[A case of hemangioma at the left renal papilla of the calix with anemia and gross hematuria].

An 18-year-old man was admitted to our hospital due to gross hematuria and proteinuria after a marathon race. Contrast-enhanced CT showed no remarkable findings. His gross hematuria and proteinuria disappeared with- out treatment. One year later, he was admitted to our hospital due to reburrent gross hematuria and anemia (serum hemoglobin level of 8.0 g/dL). Both contrast-enhanced CT and renal arteriography revealed no remarkable find- ings; however, cystoscopy showed that his hematuria came from the left ureteral orifice. Ureteroscopy revealed hemorrhage from a large hemangioma at the left renal papilla of the calix. He presented with intermittent gross hematuria, proteinuria, and hypocomplimentemia, suggesting the possibility of glomerulonephritis. His gross hematuria and proteinuria improved after laser coagulation was performed.

Role of Indoxyl Sulfate as a Predisposing Factor for Atrial Fibrillation in Renal Dysfunction.

BACKGROUND: Renal dysfunction is a major risk factor for atrial fibrillation (AF). The uremic toxin indoxyl sulfate may contribute to the progression of cardiac fibrosis and AF substrate in renal dysfunction. METHODS AND RESULTS: Male Sprague-Dawley rats were assigned randomly to the following groups: 5/6 nephrectomy (5/6Nx) with vehicle, 5/6Nx with AST-120, sham procedure with vehicle, and sham procedure with AST-120. Vehicle and AST-120 were administered for 4 weeks. Serum levels of IS were significantly increased in 5/6Nx groups. Expression of malondialdehyde, an indicator of oxidative stress, was upregulated in the left atrium of 5/6Nx groups and was accompanied by an increase in expression of NADPH oxidase 2 and 4. Monocyte-mediated inflammatory signals such as CD68, monocyte chemoattractant protein 1, and vascular cell adhesion molecule 1 were also upregulated in 5/6Nx groups. Interstitial fibrosis was promoted heterogeneously, and expression of profibrotic indicators such as transforming growth factor ß1, α-smooth muscle actin, and collagen type 1 was upregulated in left atrium tissue of 5/6Nx groups. In cultured atrial fibroblasts, incubation with IS upregulated expression of the markers of oxidative stress, inflammation, and profibrotic factors. These results suggest the direct effects of IS on the progression of AF substrate. AF was consistently and invariably induced by atrial extrastimuli in 5/6Nx groups in electrophysiological experiments. AST-120 treatment significantly alleviated renal dysfunction-induced oxidative stress, inflammation, and atrial fibrosis and, consequently, attenuated AF inducibility. CONCLUSIONS: Indoxyl sulfate facilitates atrial fibrosis and AF and thus is a novel therapeutic target for prevention of renal dysfunction-induced AF.

Effects of hydrophilic statins on renal tubular lipid accumulation in diet-induced obese mice.

Animal models of obesity show that lipid deposits can injure the kidneys,and there is evidence for the role of lipids in the development of chronic renal dis-ease (CKD). Statins exhibit a lipid-lowering effect that acts on both total cholesterol and triglyceride (TG) levels and pleiotropic effects including their ability to reduce inflammation and fibrosis. The purpose of the present study was to confirm whether obesity induced by a high-fat diet (HFD, 60% fat) promotes lipid accumulation in the tubulointerstitial and/or glomerular areas in the kidney, and whether treatment of several statins, pravastatin (30 mg/kg, p.o.), rosuvastatin (3 mg/kg, p.o.),pitavastatin (1 mg/kg, p.o.) and atorvastatin (10 mg/kg, p.o.), suppresses obesity-induced lipid accumulation. Using male C57Bl/6J mice, we examined parameters related to energy metabolism, lipid accumulation as well as macrophage infiltration in glomeruli and the tubulointerstitial area, and glomerular injury using nephrin and desmin expression. None of the statins affected body weight, glucose metabolism,serum TG and adiponectin levels, or serum inflammatory cytokine levels. However,all statins improved lipid accumulation in the proximal tubules, improved glomerular hypertrophy, increased nephrin expression and decreased desmin expression, compared to non-treated obese animals. Moreover, the reduction of proximal tubular lipid accumulation was greater with pravastatin and rosuvastatin treatment than with pitavastatin and atorvastatin treatment. We concluded that hydrophilic statins may be more effective for preventing lipid accumulation in renal tubules than lipophilic statins.

Obesity-related chronic kidney disease is associated with spleen-derived IL-10.

BACKGROUND: Obesity is associated with systemic low-grade inflammation and is a risk factor for chronic kidney disease (CKD), but the molecular mechanism remains uncertain. We noticed spleen-derived interleukin (IL)-10 because it is observed that obesity reduces several cytokines in the spleen. METHODS: We examined whether spleen-derived IL-10 regulates CKD caused by a high-fat diet (HF)-induced obesity as follows: (i) male mice were fed with HF (60% fat) during 8 weeks and IL-10 induction from the spleen was examined, (ii) glomerular hypertrophy, fibrosis, inflammatory responses in the kidney and systolic blood pressure (SBP) were evaluated in splenectomy (SPX)-treated mice fed HF, (iii) exogenous IL-10 was systemically administered to HF-induced obese mice and the alteration of obesity-induced pathogenesis caused by IL-10 treatment was assessed. (iv) IL-10 knockout (IL-10KO) mice were treated with SPX and glomerular hypertrophy, fibrosis and the inflammatory condition in the kidney and SBP were also investigated. RESULTS: Obesity decreased serum levels of only IL-10, an anti-inflammatory cytokine even though pro- and anti-inflammatory cytokine expression in the spleen was significantly lower in the obese group. SPX aggravated HF-induced inflammatory responses in the kidney and hypertension. These HF-induced alterations were inhibited by systemically administered IL-10. Moreover, SPX had little effect on inflammatory responses and SBP in the kidney of IL-10KO mice. CONCLUSIONS: We suggest that obesity reduces IL-10 induction from the spleen, and spleen-derived IL-10 may protect against the development of CKD induced by obesity.

Establishment of a model of atrial fibrillation associated with chronic kidney disease in rats and the role of oxidative stress.

BACKGROUND: An animal model of atrial fibrillation (AF) associated with chronic kidney disease (CKD) has not been available. OBJECTIVE: The purpose of this study was to test the validity of 5/6 nephrectomy (5.6Nx) as an appropriate model of AF associated with CKD and to investigate the role of oxidative stress. METHODS: Male Sprague-Dawley rats were subjected to 5.6Nx. A novel derivative of lipoic acid, sodium zinc dihydrolipoylhistidinate (DHLHZn), was subcutaneously infused. Four weeks later, hearts were isolated. RESULTS: We observed 5 main findings. (1) 5.6Nx induced renal dysfunction with elevation of systolic blood pressure and impaired glucose tolerance. (2) In the left atrium (LA), expressions of α-smooth muscle action and collagen type I, the compositional proteins of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and malondialdehyde were increased by 5.6Nx, which was reversed by DHLHZn treatment. (3) In the LA, the tissue content of angiotensin II was elevated by 5.6Nx, which was also reversed by DHLHZn. (4) Masson trichrome staining revealed that heterogeneous LA interstitial fibrosis was induced by 5.6Nx, which was attenuated by DHLHZn. (5) In isolated perfused heart experiments, 5.6Nx caused slowing of interatrial conduction. In the hearts of rats of the 5.6Nxgroup, right atrial extrastimuli invariably induced AF (8/8 [100%]), which were suppressed by DHLHZn (3/8 [38%], P <.05). CONCLUSION: We successfully established an appropriate model of AF associated with CKD in rats. Because the amount of NADPH oxidase was increased and the potent antioxidant agent DHLHZn was effective, oxidative stress may be involved in the pathogenesis of LA fibrosis and enhanced AF vulnerability in our model.

Lipoprotein (a) as a risk factor for silent cerebral infarction in hemodialysis patients.

In patients with chronic renal failure undergoing hemodialysis (HD), silent cerebral infarctions (SCIs) are associated with high mortality. Levels of lipoprotein (a) (Lp[a]) increase with renal dysfunction and may be a novel predictor for cerebrovascular events. We tested the hypothesis that increased Lp(a) levels correlate with the occurrence of SCI in HD patients. Using cranial magnetic resonance imaging findings, we divided 62 Japanese patients undergoing HD into with-SCI group (61 +/- 7 years, mean +/- SD, n = 34) and without-SCI group (60 +/- 6 years, n = 28). We compared the sex, body mass index, metabolic profiles, Lp(a) levels, and smoking habits between the 2 groups. The following observations were noted: (1) The number of patients with diabetes or hypertension did not differ between the 2 groups. (2) The levels of Lp(a) were higher in the with-SCI group in comparison with the without-SCI group (P < .0001). (3) The proportion of smokers was higher in the with-SCI group than in the without-SCI group (P < .05). (4) Plasma levels of high-density lipoprotein cholesterol were lower, whereas uric acid was higher, in the with-SCI group than in the without-SCI group (P < .001 and P < .05, respectively). (5) Multiple logistic regression analysis identified Lp(a) levels as being significantly associated with the presence of SCI (odds ratio, 1.23; 95% confidence interval, 1.09-1.38; P < .0001). This study indicates that patients with chronic renal failure, who are maintained on HD, exhibit an increased prevalence of SCI and that Lp(a) is significantly associated with the presence of SCI in HD patients.

Retinol binding protein 4 concentrations are influenced by renal function in patients with type 2 diabetes mellitus.

Retinol binding protein 4 (RBP-4), a newly discovered adipocytokine, has been involved in glucose and lipid metabolism. We assess the impacts of renal function on plasma RBP-4 levels in patients with type 2 diabetes mellitus with a wide range of nephropathy. Plasma RBP-4 levels were measured using the enzyme immunoassay method in 38 type 2 diabetes mellitus patients with nephropathy and were compared with those in 20 patients with normoalbuminuria. The levels of plasma RBP-4 were increased by 1.4- and 3.3-fold in patients with renal disease with macroalbuminuria (P = .04) and end-stage renal disease (plasma creatinine level >2.0 mg/dL) (P < .0001) compared with those in patients with normal renal function. In addition, RBP-4 levels were correlated with the creatinine level and 24-hour creatinine clearance (Ccr) on simple and multiple regression analyses in all patients. Furthermore, in patients having Ccr of more than 60 mL/min, RBP-4 levels were correlated with the homeostasis model assessment (HOMA)-r index and triglyceride (TGL) both on simple and multiple regression analyses. Interestingly, in patients having Ccr of less than 60 mL/min, RBP-4 levels were not correlated with the HOMA-r index and TGL on simple regression analysis. The RBP-4 concentrations are influenced by renal function in type 2 diabetes mellitus patients. In addition, RBP-4 levels were correlated with HOMA-r and TGL in diabetic subjects without end-stage renal disease.

High-sensitivity C-reactive protein level is a significant risk factor for silent cerebral infarction in patients on hemodialysis.

In patients with chronic renal failure on hemodialysis (HD), silent cerebral infarctions (SCIs) are associated with high mortality. The levels of high-sensitivity C-reactive protein (HSCRP), a marker of inflammation and atherosclerosis, elevate with increasing renal dysfunction. We tested the hypothesis that increased HSCRP levels correlate with the occurrence of SCI in HD patients. By brain magnetic resonance imaging findings, we divided 54 patients undergoing HD into a with-SCI group (61 +/- 8 years, n = 30) and a without-SCI group (60 +/- 7 years, n = 24). We compared sex, body mass index, metabolic profiles, HSCRP levels, and smoking habits in Japanese patients on HD with and without SCI. We made the following observations: (1) The number of patients with diabetes or hypertension did not differ between the 2 groups. (2) The levels of HSCRP were higher in the with-SCI group in comparison with the without-SCI group (P < .0001). (3) The proportion of smokers was higher in the with-SCI group than in the without-SCI group (P < .05). (4) Plasma levels of high-density lipoprotein cholesterol were lower, whereas uric acid was higher, in the with-SCI group than in the without-SCI group (P < .05 and P < .0001, respectively). (5) Multivariate logistic analysis identified HSCRP levels as being significantly associated with the presence of SCI (odds ratio, 1.61; 95% confidence interval, 1.17-2.85; P < .001). This study indicates that patients in chronic renal failure who are maintained on HD exhibit an increased prevalence of SCI and that HSCRP is significantly associated with the presence of SCI in HD patients.

Predictors for silent cerebral infarction in patients with chronic renal failure undergoing hemodialysis.

In patients with chronic renal failure undergoing hemodialysis (HD), silent cerebral infarctions (SCIs) are associated with high mortality. Levels of hepatocyte growth factor (HGF) increase with renal dysfunction and may be a novel predictor of cerebrovascular events. We examined if HGF is a predictor of SCI in HD patients. Brain magnetic resonance imaging findings were used to divide 50 patients undergoing HD into 2 groups, a group with SCI (age, 61 +/- 8 years, mean +/- SD; n = 27) and a group without SCI (age, 60 +/- 7 years; n = 23). These patients received 24-hour ambulatory blood pressure monitoring. The number of patients with diabetes or hypertension was not different between the 2 groups. We made the following observations: (1) The percentage of smokers was higher in the group with SCI than in the group without SCI (P < .05). (2) Plasma levels of high-density lipoprotein cholesterol were lower and HGF levels were higher in the group with SCI compared with the group without SCI (P < .05 and P < .005, respectively). (3) Systolic ambulatory blood pressure and mean heart rate at night were higher in the group with SCI than in the group without SCI (P < .05). Multiple logistic regression analysis identified HGF as a significant risk factor for SCI (odds ratio, 1.89; 95% confidence interval, 1.57-3.38; P < .005). Our findings indicate that HGF may be a novel useful predictor of SCI in patients with chronic renal failure undergoing HD.

Hyperhomocysteinemia is a significant risk factor for silent cerebral infarction in patients with chronic renal failure undergoing hemodialysis.

In patients with chronic renal failure undergoing hemodialysis (HD), the presence of silent cerebral infarction (SCI) is associated with high mortality. Plasma total homocysteine (tHcy), which increases with renal dysfunction, has been flagged as a novel predictor for cerebrovascular events. We tested the hypothesis that the presence of SCI correlates with tHcy in HD patients. Based on brain magnetic resonance imaging findings, 44 patients undergoing HD were divided into a with-SCI group (61+/-9 years [mean+/-SD]; n=24) and a without-SCI group (60+/-8 years, n=20), in whom 24-hour ambulatory blood pressure monitoring was performed. The number of patients with diabetes or hypertension was not different between the 2 groups. We made the following observations: (1) the percentage of smokers was higher in the with-SCI group than in the without-SCI group (P<.05); (2) plasma levels of high-density lipoprotein cholesterol were lower and tHcy was higher in the with-SCI group than in the without-SCI group (P<.05 and P<.0001, respectively); (3) and systolic ambulatory blood pressure and mean heart rate during nighttime were higher in the with-SCI group than in the without-SCI group (P<.05). Multivariate logistic analysis identified hyperhomocysteinemia as an independent and significant risk factor for SCI (odds ratio, 1.22; 95% CI, 1.10-1.36; P<.01). Our findings indicate that plasma tHcy may be a novel useful predictor for SCI in patients with chronic renal failure undergoing HD.

Dual regulatory effects of orexins on sympathetic nerve activity innervating brown adipose tissue in rats.

This study examined how orexin regulates the activity of the sympathetic nerves that innervate brown adipose tissue (BAT) in rats. Infusion of orexin A at a dose of 0.3 nmol into the third cerebral ventricle decreased BAT sympathetic nerve activity, compared with the effect of PBS (P < 0.05), whereas infusion of orexin B at the same dose caused a significant increase (P < 0.05). Pretreatment with a third cerebral ventricle injection of 2.24 micromol/kg alpha-fluoromethylhistidine, an irreversible inhibitor of the histamine-synthesizing enzyme histidine decarboxylase, attenuated the orexin B-induced response of BAT sympathetic nerve activity, but not that induced by orexin A. These results indicate that orexins may regulate both BAT energy expenditure and thermogenesis through their dual effects on sympathetic nerve activity. In particular, orexin B regulates BAT sympathetic nerve activity via neuronal histamine in the hypothalamus.

Microalbuminuria, cardiovascular autonomic dysfunction, and insulin resistance in patients with type 2 diabetes mellitus.

Urinary albumin excretion/microalbuminuria and cardiovascular autonomic dysfunction are associated with high mortality in type 2 diabetic patients. We tested the hypothesis that the presence of microalbuminuria would correlate with cardiovascular autonomic dysfunction and insulin resistance in type 2 diabetic patients. The study group consisted of 15 Japanese patients with type 2 diabetes and microalbuminuria (age: 56 +/- 10 years, mean +/- SD). The control group consisted of 19 age-matched patients with normalbuminuria (56 +/- 7 years). Cardiovascular autonomic function was assessed by baroreflex sensitivity (BRS), heart rate variability, plasma norepinephrine concentration, and cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy. BRS was lower in the microalbuminuria group than in the normalbuminuria group (P < .05). Early and delayed 123I-MIBG myocardial uptake values were lower (P < .05 and P < .005, respectively) and the percent washout rate of 123I-MIBG was higher (P < .0005) in the microalbuminuria group than in the normalbuminuria group. Fasting plasma glucose (P < .05) and insulin concentrations (P < .05), and the homeostasis model assessment (HOMA) index (P < .01) were higher in the microalbuminuria group than in the normalbuminuria group. Multiple regression analysis showed that urinary albumin excretion was independently predicted by the myocardial uptake of 123I-MIBG at delayed phase, fasting plasma insulin concentration, and the HOMA index. Our results indicate that the presence of microalbuminuria in our Japanese patients with type 2 diabetes is characterized by depressed cardiovascular autonomic function and insulin resistance, and that the myocardial uptake of 123I-MIBG at delayed phase, fasting plasma insulin, and HOMA index are independent predictors of urinary albumin excretion.

Ischemia-induced translocation of protein kinase C-epsilon mediates cardioprotection in the streptozotocin-induced diabetic rat.

The present study investigated the role of translocation of protein kinase C (PKC) during ischemia/reperfusion in cardioprotection in the streptozotocin (STZ)-induced diabetic rat. Twelve weeks after injection of STZ or vehicle, male Wister-King rat hearts were isolated and perfused in the presence or absence of 50 nmol/L staurosporine or 2 mumol/L chelerythrine using a Langendorff apparatus. Thirty minutes of global ischemia was followed by the same period of reperfusion. The time to onset of contracture was determined during ischemia. The recovery of left ventricular function, incidence of ventricular tachycardia/fibrillation (VT/VF), and amount of released creatine kinase (CK) were determined during the reperfusion period. Translocation of the PKC-alpha, -beta, -delta and -epsilon isoforms was determined by immunoblotting. Development of contracture was delayed, the recovery of left ventricular function was greater, and the incidence of VT/VF and amount of released CK were lower in diabetic than in control hearts. Ischemia caused an increase in the particulate/cytosolic fraction ratio of the PKC- epsilon isoform in the diabetic and control hearts. However, this translocation of PKC-epsilon during ischemia was transient in the control heart, but was persistent in the diabetic heart. The ischemia-induced translocation of PKC-epsilon was abolished by chelerythrine perfusion. These results suggest that persistent translocation of PKC-epsilon during ischemia plays a major role in cardioprotection against ischemia/reperfusion injury in STZ-induced diabetic rats.

Cardioprotection by streptozotocin-induced diabetes and insulin against ischemia/reperfusion injury in rats.

The effects of streptozotocin (STZ)-induced diabetes (DM) and insulin on cardiac performance were investigated during reperfusion after low-flow ischemia in rats. Hearts were isolated 4 weeks after intravenous injection of STZ (65 mg/kg) or vehicle and retrogradely perfused in the presence (throughout the perfusion period) or absence of 1 U/L insulin using a Langendorff apparatus. Normothermic low-flow global ischemia was instituted by reducing the flow rate to 5% of baseline for 30 min, followed by reperfusion for 30 min. Rate pressure product (left ventricular developed pressure x heart rate) was calculated as an index of cardiac performance. Myocardial concentrations of adenine nucleotides, creatine phosphate (CP) and glycogen were measured. Insulin perfusion increased preischemic myocardial glycogen content in both DM and control hearts. Recovery of cardiac performance and myocardial CP concentrations in the absence of insulin was greater in the DM hearts than in controls during reperfusion. Insulin perfusion improved recovery of cardiac performance and elevated CP concentrations in both DM and control hearts. These results demonstrate greater cardioprotection against ischemia/reperfusion injury in the STZ-DM state and with insulin perfusion. These protective effects may be associated with augmented resynthesis of high-energy phosphates during reperfusion.