Urinary Excretion Of Lactate Research Articles

Insulin-resistance in glycogen storage disease type Ia: linking carbohydrates and mitochondria?

Glycogen storage disease type I (GSDI) is an inborn error of carbohydrate metabolism caused by mutations of either the G6PC gene (GSDIa) or the SLC37A4 gene (GSDIb). GSDIa patients are at higher risk of developing insulin-resistance (IR). Mitochondrial dysfunction has been implicated in the development of IR. Mitochondrial dysfunction can demonstrate abnormalities in plama acylcarnitines (ACs) and urine organic acids (UOA). The aim of the study was to investigate the presence of mitochondrial impairment in GSDI patients and its possible connection with IR. Fourteen GSDIa, seven GSDIb patients, 28 and 14 age and sex-matched controls, were enrolled. Plasma ACs, UOA, and surrogate markers of IR (HOMA-IR, QUICKI, ISI, VAI) were measured. GSDIa patients showed higher short-chain ACs and long-chain ACs levels and increased urinary excretion of lactate, pyruvate, 2-ketoglutarate, 3-methylglutaconate, adipate, suberate, aconitate, ethylmalonate, fumarate, malate, sebacate, 4-octenedioate, 3OH-suberate, and 3-methylglutarate than controls (p < 0.05). GSDIb patients showed higher C0 and C4 levels and increased urinary excretion of lactate, 3-methylglutarate and suberate than controls (p < 0.05). In GSDIa patients C18 levels correlated with insulin serum levels, HOMA-IR, QUICKI, and ISI; long-chain ACs levels correlated with cholesterol, triglycerides, ALT serum levels, and VAI. Increased plasma ACs and abnormal UOA profile suggest mitochondrial impairment in GSDIa. Correlation data suggest a possible connection between mitochondrial impairment and IR. We hypothesized that mitochondrial overload might generate by-products potentially affecting the insulin signaling pathway, leading to IR. On the basis of the available data, the possible pathomechanism for IR in GSDIa is proposed.

Impact of maternal obesity on the metabolic profiles of pregnant women and their offspring at birth

Obesity is currently an increasing public health problem. The intra-uterine environment plays a critical role in foetal development. The objective of this study is to investigate the association of obesity with modifications in the metabolic profiles of pregnant women, and their new-borns. Based on the PELAGIE cohort (Brittany, France), a sample of 321 pregnant women was divided into three groups according to their body mass index (BMI) (normal, over-weight and obese). Nuclear magnetic resonance-based metabolomics analyses were performed on maternal urine and cord-blood samples. Partial least squares regression-discriminant analysis (PLS-DA), polytomous and logistic regressions were used to differentiate the metabolic profiles of the three BMI groups after adjusting for potential confounders. Specific profiles were observed for the overweight and obese women (BMI > 25) compared to the normal-weight women: they had a decrease in urinary hippurate excretion associated with a decrease in phenylalanine and an increase in creatinine. We also showed an increase in the urinary excretion of lactate, citrate, acetate, creatine, and lysine only in obese women (BMI > 30) compared to the normal-weight women. The PLS-DA modelling did not reveal any significant difference between the cord-blood metabolic profiles of newborns according to maternal BMI—although infants born of obese women had a higher birth weight and a lower Apgar score. Our results confirmed the potential link between obesity and gut microbiota disruption (changes in urinary acids), as well as energy and amino-acid metabolism but did not reveal any disruption among newborns.

Localization of members of MCT monocarboxylate transporter family Slc16 in the kidney and regulation during metabolic acidosis

The monocarboxylate transporter family (MCT) comprises 14 members with distinct transport properties and tissue distribution. The kidney expresses several members of the MCT family, but only little is known about their exact distribution and function. Here, we investigated selected members of the MCT family in the mouse kidney. MCT1, MCT2, MCT7, and MCT8 localized to basolateral membranes of the epithelial cells lining the nephron. MCT1 and MCT8 were detected in proximal tubule cells whereas MCT7 and MCT2 were located in the thick ascending limb and the distal tubule. CD147, a beta-subunit of MCT1 and MCT4, showed partially overlapping expression with MCT1 and MCT2. However, CD147 was also found in intercalated cells. We also detected SMCT1 and SMCT2, two Na(+)-dependent monocarboxylate cotransporters, on the luminal membrane of type A intercalated cells. Moreover, mice were given an acid load for 2 and 7 days. Acidotic animals showed a marked but transient increase in urinary lactate excretion. During acidosis, a downregulation of MCT1, MCT8, and SMCT2 was observed at the mRNA level, whereas MCT7 and SMCT1 showed increased mRNA abundance. Only MCT7 showed lower protein abundance whereas all other transporters remained unchanged. In summary, we describe for the first time the localization of various MCT transporters in mammalian kidney and demonstrate that metabolic acidosis induces a transient increase in urinary lactate excretion paralleled by lower MCT7 protein expression.

Urinary D-Lactate Excretion in Infants Receiving Lactobacillus johnsonii with Formula

Background/Aims: Supplementation with certain probiotics can improve gut microbial flora and immune function but should not have adverse effects. This study aimed to assess the risk of D-lactate accumulation and subsequent metabolic acidosis in infants fed on formula containing Lactobacillus johnsonii (La1®). Methods: In the framework of a double-blind, randomized controlled trial enrolling 71 infants aged 4–5 months, morning urine samples were collected before and 4 weeks after being fed formulas with or without La1 (1 × 10⁸/g powder) or being breastfed. Urinary D- and L-lactate concentrations were assayed by enzymatic, fluorimetric methods and excretion was normalized per mol creatinine. Results: At baseline, no significant differences in urinary D-/L-lactate excretion among the formula-fed and breastfed groups were found. After 4 weeks, D-lactate excretion did not differ between the two formula groups, but was higher in both formula groups than in breastfed infants. In all infants receiving La1, urinary D-lactate concentrations remained within the concentration ranges of age-matched healthy infants which had been determined in an earlier study using the same analytical method. Urinary L-lactate also did not vary over time or among groups. Conclusions: Supplementation of La1 to formula did not affect urinary lactate excretion and there is no evidence of an increased risk of lactic acidosis.

C/ebpδ Null Mouse as a Model for the Double Knock-out of slc5a8 and slc5a12 in Kidney

slc5a8 and slc5a12 represent the high affinity and low affinity Na+/lactate co-transporters, respectively, in the kidney. Here we show that these transporters are expressed in the apical membrane of the proximal tubular cells in mouse kidney, indicating that these transporters are likely to mediate the first step in the renal reabsorption of lactate. Interestingly, the renal expression of both transporters is almost completely ablated in mice homozygous for the deletion of the transcription factor c/ebpdelta. This effect is tissue-specific since the expression of the transporters is not affected in non-renal tissues. The functional role of C/EBPdelta in the expression of SLC5A8 and SLC5A12 is demonstrable in HEK293 cells in reporter assays using gene-specific promoters. The ablation of the transporters in the kidney is accompanied by a marked increase in urinary excretion of lactate as well as a decrease in blood levels of lactate in c/ebpdelta-/- mice. These data provide evidence for an obligatory role for slc5a8 and slc5a12 in the renal absorption of lactate. In addition, we show that urinary excretion of urate is significantly elevated in c/ebpdelta-/- mice even though the expression of URAT1, the transporter responsible for the apical membrane uptake of urate in renal proximal tubule, is not altered. These data provide in vivo evidence for the functional coupling between lactate reabsorption and urate reabsorption in the kidney. Thus, the fortuitous double knock-out of slc5a8 and slc5a12 in kidney in c/ebpdelta-/- mice reveals the physiologic role of these transporters in the renal handling of lactate and urate.

A neonate with macrosomia, cardiomyopathy and hepatomegaly born to an HIV-infected mother

Perinatal treatment with highly active antiretroviral drugs (HAART) is effective to prevent mother-to-childtransmission of HIV-1; however, adverse effects on the fetus may occur. We present a neonate with macrosomia, hypertrophic cardiomyopathy, and hepatomegaly, whose mother used HAART during pregnancy. The mother has been HIV infected since 1992. During her first pregnancy (1997) she used zidovudine and lamivudine; a healthy HIV-negative daughter was born. Good viral suppression and immune reconstitution was achieved with stavudine, didanosine and nelfinavir (Fig. 1). Severe lipodystrophy developed and from 1999 the viral load became detectable. In 2000 she was pregnant again; HAART was continued with a temporary switch in the 7th month, unsuccessful because of vomiting. Resistance testing showed mutations in the reverse transcriptase and protease gene leading to resistance to zidovudine and nelfinavir, respectively. At 40 weeks of gestation, decreased fetal movements and a non-reactive CTG necessitated an emergency caesarean section. An asphyctic girl was born. Macrosomia (birth weight 5290 g, >P97; length 57 cm, >P97; head circumference 37 cm, >P97) was present without dysmorphic signs. Physical examination revealed hepatomegaly and red skin lesions on the arms, back and armpits. A chest X-ray film demonstrated cardiomegaly, but no lung abnormalities. Echocardiography showed concentric hypertrophic cardiomyopathy. In the mother, normal values of glucose, HbA1c, insulin, and C-peptide excluded diabetes mellitus. Liver and kidney functions were normal and serology for syphilis, hepatitis A, B and C was negative. In the neonate, abnormal haematology, liver tests, clotting, and extreme hypoglycaemia were present (Table 1). Metabolic disorders were meticulously investigated in blood, urine, and CSF (Table 1). The plasma amino acid profile showed increased glutamine (1103 lmol/l) and decreased arginine levels (13 lmol/l) with a normal carnitine concentration (18.7 lmol/l) and high urinary lactate excretion. These biochemical abnormalities were ascribed to the coexistent asphyxia. Muscle biopsy did not show any biochemical or enzymatic abnormality compatible with a mitochondrial respiratory chain defect. Chromosomal karyotype was 46XX. All microbiological cultures of blood and secretions were negative. Serology and PCR tests excluded recent infection with Toxoplasma, enteroviruses, adenovirus, rubella, CMV and other herpes viruses. HIV-RNA was undetectable at day 5. Severe complications, including hypoglycaemia, intra-cerebral haemorrhages and seizures developed. The clinical condition worsened and the neonate died 7 days postnatally. At autopsy, the brain showed postnatally acquired ischaemic lesions and bilateral intraventricular haemorrhage. No microorganisms were found. The heart was enlarged with long-standing subendocardial ischaemia (weeks). No evidence was found for mitochondrial damage (intact cytochrome-c-oxidase components on histochemistry and electron microscopy). Hepatomegaly with extreme cholestasis compatible with long-standing drug-induced toxicity was found. There was subcutaneous fat necrosis in both armpits. A term infant with macrosomia, skin lesions, hepatomegaly and concentric hypertrophic cardiomegaly is described. These clinical findings could not be explained by asphyxia, chromosomal abnormality or any known M. H. Godfried Department of Internal Medicine, AMC, Amsterdam, The Netherlands

Urinary L-lactate excretion is increased in renal Fanconi syndrome.

Measurement of l-lactate in body fluids is an established clinical tool to identify disorders of cellular respiration. However, there is very little known about the clinical value of urinary lactate measurements. We investigated urinary lactate excretion in children with renal Fanconi syndrome. Freshly voided urine samples were obtained from children with Fanconi syndrome and controls both with and without renal disease. Urine lactate was estimated by conversion to pyruvate in the presence of lactate dehydrogenase and NAD. The NADH produced was measured photometrically. Urine lactate was factored for urine creatinine. Children with Fanconi syndrome had a significantly higher urine lactate/creatinine ratio [mean: 84 x 10(-2) mmol/mmol; 95% confidence interval (CI): 40.8-127.1 x 10(-2) mmol/mmol] than healthy controls (mean: 1.3 x 10(-2) mmol/mmol; CI: 1.1-1.5 x 10(-2) mmol/ mmol) and those with a variety of renal diseases (mean: 3.1 x 10(-2) mmol/mmol; CI: 1.8-4.5 x 10(-2) mmol/mmol). Urinary lactate is increased in Fanconi syndrome. The increase is likely to be due to reduced lactate co-transport in the proximal tubule. Urinary lactate/creatinine has clinical utility as a sensitive test of disordered proximal renal tubular function.

Hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome with evidence of mitochondrial dysfunction due to a novel SLC25A15 ( ORNT1) gene mutation in a Palestinian family

Hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome is caused by mutations in the SLC25A15 ( ORNT1) gene encoding the mitochondrial ornithine transporter, but the mechanism of pathogenesis of the encephalopathy, spastic paraparesis and hepatopathy remains undetermined. HHH syndrome was diagnosed in a 2-year-old Palestinian boy with developmental delay and seizures, and subsequently in his 13-year-old brother with developmental delay. Direct sequencing of the PCR products of SLC25A15 exon amplifications revealed that both brothers were homozygous for a novel 446G deletion in exon 3 as well as for a 760A>T (I254L) polymorphism in exon 5, which is downstream of a premature termination codon produced by the frameshift resulting from the 446G deletion. The index patient had elevated liver enzymes as well as hyperalaninemia, lactic acidemia with an elevated lactate to pyruvate ratio, and increased urinary excretion of lactate, glutarate and Krebs cycle intermediates. These findings are indicative of mitochondrial dysfunction and are in accordance with ultrastructural studies showing increased numbers of large and bizarre mitochondria in liver, muscle, leukocytes and fibroblasts of some HHH patients. Neurologic and hepatic manifestations are characteristic of some primary mitochondrial disorders. Secondary mitochondrial dysfunction may contribute to the pathogenesis of these same features in HHH syndrome.

Type I glycogen storage disease: favourable outcome on a strict management regimen avoiding increased lactate production during childhood and adolescence.

Our objective was to evaluate the long-term effects of dietary therapy of type I glycogen storage disease which avoids increased lactate production during childhood and adolescence. In order to suppress hepatic glucose and increased lactate production consistently day and night, the treatment regimen included nocturnal intragastric feeding of glucose polymer during childhood and adolescence. The aim was to keep the blood glucose concentration in the "high normal range" (4.3-5.5 mmol/l) and the lactate concentration in urine in the normal range (<0.06 mol/mol creatinine). The amounts of dietary carbohydrate required decreased in an age-related manner from 11.9+/-1.3 mg/kg body weight per min by day and 6.9+/-0.9 mg/kg body weight per min by night at 1 year of age to 5.2+/-1.0 and 2.9+/-1.2 mg/kg body weight per min, respectively, at the age of 16 years. In 15 infants, therapy started at 5.8+/-3.2 months of age and induced catch up growth over 1-2 years by which time the mean height SDS increased from -1.02+/-0.91 to -0.19+/-1.07. In the well controlled patients, further growth continued within that range. From 12 years of age, mean height SDS was in line with the respective mean SDS of mid-parental target height. The plasma lipid concentrations were markedly reduced, but were not brought into the normal range. So far, no adolescent showed liver adenoma or renal damage. Four patients with poor metabolic control due to poor compliance with treatment (frequently subnormal plasma glucose concentrations, severe hypoglycaemia, and increased urinary lactate excretion) showed retardation of growth and bone maturation. avoiding increased lactate production by keeping the blood glucose concentration permanently in the "high normal range" seems to be crucial for growth according to the genetic potential.

Urinary Lactate Excretion to Monitor the Efficacy of Treatment of Type I Glycogen Storage Disease

The purpose of this study was to investigate the usefulness of urinary lactate measurements to assess the adequacy of dietary treatment in patients with type I glycogen storage disease (GSD-I). We determined the correlation of urine and blood lactate concentrations in 21 GSD-I patients during 24-h admissions to the General Clinical Research Center (GCRC) during which hourly blood samples and aliquots of every void were obtained. In all but 1 patient, we found a good correlation between blood lactate concentrations and urinary lactate excretion. One patient did not excrete lactate in significant amounts despite elevated blood lactate concentrations. In 17 patients, the highest blood lactate concentrations occurred during the night. Markedly elevated nighttime average blood lactate concentrations above 3.5 mmol/l resulted in a urinary lactate concentration above the normal limit of 0.067 mmol/mmol creatinine in the first morning urine specimen. Mildly elevated nighttime blood lactate concentrations (between 2.2 and 3.5 mmol/l) led to urinary lactate concentrations that were either normal or moderately elevated. All patients with normal blood lactate concentrations during the night also had normal first morning urinary lactate concentrations. The degree of urinary lactate excretion in relation to blood lactate concentrations varied by individual. Urinary filter paper specimens, collected at home during the night and in the morning and mailed to the laboratory, were used to monitor the dietary compliance of 5 GSD-I patients at home over a period of 6 to 9 weeks prior to their GCRC admissions. These data suggested variable degrees of dietary control. In conclusion, the urinary lactate concentration is a useful parameter to monitor therapy of GSD-I patients at home. To be interpretable, the baseline urinary lactate concentration in relation to the blood lactate concentration has to be determined.

Measurement of the Urinary Lactate:Creatinine Ratio for the Early Identification of Newborn Infants at Risk for Hypoxic-Ischemic Encephalopathy

Because increased urinary lactate excretion can be detected by magnetic resonance spectroscopy in hypoxic newborn infants, a study was planned to learn whether the urinary lactate and creatinine levels, measured within hours after birth, are a specific and sensitive means of predicting hypoxic-ischemic encephalopathy (HIE). Forty consecutive neonates with perinatal asphyxia, all born at 36 weeks’ gestation or later, were studied. Urinary proton magnetic resonance spectroscopy was done to determine the lactate:creatinine ratio within 6 hours of birth and again at age 2 to 3 days. Fifty-eight normal infants served as a control group. Real-time ultrasonography was done at intervals up to 10 days after birth to detect increased echogenicity or encephalomalacia. Surviving infants were assessed neurodevelopmentally at age 12 months. HIE developed in 16 of the 40 asphyctic infants but none of the control group. These groups did not differ in birth weight or gestational age. Hyperechogenicity in the basal ganglia and thalamus, as well as diffuse brain edema, were frequent findings in infants who developed HIE. The mean urinary lactate:creatinine ratio within 6 hours of birth was 16.75 in those infants who later developed HIE, 88-fold higher than in asphyctic infants who did not follow this course, and 186 times higher than in normal infants. A ratio of 0.64 or higher was 94 percent sensitive and 100 percent specific in predicting HIE. The ratio tended to increase with the severity of encephalopathy, although not to a significant degree. When they were 2 to 3 days old, infants who developed HIE still had ratios 10 times higher than normal infants and nearly 5-fold higher than asphyctic infants who did not develop HIE. Ten of 16 children who developed HIE neonatally had an adverse outcome; 5 of them had severe neurodevelopmental impairment, and 5 died before age 4 months. Only one of these infants had a postdelivery lactate:creatinine ratio of <1.00, and all but one had a ratio of 3.12 or higher. These ratios were significantly higher than in infants who had a favorable outcome. Estimating the urinary lactate:creatinine ratio by magnetic resonance spectroscopy shortly after birth can help predict which asphyctic infants will develop HIE, and thereby help guide intervention. N Engl J Med 1999;341:328–335

Urinary lactate excretion in type 1 glycogenosis — a marker of metabolic control or renal tubular dysfunction?

Journal of Inherited Metabolic DiseaseVolume 19, Issue 2 p. 201-204 Short Communication Urinary lactate excretion in type 1 glycogenosis — a marker of metabolic control or renal tubular dysfunction? P. J. Lee, P. J. Lee The Medical Unit, Institute of Child Health, London, UKSearch for more papers by this authorC. Chatterton, C. Chatterton The Medical Unit, Institute of Child Health, London, UKSearch for more papers by this authorJ. V. Leonard, J. V. Leonard The Medical Unit, Institute of Child Health, London, UKSearch for more papers by this author P. J. Lee, P. J. Lee The Medical Unit, Institute of Child Health, London, UKSearch for more papers by this authorC. Chatterton, C. Chatterton The Medical Unit, Institute of Child Health, London, UKSearch for more papers by this authorJ. V. Leonard, J. V. Leonard The Medical Unit, Institute of Child Health, London, UKSearch for more papers by this author First published: 01 March 1996 https://doi.org/10.1007/BF01799429Citations: 6 Department of Child Health, St George's Hospital Medical School, Cranmer Terrace, London, SW17 ORE, UK AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume19, Issue2March 1996Pages 201-204 RelatedInformation

Neonatal De Toni-Debré-Fanconi syndrome due to a defect in complex III of the respiratory chain

A patient with neonatal expression of severe De Toni-Debré-Fanconi syndrome is presented. Because of early signs of renal tubulopathy together with a large urinary excretion of lactate, 3-hydroxybutyrate and citric acid cycle intermediates, a mitochondrial disorder was suspected and muscle and liver biopsies were performed. Biochemical investigations in both tissues revealed a defect in the respiratory chain at the level of complex III. In this patient renal dysfunction was the primary symptom, and hyperlactataemia, an important clue for a mitochondrial disorder, was lacking. CONCLUSION. Complex III deficiency should be included in the differential diagnosis of neonatal De Toni-Debré-Fanconi syndrome.

Bone mineralisation in type 1 glycogen storage disease

Radial bone mineral content (BMC) was measured using single photon absorptiometry in 11 prepubertal children, aged 3.4-12.6 years, with glycogen storage disease type 1 (GSD-1), 2 of whom were receiving granulocyte colony stimulating factor (G-CSF) therapy for chronic neutropenia. Patients were short (median height SD score -1.35, range -3.74 to -0.27), and had reduced BMC Z scores (median 1.79, range -6.35 to +0.27) and radial bone width Z scores (median -0.72, range -2.00 to +0.68). Those receiving G-CSF did not differ significantly from the rest of the group. Generally dietary calcium intake was low and urinary calcium excretion increased. Urinary lactate excretion was high but did not correlate with BMC Z scores. Factors regulating bone metabolism (parathyroid hormone and 25-hydroxy vitamin D concentrations) and markers of bone formation (osteocalcin and skeletal alkaline phosphatase) were not increased implying that there was no compensation for increased bone resorption. Patients with GSD-1 may be at increased risk of fracture in later life and require close attention to metabolic control and calcium balance.

Absence of cytochrome c oxidase activity in a boy with dysfunction of renal tubules, brain and muscle

We report on a boy who developed proximal renal tubular acidosis with loss of carnitine at the age of about 6 months. A few months later he began to suffer from progressive muscular weakness and neurological disturbances. Blood biochemistry showed elevated lactate and beta-hydroxybutyrate with increased lactate/pyruvate and beta-hydroxybutyrate/acetoacetate ratios. A high urinary excretion of lactate and citric acid cycle intermediates was found. These results indicated a defect of the mitochondrial respiratory chain. Analysis of biopsy material from skeletal muscle revealed low activities of all respiratory chain complexes. In muscle and fibroblasts cytochrome c-oxidase (complex IV) was absent. Despite high dose multi-vitamin therapy the boy died at the age of 30 months from central respiratory failure. At autopsy the neuropathological diagnosis of Leigh disease was made.

Comparative study of intravenous administration of Ringer's lactate, Ringer's acetate and 5% glucose containing these Ringer's solutions in human being.

The effects of the administration of Ringer's lactate (L) and Ringer's acetate (A) solution on blood biochemistry in human subjects operated for tympanoplasty under general anesthesia were investigated. And the feasibilities of the clinical use of Ringer's lactate (LD) and Ringer's acetate (AD) solution containing 5% glucose were also assessed. In all cases the rate of infusion was 500 ml for initial 20 min, and then 5 ml.hr(-1).kg(-1) B.W. for 3 hr and 10 min. There were significant increases in blood L- and D-lactate, pyruvate, and L-lactate/pyruvate ratio in L group. A significant increase in blood acetate but not lactate was found in A group. These metabolic changes were minimal and considered as clinically not significant. The urinary excretion of lactate, pyruvate, acetate and glucose were also negligible. In both LD and AD group, the higher blood concentrations of lactate, pyruvate, acetate and glucose were found than in L and A group. Urinary excretions of these metabolites were much higher in LD and AD group than in L and A group. So glucose containing Ringer's lactate or acetate solutions should be administered in appropriate amounts and rate not to induce clinically significant metabolic alterations.

Partial biotinidase deficiency: Clinical and biochemical features

Neonatal screening for profound biotinidase deficiency (less than 10% of the mean normal activity level) has identified a group of children with partial biotinidase deficiency (10% to 30% of mean normal activity). Because partial biotinidase deficiency may result in clinical consequences that may be prevented by treatment with biotin, we evaluated such individuals and their family members (1) to determine whether partial biotinidase deficiency is associated with symptoms and (2) to determine the inheritance pattern. We quantified serum biotinidase activity levels and obtained medical histories of probands, their parents and siblings, and additional family members. All children with partial deficiency were healthy at the time of diagnosis. One child, who was not initially treated with biotin, later developed hypotonia, hair loss, and skin rash, which resolved with biotin therapy. Four adults and three children with partial biotinidase deficiency were identified among family members of infants identified by neonatal screening. All these individuals were healthy, although one sibling had elevated urinary lactate excretion. A fifth adult with partial deficiency, found among clinically normal adult volunteers, later showed minor symptoms that resolved after biotin therapy. Like children with profound biotinidase deficiency, children with partial biotinidase deficiency are symptoms free at birth. However, the subsequent occurrence of symptoms of profound biotinidase deficiency in some persons with partial deficiency suggests that biotin therapy for this condition may be warranted.

Effect of valproate on renal metabolism in the intact dog

Valproate is an antiepileptic drug known to induce hyperammonemia in humans. This hyperammonemia might result from a reduced detoxification of ammonium in the liver and/or from an accelerated renal ammoniagenesis. Six dogs with normal acid-base equilibrium and eight dogs with chronic metabolic acidosis were infused with valproate directly into their left renal artery in order to obtain arterial concentrations around 3 to 4 mM. The arterial ammonium concentration rose only in chronically acidotic dogs, whereas the lactate concentration and the lactate/pyruvate ratio increased in both groups. The urinary excretion of lactate and pyruvate increased markedly but the urinary excretion of other relevant metabolites remained minimal. Renal glutamine utilization and ammonium production were not changed by valproate administration in normal dogs but increased modestly in acidotic dogs. However, renal lactate utilization was drastically reduced and in fact, changed into a net production of lactate. Valproate strikingly reduced the renal cortical concentrations of glutamine, glutamate, alphaketoglutarate and citrate, and more modestly those of malate, oxaloacetate, aspartate, alanine and ATP. By contrast, the tissue lactate concentration and the lactate/pyruvate ratio were markedly increased. In experiments with brush border membrane vesicles, valproate inhibited the lactate transporter. These results suggest that high concentrations of valproate drastically inhibited the proximal reabsorption and the proximal and distal oxidation of lactate and pyruvate. Valproate probably became itself a significant energetic substrate for the kidney.

Urinary excretion of lactate, 2-oxoglutarate, citrate, and glycerol in patients with glycogenosis type I.

Growth retardation and lactic aciduria are well-known abnormalities in patients with a deficiency of either glucose-6-phosphatase or glucose-6-phosphate translocase. In 19 patients with glucose-6-phosphatase and two patients with glucose-6-phosphate translocase, growth retardation was quantified by calculating the height standard deviation score. The urinary excretion of lactate and some other metabolites was quantified by calculating the lactate/creatinine, 2-oxoglutarate/creatinine, citrate/creatinine, and glycerol/creatinine ratios in urine. Significant correlations were found between the lactate/creatinine ratio, the 2-oxoglutarate/creatinine ratio, and height SD score. Urinary lactate appeared to respond promptly to changes of the diet, while urinary 2-oxoglutarate responded only slowly, as did growth itself. The citrate/creatinine ratio and the glycerol/creatinine ratio were within the normal range and varied little. It was concluded that the urinary 2-oxoglutarate excretion primarily reflects the severity of the disease as expressed in stunted growth. Thus, while urinary lactate levels are more suitable for monitoring the diet, urinary 2-oxoglutarate levels can be used as an indication for intensive treatment with hyperalimentation.

Nephrotoxic effect of tris(2,3-dibromopropyl)phosphate on rat urinary metabolites: assessment from 13C-NMR spectra of urines and biochemical and histopathological examinations.

Rats received either single oral doses of 0, 25, 50, 100 and 200 mg/kg tris(2,3-dibromopropyl)phosphate (Tris-BP) or repeated doses of 50, 100 and 200 mg/kg/day Tris-BP for 7 days. Urine was collected over a 24-hr period and subjected to 13C-NMR and biochemical examinations. Tris-BP produced significant increases of urinary glucose and lactate. Urinary gamma-glutamyltransferase, lactate dehydrogenase and alkaline phosphatase levels were significantly elevated on the first 2 days of post-treatment. Histopathologically, the kidney exhibited proximal tubular damage at a dose of 200 mg/kg. There was a good correlation among the histopathological, biochemical results, and the 13C-NMR urinary metabolite fingerprints in the assessment of Tris-BP-induced renal damage. The abnormal patterns of metabolite excretion suggested that the lesions produced by Tris-BP were caused by changes in the metabolic function of tubular epithelial cells. The urinary excretion of lactate, enzymes and inhibition of glucose reabsorption from the tubular lumina may be attributed to necrosis and desquamation of the tubular cell.