thromboxane-b2 and Glomerulosclerosis--Focal-Segmental

Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) has been shown to reduce proteinuria in experimental models of renal diseases, but their potential role in the treatment of human renal disease is unknown. We administered n-3 PUFA in the form of triglycerides [with eicosapentaenoic (EPA)+docosahexaenoic (DHA) = 3 g/day into 4 patients] and of ethyl esters (EPA+DHA = 7.7 g/day) into 10 patients (one patient twice) with chronic glomerular disease (membranous glomerulonephritis and focal glomerular sclerosis), all diagnosed histologically. Serum albumin was > 2.4 g/dl and serum creatinine < 2.5 mg/dl in all patients. Treatment was given for periods of six weeks, followed by a prolonged follow-up for 27 weeks in 10 cases. Dietary supplementation with n-3 PUFA caused the expected reduction in platelet generation of thromboxane B2 (mean +/- SEM, from 490 +/- 70 ng/ml at baseline, to 342 +/- 147 ng/ml at 6 weeks, P < 0.05) of serum triglycerides (from 236 +/- 60 to 170 +/- 43, P < 0.01), and a prolongation of the bleeding time (from 5.8 +/- 0.4 min to 7.7 +/- 0.4 min, P < 0.01) in patients treated with ethyl esters. A modest but significant reduction in serum total cholesterol was noticed (from 275 +/- 27 to 252 +/- 24 mg/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Aged, 80 and over; Blood Pressure; Cholesterol; Chronic Disease; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Female; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Humans; Male; Middle Aged; Proteinuria; Thromboxane B2

Topics: Adult; Blood Platelets; Case-Control Studies; Child; Cyclic AMP; Glomerulosclerosis, Focal Segmental; Humans; Nephrosis, Lipoid; Platelet Aggregation; Thromboxane B2

The objective of this study was to assess the effects of flaxseed and flax oil diets in the rat renal ablation model. Flaxseed is a rich source of alpha-linolenic acid, an 18:3n3 omega-3 fatty acid, which has anti-atherogenic and anti-inflammatory properties. Flaxseed, but not flax oil, is also rich in lignans, which are platelet-activating factor-receptor antagonists. Rats were subjected to 5/6 nephrectomy, fed a regular laboratory diet (RLD) for 1 week, then divided into three groups to receive either the RLD (n = 8), a 15% flaxseed diet (n = 8), or a 15% flax oil diet (n = 7). Blood pressure, proteinuria, glomerular filtration rate, and urinary prostaglandins (thromboxane B2 and 6-keto prostaglandin F1 alpha) were measured presurgery and at 1 week (before dietary allotment) and 20 weeks postnephrectomy when blood for plasma lipids and kidneys for histology and tissue-phospholipid analyses were obtained. Blood pressure increased progressively in the RLD group but not in the flax diet groups. Plasma triglycerides and cholesterol increased in all groups, but this increase was significantly attenuated by both flax diets. Proteinuria increased 1 week postsurgery and continued to increase in the RLD group but not in the flax diet groups. Glomerular filtration rate decreased progressively, but this decline in renal function was attenuated significantly by the flax diets. Both of the flax diets prevented glomerulosclerosis and mesangial expansion. Renal alpha-linolenic acid was increased by both the flax diets (flax oil > flaxseed), but eicosapentaenoic acid increased in the flax oil group only. The flaxseed group had greater renal-arachidonic acid levels than the flax oil and RLD groups. The total omega-3 fatty acids increased twofold to threefold in the flax oil group compared with the two other groups. The total saturated fatty acids were lower and the polyunsaturated fatty acids were increased in both flax diet groups. A progressive increase in urinary thromboxane B2 occurred in the RLD group but not in the flaxseed group; the level decreased in the flax oil group. The ratio of prostaglandin F1 alpha/thromboxane B2 was preserved in the flax oil group only. In conclusion, the dietary flax seed and flax oil attenuated the decline in renal function and reduced glomerular injury with favorable effects on blood pressure, plasma lipids, and urinary prostaglandins. While we have not proven any specific synergistic effects of the constituents of the flaxseed diet,

Topics: 6-Ketoprostaglandin F1 alpha; alpha-Linolenic Acid; Analysis of Variance; Animals; Blood Pressure; Disease Models, Animal; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Kidney; Kidney Failure, Chronic; Ligation; Linseed Oil; Lipids; Male; Nephrectomy; Plants, Edible; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Artery; Seeds; Thromboxane B2

Haemostatic activation was measured in patients with either non-diabetic chronic renal failure (CRF) or diabetic nephropathy. We have investigated the relationship between these haemostatic markers and the rate of progression of renal failure. When compared with age- and sex-matched healthy controls, both patient groups showed significantly elevated plasma concentrations of D dimer, von Willebrand factor antigen (vWFAg), and C-reactive protein (CRP) (all P less than 0.001), as well as an increase in spontaneous platelet aggregation (P less than 0.01). Plasma concentration of platelet factor 4 was slightly but not significantly increased. Serum thromboxane was subnormal (P less than 0.01). Multiple regression analysis showed that in non-diabetic CRF proteinuria and serum TxB2 were independently related to the rate of progression of renal failure; in diabetic nephropathy proteinuria and vWFAg were independently related to the rate of progression. In both groups the relationship was stronger with proteinuria (standardised regression coefficients 0.56 and 0.45 respectively) than with serum TxB2 (0.29) or with vWFAg (0.37). We have found haemostatic activation in both non-diabetic and diabetic progressive renal failure. Proteinuria, and also in this study serum TxB2 and vWFAg, appear to be determining factors in the progression of renal failure, and their measurement may have prognostic value.

Topics: Adolescent; Adult; Aged; Antigens; Diabetic Nephropathies; Female; Glomerulosclerosis, Focal Segmental; Hemostasis; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Platelet Activation; Proteinuria; Thromboxane B2; von Willebrand Factor

Ablation of greater than 70% of renal mass in the rat results in hypertension, proteinuria, and glomerular sclerosis of the remnant kidney. Rats with a remnant kidney have increased excretion of thromboxane in the urine when compared with normal rats. Chronic oral administration of OKY 1581, an inhibitor of thromboxane synthesis, in rats with a remnant kidney increases renal blood flow and glomerular filtration rate (GFR), decreases protein and thromboxane excretion in the urine, lowers blood pressure and cardiac index, and improves renal histology. The degree of hypertrophy of the remnant kidney was unaffected by administration of OKY 1581. Calculated values for single nephron plasma flow and GFR were significantly greater in rats with remnant kidneys given OKY 1581 than in rats given saline. Acute i.v. administration of OKY 1581 increased renal plasma flow and GFR in rats with a remnant kidney but not in normal rats or rats with a remnant kidney previously treated with acetylsalicyclic acid. OKY 1581 markedly inhibited platelet aggregation. We suggest that in this model of renal disease platelet aggregation and intraglomerular thrombosis play a key role in the development of glomerulosclerosis. Inhibition of platelet aggregation prevents development of glomerulosclerosis, hypertension, and cardiac hypertrophy. We suggest that hyperperfusion and hyperfiltration per se occurring in remnant glomeruli are not directly responsible for the development of glomerulosclerosis.

Topics: Acrylates; Animals; Blood Pressure; Disease Models, Animal; Female; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Heart; Kidney; Kidney Diseases; Methacrylates; Nephrectomy; Oxidoreductases; Platelet Aggregation; Rats; Thromboxane B2; Thromboxane-A Synthase

Topics: Adolescent; Adult; Chronic Disease; Female; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Humans; Male; Middle Aged; Nephrosis, Lipoid; Radioimmunoassay; Thromboxane B2; Thromboxanes