The early phase of experimental acute renal failure

Summary Experiments were designed to determine whether leakage of substances across the tubular epithelium, which are impermeant in the normal kidney, falsifies the measurement of glomerular filtration rate in acute renal failure. Permeability to those substances most commonly used for filtration rate determination, polyfructosan, inulin and ferrocyanide, was estimated by measuring their recoveries following perfusion through various nephron segments in haeme pigment, ischaemic and nephrotoxic models of actue renal failure. Late proximal recovery of¹⁴C ferrocyanide was only marginally decreased compared to controls, by a maximum of 6%. Distal recovery of polyfructosan,¹⁴C and³H inulin were depressed somewhat more, by a maximum of 11%. Urinary recovery of¹⁴C inulin was reduced by only 15% in kidneys showing severely restricted renal function. It is concluded that tubular leakage is not a feature of significance in the early phase of moderate acute renal failure, that ferrocyanide and inulin are reliable markers for the determination of nephron filtration rate and water reabsorption, and that the reduction in whole kidney inulin or polyfructosan clearance reflects primarily a reduction in glomerular filtration rate.     

Long-Term Safety and Efficacy of Prebiotic Enriched Infant Formula—A Randomized Controlled Trial

The present study aims to evaluate the effects of an infant formula supplemented with a mixture of prebiotic short and long chain inulin-type oligosaccharides on health outcomes, safety and tolerance, as well as on fecal microbiota composition during the first year of life. In a prospective, multicenter, randomized, double-blind study, n = 160 healthy term infants under 4 months of age were randomized to receive either an infant formula enriched with 0.8 g/dL of Orafti^®Synergy1 or an unsupplemented control formula until the age of 12 months. Growth, fever (>38 °C) and infections were regularly followed up by a pediatrician. Digestive symptoms, stool consistency as well as crying and sleeping patterns were recorded during one week each study month. Fecal microbiota and immunological biomarkers were determined from a subgroup of infants after 2, 6 and 12 months of life. The intention to treat (ITT) population consisted of n = 149 infants. Both formulae were well tolerated. Mean duration of infections was significantly lower in the prebiotic fed infants (p < 0.05). The prebiotic group showed higher Bifidobacterium counts at month 6 (p = 0.006), and higher proportions of Bifidobacterium in relation to total bacteria at month 2 and 6 (p = 0.042 and p = 0.013, respectively). Stools of infants receiving the prebiotic formula were softer (p < 0.05). Orafti^®Synergy1 tended to beneficially impact total daily amount of crying (p = 0.0594). Supplementation with inulin-type prebiotic oligosaccharides during the first year of life beneficially modulates the infant gut microbiota towards higher Bifidobacterium levels at the first 6 months of life, and is associated with reduced duration of infections.     

Evaluation of digestive tolerance of a soluble corn fibre

Background: To assess consumers’ acceptance of a new fibre, it is essential to evaluate its digestive tolerance after ingestion. We aimed to determine the tolerance of increasing dosages of Promitor? Soluble Gluco Fibre (SGF; Tate&Lyle, Hoffman Estates, IL, USA) up to 70 g fibre per day using a validated gastrointestinal composite score. Methods: A composite score of gastrointestinal tolerance integrating gastrointestinal symptoms, stool frequency and consistency was applied. To statistically validate this composite score, the gastrointestinal tolerance of inulin (10 g versus 20 g containing, respectively, 9 g versus 18 g of fibre) was assessed in 18 healthy volunteers in a randomised double‐blind placebo‐controlled cross‐over study. Second, in a double‐blind placebo‐controlled cross‐over study with 20 healthy volunteers, the gastrointestinal tolerance of SGF in both acute and ‘spread over the day’ conditions of consumption was assessed. Results: By contrast to 10 g, 20 g of inulin demonstrated a significant difference in composite score compared to placebo [P < 0.001, difference = 7.6; 95% confidence interval (CI) = 3.8–11.3]. These values were considered as reference during the second study. In acute conditions, 40 g of SGF fibre was the highest (threshold) dose tested that indicates the digestive tolerance criteria (difference from placebo on the composite score <7.6 and upper limit of the 95% CI <11.3); this is twice the amount tolerated for inulin. In ‘spread over the day’ conditions, 65 g of SGF fibre was the threshold dose (P < 0.001, difference = 6.5; 95% CI = 3.4–9.5). Conclusions: The results of the present study demonstrate that 40 g of SGF fibre, when consumed as a single dose, and 65 g of SGF fibre, when consumed in multiple‐doses, across the day are well‐tolerated by healthy volunteers.     

Creatinine and urea clearances compared to inulin clearance in preterm and mature babies

Simultaneous clearances of inulin, urea and creatinine were compared in 41 babies of 26-40 weeks gestation on 122 occasions during the first month of life. In each case creatinine was measured by a reaction rate method, and in thirty specimens it was also measured after adsorption onto resin. Urea clearance averaged only 62% of inulin clearance (P less than 0.001), and was a poor marker of glomerular filtration. Creatinine clearance measured by resin adsorption equalled inulin clearance, but the assay is manual and not suitable for routine clinical use. Creatinine clearance measured by reaction rate analysis underestimated inulin clearance by a quarter (P less than 0.01) because this automated method overestimated plasma creatinine by an average of 22 mumol/l. Urinary creatinine excretion was 72 +/- 17 nmol/kg per min (mean +/- S.D.) during the first week of life, and 66 +/- 13 nmol/kg per min in weeks two to four, and was not influenced by gestation or body size. Using these values, glomerular filtration rate, urine flow, and the urinary excretion rates of substances may be estimated from measurements made on plasma and untimed urines. Although these estimates are imprecise, with 9% confidence limits of 62-161%, they are useful in clinical practice because they avoid the need to make accurately timed collections of urine.     

Effect of cinoxacin on cellular metabolism and p-aminohippurate transport in kidney cortical slices in terms of its nephrotoxic action

Cinoxacin is a drug which, at very high doses, causes renal damage only in rats. This study compared the in vitro effects of cinoxacin and nalidixic acid on cellular metabolism and p-aminohippurate (PAH) transport in renal cortical slices. Cinoxacin had no effect on Na+ transport, ATP content, oxygen consumption, inulin space and tissue water content, in rat renal cortical slices in vitro, while nalidixic acid affected most of the parameters tested. PAH uptake by slices from rats pre-treated with a nephrotoxic dose of cinoxacin was decreased. This renal damage appeared to be due to physical trauma resulting from deposition of cinoxacin crystals in the urinary tract.     

Effect of lactobacilli, bifidobacteria and inulin on the formation of aberrant crypt foci in rats

Summary Background Our studies were aimed at investigating the effect of lactic acid producing bacteria (LAB) or inulin, a natural source of non-digestible oligosaccharides derived from chicory, on the induction by carcinogens of aberrant crypt foci (ACF) in the colon, which are considered to be early precursor lesions of neoplasia. Methods Strains of Bifidobacterium longum, Lactobacillus casei and Lactobacillus acidophilus were administered to rats fed a purified high starch diet, under a variety of treatment protocols including daily gavage, via the drinking water and in the diet. The rats were treated with methyl-N-nitrosourea, 1,2-dimethylhydrazine, or azoxymethane (AOM) to induce ACF. Results In general, no consistent significant changes in ACF numbers were detected in these experiments. In one study, the basal diet of the rats was changed to one containing a higher level of fat (corn oil). Under these conditions, a significant decrease in AOM-induced colonic ACF was seen in rats given L. acidophilus or inulin. In a concurrent group of animals fed a low fat diet, no significant decrease in ACF was observed. Conclusions The results indicate that the type of diet fed can influence the detection of protective effects of LAB and oligosaccharides and that against the background of a diet with a level of fat typical of a Western diet, evidence for a protective effect of L. acidophilus and inulin towards colon cancer was obtained Received: 26 July 2001, Accepted: 26 November 2001     

Evaluation of safety of inulin and oligofructose as dietary fiber

In the United States, most individuals consume far less dietary fiber than the daily value (DV) set at 25 g. The average daily consumption for inulin and oligofructose is estimated to be between 1 and 4 g in this country, with a higher intake of 3 to 11 g seen in Europe. Inulin and oligofructose are soluble, fermentable dietary fibers, of low net caloric value having many of the possible health benefits attributed to fiber. Such fiber consists of poly- and oligomers of fructose joined by beta(2-->1) fructosyl-fructose bonds. This class of fiber has been studied in a series of standard toxicological test systems. The studies have demonstrated that inulin-type fructans, when administered in the diet at high levels, do not result in mortality, morbidity, target organ toxicity, reproductive or developmental toxicity, or carcinogenicity. Several in vitro studies have also shown the absence of mutagenic or genotoxic potential. The only basis for limiting use of such fiber in the human diet relates to gastrointestinal tolerance. A series of clinical studies has been reported which shows that up to 20 g/day of inulin and/or oligofructose is well tolerated. As foods marketed in the United States bear labels stating both the quantity per serving size and the corresponding percentage of the daily value (% DV) of fiber, consumers can make appropriate choices and decisions about daily consumption without exceeding individual tolerance.     

Differential effects of the degree of renal damage on p-aminohippuric acid and inulin clearances in rats

Kidney disease is generally thought to affect all segments of a nephron equally. Bricker and co-workers first proposed this as the Intact Nephron hypothesis in 1971, and evidence to date has usually supported this hypothesis. However, most supporting studies have involved severe renal failure, which may not be suitable to differentiate effects on functional sites or to test the hypothesis. The work included here examines the effects of limited renal failure on two separate functions of the nephron: glomerular filtration, as measured by inulin clearance and proximal tubular organic anion secretory function, as measured by p-aminohippuric acid (PAH) clearance. Renal failure was induced in rats by intravenous administration of uranyl nitrate, a nephrotoxin. Doses used were 0.3, 1.0, and 3.0 mg/kg rat body weight. Five days later, rats were given an intravenous infusion of PAH and inulin. Renal clearance of each compound was calculated. Results obtained in these experiments show that, at the lowest uranyl nitrate dose, PAH clearance was significantly decreased but inulin clearance was not. The ratio of CL_PAH/CL_IN was decreased from 2.55 in control rats to 1.21 in rats given the low dose of nephrotoxin. At higher uranyl nitrate doses, both clearance rates were significantly decreased and the ratio of CL_PAH/CL_IN remained close to 1.0. These results indicate that the active transport functions of the nephron can be differentiated from passive transport functions. Caution should be exercised in extrapolating renal disease changes in active renal secretion to changes in passive renal elimination and the reverse.This work was supported in part by NIH grants GM 26691 and GM 36633. C.A.G. was supported in part by a fellowship from the American Foundation for Pharmaceutical Education.     

Prebiotic inulin-type fructans: nutritional benefits beyond dietary fibre source

Summary   For several years, there has been an increasing awareness of the fundamental role that the complex bacterial ecosystem plays in our health. Inulin and oligofructose are prebiotic dietary fibres naturally present in the chicory root. They escape metabolism in the small intestine, and their selective fermentation by the human colonic microflora leads to a shift in the composition of the indigenous bacterial ecosystem, in favour of health-promoting bifidobacteria. In addition to their dietary fibre effects on improved bowel regularity, several physiological advantages are linked to their specific pattern of fermentation in the colon, including improved mineral absorption, enhanced natural host defences and colonic protection, improved gut health, and beneficial influence on appetite regulation. The aim of the present review was to highlight the nutritional benefits of inulin-type fructans, focusing on key physiological functions.     

Growth characteristics and measurement of confluency of rabbit primary proximal tubule kidney cells grown on millicell-HA membrane filters

Summary We have characterized primary rabbit kidney proximal tubule cells grown on Millipore cellulose filters (Millicell-HA) in which the cells are exposed to culture medium on both the apical and basolateral sides. Cells reach confluency 12 to 14 d after plating. Methods are described for removal of the cells from the filters and measurement of the integrity of the monolayer at confluency by exclusion of [¹⁴C]inulin.