vitamin-b-12 and Renal-Insufficiency

Patients with renal failure have extremely high cardiovascular risk; in dialysis patients the risk of stroke is increased approximately 10-fold over that in the general population. Reasons include not only a high prevalence of traditional risk factors such as diabetes, hypertension and dyslipidemia, but also the accumulation of toxic substances that are eliminated by the kidneys, so have very high levels in patients with renal failure. These include plasma total homocysteine, asymmetric dimethylarginine, thiocyanate, and toxic products of the intestinal microbiome (Gut-Derived Uremic Toxins; GDUT), which include trimethylamine N- oxide (TMAO), produced from phosphatidylcholine (largely from egg yolk) and carnitine (largely from red meat). Other GDUT are produced from amino acids, largely from meat consumption. Deficiency of vitamin B12 is very common, raises plasma tHcy, and is easily treated. However, cyanocobalamin is toxic in patients with renal failure. To reduce the risk of stroke in renal failure it is important to limit the intake of meat, avoid egg yolk, and use methylcobalamin instead of cyanocobalamin, in addition to folic acid.

Topics: Bacteria; Biomarkers; Comorbidity; Diet; Dietary Supplements; Gastrointestinal Microbiome; Homocysteine; Humans; Kidney; Nutritional Status; Protective Factors; Renal Insufficiency; Risk Assessment; Risk Factors; Stroke; Treatment Outcome; Uremia; Vitamin B 12; Vitamin B 12 Deficiency

Hyperhomocysteinaemia is often the result of inherited abnormalities of the enzymes involved in homocysteine metabolism or vitamin deficiencies (vitamins B12, B6 or folate) and is present in approximately 5% of the general population. High homocysteine levels in these individuals are associated with a significant increase in relative risk for both arterial and venous thromboembolic disease. Consequently, effective homocysteine-lowering therapeutic strategies have been extensively investigated. Folic acid represents the cornerstone of treatment. In daily doses of at least 0.4 mg, it effectively reduces homocysteine levels, even in non-folate-deficient patients. The addition of vitamins B12 and/or B6, to folic acid supplementation may provide a small further reduction in homocysteine levels in certain groups of patients. Renal impairment is an important cause of hyperhomocysteinaemia. Individuals with hyperhomocysteinaemia secondary to renal disease commonly require significantly higher doses of folic acid (5-40 mg) to achieve maximal therapeutic effect. The important question of whether effective homocysteine-lowering therapy translates into a reduction in vascular disease remains unknown but is being addressed in a series of ongoing prospective trials.

Topics: Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Methionine; Pyridoxine; Renal Insufficiency; Thrombophilia; Vitamin B 12; Vitamins

We examined the plasma profile of sulfur amino acids (SAA) in patients with chronic renal failure (CRF) and looked for any correlation with serum folate (FA) and/or vitamin B12. Group 1 comprised 9 patients with CRF and glomerular filtration rate (GFR) >20 ml/min per 1.73 m2, 9 patients with GFR<20 ml/min per 1.73 m2 comprised group 2, and 14 patients on hemodialysis group 3. The control group comprised 16 healthy children. Homocysteine (Hcy), methionine (Met), cysteine (Cys), and serine (Ser) were measured with gas chromatography. FA and vitamin B12 were measured using enzymatic immunoassay. Median SAA concentrations were significantly lower in controls than in the three groups of patients. Hcy concentrations were 0.8 micromol/l in controls versus 5 micromol/(group 1), 9 micromol/l (group 2), and 20 micromol/l (group 3). Met concentrations were 26 micromol/l in controls versus 26 micromol/l (group 1), 66 micromol/l (group 2), and 281 micromol/l (group 3). Cys concentrations were 10 micromol/ in controls versus 98 micromol/l (group 1), 54 micromol/l (group 2), and 122 micromol/l (group 3). Ser concentrations were 88 micromol/ in controls versus 153 micromol/l (group 1), 239 micromol/l (group 2), and 240 micromol/l (group 3). The median concentrations of FA were lower in controls than in groups 2 and 3: 5.5 ng/ml versus 8 ng/ml and 15 ng/ml, respectively. Vitamin B12 concentrations did not differ between groups. Vitamin levels did not correlate with SAA. The only difference between patients with Hcy levels in the lower and upper quartile was in Met concentration (38 vs. 263 micromol/l, P<0.02) and GFR (P<0.01). In conclusion, patients with CRF had higher SAA concentrations than healthy children. FA concentrations are higher in CRF patients than in healthy children but did not correlate with concentrations of SAA.

Topics: Adolescent; Adult; Amino Acids, Sulfur; Child; Diet; Female; Folic Acid; Glomerular Filtration Rate; Humans; Male; Renal Insufficiency; Vitamin B 12

Topics: Humans; Renal Insufficiency; Vitamin B 12; Vitamin B 12 Deficiency

Vitamin B12 (B12) and folate are essential vitamins that play important roles in physiological processes. In the general population, many studies have evaluated the association of these vitamins with clinical outcomes, yet this association in hemodialysis (HD) patients remains unclear.. We examined the association of serum folate and B12 with mortality in a 5-year cohort of 9517 (folate) and 12 968 (B12) HD patients using Cox models with hierarchical adjustment for sociodemographics, comorbidities, and laboratory variables associated with the malnutrition and inflammation complex syndrome. The associations of baseline B12 and folate (separately) with all-cause mortality were evaluated across five categories of B12 [<400 (reference), 400-<550, 550-<650, 650-<750 and ≥750 pg/mL] and folate [<6.2, 6.2-<8.4, 8.4-<11 (reference), 11-<14.3 and ≥14.3 ng/mL].. The study cohort with B12 measurements had a mean ± standard deviation age of 63 ± 15 years, among whom 43% were female, 33% were African-American, and 57% were diabetic. Higher B12 concentrations ≥550 pg/mL were associated with a higher risk of mortality after adjusting for sociodemographic and laboratory variables. However, only lower serum folate concentrations <6.2 ng/mL were associated with a higher risk of all-cause mortality when adjusted for sociodemographic variables [adjusted hazard ratio (95% confidence-interval): 1.18 (1.03-1.35)].. Higher B12 concentrations are associated with higher all-cause mortality in HD patients independent of sociodemographics and laboratory variables, whereas lower folate concentrations were associated with higher all-cause mortality after accounting for sociodemographic variables. Further studies are warranted to determine the optimal B12 and folate level targets in this population.

Topics: Aged; Female; Folic Acid; Humans; Incidence; Male; Middle Aged; Proportional Hazards Models; Renal Dialysis; Renal Insufficiency; Risk; Vitamin B 12

Methylmalonic acidemia (MMA) is an autosomal recessive disorder that can be classified into two types: (1) vitamin B12-responsive and (2) vitamin B12-non-responsive. In MMA cases with long-term survival, renal failure is often a problem, and timing for kidney transplantation for MMA is controversial. We encountered a vitamin B12-non-responsive MMA case for which regular hemodialysis for renal failure was initiated; the patient was 16 years old when she first received regular hemodialysis and 35 years old when she developed pulmonary artery hypertension (PAH). PAH can complicate regular hemodialysis; however, PAH in this case was considered to be a complication of MMA because it was responsive to medical treatment and reversible. In this report, we discuss the role of regular hemodialysis in MMA and the causal relationship between MMA and regular hemodialysis for PAH.

Topics: Adult; Amino Acid Metabolism, Inborn Errors; Female; Humans; Hypertension, Pulmonary; Kidney Failure, Chronic; Renal Insufficiency; Vitamin B 12

Functional cobalamin (Cbl; vitamin B12) deficiency (that is, high levels of the Cbl-dependent metabolites, methylmalonic acid (MMA) and homocysteine (HCys), despite normal serum Cbl values) is common in the elderly and is associated with neurocognitive abnormalities, but its cause is unknown. As only reduced Cbls are metabolically active, the possibility that functional Cbl deficiency is associated with disorders having biomarkers indicative of increased oxidative stress (oxidant risks) was considered.. A retrospective record review of community-dwelling adults evaluated over a 12-year period for Cbl deficiency in a primary care setting who had serum Cbl values ⩾400 pg/ml (n=170).. When no oxidant risks were present, older subjects (⩾70 years) had higher metabolite values than younger individuals (<70 years). MMA values were even higher in the elderly when one oxidant risk was present and in younger subjects when two or more oxidant risks were present. Even at Cbl levels ⩾800 pg/ml, MMA values were increased in 73% of elderly subjects with at least one oxidant risk. HCys values were also higher in both age groups when at least two oxidant risks were present. Cyanocobalamin therapy decreased MMA and HCys values in 86 and 76% of subjects, respectively, with nonresponders more likely to have two or more oxidant risks.. Functional Cbl deficiency is associated with disorders marked by increased oxidative stress particularly in the elderly; it occurs even when Cbl levels are high and is not consistently corrected with high-dose cyanocobalamin therapy. Thus, current approaches to recognizing and managing this disorder may be inadequate.

Topics: Aged; Aged, 80 and over; Aging; Alcohol Drinking; Connecticut; Diabetes Mellitus; Dietary Supplements; Female; Homocysteine; Humans; Injections, Intramuscular; Male; Methylmalonic Acid; Neurocognitive Disorders; Oxidative Stress; Primary Health Care; Renal Insufficiency; Retrospective Studies; Risk Factors; Smoking; Vitamin B 12; Vitamin B 12 Deficiency

Variants in CUBN, the gene encoding cubilin, a proximal tubular transport protein, have been associated with albuminuria and vitamin B12 (B12) deficiency. We hypothesized that low levels of B12 would be associated with albuminuria in a population-based cohort.. We analyzed participants from the Framingham Heart Study (n = 2965, mean age 58 years, 53% female) who provided samples for plasma B12. Logistic regression models adjusted for covariates including homocysteine were constructed to test the association between B12 and prevalent albuminuria (UACR ≥17 mg/g [men] and ≥25 mg/g [women]) and reduced kidney function (defined as an eGFR < 60 ml/min/1.73 m(2), RKF). Because of a significant interaction between B12 and homocysteine in the prevalent RKF model (p = 0.005), the model was stratified by the median homocysteine levels. Logistic regression models were constructed to test the association between B12 and incident albuminuria and RKF. The results were replicated in 4445 participants from NHANES 2003-2004.. Baseline B12 levels ranged from 50-1690 pg/ml. Elevated B12 was associated with prevalent albuminuria (OR 1.44 per 1 SD increase, 95% CI 1.10-1.87) and RKF (OR 1.83, 95% CI 1.30-2.60). However after stratifying by median homocysteine levels, this relationship remained only in the higher homocysteine stratum. There was no association between B12 and incident albuminuria (OR 1.17, 95% CI 0.79 - 1.73) or RKF (OR 1.45, 95% CI 0.97 - 1.88). In the NHANES cohort, elevated B12 was associated with RKF after full covariate adjustment (OR 3.06, 95% CI 2.30-4.08). There was no association with albuminuria.. In participants with high baseline homocysteine levels, increased plasma B12 was associated with RKF.

Topics: Adult; Aged; Albuminuria; Biomarkers; Cohort Studies; Female; Glomerular Filtration Rate; Homocysteine; Humans; Kidney Function Tests; Logistic Models; Male; Middle Aged; Nutrition Surveys; Predictive Value of Tests; Prognosis; Renal Insufficiency; Risk Assessment; Vitamin B 12

Topics: Aged; Autoimmune Diseases; Female; France; Hematologic Diseases; Humans; Liver Diseases; Male; Metabolic Diseases; Neoplasms; Prevalence; Prognosis; Renal Insufficiency; Statistics as Topic; Vitamin B 12

Therapy to lower homocysteine with B vitamins does reduce the risk of stroke, if not myocardial infarction. The apparent lack of efficacy of vitamin therapy in most of the large clinical trials was probably determined by the failure to take account of the metabolic deficiency of vitamin B12, which is very common and often missed, and by the failure to take account of impaired renal function. Metabolic B12 deficiency is present in 20% of people over 65 years of age, and in 30% of vascular patients above 70 years, so higher doses of B12 are needed in elderly patients. However, high-dose cyanocobalamin leads to accumulation of cyanide in patients with renal failure. B vitamin therapy is beneficial in patients with good renal function, but harmful in patients with significantly impaired renal function (a glomerular filtration rate <50). It seems likely that in patients with renal impairment, methylcobalamin should be used instead cyanocobalamin.

Topics: Aged; Clinical Trials as Topic; Glomerular Filtration Rate; Humans; Renal Insufficiency; Risk Factors; Stroke; Vitamin B 12; Vitamin B 12 Deficiency

A moderate elevation of plasma total homocysteine (tHcy) is considered a potential risk factor for Alzheimer's disease (AD).. We have investigated the main determinants (age, renal impairment, cobalamin/folate status and the presence of vascular disease) of plasma tHcy in 326 patients with AD, and also in 281 patients with mild cognitive impairment (MCI), since about half of these patients develop AD during the first 5 years.. Elevated plasma tHcy in patients with AD could mainly be attributed to cobalamin/folate deficiency or renal impairment. Younger patients (below 75 years) with AD and patients with MCI without cobalamin/folate deficiency or renal impairment showed normal levels of plasma tHcy.. Our findings suggest that plasma tHcy is not primarily involved in the pathogenesis of AD but rather a reflection of changes of the main determinants of plasma tHcy in AD patients.

Topics: Age Factors; Aged; Aged, 80 and over; Aging; Alzheimer Disease; Case-Control Studies; Cognitive Dysfunction; Female; Folic Acid; Folic Acid Deficiency; Homocysteine; Humans; Hyperhomocysteinemia; Male; Middle Aged; Renal Insufficiency; Risk Factors; Vascular Diseases; Vitamin B 12; Vitamin B 12 Deficiency

In general practice, vitamin B12 levels are measured when searching an origin for an anemic status (usually megaloblastic anemia), for various neurological disorders (usually polyneuropathy) or for neurocognitive disorders. Although the pathologies associated with vitamin B12 deficiency are well known, hypervitaminemic B12 status is often fortuitous and frequent finding. The aim of this article is to present the disease entities associated with hypervitaminemia B12, the clinical implications of this dysvitaminosis and a practical approach when this laboratory abnormality is found.

Topics: Algorithms; Autoimmune Diseases; Female; Hematologic Diseases; Humans; Liver Diseases; Neoplasms; Pregnancy; Premature Birth; Renal Insufficiency; Vitamin B 12

Anemia in older persons is commonly overlooked despite mounting evidence that low hemoglobin levels are a significant marker of physiologic decline. Using the World Health Organization definition of anemia (hemoglobin level less than 13 g per dL [130 g per L] in men and less than 12 g per dL [120 g per L] in women), more than 10 percent of persons older than 65 years are anemic. The prevalence increases with age, approaching 50 percent in chronically ill patients living in nursing homes. There is increasing evidence that even mild anemia is associated with increased morbidity and mortality. Anemia warrants evaluation in all older persons, except those at the end of life or who decline interventions. About one third of persons have anemia secondary to a nutritional deficiency, one third have anemia caused by chronic inflammation or chronic kidney disease, and one third have unexplained anemia. Nutritional anemia is effectively treated with vitamin or iron replacement. Iron deficiency anemia often is caused by gastrointestinal bleeding and requires further investigation in most patients. Anemia of chronic inflammation or chronic kidney disease may respond to treatment of the underlying disease and selective use of erythropoiesis-stimulating agents. The treatment of unexplained anemia is difficult, and there is little evidence that treatment decreases morbidity and mortality, or improves quality of life. Occasionally, anemia may be caused by less common but potentially treatable conditions, such as autoimmune hemolytic anemia, malignancy, or myelodysplastic syndrome.

Topics: Aged; Algorithms; Anemia; Deficiency Diseases; Erythrocyte Indices; Female; Ferritins; Folic Acid; Hematinics; Homocysteine; Humans; Inflammation; Iron Compounds; Male; Medical History Taking; Methylmalonic Acid; Physical Examination; Renal Insufficiency; Reticulocyte Count; Vitamin B 12

Bronchioloalveolar carcinoma (BAC) and adenocarcinoma mixed subtype with bronchioloalveolar features (ADC-WBF) represent a unique anatomo-clinical entity accounting for some 20% of non-small cell lung cancers (NSCLC). These tumors seem less sensitive to chemotherapy than other NSCLC. We report two cases of advanced ADC-WBF treated with second-line and fourth-line pemetrexed. Major and durable radiological response associated with clinical and functional improvement was achieved in both patients, without important drug toxicity. After treatment arrest, the two patients experienced progressive disease but responded to retreatment with pemetrexed. Recent data suggest that paclitaxel-based chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors could be an acceptable therapeutic strategy in unresectable CBA and ADC-WBF. The cases reported here and preclinical findings suggest a therapeutic efficacy of pemetrexed in these tumors. Prospective studies are required to evaluate this hypothesis.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Aged; Antimetabolites, Antineoplastic; Bone Neoplasms; Cough; Disease Progression; Dyspnea; Folic Acid; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Neoplasm Staging; Neutropenia; Pemetrexed; Remission Induction; Renal Insufficiency; Smoking; Tomography, X-Ray Computed; Vitamin B 12

Uncertainty has arisen as to whether vitamin supplements are needed by dialysis patients, in particular those treated by means of hemofiltration or hemodiafiltration using highly permeable (high-flux) filters. We therefore measured the concentrations of vitamin C, cobalamin (vitamin B12) and folic acid in conventional (low-flux) dialysis patients and in those receiving on-line treatment (hemofiltration or hemodiafiltration).. Plasma (P-)ascorbate, serum (S-)cobalamin and S-folate concentrations were measured before and after a treatment session in 15 patients treated with low-flux hemodialysis and in 14 treated with on-line hemofiltration or hemodiafiltration. The patients' vitamin supplementations were also recorded.. P-ascorbate concentrations were lowered by 51% and 53% in the hemodialysis and on-line groups, respectively after treatment and this reduction was significant (p<0.001). Concentrations below the reference values were found in 12/14 patients not receiving vitamin C supplementation. S-cobalamin did not decrease in the hemodialysis or on-line groups. S-folates did not change significantly in the hemodialysis or filtration groups. Patients without folacin supplementation had low values.. P-ascorbate was reduced by both dialysis and filtration treatments. Neither S-cobalamin nor S-folate were reduced by dialysis or filtration treatments.

Topics: Aged; Ascorbic Acid; Cohort Studies; Dietary Supplements; Female; Folic Acid; Hemofiltration; Humans; Male; Middle Aged; Renal Dialysis; Renal Insufficiency; Vitamin B 12

Midsize molecule retention is related with renal-failure-associated mortality. Here, the authors describe a new dialysis modality, pulse push/pull hemodialysis (PPPHD), which increases convective clearance. Blood and dialysate are circulated by a pulsatile pump, but with pulsatile flow patterns that are 180 degrees out of phase. This causes blood-to-dialysate pressure gradients that oscillate between positive and negative, and which cause consecutive periods of ultrafiltration and backfiltration. The devised PPPHD was compared with conventional high-flux hemodialysis (CHFHD) in terms of solute clearances, albumin loss, and total protein levels. Human plasma containing dissolved uremic marker molecules was used as a blood substitute, and clearances were investigated for blood urea nitrogen, creatinine, vitamin B12, and inulin. Observed clearances were found to be significantly higher for PPPHD by approximately 3-14% for low-molecular-weight solutes, by 47-48% for vitamin B12, and by 38-49% for inulin than for CHFHD. No albumin loss was observed in either of these two study groups. The authors conclude that PPPHD offers a simple straightforward means of enhancing uremic molecule removal by increasing total ultrafiltration volume without the need to infuse replacement fluid.

Topics: Blood Urea Nitrogen; Convection; Creatinine; Dialysis Solutions; Hemodiafiltration; Humans; Inulin; Membranes, Artificial; Pulsatile Flow; Renal Dialysis; Renal Insufficiency; Serum Albumin; Sterilization; Vitamin B 12

Fortification of enriched cereal grain flour products with folic acid has drastically reduced the prevalence of deficient plasma folate status, a major determinant of plasma total homocysteine (tHcy) levels. We hypothesized that even more liberally defined "suboptimal" plasma folate status might no longer contribute importantly to the population attributable risk (PAR) for mild hyperhomocysteinemia, a putative atherothrombotic risk factor. We determined fasting plasma tHcy, folate, vitamin B(12), and pyridoxal 5'-phosphate levels, along with serum creatinine and albumin levels, in 267 consecutive patients (aged 61+/-9 [mean+/-SD] years, 76.4% men and 26.6% women) with stable coronary artery disease (CAD) who were nonusers of vitamin supplements or had abstained from supplement use for at least 6 weeks before examination. Subjects were evaluated a minimum of 3 months after the implementation of flour fortification was largely completed. Relative risk estimates for the calculation of PAR were derived from a multivariable-adjusted logistic regression model with >/=12 micromol/L tHcy as the dependent variable and with age, sex, pyridoxal 5'-phosphate (continuous), albumin (continuous), <5 ng/mL folate, <250 pg/mL vitamin B(12), and >/=1.3 mg/dL creatinine as the independent variables. The prevalence of >/=12 micromol/L plasma tHcy was 11.2% (30 of 267 patients). PAR estimates (percentage) for >/=12 micromol/L tHcy were as follows: <5 ng/mL folate (<1%), <250 pg/mL vitamin B(12) (24.5%), and >/=1.3 mg/dL creatinine (37.5%). In the era of folic acid-fortified cereal grain flour, renal insufficiency and suboptimal vitamin B(12) status (but not folate status) contribute importantly to the PAR for mild hyperhomocysteinemia among patients with stable CAD.

Topics: Adult; Aged; Coronary Artery Disease; Coronary Disease; Creatinine; Edible Grain; Female; Flour; Folic Acid; Food, Fortified; Homocysteine; Humans; Hyperhomocysteinemia; Male; Middle Aged; Renal Insufficiency; Risk Factors; Vitamin B 12

Whereas low cobalamin levels have been studied intensively, systematic information about high levels, especially in the clinical setting, is scarce. Therefore, a prospective comparison was done of 60 patients with high cobalamin levels and 75 with normal levels obtained by a hospital laboratory over a 2.5 month period. Associations with clinical disorders and laboratory test results were examined. Transcobalamin (TC) I and II were measured, especially the holoproteins (TC carrying circulating endogenous cobalamin) which were fractionated with microfine silica powder. High cobalamin levels (> 664 pmol/l; > 900 ng/l) occurred in 94 of 670 consecutive clinically requested assays (14%). The only independently significant associations with a high cobalamin level were renal failure among the clinical disorders (P=0.01), elevated serum creatinine (P=0.0001) and diminished albumin (P=0.0002) levels among laboratory tests. Both holo-TC I and holo-TC II levels were increased in renal failure (P=0.0001) but the increase was relatively greater in holo-TC II. The results indicate that high cobalamin levels are more frequent than low ones in clinical practice and appear to be associated often with renal failure. The elevation of both holo-TC II and holo-TC I suggests that several mechanisms are operative. The accumulation of holo-TC II suggests that cellular uptake of cobalamin by the abundant TC II receptors in the kidney may be impaired. The much better known association of high cobalamin levels with leucocytic disorders is rare, and no association was seen with liver disease.

Topics: Clinical Chemistry Tests; Diabetes Mellitus; Humans; Prospective Studies; Renal Insufficiency; Transcobalamins; Vitamin B 12

Hyperhomocysteinemia is frequent in hemodialysis patients and represents an independent risk factor for vascular disease in these patients. Elevated total homocysteine (tHcy) plasma levels can results from defective remethylation of Hcy to methionine due to decreased activity of the enzyme methylenetetrahydrofolate reductase (MTHFR). A genetic aberration in the MTHFR gene (677 C to T substitution) has been shown to result in reduced MTHFR activity. We tested the hypothesis that elevation of tHcy plasma levels in hemodialysis patients is influenced by the 677 C to T mutation of the MTHFR gene and examined the relation of the genotype with tHcy, folate and vitamin B12 plasma levels in these patients. The allelic frequency of the MTHFR mutation was evaluated in 203 patients maintained on chronic hemodialysis treatment. Total Hcy, folate, vitamin B12 levels and the MTHFR mutation were analyzed in 69 of the 203 patients and in 69 age- and sex-matched healthy control subjects. The allelic frequency of the 677 C to T transition in the MTHFR gene in hemodialysis patients was 34.7% versus 35.5% in healthy controls. Of 203 patients 26 (12.8%) were homozygous for the mutation (+/+) versus 10.2% in healthy subjects. The heterozygous (+/-) genotype was identified in 43.8% of patients versus 50.7% in controls. The mean tHcy level in hemodialysis patients was 28.7 +/- 11.0 mumol/liter versus 10.0 +/- 3.0 mumol/liter in control subjects. The mean tHcy levels were 36.4 +/- 13.4 mumol/liter in (+/+) patients and 12.2 +/- 4.5 mumol/liter in (+/+) controls, 28.7 +/- 10.8 mumol/liter in (+/-) patients and 9.9 +/- 2.7 mumol/liter in (+/-) controls and 25.4 +/- 8.5 mumol/liter in (-/-) hemodialysis patients versus 9.7 +/- 2.8 mumol/liter in (-/-) controls: There was no significant difference of folate and vitamin B12 concentrations in patients and controls with different MTHFR genotypes. Analysis of covariance including age, gender, folate concentrations, vitamin B12 levels, albumin and creatinine as covariables revealed a significant influence of the (+/+) genotype, albumin and folate status on tHcy levels in hemodialysis patients. Together, our data demonstrate that the extent of hyperhomocysteinemia in hemodialysis patients is not only the result of uremia or folate status, but is also genetically determined by the (+/+) MTHFR genotype. The presence of the 677 C to T mutation in the MTHFR gene does not appear to represent a risk factor for development of end-stage renal dise

Topics: Adult; Aged; Alleles; Cohort Studies; Female; Folic Acid; Gene Frequency; Genotype; Homocysteine; Humans; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Oxidoreductases Acting on CH-NH Group Donors; Point Mutation; Renal Dialysis; Renal Insufficiency; Vitamin B 12

Metformin is contraindicated in patients with renal failure because of the risk of lactic acidosis. This study assessed the complications of metformin treatment in patients with non-insulin-dependent diabetes mellitis with normal and raised serum creatinine. Subjects using metformin with serum creatinine above the upper reference range (120 mu mol/l) were identified (n = 17) from a hospital diabetes register; those with abnormal liver function, cardiac failure, peripheral vascular disease or recent severe illness were excluded. Reference plasma lactate levels were established, mean 1.742 mu mol/l (SD 0.819) using age-matched non-diabetic subjects. Age-matched patients treated with metformin with normal serum creatinine levels formed the control group (n = 24). Details of gastrointestinal disturbance were recorded, and plasma lactic acid and vitamin B12 levels measured. The median total daily dose of metformin in both groups was 1700 mg. The mean plasma lactate in subjects with serum creatinine 80-120 mu mol/l (2.640 mmol/l (SD 1.434) p < 0.02) was higher than non-diabetic control levels while diabetic subjects with serum creatinine 120-160 mumol/l had a mean of 2.272 mmol/l (SD 0.763) p < 0.05. There was no significant difference between the two groups taking metformin, nor any significant difference in the reporting of gastrointestinal symptoms between the groups on metformin (11.76% vs 12.5%). Plasma lactic acid levels are higher in diabetic subjects taking metformin compared with healthy volunteers but, within the diabetic groups, the small elevation of serum creatinine was not associated with higher plasma lactate levels.

Topics: Aged; Case-Control Studies; Creatinine; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Lactates; Male; Metformin; Middle Aged; Renal Insufficiency; Vitamin B 12

Homocysteine and 5-CH3-tetrahydrofolate (5-CH3-THF) are converted to methionine and THF by the CH3-cobalamin (CH3-Cbl)-dependent enzyme methionine synthase. Serum homocysteine levels are elevated in more than 95% of patients with Cbl or folate deficiency and in patients with inborn errors involving the synthesis of 5-CH3-THF or CH3-Cbl. Homocysteine and betaine are converted to methionine and N,N-dimethylglycine by betaine-homocysteine methyltransferase. It requires neither Cbl nor folate, although N,N-dimethylglycine is converted to N-methylglycine and then to glycine in reactions that both involve the formation of 5,10-CH2-THF from THF. Large amounts of betaine are often given orally to patients with inborn errors, even though little is known about its metabolism in normal subjects or these patients. Thus we developed new gas chromatographic-mass spectrometric assays for serum betaine, N,N-dimethylglycine, and N-methylglycine. In 60 blood donors, we found ranges for normal serum of 17.6 to 73.3, 1.42 to 5.27, and 0.60 to 2.67 mumol/L for the three metabolites, respectively, which were normal in the majority of 50 patients with Cbl deficiency, none of whom had increased levels of N-methylglycine. In 25 patients with folate deficiency, serum betaine level was normal in most, but 76% and 60% had elevations of N,N-dimethylglycine and N-methylglycine levels that ranged as high as 343 and 43.2 mumol/L, respectively. All of seven patients on betaine therapy for inborn errors had high values for betaine (167 to 3,900 mumol/L), N,N-dimethylglycine (15.1 to 250 mumol/L), and N-methylglycine (2.93 to 49.3 mumol/L). Serum total homocysteine levels remained very high at 47.2 to 156 mumol/L (normal, 5.4 to 16.2). In patients with cbl C and cbl D mutations, methionine levels remained low or low-normal at 8.3 to 15.6 mumol/L (normal, 13.3 to 42.7) despite betaine treatment. We conclude that (1) betaine levels are maintained in most patients with Cbl and folate deficiency; (2) levels of N,N-dimethylglycine and N-methylglycine are increased in most patients with folate deficiency; and (3) betaine therapy is relatively ineffective in patients with defective synthesis of CH3-Cbl.

Topics: Adolescent; Adult; Aged; Animals; Betaine; Betaine-Homocysteine S-Methyltransferase; Chromatography; Creatinine; Cystathionine beta-Synthase; Female; Folic Acid Deficiency; Gas Chromatography-Mass Spectrometry; Homocysteine; Humans; Male; Metabolism, Inborn Errors; Methionine; Methyltransferases; Middle Aged; Rats; Rats, Sprague-Dawley; Reference Values; Renal Insufficiency; Sarcosine; Vitamin B 12; Vitamin B 12 Deficiency

Homocysteine can be methylated to form methionine by the cobalamin- (Cbl) and folate-dependent enzyme, methionine synthase; serum levels of total homocysteine are elevated in greater than 95% of patients with either Cbl or folate deficiency. Homocysteine can also condense with serine to form cystathionine in a pyridoxal phosphate-dependent reaction catalyzed by cystathionine beta-synthase. Cystathionine is subsequently cleaved to cysteine and alpha-ketobutyrate by the pyridoxal phosphate-dependent enzyme gamma-cystathionase. To assess levels of cystathionine in Cbl and folate deficiency, we developed a new capillary gas chromatographic-mass spectrometric assay and measured cystathionine in the serum of normal subjects and patients with clinically confirmed deficiencies of these vitamins. The normal range for serum cystathionine was 65 to 301 nmol/L (median = 126 nmol/L) for 50 normal blood donors. In 30 patients with clinically confirmed Cbl deficiency, values for cystathionine ranged from 208 nmol/L to 2,920 nmol/L (median = 816 nmol/L) and 26 (87%) had levels above the normal range. In 20 patients with clinically confirmed folate deficiency, cystathionine concentrations ranged from 138 nmol/L to 4,150 nmol/L (median = 1,560 nmol/L) and 19 (95%) had values above the normal range. Five homozygotes for cystathionine beta-synthase deficiency had high values for serum-total homocysteine and low or low-normal values for serum cystathionine that ranged from 30 nmol/L to 114 nmol/L even though they were on treatment with pyridoxine and had partially responded. One patient with a defect in the synthesis of 5-CH3-tetrahydrofolate and five patients with defects in the synthesis of CH3-Cbl had high values for serum-total homocysteine and high values for cystathionine that ranged from 311 nmol/L to 1,500 nmol/L even though they were on treatment with folic acid and Cbl, respectively, and had partially responded. We conclude that levels of cystathionine are evaluated in the serum of most patients with Cbl and folate deficiency and that they are useful in the differential diagnosis of an elevated serum-total homocysteine level.

Topics: Animals; Cystathionine; Cystathionine beta-Synthase; Folic Acid; Folic Acid Deficiency; Gas Chromatography-Mass Spectrometry; Humans; Reference Values; Renal Insufficiency; Species Specificity; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Acute Kidney Injury; Biological Assay; Blood Chemical Analysis; Glomerulonephritis; Kidney Diseases; Kidneys, Artificial; Mercury Poisoning; Nephritis; Nephritis, Interstitial; Postoperative Complications; Pyelonephritis; Renal Insufficiency; Solvents; Toxicology; Tuberculosis; Tuberculosis, Renal; Vitamin B 12; Wounds and Injuries

The serum vitamin B(12) level was abnormally high in 14 out of 32 cases of renal failure. This was probably due to impaired excretion of the vitamin, but the results of measurements of the rate of excretion of radioactive vitamin B(12) did not provide unequivocal evidence on this point; other possible explanations are discussed. Renal failure must be added to the causes of high serum B(12) levels.

Topics: Arteriosclerosis; Glomerulonephritis; Humans; Hypertension; Hypertension, Malignant; Kidney; Kidney Diseases; Nephritis; Nephrocalcinosis; Polycystic Kidney Diseases; Pyelonephritis; Renal Insufficiency; Vitamin B 12

Topics: Kidney Diseases; Renal Insufficiency; Vitamin B 12