Prostaglandins and related compounds are active mediators of inflammation, but data concerning their role in the pathogenesis of the glomerulonephritis of New Zealand Black x New Zealand White (NZB x NZW) F1 mice are conflicting. Dietary eicosapentaenoic acid (EPA, C20:5), a fatty acid analogue of arachidonic acid (C20:4), has been shown to impair platelet aggregation in humans, apparently through inhibition of the synthesis of prostaglandins and thromboxanes from arachidonic acid. We report here the effects of a diet high in EPA on the development of renal disease and survival in female NZB x NZW F1 mice. Animals from 4--5 wk of age were fed diets containing 25% lipid, supplied either as beef tallow or menhaden oil, with fatty acid analysis of less than 0.05 and 14.4% EPA, respectively. In the first experiment, by 13.5 mo of age, mice on the beef tallow diet had all (9/9) developed proteinuria and the majority (6/9) had died, with renal histologic examination revealing severe glomerulonephritis. In contrast, none of 10 menhaden oil-fed animals had developed proteinuria, and all were alive at this time (P less than 0.005 for both proteinuria and survival). In a second experiment using 50 mice in each dietary group, 56% of the beef tallow group vs. none of the menhaden oil group had developed proteinuria at 9 mo of age (P less than 0.005). Native DNA binding at 6 mo of age was 23.9 +/- 14.7 vs. 10.1 +/- 9.7% in the beef and menhaden oil groups, respectively (P less than 0.01). Weights were similar in all groups, and there was no evidence of essential fatty acid deficiency in any group. These results demonstrate that a diet high in EPA protects NZB x NZW F1 mice from the development of glomerulonephritis.

Several retrospective and prospective studies confirmed the beneficial effect of dietary protein restriction (DPR) on the downhill course of renal function in chronic kidney disease. The long-term results of this therapeutic modality may be different than the short-term effects. In our nephrology outpatient department, a prospective randomized trial has been in progress since April, 1982. In 1984, we reported a general beneficial effect of our diet after two years of follow-up. Two hundred and forty-eight patients with initial creatinine clearances between 10 and 60 ml/min entered the trial. Patients were stratified for sex, age and degree of renal insufficiency. One hundred and twenty-nine patients were randomly assigned to a DPR-group (0.4 to 0.6 g/kg/day); 118 patients to a control group. Patients on DPR visited the dietitian every three months during the first 24 months of the study; thereafter, as with the controls, the dietitian visits were only for specific needs. Urea excretion decreased significantly in DPR patients as a sign of good compliance and stayed at that level, even without frequent visits to the dietitian. Biochemical parameters showed no signs of malnutrition. Amino acid profiles were related to the degree of renal failure. The diet appeared to have a selective effect on the progression rate of renal failure: only patients with primary glomerular disease responded to the diet. Furthermore, there were striking intersex differences. Males showed a more rapid decline towards end-stage renal failure, but responded in a positive way to the diet, whereas female patients did not benefit from the dietary manipulation at all.(ABSTRACT TRUNCATED AT 250 WORDS)

It has recently been established that the rate of progression of chronic renal failure in man can be slowed by restricting dietary protein. Consequently, the short term and long term effects of a low protein diet on the course of different chronic nephropathies were studied in an attempt to delineate the factors that determine the response to such a diet. When a low protein diet was given for six months renal function improved significantly in nine patients with chronic tubulointerstitial nephritis (p less than 0.025); the diet had a marginally beneficial effect in 12 patients with chronic glomerulonephritis (p less than 0.05) and no effect in nine with hypertensive nephrosclerosis. The heterogeneous functional response in the patients with chronic glomerulonephritis correlated closely with the effect of the diet on these patients' proteinuria (r = 0.76, p less than 0.01). In a short term study (four weeks) of 12 patients with chronic renal failure changes in renal plasma flow were proportional to dietary protein intake. Renal vascular resistance fell during a high protein diet and increased when dietary protein was restricted. The changes in renal plasma flow during the low protein diet correlated well with the patients' long term functional response to the diet (r = 0.76, p less than 0.01). It is concluded that the response to a low protein diet in chronic renal failure is determined, firstly, by the nature of the underlying nephropathy, with maximal benefit being observed in non-glomerular disorders; secondly, by the effect of the diet on the proteinuria in chronic glomerulonephritis; and, thirdly, by the haemodynamic response to the diet, with patients with a reactive renal vascular bed improving with a low protein diet.

Dietary protein restriction has been shown to slow the rate of loss of kidney function in humans with progressive glomerulosclerosis due to glomerulonephritis or diabetes mellitus. A central feature of glomerulosclerosis is the pathological accumulation of extracellular matrix within the diseased glomeruli. Transforming growth factor beta 1 (TGF-beta 1) is known to have widespread regulatory effects on extracellular matrix and has been implicated as a major cause of increased extracellular matrix synthesis and buildup of pathological matrix within glomeruli in experimental glomerulonephritis. In the present study, it is shown that administration of a low protein diet to rats rapidly reduces the elevated expression of TGF-beta 1 mRNA and TGF-beta 1 protein that is known to occur within glomeruli after induction of glomerulonephritis. Compared to a normal protein diet, glomerulonephritic rats receiving the low protein diet did not develop an increase in glomerular extracellular matrix and showed significantly less proteinuria. Glomeruli isolated from glomerulonephritic rats fed the normal protein diet showed a marked increase in proteoglycan synthesis on day 7 of disease and were demonstrated to be secreting increased amounts of TGF-beta 1 into the medium, whereas glomeruli at the same point in time isolated from rats on a low protein diet showed no increase in proteoglycan production or TGF-beta 1 secretion. These results suggest that a mechanism of the rapid therapeutic effect of a low protein diet on experimental glomerulonephritis is through suppression of TGF-beta 1 expression and prevention of the induction of extracellular matrix synthesis within the injured glomeruli.

We have examined the effects of various levels of dietary protein intake on the course of nephrotoxic serum nephritis in the rat by feeding low (4.6% casein), standard (23% casein), and high (57.5% casein) protein diets which were identical in calorie, mineral, and electrolyte content. Nephritic rats on a high protein diet manifested heavy proteinuria, hypoalbuminemia, hypercholesterolemia, azotemia, and elevated serum creatinine levels. In those subjected to dietary protein restriction, proteinuria remitted and azotemia did not develop. While mesangial widening, interstitial abnormalities, and segmental proliferation and sclerosis of glomeruli occurred regularly in nephritic rats fed high protein diets, histologic abnormalities were virtually absent in those on low protein intake. Animals on a standard protein intake manifested histologic and clinical features intermediate in severity. We conclude that the renal functional and histologic consequences of nephrotoxic serum nephritis can be averted by dietary protein restriction.

To evaluate the protective effect of dietary phosphorus restriction in an immunologic model of experimental renal disease, we randomized 24 Sprague-Dawley rats with established nephrotoxic serum nephritis into two groups. Group A animals (N = 13) were fed a diet with a normal phosphorus content (0.5% phosphorus), and group B animals (N = 11) received an identical diet low in phosphorus (0.04% phosphorus). Over the ensuing 133 days, group A rats developed progressive renal failure and had a mean serum creatinine concentration of 3.0 +/- 0.5 mg/dl at the time of death or completion of the study. In contrast, group B animals maintained near normal renal function and had a final mean serum creatinine concentration of 0.93 + 0.2 mg/dl (P < 0.001). Survival was markedly improved in group B animals (P < 0.001). Histologic damage was diminished greatly in group B animals by both light and electron microscopy; immunofluorescence was positive in all animals. Group A animals had increased kidney calcium concentration (30 +/- 6 mmoles/kg) when compared to group B animals (18 +/- 1 mmoles/kg) and animals with normal kidneys (13 +/- 1 nmoles/kg, P< 0.001). Conclusion. Dietary restriction of phosphorus retards functional deterioration and reduces histologic damage in experimental immunologic renal disease. The mechanism for this protective effect has not been elucidated.

The dietary protein intake (DPI) of 766 patients (aged 7 to 88 yr) was determined from 24-h urinary urea and protein excretion by urea kinetic modelling. Five hundred sixty-five patients had a normal serum creatinine concentration, and of these 565, 385 patients had no dietary modification advised and 180 were advised to follow a low-protein diet. The remaining 201 patients had an increased serum creatinine concentration; 148 of these 201 patients had been advised to restrict their DPI. Patients with a normal serum creatinine concentration who had no dietary restriction had a significantly higher DPI than those advised to restrict their protein intake (1.08 +/- 0.01 versus 0.96 +/- 0.02 g/kg per day (mean +/- SEM), P < 0.01). Similarly, patients with abnormal renal function who were advised to follow a low-protein diet had a reduced DPI (0.93 +/- 0.01 versus 0.87 +/- 0.02 g/kg per day; P < 0.05). A lower DPI correlated with level of renal dysfunction, independent of dietary advice (P < 0.0001). In the overall population, DPI correlated with body mass index (BMI; P < 0.0001) and serum albumin (P < 0.0001), and inverse correlations were evident between age (P < 0.0001), blood glucose level (P < 0.01), serum cholesterol level (P < 0.0001), and triglyceride levels (P < 0.0001) independently of renal function. Fifty-two patients were assessed within the 3 months before the commencement of dialysis, and 47 were reassessed within 3 months after the commencement of dialysis. Despite advice regarding an increase in dietary protein after the commencement of dialysis, this increase failed to occur within the 3 months of commencement of dialytic therapy (0.79 +/- 0.04 versus 0.82 +/- 0.03 g/kg per day); P = 0.64). However, 6 to 9 months after the commencement of dialysis, a significant increase in protein intake was evident (1.04 +/- 0.04 g/kg per day; P < 0.005 versus both prior measurements). Hence a low DPI in renal impairment occurs independently of dietary advice, but compliance with such advice is evident because patients advised to consume a low-protein diet had significantly lower protein intake than did patients receiving no dietary advice. Adaptation to a high-protein diet after instigation of dialysis is unsuccessful in the short term, irrespective of whether or not advice is given regarding a low-protein diet before dialysis is initiated. However, 6 to 9 months after the commencement of dialysis, a significant increase in protein intake occurs, which in the hemodialysis population correlates with dialysis delivery.

We have previously shown beneficial effects of dietary protein restriction on transforming growth factor beta (TGF-beta) expression and glomerular matrix accumulation in experimental glomerulonephritis. We hypothesized that these effects result from restriction of dietary L-arginine intake. Arginine is a precursor for three pathways, the products of which are involved in tissue injury and repair: nitric oxide, an effector molecule in inflammatory and immunological tissue injury; polyamines, which are required for DNA synthesis and cell growth; and proline, which is required for collagen production. Rats were fed six isocaloric diets differing in L-arginine and/or total protein content, starting immediately after induction of glomerulonephritis by injection of an antibody reactive to glomerular mesangial cells. Mesangial cell lysis and monocyte/macrophage infiltration did not differ with diet. However, restriction of dietary L-arginine intake, even when total protein intake was normal, resulted in decreased proteinuria, decreased expression of TGF-beta 1 mRNA and TGF-beta 1 protein, and decreased production and deposition of matrix components. L-Arginine, but not D-arginine, supplementation to low protein diets reversed these effects. These results implicate arginine as a key component in the beneficial effects of low protein diet.

Our aim was to determine whether a longer period of treatment with a vegetarian soy diet with addition of fish oil supplements would accentuate the beneficial effects on hyperlipidemia and proteinuria of nephrotic patients we found in a previous study. After an 8-week baseline period on free diet, patients were randomly allocated either on soy diet alone (SD) or to SD plus 5 g/day of fish oil (SD + FO) orally for two months. Then they crossed over to the other treatment for two additional months. They finally resumed eating the free diet for 3 months. We selected 20 outpatients with chronic glomerulonephritis, proteinuria in the nephrotic range, fasting serum cholesterol > 250 mg/dl, mean serum creatinine concentrations 1.75 +/- 0.23 mg/dl. Serum lipid profile, urinary protein loss and nutritional parameters were monitored. With the soy diet, we obtained a significant decrease both of hyperlipidemia and of proteinuria. The effect of the soy diet on proteinuria increased over the 4 months. The addition of a moderate amount (5 g/day) of fish oil in a randomized cross-over design had no further beneficial effect. Stability of serum albumin, transferrin and the body mass index documented good nutritional status. In conclusion, the dietary manipulation with our vegetarian soy diet confirmed the beneficial effects on hyperlipidemia and proteinuria of nephrotic patients. Such effects persisted and even ameliorated after 4 months of diet. The addition of moderate oral supplements of fish oil did not potentiate the beneficial effect.

Passive Heymann nephritis (PHN) is a rat model of membranous nephropathy induced by injecting anti-Fx1A. The onset of proteinuria in PHN is caused by complement-mediated injury to glomerular epithelial cells (GEC) accompanied by enhanced glomerular eicosanoid production. In addition, sublethal injury by complement of rat GECs in culture leads to phospholipase activation, phospholipid hydrolysis and release of arachidonic acid and dienoic prostanoids. Based on these findings, we undertook to determine if substituting arachidonic acid (omega-6) in GEC membrane phospholipids with omega-3 fatty acids derived from fish oil would alter the development and course of proteinuria in PHN. We found that rats fed a diet containing 10% fish oil for four weeks prior to antibody injection developed 50 to 60% less proteinuria between two and six weeks after anti-Fx1A than rats fed an equivalent diet containing 10% safflower oil, and had substantial enrichment of glomerular phospholipids with omega-3 fatty acids and displacement of arachidonic acid. This outcome was associated with a 50% reduction in release of glomerular thromboxane B2 (stable metabolite of thromboxane A2) in the fish oil group. More importantly, when PHN rats with well established proteinuria while on regular chow were randomized to three dietary groups, those fed fish oil had a 25 to 50% decline in proteinuria as compared to those fed lard or safflower oil. This difference was evident within two weeks of randomization and persisted until the end of the study after eight weeks. In neither study could the differences in urine protein excretion be accounted for by protein or calorie deprivation, or by differences in blood pressure, renal function, immune response to sheep IgG, or glomerular deposition of IgG or complement. Thus, our results indicate that dietary fish oil has protective and therapeutic effects with regard to proteinuria in PHN. These benefits may relate to alterations in membrane phospholipid composition in favor of omega-3 fatty acids and release of less reactive trienoic eicosanoids.