Effects of dietary protein on uranyl-nitrate-induced acute renal failure

The effects of dietary protein both before and after uranyl-nitrate-induced acute renal failure were investigated. Male Sprague-Dawley rats were maintained on high-protein (60%), normal-protein (20%), low-protein (5%) and no-protein diets for 8 days prior to intravenous administration of uranyl nitrate (10 mg/kg). Immediately following uranyl nitrate injection, some rats on normal-protein diets were switched to no-protein, low-protein or high-protein diets, while some of the rats on high-protein diets were switched to low-protein diets. Serum and urine creatinine levels and urine volumes were monitored for 2 weeks following uranyl nitrate treatment. Rats conditioned to no-protein and low-protein diets exhibited significantly lower mortalities than rats maintained on normal-protein diets. Rats maintained on high protein diets exhibited better renal function than rats maintained on lower dietary protein regimes, but these rats had mortality rates similar to rats maintained on normal-protein diets. Shifting the rats on normal-protein diets to low- or no-protein diets immediately after uranyl nitrate administration did not improve their renal function or survival rates. However, shifting the rats on normal-protein diets to high-protein diets immediately following uranyl nitrate injection resulted in significantly higher mortalities (93%) than in rats maintained on either normal or high dietary protein throughout the experimental period. Finally, shifting rats on high dietary protein to low-protein diets immediately following uranyl nitrate administration resulted in both improved renal function and survival compared with rats shifted from normal to restricted dietary protein (5%) immediately following uranyl nitrate injection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of dietary protein restriction on the progression of renal failure: a prospective randomized trial

One hundred twenty-eight patients with different renal diseasesand chronic renal failure, stratified according to the underlyingdisease, were enrolled in a randomized controlled trial to investigatethe effects on the rate of decline of renal function of twodiets, a controlled protein diet (CPD) of 1 g protein/kg idealbody-weight (i.b.w.)/day, and a low-protein diet (LPD) of 0.6g protein/kg i.b.w./day, given for 27.1±21.8 months.Dietary compliance was assessed by a dietary questionnaire,dietary interviews and measurement of 24-h urinary urea excretion.At the end of 6 months, actual mean protein intake was higherthan expected (1.06±0.25 g/kg i.b.w./day) in CPD patients,and (0.80±0.21 g/kg i.b.w./day) in LPD patients: valueswere similar at 12 and 18 months after the time of enrollment.The end-point, defined as halving of creatinine clearance, wasreached in 40% of patients on CPD, and in 28.6% of those onLPD (P= 0.038 by comparative life-table analysis). Multivariateregression analysis confirmed that CPD was associated with ahigher risk of progression than LPD, and that two additionalparameters (creatinine clearance at the time of randomizationand average proteinuria during the follow-up) were significantindependent risk factors, even more important than protein intake.     

Effect of dietary protein restriction and influence of proteinuria on progression of type 2 diabetic renal failure

PURPOSE: This study investigated the effect of dietary protein restriction on disease progression and how it is influenced by proteinuria in patients with type 2 diabetic nephropathy(DN) and renal failure. METHODS: One hundred and six type 2 DN patients whose baseline creatinine clearance(Ccr) values were 29 +/- 12 ml/min/1.73 m2 were maintained on a diet containing 0.66 +/- 0.05 g/kg/day of protein. They were classified into 3 groups according to mean dietary protein intake(DPI) estimated from urinary urea nitrogen excretion during the follow-up period of 23 +/- 14 months(I, < 0.7 g/kg/day; II, 0.7-0.89 g/kg/day; III, > or = 0.9 g/kg/day). Furthermore, they were divided into 3 subgroups according to mean urinary protein excretion(UP) during the follow-up period (a, > or = 5.0 g/day; b, 2.0-4.99 g/day; c, < 2.0 g/day). Their rates of decline of Ccr(D-Ccr) and the changes in UP were examined. RESULTS: There were no significant differences in D-Ccr among Group Ia, IIa, and IIIa(1.1 +/- 0.6, 1.5 +/- 0.7, 1.2 +/- 0.6 ml/min/1.73 m2/month), among Group Ib, IIb, and IIIb(0.6 +/- 0.3, 0.7 +/- 0.4, 0.8 +/- 0.4 ml/min/1.73 m2/month), and also among Group Ic, IIc, and IIIc(0.1 +/- 0.3, 0.2 +/- 0.2, 0.2 +/- 0.6 ml/min/1.73 m2/month). On the other hand, significant differences were revealed in D-Ccr among Group Ia, Ib, and Ic, among Group IIa, IIb, and IIc, and among Group IIIa, IIIb, and IIIc. There were no significant differences in final UP and minimum UP during follow-up among 3 groups of different DPI levels in patients with 5.0 g/day < or = baseline UP(n = 49) and in patients with 2.0 < or = baseline UP < 5.0 g/day(n = 37). However, significant correlations were demonstrated between D-Ccr and the relative changes in UP between baseline and minimum during the follow-up period in both patients(r = 0.49, 0.48, p < 0.001, p < 0.01). CONCLUSIONS: Irrespective of the level of dietary protein restriction, proteinuria has a great influence on disease progression, and the reduction in UP correlates with retardation of renal function loss in patients with type 2 DN and renal failure.     

Effects of nephron reduction and dietary protein content on renal ammoniagenesis in the rat.

Urinary ammonium excretion, in vitro ammoniagenesis and the activities of renal cortical phosphate-dependent glutaminase (PDG) and glutamic dehydrogenase (GLDH) were measured in rats with a reduced renal mass. Following contralateral nephrectomy, ammonium excretion per nephron, ammonia production and the activities of PDG and GLDH were all increased significantly in remnant kidneys of rats fed high protein diets. In rats fed low protein diets, although PDG activity increased, GLDH activity and ammonia production and excretion did not increase in remnant kidneys following contralateral nephrectomy. Ammonia production and excretion were greater in rats fed high than low protein diets, a difference that was corrected by the addition of mineral acid to the diets of low protein-fed rats. Acid supplementation to the low protein group did not result in enhanced ammonia production or GLDH activity following a reduction in renal mass. The data indicate that the increased rate of ammoniagenesis which occurs following nephron reduction is markedly influenced by dietary protein content. A lack of enhanced GLDH activity may underlie the lack of increased ammonia production of low protein-fed rats following nephron reduction.     

Effects of dietary protein intake on muscle protein synthesis and degradation in rats with gentamicin-induced acute renal failure

In the study presented here, the muscle protein synthesis and degradation in gentamicin-induced acute renal failure were examined in rats fed a low (7%)-, normal (22%)-, and high (35%)-isocaloric protein diet. Male Sprague-Dawley rats were fed equivalent amounts of these diets for 10 days and then received daily subcutaneous injections of either 1 mL of sterile isotonic saline or 100 mg/kg of gentamicin for 7 consecutive days. The rats were sacrificed the following day, and epitrochlearis muscles were obtained for measurement of protein turnover. The serum creatinine in each of the gentamicin-treated groups were significantly higher than that in the saline-treated controls but were no different from each other. Muscle protein synthesis (calculated from the incorporation of radiolabeled (U-14C) phenylalanine) was slightly but not significantly decreased in gentamicin-treated rats as compared with that of the corresponding saline controls in each of the dietary groups. Net protein degradation (the rate of tyrosine release into media) in the 7 and 22% gentamicin-treated groups was similar to that in the corresponding saline controls. In contrast, net protein degradation was significantly greater in the 35% gentamicin group of rats when compared with that in the 7 and 22% gentamicin groups and its own control. In the 7 and 22% saline- and gentamicin-treated protein groups, there was a reduction in net protein degradation in response to insulin. In contrast, the net protein degradation continued to remain significantly elevated in the 35% gentamicin-treated group, despite addition of insulin, when compared with that in the 7 and 22% gentamicin groups and its own control.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of oral adsorbent AST-120 in rats with chronic renal failure--mechanism of progression of renal failure by dietary protein]

Progression of renal insufficiency was evaluated in partially nephrectomized Sprague-Dawley rats at the age of 10 weeks, fed on the low (6%), usual (20%), and high (36%) protein diet (group 6C, 20C, and 36C). Effects of oral adsorbent AST-120 on these experimental uremic models were also examined (group 6A, 20A, 36A). All the rats underwent paired feeding, and survived during the experimental period of 3 weeks. GFR (inulin clearance) and RPF (para-amino hippurate clearance), as well as Ccr was measured before the sacrifice. Initial serum creatinine and Ccr were 1.7 mg/dl and 0.27 ml/min. The rats of group 36C showed progressive elevation of serum creatinine level and decrease in Ccr. At the end of the study, GFR was significantly lower in group 36C than in group 6C and 20C (0.19, 0.68, 0.87 ml/min respectively). Significant elevation of filtration fraction in group 36C suggested that the decrease in GFR mainly resulted from low RPF. Even in group 36C, no glomerular sclerosis was histologically demonstrated in the remnant kidney, and the mean planar area of the remnant glomeruli was significantly small, which might reflect low RPF. Tubulo-interstitial changes like dilatation of the urinary space and tubular epithelial flattening were prominent in group 36C. Beneficial effect of AST-120 was obvious in high protein diet groups. GFR and RPF were rather well preserved in group 36A (0.36 and 0.78 ml/min) with normal filtration fraction. Tubulo-interstitial damage was evidently mild in group 36A. These data suggested the presence of some humoral factors, which can be adsorbed by AST-120 in gastrointestinal tract, and responsible for the deterioration of renal function and tubulo-interstitial damage induced by high protein diet in the uremic condition. Besides hyperfiltration and glomerular hypertrophy, such humoral factors as suggested in this study may contribute to the progression of chronic renal failure to some extent.     

The estimation of dietary protein intake in chronic renal failure

Forty-five adult clinic patients with chronic renal failure each supplied a 4-day weighed dietary record, a 24-h urine collection, and a nocturnal spot urine sample. Total nitrogen (N) losses derived from the urines were corrected for proteinuria and non-urea nitrogen excretion. Individual estimates of N intake were compared by correlation and assessing the level of agreement. Daily urea N excretion derived from the spot sample correlated well with the 24-h collection P less than 0.001, but the degree of agreement was poor, mean difference being +1.62 g with 95% limits of +5.7 to -2.47 g. The correlation between the spot-sample-derived N loss and dietary N intake was poor, r = 0.42; P less than 0.05. For 12 patients taking a low-protein diet, N intake correlated well with 24-h urine derived N losses, P less than 0.001, mean difference being +0.59 g, 95% limits +2.39 to -1.21 g. The correlation and agreement was less satisfactory for the subjects who had not received dietary instruction, due largely to individual variation in day-to-day protein intake. Use of spot urine samples is too inaccurate for routine clinical practice. Single 24-h urine derived estimates of N intake are only of value for assessing patients previously prescribed a low-protein intake.     

The suppressive effects of dietary protein restriction on the progression of renal impairment in OLETF rats

Background The suppressive effect of dietary protein restriction on the progression of diabetic nephropathy remains controversial. We investigated the effects of protein and energy restrictions on both albuminuria and morphology using diabetic-prone Otsuka Long-Evans Tokushima fatty (OLETF) rats. Methods In this study, male OLETF rats were divided into two groups according to their energy intake. They were then further divided into three subgroups based on their amount of dietary protein, which ranged between 10% and 30% of their total intake. Urinary albumin excretion (UAE) was used as a marker of renal impairment, and body weight fasting (F) and postchallenge (P), blood glucose (BG) levels, and systolic blood pressure (SBP) were all measured during various experimental periods up to 28 weeks of age. Results The OLETF rats fed with the high-calorie diet started to gain weight at 12 weeks, and their FBG and PBG were elevated at 22 weeks, while SBP did not differ between the two groups. In addition, UAE increased significantly in the rats fed with the high-calorie diet. However, the increasing rates of UAE with age were higher in the rats with a higher protein diet within the same energy groups. UAE correlated well with the amounts of dietary energy and protein at 16 and 28 weeks of age, while it correlated with both the FBG and PBG at only 28 weeks of age. A linear regression analysis, using the data obtained at 28 weeks, showed that the amount of protein intake and FBG explained 63.4% and 23.9% of the variation in UAE, respectively. Histological studies revealed that protein and energy restriction markedly reduced the sclerotic changes of the glomeruli. Conclusion Dietary protein restriction starting very early in the life of OLETF rats, in combination with energy restriction, clearly suppressed UAE and the typical morphological changes that otherwise occurred at around 16 weeks of age. This method also seemed to be more effective than energy restriction alone in slowing down any increase in UAE. The influence of BG levels on UAE was lower at an early age, while it became an increasingly important factor at later ages in the experimental rat model.     

Slowing the progression of renal failure

In recent years several multicentric prospective studies have demonstrated the efficacy of some therapeutic measures to slow the progression of renal diseases. Inhibition of renin-angiotensin system (RAS) both by ACE inhibitors (ACEI) and angiotensin II receptor antagonists (ARA) is probably the strongest therapeutic alternative: The antiproteinuric effect of these drugs is an excellent surrogate marker and a predictor of the beneficial influences on the progression of renal failure. The type of renal disease, an inadequate control of blood pressure, and the presence of obesity may counteract the beneficial influences of RAS inhibition, whereas early treatment of all patients with significant proteinuria before the appearance of renal insufficiency and combined therapy with an ACEI and an ARA may augment it. Dietary protein restriction is a classic treatment of chronic renal insufficiency whose effectiveness has been validated by multicentric studies. However, a poor compliance of the patient and the risk of malnutrition with very strict protein restriction could limit the benefits of this treatment. Treatment of hyperlipidemia, prevention of obesity, avoidance of smoking, and regular physical exercise are interventions whose therapeutic potential is progressively recognized, particularly in type 2 diabetic nephropathy. Early correction of anemia may contribute to the slowing of renal disease progression. Although further studies are required, the accumulated evidence and the likelihood of additive beneficial effect of these therapeutic measures advise their combined implementation in patients with chronic renal diseases.     

Effects of reduced renal function and dietary protein on muscle protein synthesis

We describe a rat model of renal failure that separates catabolic and anabolic states from each other. Muscle protein synthesis was compared during the anabolic period between sham (S) operated and renal failure (RF) rats that were fed different levels of dietary protein. Male rats weighing between 60 and 80 g first had a partial left nephrectomy and then were given a tryptophan deficient diet from four to six days to induce weight loss. On the second day of the diet either a renal decapsulation (S rats) or a simple right nephrectomy (RF rats) was done to enhance the catabolic response in both and to induce renal failure in the RF rats. Following the period of feeding the deficient diet, both groups were fed a nutritionally complete 14, 17, 20 or 30% protein diet for three to five days. This induced a brisk anabolic response as measured by weight gain. Differences in body weight between the S and RF rats after three to five days on the repletion diet generally was less than 10%. The rats then were fasted overnight, fed a standard meal and muscle protein synthesis (Sm%) was measured two hours post-feeding. Sm% was estimated from the incorporation of 3H phenylalanine (PHE) into muscle 10 minutes following the i.v. injection of 3HPHE (25 muCi/100 g body wt) with carrier PHE to flood all the precursor amino acid pools. Weight loss in the catabolic phase was greater and the net weight gain for the two phases was less in the RF group. Overall, renal failure resulted in a significant reduction in Sm% (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Extrarenal clearance of oxalate increases with progression of renal failure in the rat.

Oxalic acid is an end product of metabolism, and no significant degradation of oxalate occurs in mammals. The sole route of oxalate excretion is believed to be via the kidney. The extrarenal clearance of oxalate in control rats (N = 16) and in 5/6 nephrectomized rats (N = 25) with renal insufficiency was investigated. [14C]oxalic acid, approximately 2 microCi/day, was infused sc by a mini osmotic pump over 4 days. Excretion of 14C was measured in urine, in feces, and in expired CO2. The 14C content of kidney, heart, liver, muscle and bone was also determined at the time the animals were killed. Plasma oxalate was determined by an enzymatic method and by an isotopic dilution procedure. Creatinine clearance in the controls was 1.82 +/- 0.1 mL/min (mean +/- SE) compared with 0.31 +/- 0.04 mL/min (P < 0.0005) in the nephrectomized rats. Plasma oxalate was 5.6 +/- 0.6 mumol/L in controls and 27.0 +/- 3.9 (mean +/- SE; N = 24) in nephrectomized animals (P < 0.0005). The total 14C recovered in urine, feces, and CO2 combined was similar in both groups. The 14C excreted in the feces over the 4-day period was 27.8 +/- 1.5% (of the 14C recovered) in rats with renal failure and 6.5 +/- 0.5% in controls (P < 0.0005). Percent fecal 14C excretion in nephrectomized rats was inversely correlated with creatinine clearance (r = 0.80; P < 0.0001) and directly correlated with plasma oxalate (r = 0.66; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Nutritional status, protein intake and progression of renal failure in children

Nutritional status and progression of renal failure in 35 children (22 males and 13 females; mean age: 8.85±4.13 years) with moderate renal failure were followed for 2 years. All children were on an “ad libidum” diet. Protein intake was determined by a minimum of two dietary diaries kept by the parents and the appearance of urea nitrogen. The children were divided into two groups according to their protein intake: Group 1 – sub-optimal intake (46% of the children, all with significantly lower protein intake); Group 2 – adequate protein intake. The mean protein intake (expressed as a percentage of the WHO recommendations) based on the diets of the patients was 94.79% in Group 1 children and 175.45% in Group 2 children (p<0.05). All patients had a calorie intake of at least 80% of the WHO recommendations. Nutritional status was determined by anthropometric measurements expressed as a standard deviation score. There was no significant anthropometric or biochemical evidence of malnutrition in children with moderate chronic renal failure (CRF). The glomerular filtration rate (GFR) in patients with a sub-optimal intake of protein was −5.41±2.87 ml/2 year versus−9.53±8.61 ml/2 year in the normal protein intake group. There was no correlation between protein intake, nutritional status and progression of renal failure in children with moderate CRF within the 2-year study period.     

Phosphate depletion arrests progression of chronic renal failure independent of protein intake

Following 5/6 nephrectomy, 18 rats were fed a normal diet. After 30 days, serum creatinine (SCr), urine protein excretion and urine volume were increased compared to pre-nephrectomy (0.27 +/- 0.1 vs. 1.62 +/- 0.6 mg/deciliter, 17.0 +/- 10.3 vs. 257.6 +/- 13.4 mg/24 hr, and 16.6 +/- 4.4 vs. 39.2 +/- 11.7 ml/24 hr, respectively, all P less than 0.001). At this time, when serum phosphorus (SPi) and serum calcium (SCa2+) were normal, the rats were separated into two groups, matched and paired by body weight and SCr, and housed separately in metabolic cages. Animals of one group ingested a normal diet supplemented with dihydroxyaluminum aminoacetate (DHAAA), 15 g%, to induce phosphate depletion (PD). The second group ingested the same diet supplemented with 7.5% glycine and was the phosphate replete (PR) group. All rats were pair fed throughout the study to maintain similar caloric, protein, carbohydrate, vitamin, and mineral intakes. At six weeks after separation, SPi was decreased in PD vs. PR group (2.85 +/- 0.8 vs. 6.71 +/- 1.2 mg/deciliter, P less than 0.001) and SCa2+ was increased in the PD group (11.98 +/- 0.7 vs. 10.03 +/- 0.7 mg/deciliter, P less than 0.001). Urine urea nitrogen, body weight, and sodium, potassium and solute excretion were similar between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of furosemide diuresis on mercuric chloride-induced acute renal failure in the rat

In previous studies in rats given mercuric chloride (HgCl2), administration of furosemide has been found to either attenuate, exacerbate, or not affect the severity of the acute renal failure (ARF) otherwise expected to obtain. In the current study in rats given large doses of furosemide and in which urinary fluid losses were replaced by intravenous infusions of saline, administration of HgCl2 induced less severe ARF than that induced in rats not given furosemide and saline infusions. In rats not given furosemide, a diuresis induced by continuous reinfusion of urine also conferred protection against the nephrotoxic effect of HgCl2. These findings suggest that in rats given HgCl2: diuresis per se is the critical determinant of any salutary effect of furosemide and the protective effect of diuresis does not depend on renal elimination of mercury.     

Effect of ibopamine on the progression of chronic renal failure

Persistent changes in the slope of the reciprocal of serum creatinine concentration against time after medical intervention are likely to reflect the influence of therapy on progression of chronic renal failure. This observation allowed us to demonstrate the ability of ibopamine, a new orally active dopamine-related drug, to improve renal function or at least to slow its deterioration in 20 patients studied over a period of 6 months. We also noted that the therapeutic response to the drug varied considerably according to the nature of the underlying nephropathy, with maximal benefit being observed in nonglomerular diseases.     

Lipids in the progression of chronic renal failure.

Lipid disturbances have been linked to the progression of chronic renal disease. We examined 52 patients with a creatinine clearance (CCr) of 38.5 +/- 7.9 ml/min due to various nephropathies, on free diet. Bimonthly, over a 12-month period, we assessed: serum creatinine (Cr); CCr; daily urinary urea excretion; urinary protein excretion per unit of residual renal function (UProt/CCr); total, HDL, VLDL and LDL cholesterol; triglycerides; Apo A, Apo B. Chronic renal failure was progressive in 22 patients with a slope of 1/Cr-0.00358 +/- 0.00247, stable in 30 with a slope of 0.00420 +/- 0.00285. Lipid parameters did not differ significantly between the two groups but for the lower Apo A and Apo A/Apo B ratio values in the progressive group. Overall slope inversely correlated with basal CCr; in the progressive patients the slope correlated with the percentage variation of UProt/CCr and only partially with the altered Apo profile.     

Dyslipidemia and the progression of renal disease in chronic renal failure patients

Dyslipidemia is a common complication of progressive kidney disease and contributes to the high cardiovascular morbidity and mortality of chronic kidney disease (CKD) patients. Recent evidence also suggests a role for dyslipidemia in the development and progression of renal disease. Experimental studies have demonstrated that lipids may induce glomerular and tubulointerstitial injury, and that lipid-lowering treatments ameliorate renal injury. Various lipid abnormalities have been associated with the development and progression of renal disease in diabetic and nondiabetic patients. Population-based studies and studies of diabetic patients have reported associations of various lipid abnormalities with the development of renal disease. In patients with CKD, lipid abnormalities have also been associated with renal disease progression. Post hoc analyses of some large clinical trials on patients with vascular disease, diabetes, or dyslipidemia, and a meta-analysis of small, prospective, controlled studies on patients with CKD (diabetics and nondiabetics) suggest that statins may slow the progression of kidney disease. It is unclear whether the beneficial renal effects of statins are due to the reduction of serum cholesterol levels and/or their pleiotropic effects. There is also evidence for synergistic renoprotective effects between statins and renin-angiotensin system inhibitors. According to the results of post hoc analysis of several studies, treatment with fibrates does not seem to confer renoprotection, but evidence is scarce. In summary, there is growing evidence that lipid abnormalities may be a risk factor for renal disease, and that statins appear to confer a renoprotective effect.