Feeding flaxseed oil but not secoisolariciresinol diglucoside results in higher bone mass in healthy rats and rats with kidney disease.

Flaxseed's oil and lignan, secoisolariciresinol diglucoside (SDG), are implicated in attainment of health and treatment of renal injury and osteoporosis. To test for these benefits, weanling Han:SPRD-cy rats (n=171) with or without kidney disease were randomized to diets made with either corn oil or flaxseed oil and with or without SDG for 12 weeks. In females, weight was lower with the SDG diet. In males fed flaxseed oil, lean mass was higher and fat % was lower. In both sexes, fat % was lower in diseased rats. Bone mineral content (BMC) and density were higher in rats fed flaxseed oil and lower in diseased rats, additionally; BMC was lower in SDG-supplemented females. The benefit of flaxseed oil on body composition is sex specific but the effect on bone mass is not. Lastly, reduced weight due to early rat kidney disease is not due to loss of lean body mass.

Increased renal fibrosis and expression of renal phosphatidylinositol 4-kinase-beta and phospholipase C(gamma1) proteins in piglets exposed to ochratoxin-A.

Endemic nephropathy has been linked to exposure of ochratoxin-A (OA) in grains and animal products. The underlying events surrounding this form of renal injury are not well known, partly due to the lack of a suitable animal model of the disease. Therefore, in this study, a pig model of OA-induced renal injury was established and used to examine whether elements of the phosphoinositide signalling pathway are altered in this disease. Weanling piglets were fed diets containing 0, 2, and 4 ppm OA for 6 weeks. Serum creatinine and urea and renal fibrosis were monitored biweekly using serial blood samples and renal biopsies. At termination, the protein levels of renal phosphatidylinositol 4-kinase-beta (PtdIns4Kbeta) and phospholipase C(gamma1) (PLC(gamma1)) were determined using immunoblotting and scanning densitometry. Serum creatinine was elevated by 2 weeks and renal fibrosis was elevated by 4 weeks at both levels of inclusion of OA. At the end of the experimental period, kidney size and water content were elevated, as were the protein levels of renal PtdIns4Kbeta and PLC(gamma1) in OA-exposed animals. Therefore, serial biopsies can be used to track changes in renal pathology in the OA-exposed piglet. We conclude that this is a useful model for OA-induced renal injury in which the underlying molecular events associated with this form of renal injury can be studied.

Dietary betaine modifies hepatic metabolism but not renal injury in rat polycystic kidney disease.

We undertook a morphometric and proton nuclear magnetic resonance ((1)H-NMR) study to test the hypothesis that 1% dietary betaine supplementation would ameliorate renal disease in the heterozygous Han:SPRD-cy rat, a model of polycystic kidney disease (PKD) and progressive chronic renal failure. After 8 wk of pair feeding, betaine had no effect on renal cystic change, renal interstitial fibrosis, serum creatinine, serum cholesterol, or serum triglycerides. (1)H-NMR spectroscopy of renal tissue revealed no change in renal osmolytes, including betaine, or renal content of other organic anions in response to diet. (1)H-NMR spectroscopy of hepatic tissue performed to explore the metabolic fate of ingested betaine revealed that heterozygous animals fed the control diet had elevated hepatic levels of gluconeogenic amino acids, increased beta-hydroxybutyrate, and increased levels of some citric acid cycle metabolites compared with animals without renal disease. Betaine supplementation eliminated these changes. Chronic renal failure in the Han:SPRD-cy rat is associated with disturbances of hepatic metabolism that can be corrected with betaine therapy, suggesting the presence of a reversible methylation defect in this form of chronic renal failure.

Modification of polycystic kidney disease and fatty acid status by soy protein diet.

UNLABELLED: Modification of polycystic kidney disease and fatty acid status by soy protein diet. BACKGROUND: Previous studies have demonstrated that soy protein can slow progression of renal injury in the Han:SPRD-cy rat. We undertook a study to establish whether this benefit was independent of any nutritional deprivation, and whether or not it was associated with changes in polyunsaturated fatty acid status that have been previously linked to the anti-inflammatory or antineoplastic potential of soy diets. METHODS: Male Han:SPRD-cy rats were pair fed a 20% casein or 20% soy protein diet for six weeks from weaning. Tissue was harvested for analysis of cystic change, cell proliferation, macrophage infiltration, and fibrosis. Renal and hepatic tissues were also harvested for lipid analysis using gas chromatography. RESULTS: Animals thrived on both diets. Soy protein feeding was associated with reduced cystic change (4.3 vs. 7.0 mL/kg, P < 0.0001), epithelial cell proliferation (15.7 vs. 21.0 cells/mm epithelium, P < 0.0001), macrophage infiltration (25.3 vs. 43.5 cells/high-power field, P < 0.0001), and fibrosis (0.6 vs. 1.07 mL/kg, P < 0.0001). The soy diet prevented a significant elevation in serum creatinine in diseased versus normal animals. Soy feeding was associated with higher renal and hepatic linoleic acid content and higher hepatic alpha-linolenic acid, but lower hepatic arachidonic acid content. CONCLUSIONS: Isocaloric soy protein feeding ameliorates both epithelial and interstitial changes in the Han:SPRD-cy rat independent of a hypocholesterolemic effect. The histologic benefit is associated with changes in polyunsaturated fatty acid metabolism that may influence both inflammatory and proliferative pathways.

Renal remodelling in dietary protein modified rat polycystic kidney disease.

Dietary protein restriction slows progression of the Han:SPRD-cy rat model of polycystic kidney disease. We undertook studies to examine the relative changes in interstitial and tubular pathology as a result of feeding an 8% casein (LP) diet to Han:SPRD-cy rats. Archival tissue from a previous study comparing LP and 20% casein (NP) diets was examined morphometrically after immunohistochemical or histochemical staining for apoptosis, proliferation antigens, interstitial fibrosis, and macrophage infiltration. Expression of common extracellular matrix genes was measured by Northern analysis. Animals fed LP diet demonstrated reduced tubular epithelial remodelling compared with animals fed NP diet by both proliferating cell nuclear antigen-positive cells (57.5 vs. 71.6 cells/mm epithelium, P=0.007) or apoptosis (31.2 vs. 35.6 cells/mm epithelium, P=0.006). Interstitial pathology demonstrated that LP feeding was associated with proportionately greater reductions in interstitial fibrosis (0.3 vs. 1.3 ml/kg body weight, P=0.003), interstitial cellularity (361 vs. 604 cells/high-power field, P=0.0002), and interstitial macrophages (67 vs. 149 cells/high-power field, P=0. 0002). Northern analysis only revealed significantly lower levels of monocyte chemoattractant protein mRNA (P=0.04) in animals fed the LP diet. Dietary protein restriction modifies both tubule and interstitium, with significant impact upon interstitial inflammation and fibrosis in the Han:SPRD-cy rat.

Flaxseed ameliorates interstitial nephritis in rat polycystic kidney disease.

BACKGROUND: Flaxseed has demonstrated useful antiinflammatory properties in a number of animal models and human diseases. We undertook a study to determine if flaxseed would also modify clinical course and renal pathology in the Han:SPRD-cy rat. METHODS: Male Han:SPRD-cy rats were pair fed a 10% flaxseed of control rat chow diet for eight weeks from weaning. Tissue was harvested for analysis of cystic change, apoptosis, cell proliferation, and fibrosis. Tissue was also harvested for lipid analysis using gas chromatography. RESULTS: Animals thrived on both diets. Flaxseed-fed animals had lower serum creatinine (69 vs. 81 mumol/liter, P = 0.02), less cystic change (1.78 vs. 2.03 ml/kg, P = 0.02), less renal fibrosis (0.60 vs. 0.93 ml/kg, P = 0.0009), and less macrophage infiltration (13.8 vs. 16.7 cells/high-power video field) of the renal interstitium than controls. The groups did not differ in renal tubular epithelial cell apoptosis and proliferation. Lipid analysis revealed significant renal enrichment of 18 and 20 carbon omega 3 polyunsaturated fatty acids (total omega 6:omega 3 ratio 3.6 vs. 9.1, P < 0.0001). CONCLUSIONS: Flaxseed ameliorates Han:SPRD-cy rat polycystic kidney disease through moderation of the associated chronic interstitial nephritis. The diet alters renal content of polyunsaturated fatty acids in a manner that may promote the formation of less inflammatory classes of renal prostanoids.

Soy protein modification of rat polycystic kidney disease.

We undertook a study to determine whether soy protein feeding would ameliorate renal injury in the Han:SPRD-cy rat model of polycystic kidney disease (PKD). Male offspring of Han:SPRD-cy heterozygotes received isocaloric diets based on 20% casein or 20% heat-treated soy protein at weaning ad libitum for 8 wk. Soy-fed animals demonstrated lower serum creatinine (66 vs. 125 mumol/l; P = 0.002), lower urinary ammonium excretion (0.080 vs. 0.173 mmol/kg; P = 0.01), reduced renal cysts (0.98 vs. 4.92 ml/kg body wt, P < 0.0001), renal fibrosis (0.79 vs. 1.4 ml/kg; P = 0.016), macrophage infiltration, renal tubular cell proliferation, and apoptosis. Proton nuclear magnetic resonance (1H-NMR) studies of urine demonstrated that soy diet was associated with increased losses of citric acid cycle organic anions. 1H-NMR of perchloric acid-extracted tissue found that levels of succinate were not depleted in soy-fed animals, despite increased urinary losses. Soy-fed animals had marked elevation of tissue betaine (P < 0.001), with reduced taurine and cholines, compared with casein-fed animals (P < 0.001). Soy feeding dramatically reduces both tubular and interstitial pathology in the Han:SPRD-cy rat model of PKD, through mechanisms that remain to be determined.

The effect of dietary flaxseed supplementation on organic anion and osmolyte content and excretion in rat polycystic kidney disease.

Progression of chronic renal failure in the Han:SPRD-cy rat polycystic kidney disease is associated with renal depletion of citric acid cycle metabolites and betaine. Amelioration of this disease by a soy protein diet is associated with retention of citric acid cycle anions, despite increased excretion, and preservation of tissue levels of betaine. As we have recently found that modest dietary supplementation with flaxseed preserves renal function and reduces histologic injury in the Han:SPRD-cy rat, we undertook a high-resolution 1H NMR spectroscopic study of urine and renal tissue extracts from Han:SPRD-cy rats to explore the renal biochemical consequences of a flaxseed diet. There was no significant dietary effect upon organic anion, methylamine, or osmolyte excretion in healthy animals. There was increased citrate excretion in Han:SPRD-cy rats fed flaxseed. Urinary ammonium excretion did not differ, suggesting that the observed increase in citrate excretion was not due to an alkaline effect of diet. Tissue extract studies revealed that disease amelioration was associated with tissue retention of succinate and betaine. Amelioration of Han:SPRD-cy rat polycystic kidney disease by diet is associated with alteration in the handling of citric acid cycle metabolites. Betaine may have a metabolic role in the reduction of chronic renal injury.

[Idiopathic membranoproliferative glomerulonephritis (structural-functional relationship)]. / Idiopatski membranoproliferacioni glomerulonefritisi (strukturno-funkciona zavisnost).

We investigated 12 patents with idiopathic membranoproliferative glomerulonephritis. Discriminatory analysis was used for structural functional relationship in order to determine discriminatory power of certain clinical and pathohistological parameters. Semiquantitatively were determined pathohistological parameters: glomerular index in range 0-10, vascular index 1-4, interstitial fibrosis 0-10, interstitial infiltration 0-3, tubular atrophy 0-3. Nephrotic syndrome (symbolic value), quantitative proteinuria and creatinine clearance (continual variable) were used as clinical parameters. Discriminatory power was determined as a degree of decreasing Shennon's entropy dy distinction of patients according to value of creatinine clearance at the time of biopsy. Discriminatory power was measured in the information measurement units (bit). The most powerful was glomerular index (discriminatory power 0.29) in moderately reduced glomerular filtration rate (creatinine clearance 80 ml/min) at the time of biopsy. In severely reduced glomerular filtration rate (creatinine clearance 40 ml/min) vascular index had the greatest discriminatory power (0.24) while interstitial infiltration and interstitial fibrosis had less powerful discriminatory power (0.13). Negative predictive value of reduced glomerular filtration rate at the time of biopsy in membranoproliferative glomerulonephritis has been confirmed in other studies.

[Renal function and histologic findings in immunoglobulin A nephropathy]. / Funcija bubrega i histoloski nalaz u nefropatiji imunoglbulina A.

We investigated 28 patients with IgA nephropathy. Discriminatory analysis was the method used to determine discriminatory power of certain clinical and pathohistological parameters. Semiquantitatively were determined pathohistological parameters: glomerular index in range 0-10, vascular index 1-4, interstitial fibrosis 0-10, interstitial infiltration 0-3, tubular atrophy 0-3. Nephrotic syndrome (symbolic value), quantitative proteinuria and creatinine clearance at the time of biopsy and year after (continual variable) were used as clinical parameters. Discriminatory power was determined as a degree of decreasing Shennon's entropy by distinction of patients according to value of creatinine clearance at the time of biopsy, and a year after biopsy. Discriminatory power was measured in he information measurement units (bit). Based on discriminatory-predictive analysis we determined that glomerula changes and interstitial fibrosis had an equal effect (discriminatory power) on renal function at the time of biopsy and a year latter, as well as predictive value of these histological parameters and creatinine clearance at the time of biopsy.

[Cyclosporine in the treatment of primary focal-segmental glomerulosclerosis]. / Ciklosporin u lecenju primarne fokusno-segmentne glomeruloskleroze.

Cyclosporin A (CyA) was administered at the Clinic of Nephrology, CCS, in treatment of 8 patients with steroid-resistant nephrotic syndrome (NS) caused by focal segmental glomerulosclerosis (FSG), Cyclophosphamide (CP) treatment was attempted in 6 of these cases, but without success. Prior to the onset of CyA therapy, CP treatment was interrupted, and the dose of prednisone was reduced to 0.4 mg/kg/48 h. CyA was applied in the initial dose of 5 mg/kg/bw/24h, and then adjusted so that CyA blood level was 80-120 ng/ml. Although CyA treatment caused proteinuric decrease in most of the patients (from 12.1 g/24 h to 8.2 g/24 h), complete NS remission was achieved in only one patient, the same as the incomplete one. The female patient with a positive response to CyA treatment behaved as "CyA-dependent" and each discontinuation of CyA therapy soon led to recurrent NS. Insignificant CyA effect on NS or renal function was registered in 4 patients, and the therapy was interrupted in two cases due to renal function impairment. Apart from nephrotoxicity, other CyA side effects were absent.