The Effect of Lipotoxicity on Renal Dysfunction in a Nonobese Rat Model of Metabolic Syndrome: A Urinary Proteomic Approach.

INTRODUCTION: The development of metabolic syndrome-associated renal dysfunction is exacerbated by a number of factors including dyslipidemia, ectopic deposition of lipids and their toxic metabolites, impairment of lipid metabolism, and insulin resistance. Renal dysfunction is also affected by the production of proinflammatory and profibrotic factors secreted from adipose tissue, which can in turn directly impair kidney cells and potentiate insulin resistance. In this study, we investigated the manifestation of renal lipid accumulation and its effect on renal dysfunction in a model of metabolic syndrome-the hereditary hypertriglyceridemic rat (HHTg)-by assessing microalbuminuria and targeted urinary proteomics. Male Wistar control rats and HHTg rats were fed a standard diet and observed over the course of ageing at 3, 12, and 20 months of age. RESULTS: Chronically elevated levels of triglycerides in HHTg rats were associated with increased levels of NEFA during OGTT and over a period of 24 hours (+80%, P < 0.01). HHTg animals exhibited qualitative changes in NEFA fatty acid composition, represented by an increased proportion of saturated fatty acids (P < 0.05) and a decreased proportion of n-3 PUFA (P < 0.01). Ectopic lipid deposition in the kidneys of HHTg rats-triglycerides (+30%) and cholesterol (+10%)-was associated with markedly elevated microalbuminuria as ageing increased, despite the absence of microalbuminuria at the young age of 3 months in these animals. According to targeted proteomic analysis, 3-month-old HHTg rats (in comparison to age-matched controls) exhibited increased urinary secretion of proinflammatory parameters (MCP-1, IL-6, IL-8, P < 0.01) and decreased urinary secretion of epidermal growth factor (EGF, P < 0.01) before manifestation of microalbuminuria. Elevation in the urinary secretion of inflammatory cytokines can be affected by increased relative expression of MCP-1 in the renal cortex (P < 0.05). CONCLUSIONS: Our results confirm dyslipidemia and ectopic lipid accumulation to be key contributors in the development of metabolic syndrome-associated renal dysfunction. Assessing urinary secretion of proinflammatory cytokines and epidermal growth factor can help in detecting early development of metabolic syndrome-associated renal dysfunction.

Associations of sodium intake with obesity, metabolic disorder, and albuminuria according to age.

Sodium intake is associated with obesity and metabolic disorder in the general population. However, sodium intake is significantly reduced according to the decrease of energy intake in older adults although the prevalence of obesity is higher than younger adults. We evaluate the association of sodium excretion (UNa) with blood pressure, obesity, metabolic disorders, and albuminuria according to age. An observational study using data from the Korean National Health and Nutrition Examination Survey IV-V (2008-2011) was performed (N = 18,146). The 24 hour UNa was estimated from a single fasting urine sample.Participants aged≥75 years showed the highest risk for hypertension (HTN) in the highest quartile of UNa (1.769, 95% CI, 1.174-2.665), and the risks for HTN increased with advancing age. Obesity was not associated with UNa in participants aged≥75 years, and hypertriglyceridemia and body fat were not related to UNa in participants aged≥65 years, although these values were significantly associated with UNa in participants aged<65 years. Impaired fasting glucose (IFG) and insulin resistance (IR) were associated with UNa only in participants aged 20-39 years. The highest quartile of UNa showed a 3.777 fold increased risk for albuminuria in those aged 20-39 years (95% CI, 1.130-12.630), and a 1.885 fold increased risk (95% CI, 1.156-3.075) among participants aged 40-64 years. In participants aged≥65 years, albuminuria was not associated with UNa. In contrast with HTN, UNa was not associated with albuminuria, obesity, hypertriglyceridemia, IFG, and IR in older adults despite a strong association in younger adults.

Biochemical profile of idiopathic uric acid nephrolithiasis.

BACKGROUND: The objective of this study was to elucidate a biochemical profile of patients with idiopathic uric acid nephrolithiasis, without secondary causes (such as dehydration or diarrhea). Study subjects comprised 56 patients with idiopathic uric acid nephrolithiasis (UA stone group) who underwent a full outpatient evaluation. The control group was composed of 54 with absorptive hypercalciuria and 2 normal subjects, matched with the UA stone group according to age, body mass index, and gender. METHODS: Urinary pH and ammonium and serum and urinary uric acid were measured. The fractional excretion of urate was calculated. RESULTS: Compared with the control group, the UA stone group had a significantly higher serum uric acid and significantly lower urinary uric acid, pH (5.34 +/- 0.23 vs. 6.17 +/- 0.36, P < 0.001), and fractional excretion of urate (0.052 +/- 0.028 vs. 0.080 +/- 0.029, P < 0.001), but individual values overlapped considerably between the two groups. Discriminant analysis of the relationship between urinary pH and fractional excretion of urate yielded a "discriminant score," which provided a much better separation between the two groups, with a correct classification in 95.5% of subjects. In contrast, urinary ammonium, citrate, sulfate, and potassium did not differ between two groups. CONCLUSIONS: In idiopathic uric acid nephrolithiasis, urinary pH and fractional excretion of urate are significantly lower than in control subjects, suggestive of defects in urinary acidification and urate excretion. Since these impairments are believed to be associated with primary gout, the underlying disturbance in idiopathic uric acid nephrolithiasis may be primary gout.

Dietary alterations in plasma very low density lipoprotein levels modify renal excretion of urates in hyperuricemic-hypertriglyceridemic patients.

Hyperuricemic-hyperlipidemic patients exhibit decreased renal excretion of urates relative to purely hyperuricemic patients; also, very low density lipoprotein (VLDL) levels are inversely proportional to the amount of urate excreted. Based on this knowledge, the aim of this study was to alter VLDL levels by dietary manipulation and assess its effect on uric acid levels and renal excretion of uric acid. Thirty-six men were studied in 2 groups consisting of 20 primary hyperuricemic (group I) and 16 primary hyperuricemic-hypertriglyceridemic patients (group II). The patients were analyzed for apoproteins and lipoproteins, urate levels, and renal excretion of uric acid in a first, basal determination, after 3 weeks of a 1200-Cal diet, and after another 3 weeks of a 2500-Cal diet. After the 1200-Cal diet, patients in group I exhibited significantly decreased levels of cholesterol (P < 0.05) and apoprotein CIII (P < 0.05). There were significant differences in renal excretion of uric acid (P < 0.05) between the basal and third determinations. Patients in group II exhibited significantly decreased levels of triglycerides (P < 0.01), VLDL cholesterol (P < 0.01), VLDL triglycerides (P < 0.01), and VLDL apoprotein B (P < 0.05) after the 1200-Cal diet; all of these parameters returned to values similar to the basal levels on completion of the 2500-Cal diet. With regard to purine parameters, the low calorie diet led to significantly increased fractional excretion of uric acid (P < 0.01) and uric acid clearance (P < 0.01), both of which decreased significantly to values near basal after the 2500-Cal diet. The results obtained in this study reveal that the decreased levels of triglyceride and VLDL components that arise from a low calorie diet are accompanied by increased renal excretion of urates and that the increase in the amount of this type of lipoprotein particle with an increase in dietary energy offsets the increase in renal excretion of urate.

Increased VLDL levels and diminished renal excretion of uric acid in hyperuricaemic-hypertriglyceridaemic patients.

The objective was to study the lipoprotein levels in primary hyperuricaemic patients and to analyse their renal management or urates in order to check for some potential influence of altered lipid levels on the renal excretion of urates by this type of patient. Overall 115 male individuals were studied in five groups, namely: 30 primary hyperuricaemic (group I); 27 primary hyperuricaemic-hypercholesterolaemic (group II); nine primary hyperuricaemic-hypertriglyceridaemic (group III); 33 primary hyperuricaemic-mixed hyperlipidaemic (group IV); and 16 normouricaemic-normolipidaemic subjects (group C). All patients were subjected to blood analyses for uric acid, total triglycerides, total protein, creatinine, high density lipoprotein (HDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, low density lipoprotein (LDL) cholesterol, apoprotein (apo) AI, apoprotein B, apoprotein CII and apoproteins CIII1 and CIII2. For urine analysis creatinine, creatinine clearance, uric acid excretion, clearance and fractional excretion were measured in 24 h urine samples. Mixed and pure hyperuricaemic-hypertriglyceridaemic patients exhibited increased levels of VLDL components, decreased fractional excretion of uric acid and increased apo CIII/CII ratios. The increased levels of structural VLDL components were negatively (and statistically significantly) correlated with the fractional excretion of uric acid; this suggests a close biological relationship between the two parameters. Taking into account the role played by apo C in VLDL metabolism, the altered apo CIII/CII ratios found in hyperuricaemic-hypertriglyceridaemic patients (both pure and mixed) suggest that this apoprotein plays a central role in the physiopathology of the alterations observed.

UK Prospective Diabetes Study (UKPDS). X. Urinary albumin excretion over 3 years in diet-treated type 2, (non-insulin-dependent) diabetic patients, and association with hypertension, hyperglycaemia and hypertriglyceridaemia.

Urinary albumin excretion has been assessed in 585 newly-presenting Type 2 (non-insulin-dependent) diabetic patients (aged 53 (8) years, 67% male) at diagnosis with fasting plasma glucose 10.3 (3.2) mmol/l and over 3 years of dietary treatment. Urinary albumin at diagnosis, geometric mean (1 SD interval) corrected for dilution by regression on urine creatinine concentration of 10 mmol/l, was 17 (5-58) mg/l compared with 8 (3-18) mg/l in an age-matched non-diabetic reference population. Values greater than 50 mg/l were found in 17% of diabetic patients compared with 4% in the reference group. After diet therapy for 3 months, fasting plasma glucose decreased to 6.9 mmol/l and urinary albumin to 12 (4-31) mg/l (p < 0.0001). This suggests that increased urinary albumin excretion at diagnosis is in part functional, possibly secondary to glomerular hyperfiltration caused by hyperglycaemia and raised blood pressure. Over the next 3 years, mean fasting plasma glucose was 7.2 mmol/l, albumin excretion changed little, without significant increase either in patients with raised or normal albumin at diagnosis. Both at diagnosis and over 3 years, urinary albumin excretion was independently associated with fasting plasma glucose and triglyceride levels and with systolic blood pressure, but the combination of these factors only explained 10% of the total variance. This suggests the presence of additional pathological processes in patients with increased urinary albumin. Urinary albumin was not associated with other variables included in syndrome X, such as HDL cholesterol, fasting plasma insulin, obesity or central adiposity.(ABSTRACT TRUNCATED AT 250 WORDS)