Inflammation,insulin resistance,and obesity

Obesity, in particular visceral obesity, has strong associations with cardiovascular disease and is related to many factors that are constituents of the metabolic syndrome. Increasing evidence suggests that features of the metabolic syndrome, including visceral obesity, are associated with a low-grade inflammatory state. Indeed, visceral fat is a source of several molecules, such as leptin, adiponectin, tumor necrosis factor-α, and interleukin 6, that are collectively called adipokines. All of them may induce a proinflammatory state and oxidative damage, leading to initiation and progression of atherosclerosis. Reducedenergy diets might represent an effective and healthful approach for long-term weight loss in patients with metabolic syndrome by reducing the underlying inflammatory condition.     

Association of low-grade inflammation and platelet activation in patients with hypertension with microalbuminuria

Increased levels of sCD40L (soluble CD40 ligand) have been associated with enhanced in vivo platelet activation, and may represent a molecular link between inflammation and a prothrombotic state. The aim of the present study was to analyse the relationship between platelet activation, endothelial dysfunction, low-grade inflammation and sCD40L in patients with hypertension with or without MA (microalbuminuria). A cross-sectional comparison of sCD40L levels was performed in 25 patients with MH (essential hypertension with MA) pair-matched for gender and age with 25 patients with EH (essential hypertension) and 25 HS (healthy subjects with normotension). Circulating levels of CRP (C-reactive protein), a marker of inflammation, sP-selectin (soluble P-selectin), a marker of in vivo platelet activation, and ADMA (asymmetric dimethylarginine) and vWF (von Willebrand factor), markers of endothelial dysfunction, were analysed in each subject. sCD40L levels were increased in patients with MH compared with either patients with EH (P<0.001) or HS (P<0.0001). A highly significant correlation between plasma sCD40L and sP-selectin (P<0.0001), vWF (P<0.001) or CRP levels (P<0.05) was observed in patients with MH. Multivariate regression analysis showed that sP-selectin was the strongest independent predictor of sCD40L levels (P<0.0001) in patients with MH. Patients with hypertension with both vWF and CRP levels above the median had the highest sCD40L levels (P<0.0001). Factorial ANOVA of all of the patients with hypertension confirmed that only patients with MH with low-grade inflammation had elevated levels of sCD40L. In conclusion, sCD40L levels appear to discriminate a subset of patients characterized by MA and low-grade inflammation, suggesting that inhibition of the CD40/CD40L system may represent a potential therapeutic target in subjects with hypertension at a high risk of cardiovascular events.     

In vivo platelet activation is responsible for enhanced vascular endothelial growth factor levels in hypertensive patients

BACKGROUND: Essential hypertension may be a consequence of an abnormal regulation of vascular endothelial growth factor (VEGF). In vivo activation of platelets does result in the release of VEGF. Thus, we investigated whether VEGF production in hypertensive patients is related to in vivo platelet activation, and whether it may be modified by aspirin treatment. METHODS: Plasma VEGF, soluble (s)P-selectin and thrombin-anti-thrombin complex (TATc) were analyzed in 80 patients with therapeutically controlled essential hypertension and 40 age and sex-matched healthy normotensive controls. The effects of a 6-month treatment with aspirin 100 mg/day on VEGF levels of 20 hypertensive patients were also studied. RESULTS: Plasma VEGF (p<0.0001), sP-selectin (p=0.01) and TATc (p=0.02) levels were higher in hypertensives compared to controls. Multivariate analysis including age, sex, risk factors, cardiovascular disease, anti-hypertensive treatment, sP-selectin and TATc showed that only sP-selectin was an independent predictor of VEGF (beta=0.40, p<0.03). Aspirin treated hypertensives showed a significant reduction of sP-selectin (-26%, p<0.01) and VEGF (-33%, p<0.01) levels. Moreover, the reduction of plasma VEGF levels directly correlated with that of sP-selectin (Rho=0.46, p=0.04). CONCLUSIONS: In vivo activation of platelets in hypertensive patients is responsible for enhanced circulating VEGF levels, which are significantly lowered by aspirin treatment.     

Oxidative stress and platelet activation in subjects with moderate hyperhomocysteinaemia due to MTHFR 677 C →T polymorphism

The methylenetetrahydrofolate reductase (MTHFR) 677 C→T polymorphism may be associated with elevated total homocysteine (tHcy) levels, an independent risk factor for cardiovascular disease. It was the study objective to evaluate in vivo lipid peroxidation and platelet activation in carriers of the MTHFR 677 C→T polymorphism and in non-carriers, in relation to tHcy and folate levels. A cross-sectional comparison of urinary 8-iso-prostaglandin (PG)F2α and 11-dehydro-thromboxane (TX)B2 (markers of in vivo lipid peroxidation and platelet activation, respectively) was performed in 100 carriers and 100 non-carriers of the polymorphism. A methionine-loading test and folic acid supplementation were performed to investigate the causal relationship of the observed associations. Urinary 8-iso-PGF2α and 11-dehydro-TXB2 were higher in carriers with hyperhomocysteinaemia than in those without hyperhomocysteinaemia (p<0.0001). Hyperhomocysteinaemic carriers had lower folate levels (p=0.0006), higher urinary 8-iso-PGF2α (p<0.0001) and 11-dehydro-TXB2 (p<0.0001) than hyperhomocysteinaemic non-carriers. On multiple regression analysis, high tHcy (p<0.0001), low folate (p<0.04) and MTHFR 677 C→T polymorphism (p<0.001) independently predicted high rates of 8-iso-PGF2α excretion. Methionine loading increased plasma tHcy (p=0.002), and both urinary prostanoid metabolites (p=0.002). Folic acid supplementation was associated with decreased urinary 8-iso-PGF2α and 11-dehydro-TXB2 excretion (p<0.0003) in the hyperhomocysteinaemic group, but not in the control group, with substantial inter-individual variability related to baseline tHcy level and the extent of its reduction. In conclusion, hyperhomocysteinaemia due to the MTHFR 677 C→T polymorphism is associated with enhanced in vivo lipid peroxidation and platelet activation that are reversible, at least in part, following folic acid supplementation. An integrated biomarker approach may help identifying appropriate candidates for effective folate supplementation.     

Reflex anuria from unilateral ureteral obstruction

Renal function is usually normal or only marginally affected in patients with unilateral ureteral obstruction due to the vicarious function of the contralateral kidney. Few reports exist in which unilateral renal obstruction is associated with anuria (reflex anuria, RA) and acute renal failure. We report the clinical case of a female patient who was referred to the emergency department due to anuria of 72 h duration and acute renal failure (serum creatinine 9 mg/dl) associated with several episodes of violent right flank pain with hematuria following extracorporeal shock wave lithotripsy (ESWL). A few weeks before ESWL, urography showed a 2-cm stone located in the right pelvis whilst the left kidney was functionally normal. On admission, renal ultrasound documented a normal left kidney, whilst the right pelvis was hydronephrotic and there were two indwelling stones at the right pyeloureteral junction. After the patient passed a urinary stone, diuresis restarted and acute renal failure was resolved. Thereafter, urography confirmed that the left kidney, the left ureter and bladder were functionally and morphologically normal. RA with acute renal failure has been so scarcely documented that it is considered to be legend by many clinicians. Major textbooks do not discuss RA with acute renal failure. Vascular or ureteral spasm related in part to a peculiar hyperexcitability of the autonomic nervous system may explain RA. We suggest that nephrologists should always consider RA when evaluating acute renal failure. On the other hand, RA might be relatively common and we cannot rule out that only the most severe and/or better-documented cases have been reported in the medical literature.