Dietary phosphate restriction attenuates polycystic kidney disease in mice.

Studies in rodents with reduced nephron mass have suggested a strong positive correlation between dietary phosphate consumption and CKD progression. Prior work by our group demonstrated that dietary phosphate restriction can prevent tubular injury and microcyst formation in rodents with glomerulonephritis. Tubular injury and cystic dilation of tubules are key contributors to kidney function decline in polycystic kidney disease (PKD). Here, we determined whether dietary phosphate restriction slows renal cyst growth and fibrosis in a mouse model of PKD. Pcy/pcy mice received a normal phosphate (0.54%) or a phosphate-restricted (0.02%) diet (n = 10/group) from 7 to 20 wk of age. All of the other major dietary constituents, including protein source and content, were comparable between the two diets. At 20 wk, body weight, kidney weight-to-body weight ratio (KW/BW), cystic area, cyst number, and kidney fibrosis were quantified. Pcy/pcy mice fed a phosphate-restricted diet had lower serum phosphate, fibroblast growth factor 23, and parathyroid hormone levels, along with elevated serum calcium levels and increased kidney Klotho gene expression compared with mice that consumed the control diet. Dietary phosphate restriction resulted in a 25% lower KW/BW ratio and reduced the cyst number, cystic index, and gene expression for the tubular injury markers neutrophil gelatinase-associated lipocalin and interleukin-18. Mice fed the phosphate-restricted diet exhibited lower kidney expression for pathways involved in collagen deposition and myofibroblast activation (collagen type I-α1, phosphorylated SMAD3, and α-smooth muscle actin); however, histological differences in kidney fibrosis were not appreciated. Dietary phosphate restriction slows cystogenesis and inhibits the activation of key pathways in the generation of kidney fibrosis in PKD mice.

Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease.

Mild reduction in food intake was recently shown to slow polycystic kidney disease (PKD) progression in mouse models, but whether the effect was due to solely reduced calories or some other aspect of the diet has been unclear. We now show that the benefit is due to the induction of ketosis. Time-restricted feeding, without caloric reduction, strongly inhibits mTOR signaling, proliferation, and fibrosis in the affected kidneys in a PKD rat model. A ketogenic diet had a similar effect and led to regression of renal cystic burden. Acute fasting in rat, mouse, and feline models of PKD results in rapid reduction of cyst volume, while oral administration of the ketone ß-hydroxybutyrate (BHB) in rats strongly inhibits PKD progression. These results suggest that cystic cells in PKD are metabolically inflexible, which could be exploited by dietary interventions or supplementation with BHB, representing a new therapeutic avenue to treat PKD.

Increased salt intake does not worsen the progression of renal cystic disease in high water-loaded PCK rats.

The anti-diuretic hormone arginine vasopressin is thought to be a detrimental factor in polycystic kidney disease (PKD). We previously reported that high water intake (HWI) reduced urine osmolality and urinary arginine vasopressin, improved renal function, and reduced the kidney/body weight ratio in PCK rats, an orthologous model of human PKD. In PKD patients, however, it is reported that HWI increases total kidney volume, urine volume, and urine sodium excretion, which could be a consequence of high salt intake. In the current study, we loaded PCK rats with high salt concurrently with HWI to determine whether this human-imitated condition exacerbates disease progression. PCK rats were assigned into 4 groups: control group (CONT: distilled water), HWI group (HWI: 5% glucose in water), HWI with 0.2% NaCl group (HWI+0.2%NaCl), and HWI with 0.45% NaCl group (HWI+0.45%NaCl). Total water intake during the experimental period was increased by 1.86-, 2.02-, and 2.42-fold in HWI, HWI+0.2%NaCl, and HWI+0.45%NaCl, and sodium intake was increased by 2.55- and 5.83-fold in HWI+0.2%NaCl and HWI+0.45%NaCl, respectively, compared with CONT. Systolic blood pressure was higher in HWI+0.2%NaCl and HWI+0.45%NaCl than in both CONT and HWI. Serum urea nitrogen, kidney/body weight ratio, cAMP, cystic area, and fibrosis index were significantly lower in HWI compared with CONT, and these ameliorative effects were not abrogated in either HWI+0.2%NaCl or HWI+0.45%NaCl. The amount of sodium excreted into the urine was increased by 2.50- and 8.38-fold in HWI+0.2%NaCl and HWI+0.45%NaCl, respectively, compared with HWI. Serum sodium levels were not different between the groups. These findings indicate that the beneficial effect of HWI against the progression of cystic kidney disease was not affected even by high salt-overload in this rodent model of PKD.

Distinct effects of dietary flax compared to fish oil, soy protein compared to casein, and sex on the renal oxylipin profile in models of polycystic kidney disease.

Oxylipins are bioactive lipids derived from polyunsaturated fatty acids (PUFA) that are important regulators of kidney function and health. Targeted lipidomic analyses of renal oxylipins from four studies of rodent models of renal disease were performed to investigate the differential effects of dietary flax compared to fish oil, soy protein compared to casein, and sex. Across all studies, dietary fish oil was more effective than flax oil in reducing n-6 PUFA derived oxylipins and elevating eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derived oxylipins, whereas dietary flax oil resulted in higher α-linolenic acid (ALA) oxylipins. Dietary soy protein compared to casein resulted in higher linoleic acid (LA) derived oxylipins. Kidneys from females had higher levels of arachidonic acid (AA) oxylipins, but similar or lower levels of oxylipins from other PUFA. Modulation of the oxylipin profile by diet and sex may help elucidate their effects on renal physiology and health.

Experiences and Perspectives of Polycystic Kidney Disease Patients following a Diet of Reduced Osmoles, Protein, and Acid Precursors Supplemented with Water: A Qualitative Study.

BACKGROUND: Salt, protein, acid precursors, and fluid intake have been identified as factors that influence cyst growth in ADPKD. Unfortunately, the feasibility of following these dietary restrictions/enhancements from a patient's point-of-view has yet to be studied. The purpose of this study is to understand better the experiences of patients following a relatively complex dietary prescription targeting these factors. METHODS: Twelve adults with ADPKD and kidney function >30ml/min/1.73m2 were recruited from the University of Kansas Medical Center Polycystic Kidney Disease clinic. In a qualitative design, semi-structured interviews of participants were conducted following a four week dietary intervention (experimental diet lower in sodium, protein, and acid precursors, and supplemented with water) either face-to-face or by telephone. All interviews were recorded, transcribed verbatim, and checked for accuracy. Transcripts were analyzed thematically for emerging themes. RESULTS: Participants reported that eating less meat and more fruits and vegetables were the easiest components of the diet, whereas reaching the daily goal amount of fruits and vegetables and tracking the diet constantly were the most difficult components. Participants had little difficulty with fluid intake and reported the prescribed fluid goal as achievable. The tracking system for fruits and vegetables and protein was reported to be both helpful and intuitive, but tracking their intake on paper was tedious. Eating out was the most significant barrier to following the diet with some individuals avoiding restaurants in order to comply with the dietary prescription. CONCLUSION: Participants on the experimental diet heightened their awareness of the consumption of dietary salt, protein, acid precursors, and fluid intake. Additionally, most participants believed adherence to the prescribed diet was feasible. However, participants wanted less cumbersome ways to track and monitor the diet, especially given that the prescribed diet is designed for lifelong adherence. Future studies should focus on targeting these specific dietary factors in larger groups of more ethnically and culturally diverse populations to help inform clinicians and how best to help diverse populations adhere to the dietary intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT01810614.

Lack of Benefit of Early Intervention with Dietary Flax and Fish Oil and Soy Protein in Orthologous Rodent Models of Human Hereditary Polycystic Kidney Disease.

Rationale for dietary advice in polycystic kidney disease (PKD) is based in part on animal studies that have examined non-orthologous models with progressive development of cystic disease. Since no model completely mimics human PKD, the purpose of the current studies was to examine the effects of dietary soy protein (compared to casein) or oils enriched in omega-3 fatty acids (fish or flax oil compared to soy oil) on early disease progression in two orthologous models of PKD. The models studied were Pkd2WS25/- mice as a model of autosomal dominant PKD, and PCK rats as a model of autosomal recessive PKD. After 13 weeks of feeding, dietary fish (but not flax) oil resulted in larger kidneys and greater kidney water content in female Pkd2WS25/- compared to control mice. After 12 weeks of feeding male PCK compared to control rats, both fish and flax compared to soy oil resulted in enlarged kidneys and livers, greater kidney water content and higher kidney cyst area in diseased rats. Dietary soy protein compared to casein had no effects in Pkd2WS25/- compared to control mice. In PCK rats, kidney and liver histology were not improved, but lower proteinuria and higher urine pH suggest that soy protein could be beneficial in the long term. Therefore, in contrast to studies in non-orthologous models during the progressive development phase, these studies in orthologous PKD models do not support dietary advice to increase soy protein or oils enriched in omega-3 oils in early PKD.

A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease.

Autosomal-dominant polycystic kidney disease (ADPKD) is a common cause of end-stage renal disease, and no approved treatment is available in the United States to slow disease progression. The mammalian target of rapamycin (mTOR) signaling pathway is aberrantly activated in renal cysts, and while mTOR inhibitors are highly effective in rodent models, clinical trials in ADPKD have been disappointing due to dose-limiting extrarenal side effects. Since mTOR is known to be regulated by nutrients and cellular energy status, we hypothesized that dietary restriction may affect renal cyst growth. Here, we show that reduced food intake (RFI) by 23% profoundly affects polycystic kidneys in an orthologous mouse model of ADPKD with a mosaic conditional knockout of PKD1. This mild level of RFI does not affect normal body weight gain, cause malnutrition, or have any other apparent side effects. RFI substantially slows disease progression: relative kidney weight increase was 41 vs. 151% in controls, and proliferation of cyst-lining cells was 7.7 vs. 15.9% in controls. Mice on an RFI diet maintained kidney function and did not progress to end-stage renal disease. The two major branches of mTORC1 signaling, S6 and 4EBP1, are both suppressed in cyst-lining cells by RFI, suggesting that this dietary regimen may be more broadly effective than pharmacological mTOR inhibition with rapalogs, which primarily affects the S6 branch. These results indicate that polycystic kidneys are exquisitely sensitive to minor reductions in nutrient supply or energy status. This study suggests that a mild decrease in food intake represents a potential therapeutic intervention to slow disease progression in ADPKD patients.

Urinary MCP1 and Microalbumin increase prior to onset of Azotemia in mice with polycystic kidney disease.

Urinary biomarkers may offer a more sensitive and less invasive means to monitor kidney disease than traditional blood chemistry biomarkers such as creatinine. CD1(pcy/pcy) (pcy) mice have a slowly progressive disease phenotype that resembles human autosomal dominant polycystic kidney disease with renal cyst formation and inflammation. Previous reports suggest that dietary protein restriction may slow disease progression in mice and humans with polycystic kidney disease. Accordingly, we fed pcy mice either a standard chow (22.5% protein) or a protein-restricted (11.5% soy-based protein) diet from weaning until 34 wk of age. Every 6 wk we measured markers of kidney disease, including serum creatinine, BUN, and serum albumin as well as urinary monocyte chemoattractant protein 1 (MCP1), microalbumin, and specific gravity. Progression of kidney disease was equivalent for both diet groups despite dietary protein restriction. Urinary biomarkers proved useful for early detection of disease, in that urinary microalbumin was elevated as early as 22 wk of age and urinary MCP1 was increased by 28 wk of age, whereas increases in serum creatinine and BUN were detected later (at 34 wk of age) in both diet groups. Thus, urinary microalbumin and MCP1 analyses provided earlier, noninvasive indicators for detection of kidney disease and disease progression in pcy mice than did serum creatinine and BUN.

Renal cyclooxygenase and lipoxygenase products are altered in polycystic kidneys and by dietary soy protein and fish oil treatment in the Han:SPRD-Cy rat.

SCOPE: Dietary fish oil (FO) and soy protein (SP) are two interventions that slow disease progression in the Han:SPRD-Cy rat model of polycystic kidney disease (PKD). Inhibition of cyclooxygenase (COX)-derived eicosanoids also reduces disease progression, but the role of lipoxygenase (LOX) products in this disease is not known. METHODS AND RESULTS: Since dietary FO and SP have been shown to alter eicosanoid formation via differing mechanisms, Han:SPRD-Cy rats were given diets containing either casein protein (CP) or SP, and soy oil (SO) or FO. Analysis of eicosanoids revealed that renal COX products were higher and LOX products were lower in diseased kidneys. SP feeding resulted in lower COX products, activity and COX1 protein and higher LOX products in the diseased kidneys in parallel with reduced renal cyst growth and fibrosis. By comparison, FO reduced both COX and LOX products produced from n-6 fatty acids and increased 3-series prostanoids in both normal and diseased cortex and medulla, but these differences did not parallel effects on disease. CONCLUSION: Renal COX-derived eicosanoids are elevated and LOX products are reduced in this model of kidney disease. The effects of dietary SP, but not FO, on renal eicosanoids parallel the effects on disease.

Evidence for a role of proteins, lipids, and phytochemicals in the prevention of polycystic kidney disease progression and severity.

Polycystic kidney disease (PKD) is a heritable disease characterized by renal cysts and is a leading cause of end-stage renal disease. Dietary intervention offers a potentially efficacious, cost-effective, and safe therapeutic option for PKD. The aim of this article was to review studies investigating the effect of dietary components on PKD and potential mechanisms of action. Low-protein diets are commonly recommended for PKD patients, but inconsistent findings in human and animal PKD studies suggest that the type rather the amount of protein may be of greater importance. Dietary soy protein has been shown to have renal protective effects in various animal models of PKD. Other than dietary proteins, studies investigating the role of the amount and type of dietary lipids on PKD progression are increasing. The omega-3 polyunsaturated fatty acids can alter multiple steps in PKD pathogenesis. Phytoestrogens and phytochemicals are other dietary compounds shown to attenuate cyst pathogenesis in animal studies. A better understanding of the role of nutrition in PKD can contribute to the development of dietary recommendations and diet-based therapies to reduce PKD progression and severity.

Dietary soy protein benefit in experimental kidney disease is preserved after isoflavone depletion of diet.

Soy diet ameliorates renal injury in the Han:SPRD-cy rat. The relative roles of protein, isoflavones and changes in polyunsaturated fatty acid (PUFA) status are not determined. We fed male Han:SPRD-cy heterozygotes casein (C), high isoflavone soy protein (HIS), alcohol-extracted low isoflavone soy protein (LIS) or mixed soy protein diet (MIS). LIS and MIS were associated with a small decrease in animal weight compared with HIS or C. Soy diets preserved normal renal function and reduced relative renal weight (10.9-14.6 g/kg, cf. 23.6, P < 0.001), scores for cystic change (0.168-0.239, cf. 0.386, P < 0.05), fibrosis (0.013-0.015, cf. 0.032, P < 0.05), tissue oxidized LDL content (0.012-0.021, cf. 0.048, P < 0.05), inflammation (8.5-12.9, cf. 31.2, P < 0.05) and epithelial cell proliferation (6.5-13.8, cf. 26.3, P < 0.05). In post hoc testing, LIS produced a greater reduction in relative renal weight, cystic change and epithelial proliferation, whereas HIS produced a significantly greater reduction in oxidized-LDL. Soy diets were associated with increased hepatic content of 18C PUFA (P < 0.001). LIS and HIS diets were associated with a small increase in body fat content (P < 0.001). Alcohol-extracted soy protein retains its major protective effects in this model with subtle differences attributable to isoflavones.

Effects of dietary conjugated linoleic acid in advanced experimental polycystic kidney disease.

BACKGROUND/AIMS: Several dietary interventions, including those involving conjugated linoleic acid (CLA), slow progression of polycystic kidney disease (PKD) when initiated in the early stages of disease in Han:SPRD-cy rats. However, in humans, kidney disease is often undetected until extensive renal injury has developed. The objective of this study therefore was to determine whether initiating dietary CLA intervention in advanced PKD would slow disease progression. METHODS: Adult male Han:SPRD-cy rats with advanced kidney disease were fed diets with or without 1% CLA for 16 weeks. Disease progression was assessed by serum urea, proteinuria, and creatinine clearance, and morphological and immunohistochemical measurements for pathologic change. RESULTS: Renal injury was lower in the PKD rats given CLA compared to those given the control diet as indicated by a reduction in inflammation (42% less), fibrosis (28% less), oxidative damage (30% less) and proliferating cells (35% less). Diet had no effect on body, kidney, or liver weight, serum urea, serum creatinine, creatinine clearance, proteinuria, or cyst volume. CONCLUSIONS: Late dietary intervention with CLA reduced some disease-associated pathologies, but did not alter renal function in adult Han:SPRD-cy rats. The long-term anti-inflammatory, antioxidant, and antiproliferative benefits of CLA in advanced kidney disease remain to be determined.

Late dietary intervention limits benefits of soy protein or flax oil in experimental polycystic kidney disease.

BACKGROUND/AIMS: Dietary soy protein and flax oil retard kidney disease progression when initiated in the early stages of disease in several experimental models, including the Han:SPRD-cy rat. However, individuals with kidney disease often do not become aware of their condition until injury to the kidney is extensive. The objective of this study was to determine whether initiating these interventions in established disease would alter further progression of renal injury. METHODS: Two-month-old adult male Han:SPRD-cy rats were given either a flax oil diet (7% flax oil), a soy protein diet (20% soy protein) or a control diet (7% corn oil, 20% casein) for 4 months. Renal disease progression was assessed by examining morphological, immunohistochemical and biochemical parameters. RESULTS: Compared to controls, there was 21-24% less staining of proliferating cells, 21-24% less oxidative damage and 13-15% less renal inflammation in kidneys from rats given dietary soy protein and flax oil. Renal cystic growth and fibrosis and serum creatinine levels were not altered by these dietary treatments. CONCLUSIONS: Late intervention with dietary soy protein and flax oil reduces some disease-associated pathologies in established renal disease in Han:SPRD-cy rats. The potential benefits of the antioxidant and anti-inflammatory effects on ultimate renal disease outcome in the long term remains to be determined.

Effect of dietary protein restriction on the progression of kidney disease: long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study.

BACKGROUND: The long-term effect of a low-protein diet on the progression of chronic kidney disease is unknown. We evaluated effects of protein restriction on kidney failure and all-cause mortality during extended follow-up of the Modification of Diet in Renal Disease Study. METHODS: Study A was a randomized controlled trial from 1989 to 1993 of 585 patients with predominantly nondiabetic kidney disease and a moderate decrease in glomerular filtration rate (25 to 55 mL/min/1.73 m(2) [0.42 to 0.92 mL/s/1.73 m(2)]) assigned to a low- versus usual-protein diet (0.58 versus 1.3 g/kg/d). We used registries to ascertain the development of kidney failure (initiation of dialysis therapy or transplantation) or a composite of kidney failure and all-cause mortality through December 31, 2000. We used Cox regression models and intention-to-treat principles to compute hazard ratios for the low- versus usual-protein diet, adjusted for baseline glomerular filtration rate and other factors previously associated with the rate of decrease in glomerular filtration rate. We estimated hazard ratios for the entire follow-up period and then, in time-dependent analyses, separately for 2 consecutive 6-year periods of follow-up. RESULTS: Kidney failure and the composite outcome occurred in 327 (56%) and 380 patients (65%), respectively. After adjustment for baseline factors, hazard ratios were 0.89 (95% confidence interval [CI], 0.71 to 1.12) and 0.88 (95% CI, 0.71 to 1.08), respectively. Adjusted hazard ratios for both outcomes were lower during the first 6 years (0.68; 95% CI, 0.51 to 0.93 and 0.66; 95% CI, 0.50 to 0.87, respectively) than afterward (1.27; 95% CI, 0.90 to 1.80 and 1.29; 95% CI, 0.94 to 1.78; interaction P = 0.008 and 0.002, respectively). Limitations include lack of data for dietary intake and clinical conditions after conclusion of the trial. CONCLUSION: The efficacy of a 2- to 3-year intervention of dietary protein restriction on progression of nondiabetic kidney disease remains inconclusive. Future studies should include a longer duration of intervention and follow-up.

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.

Dietary protein restriction and the progression of chronic renal disease: what have all of the results of the MDRD study shown? Modification of Diet in Renal Disease Study group.

The Modification of Diet in Renal Disease (MDRD) Study was the largest randomized clinical trial to test the hypothesis that protein restriction slows the progression of chronic renal disease. However, the primary results published in 1994 were not conclusive with regard to the efficacy of this intervention. Many physicians interpreted the failure of the MDRD Study to demonstrate a beneficial effect of protein restriction over a 2- to 3-yr period as proving that this therapy does not slow disease progression. The authors believe that this viewpoint is incorrect, and is the result of misinterpretation of inconclusive evidence as evidence in favor of the null hypothesis. Since then, numerous secondary analyses of the MDRD Study have been undertaken to clarify the effect of protein restriction on the rate of decline in GFR, urine protein excretion, and onset of end-stage renal disease. This review describes some of the principles of secondary analyses of randomized clinical trials, presents the results of these analyses from the MDRD Study, and compares them with results from other randomized clinical trials. Although these secondary results cannot be regarded as definitive, the authors conclude that the balance of evidence is more consistent with the hypothesis of a beneficial effect of protein restriction than with the contrary hypothesis of no beneficial effect. Until additional data become available, physicians must continue to make recommendations in the absence of conclusive results. The authors suggest that physicians incorporate the results of these secondary analyses into their interpretation of the findings of the MDRD Study.

Effect of dietary soy protein and genistein on disease progression in mice with polycystic kidney disease.

The effects of feeding a soy protein isolate or genistein, an isoflavonoid present in soy protein, on cyst development were examined in the DBA/2FG-pcy (pcy) mouse, an accepted animal model of polycystic kidney disease, before the appearance of clinical symptoms. In study 1, 60-day-old male pcy mice were evenly divided into two groups and fed semipurified diets, based on casein or a soy protein isolate (15 g protein/100 g diet) for 90 days. In study 2, the animals were fed a casein-based diet (25 g casein/100 g diet) with or without genistein (0.05 g/100 g diet) for 60 days. In study 1, total kidney weight and kidney weight relative to body weight were significantly reduced (by 24% to 25%) in the animals fed the soy protein-based diet, relative to the casein-fed group, as was kidney water content (by 38%). In addition, mean cyst volume, as measured by morphometry, were lower (by 25%) in kidneys from the soy protein-fed group. No differences were found between these two groups with respect to final body weight, plasma creatinine, and protein content; however, plasma urea values were significantly lower in the soy protein-fed animals. Genistein supplementation of a casein-based diet in study 2 did not reduce the renal enlargement and cyst development associated with progression of polycystic kidney disease. These results suggest that soy protein is effective in retarding cyst development in the pcy mouse and that this beneficial effect may be unrelated to its genistein content.

Amelioration of polycystic kidney disease by modification of dietary protein intake in the rat.

Polycystic kidney disease is the most common potentially lethal single- gene inherited disease in man. There is no specific therapy. Previous studies in the pcy mouse model of polycystic kidney disease have shown amelioration of cystic change by reduction in dietary protein intake. The Han:SPRD-cy rat is a model of autosomal dominant polycystic kidney disease that closely resembles human disease in its histology and clinical course. We compared the morphometric assessment of cystic change and standard laboratory measures of renal function in heterozygous Han: SPRD-cy rats that received isocaloric diets containing either 8% or 20% protein as casein. This level of dietary protein restriction was associated with a significant reduction of mean body weight in the 8% protein group (358 g) compared with 20% protein (490 g; P = 0.027). Mean renal volume, adjusted for the difference in body weight, was significantly lower in the 8% protein group (6.2 mL/kg) compared with the 20% protein group (11.6 mL/kg; P = 0.016). The major component in this reduction was a reduction in total cyst volume to a mean 0.47 mL in the 8% protein group from 2.68 mL in the 20% protein group (P < 0.0001). All 8% protein diet animals survived to 6 months of age, but 3 of 11 20% protein diet animals died between 5 and 6 months of age. Mean serum creatinine and urea levels were significantly lower in the 8% protein group (118 mmol/L and 15.6 mmol/L) compared with the 20% protein group (272 mmol/L, P = 0.0033, and 81.5 mmol/L, P = 0.0002, respectively). Dietary protein restriction is a potent method for modifying the course of polycystic kidney disease in the Han:SPRD-cy/+ rat. These findings emphasize the potential for diet to alter the physiology of the renal tubulointerstitium.

Diet and disease alter phosphoinositide composition and metabolism in murine polycystic kidneys.

Because diet can affect the progression of polycystic kidney disease (PKD) and because renal phosphoinositide metabolism is altered in mice with PKD, the effects of diet and disease on phosphoinositide composition and metabolism were examined in kidneys of mice with PKD. The phosphatidylinositol-phosphate (PIP) to phosphatidylinositol (PI) molar ratio was higher (0.034 +/- 0.003 vs. 0.023 +/- 0.001, P < 0.01) and the PI-bisphosphate (PIP2) to PIP molar ratio was lower (0.70 +/- 0.08 vs. 1.19 +/- 0.10, P < 0.05) in kidneys of mice with PKD [DBA/2FG-pcy (pcy)] compared with normal controls (DBA/2J). When initial incorporation (reflecting synthesis) of [3H]inositol into renal phosphoinositides in mice injected with [3H]inositol was measured, the [3H]PIP to [3H]PI ratio was higher in the diseased kidneys compared with normal kidneys (0.016 +/- 0.001 vs. 0.013 +/- 0.001, P < 0.05), whereas the [3H]PIP2 to [3H]PIP ratio was not significantly different. In a study using dietary manipulations that alter the progression of PKD in pcy mice (6 vs. 25% casein and sunflower seed oil vs. fish oil in a 2 x 2 design), animals were injected intraperitoneally with [3H]inositol 5 h before killing. In these animals, the [3H]PIP2 to [3H]PIP ratio seemed to be the best indicator of disease progression. In addition, kidney weight (as altered by diet) was positively correlated (r = 0.62, P = 0.02) with the level of the [3H]PI-3-P isomer relative to total [3H]PIP in the kidney. These results demonstrate that alterations in dietary protein level and lipid composition can modulate renal phosphoinositide signal transduction in mice with PKD.