAPK pathway in VSMCs and that it possibly contributes to the acceleration of atherosclerosis.

A Low Intact PTH Is Associated with Simple Vascular Calcifications in Hemodialysis Patients / 대한신장학회지

PURPOSE: Cardiovascular diseases are a common cause of mortality in patients with end stage renal disease and are associated with vascular calcification (VC) and arterial stiffness. In addition to high turnover bone disease, there is substantial evidence that low levels of serum intact PTH (iPTH) are associated with vascular calcium deposition. The objective was to evaluate the association of iPTH levels with VC, arterial stiffness, and to identify risk factors contributing to VCs and arterial stiffness. METHODS: One hundred five hemodialysis (HD) patients were divided into three groups according to iPTH levels: A, 400 pg/mL. The simple vascular calcification score (SVCS) was obtained by X-ray; the brachial ankle-pulse wave velocity (ba-PWV) and the serum fetuin-A level was mesured. RESULTS: Patients in group A were older and had a higher SVCS, a prevalence of diabetes, and an increased arterial stiffness. Severe VCs (SVCS> or =3) were associated with the low iPTH group (iPTH<150)/a higher CRP/a lower diastolic blood pressure (DBP)/diabetes/ increased arterial stiffness/older age and a lower serum fetuin-A level. The log [ba-PWV] had a positive correlation with age, systolic blood pressure (SBP)/DBP/PP/CRP/presence of diabetes and low iPTH and a negative correlation with serum albumin. Based on multivariate analysis, the low iPTH group and diabetes were identified as independent risk factors of severe VC and age/SBP/CRP and diabetes were risk factors for arterial stiffness. CONCLUSION: Low iPTH levels and/or diabetes had a greater risk of developing VCs and age/SBP/CRP/diabetes were associated with increased arterial stiffness in HD patients.

Renovascular Hypertension and Nephrotic Range Proteinuria Developed after the Renal Artery Ligation: Successful Treatment by Combination of ACE Inhibitor and Angiotensin II Type 1 Receptor Blocker / 대한신장학회지

A 27-year-old woman presented with severe hypertension and nephrotic range proteinuria. She had a blunt renal trauma 4 weeks ago and was treated by the left main renal artery ligation. The plasma renin activity, angiotension II and aldosterone levels were very high and the abdominal angiography showed the occlusion of the left main renal artery with relatively preserved blood flow in upper pole of the left kidney. In captopril renal scan, relatively preserved perfusion in upper pole of left kidney was further compromised after captopril administration. The massive proteinuria and hypertension were improved after combination of ACE inhibitor and angiotensin II type 1 receptor blocker treatment.

A Case of Renal Infarct Developed in Acute Pancreatitis / 대한신장학회지

A renal infarct is too rare a disease for early diagnosis and treatment. Furthermore, it presents nonspecific symptoms in many patients. Cardiac diseases such as valvular heart disease and arterial fibrillation are the most common causes of renal infarct. Vascular disease such as renal artery dissection or aortic dissection, trauma, inflammation, vasculitis, malignancy and antiphospholipid syndrome have been also known as possible causes of renal infarct. In acute pancreatitis, adjacent vessels can be involved, and were reported to induce splenic infarction, portal vein thrombosis and superior mesenteric vein thrombosis etc. However, the renal infarct from renal artery involvement in acute pancreatitis has not yet been reported. In our case, a 46 year old male patient had an abdominal trauma due to an in-car accident to develop a rupture of pancreatic tail. The progression of acute pancreatitis caused the inflammation of left renal artery, leading to renal artery obstruction. We report a case of renal infarct developed in acute pancreatitis.

A Case of Splenectomy in a Patient with Refractory Thrombotic Thrombocytopenic Purpura / 대한신장학회지

The introduction of plasma exchange has significantly improved the outcome of thrombotic thrombocytopenic purpura (TTP) and the survival rate was increased from 10 to 80-90%. TTP refractory to plasma exchange therapy, however, is still a therapeutic challenge. We describe here a patient who partially responded to plasma exchange therapy, but remained dependent on plasma infusions. To discontinue plasma therapy, several attempts using agents such as rituximab, vincristine, and cyclosporine A had been tried, but all failed. After splenectomy, serum LDH and blood platelet count were normalized. Plasmapheresis were we able to discontinue after 2 weeks of splenectomy. Steroid and cyclosporine were tapered off after 3 months and 5 months after splenectomy respectively, and the patient has been staying in remission ever since. We suggest that splenectomy is a worthwhile treatment option in patients with refractory TTP.

Association of Depression with Inflammation and Cardiovascular Risk Factors in End Stage Renal Disease Patients on Hemodialysis / 대한신장학회지

PURPOSE: Depression is associated with increased inflammation and cardiovascular disease. And in patients with end stage renal disease (ESRD), depression is a common problem and cardiovascular disease is the main cause of death. The aim of this study is to investigate the association of depression with various inflammatory markers and with some cardiovascular risk factors in ESRD patients on hemodialysis METHODS: 53 patients with ESRD on maintenance hemodialysis were divided into depressive symptom (BDI> or =11) group and control (BDI < 11) group by the 21-items Becks depression inventory (BDI). We collected patients characteristics and laboratory measurements by medical records. And then, we measured the levels of IL-10 and TNF-alpha a and analyzed the genotype of IL-10 and TNF-alpha a promoter area. RESULTS: The levels of TNF-alpha, CRP and ferritin were significantly higher in depressive symptom group (p=0.001, 0.04, 0.02) and IL-10 concentration tended to be lower in depressive symptom group (p= 0.05). The prevalence of left ventricular hypertrophy was higher in depressive symptom group than in the control group (44% vs 9%, p=0.01). GG genotype known as high IL-10 producer was less common in depressive symptom group than in control group (8% vs 36%, p=0.039). CONCLUSION: Increased inflammation, high left ventricular hypertrophy prevalence and low ejection fraction were observed in depressive hemodialysis patients. Further prospective study is needed to clarify the role of depression in the development of inflammation and cardiovascular disease in ESRD patients.