A Pharmacokinetic Analysis of Hemodialysis for Metformin-Associated Lactic Acidosis.

OBJECTIVE: Although hemodialysis is recommended for patients with severe metformin-associated lactic acidosis (MALA), the amount of metformin removed by hemodialysis is poorly documented. We analyzed endogenous clearance and hemodialysis clearance in a patient with MALA. METHODS: A 62-year-old man with a history of type II diabetes mellitus presented after several days of vomiting and diarrhea and was found to have acute kidney injury (AKI) and severe acidemia. Initial serum metformin concentration was 315.34 µmol/L (40.73 µg/mL) (typical therapeutic concentrations 1-2 µg/mL). He underwent 6 h of hemodialysis. We collected hourly whole blood, serum, urine, and dialysate metformin concentrations. Blood, urine, and dialysate samples were analyzed, and clearances were determined using standard pharmacokinetic calculations. RESULTS: The total amount of metformin removed by 6 h of hemodialysis was 888 mg, approximately equivalent to one therapeutic dose. Approximately 142 mg of metformin was cleared in the urine during this time. His acid-base status and creatinine improved over the following days. No further hemodialysis was required. CONCLUSION: We report a case of MALA likely secondary to AKI and severe volume depletion. The patient improved with supportive care, sodium bicarbonate, and hemodialysis. Analysis of whole blood, serum, urine, and dialysate concentrations showed limited efficacy of hemodialysis in the removal of metformin from blood, contrary to previously published data. Despite evidence of acute kidney injury, a relatively large amount of metformin was eliminated in the urine while the patient was undergoing hemodialysis. These data suggest that clinical improvement is likely due to factors besides removal of metformin.

[An acidosis not so basic]. / Une acidose pas si basique.

We present the case of a four-year-old girl, who was hospitalized in intensive care unit for a coma resulting from metabolic acidosis with increased anion gap. The patient was treated for short bowel syndrome, following necrotising enterocolitis, which occurred 51 days after birth. In our initial evaluation of the patient's metabolic acidosis, we were unable to identify the cause of the increased anion gap. Urinary organic acids chromatography identified a large peak of lactate (quantified at 15 mmol/mol of creatiniuria), as well as its metabolites. The discrepancy between normal blood lactate concentration assayed by enzymatic assay, and the large amount of lactate found by gas-chromatography/mass spectrometry (GC/MS) in urine highlights the limit of the stereospecificity of enzymatic assays. Indeed, most lactates assay use enzymatic assays that are specific for L-lactate, whereas organic acids chromatography, whose column is mostly achiral, can detect both stereoisomers, D- and L-lactate. Organic acids in urine analysis, in addition to the clinical context, suggested a diagnosis of D-lactic acidosis. Following a review of the physiopathology and treatment of short bowel syndrome, we will discuss the mechanism and diagnosis of the D-lactic acidosis in our patient. This case highlights the need to perform an organic acid profile in urine in the presence of any unexplained increased anion gap to determine its cause.

Follow-up of glycemic index before and after Ramadan fasting in type 2 diabetes patients under antidiabetic medications.

INTRODUCTION: Fasting has no adverse effects on healthy Muslims during Ramadan. However, it can induce serious complications for patients with type 2 diabetes (T2D). We aimed to follow the variation of some biochemical and clinical parameters in T2D patients before and after Ramadan; and to determine the incidence of fasting on hypoglycaemia and lactic acidosis associated with antidiabetic agents such as metformin. MATERIALS AND METHODS: This work is a prospective study conducted during Ramadan on 150 patients, recruited 2 to 3 weeks prior to the start. These patients were sensitized about the Ramadan lifestyle and diet as well as the medications to take. RESULTS: This study results indicated a significant decrease of glycated haemoglobin (from 8.06% to 7.42%) and a similar trend in the fasting plasma glucose (from 1.81 to 1.36g/L) before and after Ramadan respectively. The serum lipid profile showed significant variations during the study period, and antidiabetic medications was associated with low serum lactate. The plasma creatinine and uric acid were reduced but remained insignificant. DISCUSSION AND CONCLUSION: Based on data from our study, we concluded that a safe fasting with a lower risk hypoglycaemia, can be achieved in a well-controlled patients, under antidiabetic drugs. However, the diabetes medication was associated with a small increase in serum lactate levels that seemed to be dose-independent and not affected by treatment duration.

Dihydrolipoamide dehydrogenase deficiency: a still overlooked cause of recurrent acute liver failure and Reye-like syndrome.

The causes of Reye-like syndrome are not completely understood. Dihydrolipoamide dehydrogenase (DLD or E3) deficiency is a rare metabolic disorder causing neurological or liver impairment. Specific changes in the levels of urinary and plasma metabolites are the hallmark of the classical form of the disease. Here, we report a consanguineous family of Algerian origin with DLD deficiency presenting without suggestive clinical laboratory and anatomopathological findings. Two children died at birth from hepatic failure and three currently adult siblings had recurrent episodes of hepatic cytolysis associated with liver failure or Reye-like syndrome from infancy. Biochemical investigation (lactate, pyruvate, aminoacids in plasma, organic acids in urine) was normal. Histologic examination of liver and muscle showed mild lipid inclusions that were only visible by electron microscopy. The diagnosis of DLD deficiency was possible only after genome-wide linkage analysis, confirmed by a homozygous mutation (p.G229C) in the DLD gene, previously reported in patients with the same geographic origin. DLD and pyruvate dehydrogenase activities were respectively reduced to 25% and 70% in skin fibroblasts of patients and were unresponsive to riboflavin supplementation. In conclusion, this observation clearly supports the view that DLD deficiency should be considered in patients with Reye-like syndrome or liver failure even in the absence of suggestive biochemical findings, with the p.G229C mutation screening as a valuable test in the Arab patients because of its high frequency. It also highlights the usefulness of genome-wide linkage analysis for decisive diagnosis advance in inherited metabolic disorders.

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 x 10(8)/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.

The measurement of urine pH to predict the amount of buffer used in the treatment of acute rumen lactic acidosis in cattle

The purpose of the present study was to establish a practical, fast, precise and low-cost procedure to estimate the degree of metabolic acidosis in cattle with acute rumen lactic acidosis for further treatment. The rumen acidosis was induced experimentally in 40 crossbreed rumen-cannulated 1.5-year-old steers. The induction caused the development of the most characteristic clinical signs of acute rumen lactic acidosis, severe rumen acidosis and a moderate metabolic acidosis, which was evidenced by low blood pH, and blood bicarbonate concentration and base excess (BE). A highly positive correlation (r=0.80) between urinary pH and BE concentration, and between urinary pH and blood pH (r=0.75) was observed. The BE concentration estimated by urinary pH was similar to that determined by venous blood gas analysis (P>0.99). Furthermore, the results presented by the predictive formula were very significant. In conclusion, urinary pH is a good tool to predict the quantity of buffers needed to treat metabolic acidosis in cattle with acute rumen lactic acidosis.

O presente estudo teve como objetivo desenvolver um procedimento de baixo custo, preciso, rápido e prático para estimar o grau de acidose metabólica, para tratar bovinos com quadros de acidose láctica ruminal. A acidose ruminal foi induzida experimentalmente em 40 novilhos mestiços de 1,5 anos de idade, implantados com cânula ruminal. Essa indução causou o surgimento de sinais clínicos muito típicos da enfermidade aguda, com o aparecimento de pronunciada acidose ruminal e acidose metabólica de grau moderado, caracterizado por baixo pH sangüíneo e diminutos teores de bicarbonato e excesso de base (BE) no sangue. Verificou-se uma alta correlação positiva (r = 0,80) entre o pH urinário e o BE e entre o pH urinário e o pH sangüíneo (r = 0,75). A concentração de BE estimado pelo pH urinário foi similar à obtida pela análise do hemogasômetro (P = 0,99). Além disso, os resultados apresentados pela fórmula de predição foram muito significativos. Dessa forma, conclui-se que a mensuração do pH urinário é uma boa alternativa para estimar a quantidade necessária de tampão para tratar o quadro de acidose metabólica em bovinos com acidose láctica ruminal aguda.

Yeast mediates lactic acidosis suppression after antibiotic cocktail treatment in short small bowel?

During acidotic periods in a girl with a short small bowel, very high D-lactic acid concentrations were measured in blood and urine; the patient's characteristic faecal flora contained mainly lactobacilli, and during antibiotic cocktail treatment also many yeasts. In this case report we sought to understand the beneficial effect of the antibiotic cocktail. Microbiological analysis was performed in faecal samples. Total lactic acid in serum and urine was studied using capillary gas chromatography-mass spectrometry, and D- and L-lactic acid in serum and urine by enzymatic assay. The results were coupled to patient's condition. Antibiotic cocktail therapy reduced the acidosis-associated symptoms, faecal lactobacilli and D-lactic acid production, but simultaneously the antibiotic therapy strongly increased the percentage of yeast in the faecal flora. Four to six weeks after each course of treatment the percentage of yeast decreased, whereas the percentage of intestinal lactobacilli increased; D-lactic acid also simultaneously increased in blood and urine. The patient felt well and showed a high percentage of intestinal yeast, but she often suffered from acidosis owing to a high percentage of lactobacilli. The yeast was identified as the pathogenic Candida glabrata. From the mentioned data together with data from the literature it was concluded that during several weeks the selected pathogenic yeast, C. glabrata, acted as a microbiological and metabolic buffer. Shortly after the course of antibiotic treatment this intestinal yeast strongly competed with the intestinal lactobacilli and thus prevented renewed rapid growth, massive D-lactic acid production from glucose and consequently also D-lactic acid-associated acidosis. The emergence of this yeast led us to consider probiotic lactobacilli or yeast for therapeutic use. The lack of knowledge regarding bile acid-deconjugating activity in both lactobacilli and probiotic yeast means that a final recommendation is not yet possible.

[Metabolic acidosis in children: the usefulness of 'anion gap']. / Metabole acidose bij kinderen: het nut van de 'anion gap'.

Metabolic acidosis occurs frequently in small children. The most common causes are hypoxia, sepsis, gastroenteritis and hypovolaemia. Calculation of the anion gap is useful in establishing the cause. An increased anion gap represents unmeasured anions, e.g. lactate in lactic acidosis. Metabolic acidosis was diagnosed in two boys aged one year and six weeks respectively. The first patient had a normal, the second an increased anion gap in blood. By determining the pH and the anion gap in urine it is possible to distinguish between a proximal and a distal tubular disease. The first patient had distal renal tubular acidosis; he recovered after correction of the acidosis. The second patient had a defect in the mitochondrial respiratory chain; he died at the age of seven months.

3-Methylglutaconic aciduria associated with Pearson syndrome and respiratory chain defects.

3-Methylglutaconic aciduria was detected in four patients with Pearson syndrome, a multitissue disorder with hematologic abnormalities, lactic acidosis resulting from defective oxidative phosphorylation, and deletions in the mitochondrial genome. 3-Methylglutaconic acid may be an additional useful marker for Pearson syndrome and may be a more specific marker than other organic acids identified in this disorder.

Experimentally induced lactic acidosis in the goat.

Lactic acidosis was produced experimentally twice in each of 4 adult, female goats, by giving sucrose orally at the rate of 18 g/kg bodyweight. Changes in pH, osmolality, lactic acid concentration, and other constituents in ruminal fluid, plasma and blood were monitored over a period of 48 h. Also changes in urinary pH and sediment were examined. To ameliorate the metabolic disturbance, calcium hydroxide and bicarbonate treatment was employed after the 24 h samples had been collected and their acid-base status determined. A feature of the disturbance in the goats was that a metabolic alkalosis preceded the onset of lactic acidosis.

Episodes of severe metabolic acidosis in a patient with 3-methylglutaconic aciduria.

Persistent excretion of 3-methylglutaconic acid was found in a 6-month-old infant with multiple minor physical malformations and delayed development. During two episodes of intercurrent viral illness, the patient developed severe metabolic acidosis and excreted large amounts of lactate, 3-hydroxybutyrate and acetoacetate. The excretion of 3-methylglutaconic acid did not change during these episodes, nor did it increase following leucine loading. In vitro studies suggest that in this patient, as in the majority of other patients with 3-methylglutaconic aciduria, a primary defect in leucine metabolism is not responsible for the biochemical abnormality.

Renal effects of dichloroacetate in vivo.

We have investigated the effect of dichloroacetate (DCA) on the urinary excretion of lactate and pyruvate in a patient with congenital lactic acidosis and in healthy human controls. DCA administered orally in doses of 50 mg/kg and 30 mg/kg decreased plasma lactate and pyruvate of both the patient and the controls, while the urinary excretion of lactate and pyruvate was increased. However, these urinary increments were too small to contribute to the decrease of plasma lactate and pyruvate.