Contribution of dietary oxalate to urinary oxalate excretion.

BACKGROUND: The amount of oxalate excreted in urine has a significant impact on calcium oxalate supersaturation and stone formation. Dietary oxalate is believed to make only a minor (10 to 20%) contribution to the amount of oxalate excreted in urine, but the validity of the experimental observations that support this conclusion can be questioned. An understanding of the actual contribution of dietary oxalate to urinary oxalate excretion is important, as it is potentially modifiable. METHODS: We varied the amount of dietary oxalate consumed by a group of adult individuals using formula diets and controlled, solid-food diets with a known oxalate content, determined by a recently developed analytical procedure. Controlled solid-food diets were consumed containing 10, 50, and 250 mg of oxalate/2500 kcal, as well as formula diets containing 0 and 180 mg oxalate/2500 kcal. Changes in the content of oxalate and other ions were assessed in 24-hour urine collections. RESULTS: Urinary oxalate excretion increased as dietary oxalate intake increased. With oxalate-containing diets, the mean contribution of dietary oxalate to urinary oxalate excretion ranged from 24.4 +/- 15.5% on the 10 mg/2500 kcal/day diet to 41.5 +/- 9.1% on the 250 mg/2500 kcal/day diet, much higher than previously estimated. When the calcium content of a diet containing 250 mg of oxalate was reduced from 1002 mg to 391 mg, urinary oxalate excretion increased by a mean of 28.2 +/- 4.8%, and the mean dietary contribution increased to 52.6 +/- 8.6%. CONCLUSIONS: These results suggest that dietary oxalate makes a much greater contribution to urinary oxalate excretion than previously recognized, that dietary calcium influences the bioavailability of ingested oxalate, and that the absorption of dietary oxalate may be an important factor in calcium oxalate stone formation.

Genetic and dietary influences on urinary oxalate excretion.

Several genes contribute to the development of calcium oxalate nephrolithiasis as it is a polygenic disease. To explore the influence of genetic factors on oxalate excretion we have examined the distribution of oxalate excretions in 101 normal individuals who consumed self-selected diets. The distribution was apparently trimodal, consistent with the existence of three classes of oxalate excretors reflecting two allelic genes determining high and low oxalate excretion occurring with frequencies of 0.32 and 0.68 respectively. The pattern of inheritance in eight families was compatible with the expression of a pair of codominant alleles. A comparison of the distribution of excretory classes among the 101 normal individuals with that of 101 calcium oxalate stone formers suggests that high oxalate excretion may be associated with a 4-fold increased risk of stone disease and intermediate excretion with a 1.6-fold increase. Control of dietary factors influencing oxalate excretion apparently improved the discrimination between excretory classes in 17 individuals but the intra-individual variability in oxalate excretion was not reduced in four of nine individuals in whom this parameter was evaluated. More stringent dietary control than that applied in this study may be required before more extensive genotyping of individuals is attempted.

Molecular basis of inherited renal lithiasis.

Idiopathic calcium oxalate stone formation results from an interaction between genetic and environmental factors. Clearly identifiable risk factors for the disease that have a significant genetic influence are the excretions of calcium, oxalate and citrate. Candidate genes that may be responsible for these effects have been proposed. With the large-scale sequencing of the human genome and the identification of genetic polymorphisms, it is only a matter of time before these genes and the sequence differences within them that are associated with susceptibility to the disease are conclusively identified.

Genes in idiopathic calcium oxalate stone disease.

An examination of the urinary excretions of 101 normal subjects indicated that the major genetic influence on calcium excretion is a codominant pair of alleles giving rise to three phenotypes, low, intermediate and high (hypercalciuric) excretors. This inference was based on variance, Hardy-Weinberg and segregation analyses. Similar independent gene pairs also appear to influence oxalate and citrate excretion, A 3-locus Hardy-Weinberg table using estimates of gene frequencies derived from the study of normals suggests that only 3 or 4 leading genes are involved in oxalate stone disease. Strong candidate genes identified from molecular and physiological studies cannot be proposed at present, but it is assumed that they influence the transport of these ions in either the intestine, kidney or both organs. The identification of the genes involved should be facilitated by the reduction of dietary influences on urinary excretions through the use of formula diets.

Glucagon increases urinary oxalate excretion in the guinea pig.

Factors that influence hepatic oxalate synthesis are poorly defined. Hormones are important regulators of hepatic metabolism and could potentially be involved. The effects of hyperglucagonemia were examined in guinea pigs injected with either saline or pharmacological doses of glucagon for 4 days. Glucagon treatment increased mean urinary oxalate excretion by 77% in male and 34% in female animals. The levels of hepatic peroxisomal enzymes involved in oxalate synthesis declined with glucagon treatment, but experiments with isolated peroxisomes indicated that oxalate synthesis in vitro was unaffected. Glucagon decreased hepatic alanine levels by 66%, lactate by 69%, and pyruvate by 73%, but glycolate and glyoxylate levels were unaffected. This decrease in alanine would substantially lower the activity of alanine-to-glyoxylate aminotransferase activity in vivo and make more glyoxylate available for oxalate synthesis. The decrease in lactate and pyruvate concentrations would stimulate the enzymatic conversion of glyoxylate to oxalate and may account for the increase in oxalate synthesis without an increase in glyoxylate concentration. These results demonstrate that hepatic oxalate synthesis is influenced by metabolic changes and that alterations in hepatic alanine, lactate, and pyruvate concentrations may be important elements.

Dietary oxalate and its intestinal absorption.

Dietary oxalate is currently believed to make only a minor contribution (< 20%) to urinary oxalate excretion. A recent prospective study of stone disease suggested that dietary oxalate may be a significant risk factor. This observation led us to re-evaluate the contribution of dietary oxalate to urinary oxalate excretion. Previous studies have been hampered by inaccurate food composition tables for oxalate and inadequate methods for studying intestinal oxalate absorption. This evidence as well as factors that modify oxalate absorption are reviewed. New approaches to measure food oxalate and intestinal oxalate absorption have been examined. Capillary electrophoresis appears to be well suited for the analysis of the oxalate content of food. Two individuals consumed an oxalate-free formula diet for 7 days. This diet decreased urinary oxalate excretion by an average of 67% (18.6 mg per 24 hours) compared to oxalate excretion on self-selected diets. The absence of detectable oxalate in feces by day 6 of the diet suggested that the intestinal absorption was minimal. However, an effect of the formula diet on endogenous oxalate synthesis cannot be excluded. Restoring oxalate to the formula diet increased urinary oxalate excretion and illustrates that this experimental protocol may be well-suited for studying oxalate absorption and factors that modify it. Our results suggest that the intestinal absorption of dietary oxalate makes a substantial contribution to urinary oxalate excretion and that this absorption can be modified by decreasing oxalate intake or increasing the intakes of calcium, magnesium, and fiber.

Relationship of protein intake to urinary oxalate and glycolate excretion.

The relationship of protein intake to urinary oxalate and glycolate excretion was examined in a large cohort (N = 101) of normal individuals on self-selected diets and in 11 individuals on controlled protein diets. On self-selected diets no correlation was detected between protein intake and urinary oxalate or glycolate excretion. A moderate but significant correlation (r = 0.45; P < 0.001) of oxalate with urea excretion was observed in males but not females, suggesting that there may be a link between urea and oxalate synthesis in males. On controlled protein diets mean oxalate excretion in females on days 7 to 10 of a high protein diet (1.8 g/kg body wt) was 20% higher than on a low protein diet (0.6 g/kg body wt; P = 0.02), but there was no difference in males. Glycolate excretion was significantly higher (P < 0.001) on the high protein diet than on the low protein diet in both sexes. Only a weak precursor-product relationship was observed between glycolate and oxalate. A gender effect was apparent on both self-selected and control diets with females excreting more oxalate and glycolate relative to creatinine than males. A pronounced inter- and intra-individual variability in the excretion of oxalate was observed, even on controlled diets. This suggests that genetic factors and physiological changes such as hormonal fluctuations may contribute more to the variability in oxalate excretion than the dietary intake of protein.

The taurine and hypotaurine content of human semen.

Taurine and hypotaurine levels were measured in human sperm and seminal fluid. Sperm taurine ranged from 17 nmol/mg DNA to 348 nmol/mg DNA, and hypotaurine from 0 nmol/mg DNA to 251 nmol/mg DNA. Seminal fluid contained 319 mumol/L to 1590 mumol/L of taurine, but no detectable hypotaurine. The coefficient of variation in multiple ejaculates from a single man for these components ranged from 12% for hypotaurine to 24% for seminal fluid taurine, indicating a relative constancy in their concentrations. Sperm hypotaurine content was significantly correlated with sperm morphology, sperm relative forward progression, the percentage of motile sperm, and the total number of sperm in the ejaculate. By contrast, sperm taurine content was negatively correlated with these parameters. The mean hypotaurine content of sperm from 8 fertile men was 149 +/- 92 nmol/mg DNA, four times higher than that of sperm from 9 infertile men, which was 35 +/- 19 nmol/mg DNA (P = 0.011). In contrast, the mean sperm taurine content of the fertile men was lower than that of the infertile men (83 +/- 33 nmol/mg DNA versus 168 +/- 119 nmol/mg DNA, respectively; P = 0.07). Seminal fluid taurine concentrations, however, were similar for both groups. Hypotaurine, an antioxidant, may play an important role in protecting sperm from reactive oxygen species. Higher concentrations of taurine in the sperm of infertile men suggest that accelerated oxidation of hypotaurine to taurine may accompany the observed decline in other sperm parameters.

Allan-Herndon syndrome. I. Clinical studies.

A large family with X-linked mental retardation, originally reported in 1944 by Allan, Herndon, and Dudley, has been reinvestigated. Twenty-nine males have been affected in seven generations. Clinical features include severe mental retardation, dysarthria, ataxia, athetoid movements, muscle hypoplasia, and spastic paraplegia with hyperreflexia, clonus, and Babinski reflexes. The facies appear elongated with normal head circumference, bitemporal narrowing, and large, simple ears. Contractures develop at both small and large joint. Statural growth is normal and macroorchidism does not occur. Longevity is not impaired. High-resolution chromosomes, serum creatine kinase, and amino acids are normal. This condition, termed the Allan-Herndon syndrome, appears distinct from other X-linked disorders having mental retardation, muscle hypoplasia, and spastic paraplegia.

Allan-Herndon syndrome. II. Linkage to DNA markers in Xq21.

The original family with the Allan-Herndon type of X-linked mental retardation has been investigated for linkage by using DNA probes spanning the length of the X chromosome. Available for study, over 3 generations, were 13 affected males, three obligate carriers, and three normal sons of the obligate carriers. Initial disease-to-marker analysis suggested linkage to three markers (DXYS2 [7b], DXS250 [GMGX22], and DXS3 [p19-2]) located in Xq21. All three exhibited the same maximum lod score of 2.3 at a maximum theta of .05. Multipoint analysis using LINKMAP and a set of four DNA markers (DXYS1-DXYS2-DXS3-DXS94) gave a multipoint lod score of 3.58 for a location of the Allan-Herndon syndrome near locus DXYS1 (pDP34). Therefore, our data indicate that the gene for the Allan-Herndon syndrome is likely located in Xq21.

Supplemental taurine in diabetic rats: effects on plasma glucose and triglycerides.

The present study has indicated that significant shifts in plasma, urinary, and tissue taurine and in non-taurine dialyzable amines occur in the STZ-induced diabetic rat, especially in the kidney. Taurine administration at relatively low dosage ameliorated only kidney taurine concentration. Anticipated alterations in plasma glucose and creatinine were observed but neither of these changes was affected by taurine administration. Similarly, urinary output of creatinine, glucose, and NAG increased significantly among diabetic rats, but none of these were detectably influenced by taurine. Increases in plasma triglycerides observed in STZ-induced diabetes appear to be attenuated by taurine administration, and although cholesterol concentrations were lower in taurine-treated rats, the differences were not statistically significant. These findings should encourage further studies of these effects in rats as a useful model for several complications of human diabetes including atherosclerosis, retinopathy, and nephropathy.

Microtransferrinuria and microalbuminuria. II. In the rat.

We studied albumin and transferrin excretion in the normal and diabetic rat: (1) The rat secretes small concentrations of albumin and transferrin in the urine. (2) The secretion depends on the strain and was highest in the Kyoto spontaneously hypertensive rat. (3) The secretion of these two proteins in the rat is quite dependent on age and sex. The level increases dramatically with age. The secretion is much higher in the male compared to the female. This difference is observed after puberty. The changes in transferrin relative to those in albumin are much higher. (4) In streptozotocin-induced diabetes, the concentration of albumin and transferrin expressed as milligrams per liter decreases; however, the output/24 h or per gram creatinine is increased with a greater increase in transferrin output relative to that of albumin. The similarities and differences between excretion of these two proteins in the human and the rat as well as their importance are discussed.

Antiepileptic drugs and plasma and platelet taurine in epilepsy.

Although older studies have reported elevated plasma taurine concentrations, more recent studies have reported the same or lower plasma taurine concentrations in epileptic than in control subjects. The present study determined plasma taurine concentrations in 114 epileptic and 99 control subjects. In addition, taurine concentrations in platelets, known to be rich in taurine, were assayed. Serum drug concentrations were also determined to detect possible effects on plasma or platelet taurine concentrations. The plasma and platelet taurine concentrations of epileptic subjects were significantly more variable than corresponding control data. Mean platelet taurine was significantly lower for epileptic patients than for controls. Analysis of variance (ANOVA) on data from epileptic patients revealed no significant association between platelet or plasma taurine concentrations and drug or seizure groups. However, t tests revealed a higher mean plasma taurine concentration for patients with primary generalized seizure disorders (group II) receiving valproate (VPA) (p less than 0.004). Utilizing serum drug concentrations, a significant negative correlation (rxy = -0.552) was found between log-converted platelet taurine and serum VPA concentrations (p less than 0.01) among group II patients. Results were interpreted as having potential value for less empiric drug use and as indicating that cellular rather than plasma studies will prove more informative in gaining an understanding of the idiopathic epilepsies.

Urinary excretion of taurine in epilepsy.

Evidence that taurine (2-aminoethanesulfonic acid) is related to the epilepsies is supported by work with both experimental animals and humans. It may function as a neurotransmitter or modulator of neurotransmission. Investigators using an automated amino acid analyzer reported lower mean urinary taurine excretion among epileptics. However, Rao et al. reported higher taurine excretion among epileptics using an older method. Analyses of the same epileptic and control urines by both methods coupled with paper and molecular size chromatography indicate that substances in addition to taurine are co-eluted with taurine using the older method, yielding spuriously high values. The resolution of this disparity is important because the urinary excretion of taurine may reflect primarily the influence of taurine transport alleles which may be polygenic components in the idiopathic epilepsies.

Plasma and urinary taurine in epilepsy.

A previous study showed that significantly less taurine is excreted in the urine by epileptics than by control subjects. The difference is ascribed to genetic variation in taurine transport governed by a pair of codominant polymorphic alleles. The present study of plasma taurine concentrations and urinary taurine output confirms previous findings among epileptics and provides evidence that some anticonvulsant medications may affect taurine transport. The posited codominant alleles represent the first single-locus component in the polygenic complexes creating susceptibility to seizures and epitomizes the small additive effects classically attributed to such genes.

Possible association of MN locus haplotypes with essential hypertension.

Five multigenerational kindreds with familial hypertension were typed for human leukocyte antigen (HLA) and blood group antigens to investigate genetic factors that influence variability in blood pressure. Pedigree analysis revealed that children of matings in which both parents were hypertensive had a significantly greater risk of hypertension than children of matings in which one parent or neither parent was hypertensive. Blood types N and MN were abnormally distributed among hypertensive as compared with normotensive members of white but not black families. The distribution of ABO and Rh types was not significantly different between hypertensive and normotensive siblings. When all possible pairings of siblings were examined for HLA haplotype sharing, abnormal distributions were observed among hypertensive sib pairs whereas the expected mendelian segregation was observed among hypertensive-normotensive sib pairs and normotensive-normotensive sib pairs. These results suggest the genetic factors controlling variation in blood pressure may include loci in the region of the MN locus on chromosome 4 and, possibly, the major histocompatibility complex on chromosome 6.