Search

Background: Niacin compounds lower serum phosphorus concentrations in patients with end-stage renal disease. Methodology: We evaluated the impact of extended release niacin, given in fixed-dose combination with laropiprant, a specific inhibitor of prostaglandin-mediated, niacin-induced flushing, versus placebo, on serum phosphorus concentrations measured serially (at weeks 0, 4, 8, 12, 18, 24, 30, and 36) during a 36-week randomized, controlled trial. All subjects had a confirmed diagnosis of type 2 diabetes (n = 446 niacin/laropiprant; n = 339 placebo). Estimated glomerular filtration rate ranged from 36 to 184 mL/min/1.73 m2, with n = 111 (14.1%) having a value <60 mL/min/1.73 m2. Subjects received one tablet daily of extended-release niacin/laropiprant (1g niacin/ 20 mg laropiprant) for the first 4 weeks, and 2 tablets once daily, thereafter, or matched placebo. Niacin lowered serum phosphorus concentrations by 0.36 mg/dL (95% CI: −0.40, −0.31; P < .001), relative to placebo, from baseline values of 3.57 and 3.56 mg/dL in the niacin and placebo groups, respectively. Subgroup analyses revealed no evidence for phosphorus-lowering effect modification by these baseline variables: glomerular filtration rate <60 (n = 111;14.1%) vs ≥60 mL/min/m2 (n = 674; 85.9%); phosphorus ≤3.5 mg/dL (n = 392; 49.9%) vs >3.5 mg/dL (n = 393; 50.1%); or prior statin use (n = 618; 78.7%) vs nonuse (n = 167; 21.3%). Conclusions and Implications: These data confirm that niacin’s phosphorus-lowering effects—which may have therapeutic implications for the management of hyperphosphatemia and possible prevention of cardiorenal outcomes in renal disease—extend across a broad spectrum of renal function in type 2 diabetics without stage 4 or 5 chronic kidney disease (a glomerular filtration rate ≥30 mL/min/1.73 m2). [Copyright &y& Elsevier]

Background: Hyperhomocysteinemia may be a modifiable risk factor for the prevention of arteriosclerotic outcomes in patients with chronic kidney disease (CKD). Few clinical trials of homocysteine lowering have been conducted in persons with CKD before reaching end-stage renal disease. Kidney transplant recipients are considered individuals with CKD.Objectives: To describe the baseline characteristics of renal transplant recipients enrolled in a clinical trial of homocysteine lowering with a standard multivitamin containing high doses of folic acid and vitamins B(6) and B(12) aimed at reducing arteriosclerotic outcomes. Factors considered were level of kidney function, total homocysteine concentration, and prevalence of diabetes and previous cardiovascular disease (CVD).Study Design: Cross-sectional survey within a randomized controlled trial cohort.Setting& Participants: Participants were recruited from kidney transplant clinics in the United States, Canada, and Brazil. Eligible participants had increased levels of homocysteine (> or =12.0 micromol/L in men and > or =11.0 micromol/L in women) and kidney function measured by means of Cockroft-Gault estimated creatinine clearance of 30 mL/min or greater.Results: Of 4,110 randomly assigned participants, 38.9% had diabetes and 19.5% had previous CVD. Mean total homocysteine concentration was 17.1 +/- 6.3 (SD) micromol/L, whereas mean creatinine clearance was 66.4 +/- 23.2 mL/min. Approximately 90% of the trial cohort had an estimated glomerular filtration rate consistent with stages 2 to 3 CKD (i.e., 30 to 89 mL/min).Limitations: Analysis is based on cross-sectional data from a randomized controlled trial, self-report of comorbid illnesses, and level of kidney function was estimated.Conclusions: A large population of stable renal transplant recipients who are at high risk of the development of CVD (both de novo and recurrent) has been recruited into the Folic Acid for Vascular Outcome Reduction in Transplantation Trial and are likely to experience a sufficient number of events to address the primary hypothesis of the trial. [ABSTRACT FROM AUTHOR]

The metabolism of homocysteine requires contributions of several enzymes and vitamin cofactors. Earlier studies identified a common polymorphism of methylenetetrahydrofolate reductase that was associated with mild hyperhomocysteinemia. Common variants of two other enzymes involved in homocysteine metabolism, methionine synthase and methionine synthase reductase, have also been identified. Methionine synthase catalyzes the remethylation of homocysteine to form methionine and methionine synthase reductase is required for the reductive activation of the cobalamin-dependent methionine synthase. The methionine synthase gene (MTR) mutation is an A to G substitution, 2756A→G, which converts an aspartate to a glycine codon. The methionine synthase reductase gene (MTRR) mutation is an A to G substitution, 66A→G, that converts an isoleucine to a methionine residue. To determine if these polymorphisms were associated with mild hyperhomocysteinemia, we investigated subjects from two of the NHLBI Family Heart Study field centers, Framingham and Utah. Total plasma homocysteine concentrations were determined after an overnight fast and after a 4-h methionine load test. MTR and MTRR genotype data were available for 677 and 562 subjects, respectively. The geometric mean fasting homocysteine was unrelated to the MTR or MTRR genotype categories (AA, AG, GG). After a methionine load, a weak positive association was observed between change in homocysteine after a methionine load and the number of mutant MTR alleles (P-trend=0.04), but this association was not statistically significant according to the overall F-statistic (P=0.12). There was no significant interaction between MTR and MTRR genotype or between these genotypes and any of the vitamins with respect to homocysteine concentrations. This study provides no evidence that these common MTR and MTRR mutations are associated with alterations in plasma homocysteine. [Copyright &y& Elsevier]

Background: Established determinants of fasting total homocysteine (tHcy) concentration include folate and vitamin B-12 status, serum creatinine concentration, and renal function. Objective: Our objective was to examine the relation between known and suspected determinants of fasting plasma tHcy in a population-based cohort. Design: We examined the relations between fasting plasma tHcy concentrations and nutritional and other health factors in 1960 men and women, aged 28-82 y, from the fifth examination cycle of the Framingham Offspring Study between 1991 and 1994, before the implementation of folic acid fortification. Results: Geometric mean tHcy was 11% higher in men than in women and 23% higher in persons aged ≥65 y than in persons aged <45 y (P < 0.001). tHcy was associated with plasma folate, vitamin B-12, and pyridoxal phosphate (P for trend < 0.001). Dietary folate, vitamin B-6, and riboflavin were associated with tHcy among non--supplement users (P for trend < 0.01). The tHcy concentrations of persons who used vitamin B supplements were 18% lower than those of persons who did not (P < 0.001). tHcy was positively associated with alcohol intake (P for trend = 0.004), caffeine intake (P for trend < 0.001), serum creatinine (P for trend < 0.001), number of cigarettes smoked (P for trend < 0.001), and antihypertensive medication use (P < 0.001). Conclusions: Our study confirmed, in a population-based setting, the importance of the known determinants of fasting tHcy and suggested that other dietary and lifestyle factors, including vitamin B-6, riboflavin, alcohol, and caffeine intakes as well as smoking and hypertension, influence circulating tHcy concentrations. [ABSTRACT FROM AUTHOR]

Examines the treatment of hyperhomocysteinemia in hemodialysis patients and renal transplant recipients in Rhode Island. Combination of oral vitamin B featuring the physiological basis of folic acid; Assessment of treatment compliance by pill counts and change in plasma vitamin status; Measurement of plasma total folate levels by microbiological assay.

The article presents a study on the effects of once-daily extended-release niacin on the phosphorus concentrations of patients suffering from metabolic syndrome dyslipidemia. For the study, researchers analyzed 60 respondents through the use of the National Cholesterol Education Program Adult Treatment Panel III definition of metabolic syndrome. Key findings indicated hypophosphatemic effects of niacin preparation in metabolic sundrome patients without reduced kidney function.

A letter to the editor is presented in response to a study on iodixanol plasma concentration during and after angiography.

• Nicotinamide did not decrease actinic keratoses in kidney transplant recipients. • Nicotinamide dosage was decreased during the trial due to gastrointestinal effects. • Limitations include difficult recruitment leading to underpowered analysis. • Nicotinamide's therapeutic potential may be limited in kidney transplant recipients. Oral nicotinamide (NAM) has shown promise in preventing actinic keratoses (AKs) in trials based outside of the United States. We assessed the efficacy of oral NAM supplementation in kidney transplant recipients with a history of keratinocyte carcinoma. Patients enrolled in a 2-week run-in phase, during which NAM 1000 mg was taken twice daily. After a washout period, patients who tolerated the run-in phase were randomized to NAM 500 mg twice daily or placebo. At baseline, 4, 8, and 12 months, dermatologists conducted full-body skin exams to document area-specific AKs. Routine lab work was collected to ensure the stability of renal allograft function. The dosage was reduced from 1000 to 500 mg due to gastrointestinal symptoms in the run-in phase. Patients were randomized to NAM (n = 10) or placebo (n = 11). At 12 months, mean AK count was 30.8 (95% CI -11.7-73.4) for NAM and 26.6 (95% CI 10.8-42.5) for placebo. The difference in percent AK count change at 12 months compared with baseline was 259.8% (95% CI -385.9 to 905.5) for NAM and 72.4% (95% CI -118.6 to 263.5) for placebo. The between-group difference in percent AK change was not significant (P =.38). There was no attrition in the placebo group and 40% attrition in the NAM arm. Nicotinamide did not decrease AK development among kidney transplant recipients. Limitations include drug tolerability, small sample size, and single-center trial nature. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "New Evidence for the Phosphorus-Lowering Effects of Niacin," in the April 2010 issue.

Background: Type III hyperlipoproteinemia usually results from an inherited defect in the composition of apolipoprotein E and is associated with atherosclerosis. An acquired form of the type III phenotype may rarely be associated with myeloma and immunoglobulin-lipoprotein complexes. Observation: We present the case of a 72-year-old man with a history of well-controlled, unclassified hypercholesterolemia and hypertriglyceridemia, without evidence of atherosclerotic disease. He subsequently developed refractory dyslipidemia, palmar crease, and tuberous xanthomas. Type III hyperlipoproteinemia was confirmed, and nonclassic defective apolipoprotein E. Common secondary causes of hyperlipidemia were ruled out. A workup for malignancy revealed monoclonal IgA gammopathy. Immunostaining confirmed IgA antibodies complexed to the patient''s very low-density lipoprotein (VLDL) fraction, causing gross impairment of VLDL metabolism. Conventional therapy for type III hyperlipoproteinemia was attempted but ineffective. Thus, chemotherapy was initiated for his myeloma, with subsequent lowering of his IgA, cholesterol, and triglyceride levels, and improvement of his xanthomas. Conclusion: There are several unusual features to this case. Planar xanthomas can be associated with myelomas, but usually in the setting of normal lipids. Type III hyperlipoproteinemias are not usually refractory to standard therapy and are only rarely associated with IgA myeloma. IgA antibodies complexed to the patient''s VLDL caused gross impairment of VLDL metabolism. The patient''s apolipoprotein E genotype (heterozygote E2/E3) is not typical for expression of the heritable type III phenotype (homozygote E2/E2). These features support a causal relationship between this patient''s multiple myeloma and type III hyperlipoproteinemia rather than two independent, coexistent conditions. [Copyright &y& Elsevier]

Background: The inflammatory marker C-reactive protein (CRP) has been found in most, but not all, prospective studies to be associated with future cardiovascular outcomes. However, CRP has not been tested in the high-cardiovascular risk population of type 2 diabetic nephropathy.Methods: We studied the independent relationship between CRP and the subsequent development of incident or recurrent arteriosclerotic outcomes (primary) and congestive heart failure events (secondary) in 1560 individuals with diabetic nephropathy, overt proteinuria, and hypertension enrolled in the prospective Irbesartan Diabetic Nephropathy Trial.Results: Traditional cardiac risk factors were highly prevalent, CRP levels were high overall [quintiles (mg/L) 1st, 0 to 1.2; 2nd, 1.3 to 2.5; 3rd, 2.6 to 5.0; 4th, 5.1 to 10.0; and 5th, >10), and subsequent cardiovascular events were very common. A univariate relationship existed between CRP and total arteriosclerotic outcomes (P < 0.0001). However, after adjusting for study intervention and traditional risk factors, the relationship no longer remained. In fact, controlling for previous cardiovascular disease alone caused the association to become nonsignificant. The secondary analysis found a significant univariate relationship between CRP and congestive heart failure events (P= 0.007) that persisted in multivariate analyses (P= 0.006). However, this relationship was confined to the highest CRP quintile [RR (95% CI) 2.0 (1.27, 3.16)].Conclusion: In diabetic patients with nephropathy, CRP does not add predictive information above and beyond that provided by traditional established risk factors. Whether this holds true for other populations with similar risk burdens is an important public health question that should be addressed. A secondary finding of a link between CRP and congestive heart failure requires further confirmation. [ABSTRACT FROM AUTHOR]

Background: Patients with diabetic nephropathy are at elevated cardiovascular risk. C-reactive protein (CRP) has been used to successfully predict cardiovascular events. Objective: We identified clinical and biochemical characteristics that correlate with CRP levels in diabetic nephropathy patients. Design: Baseline data obtained from 722 patients in the Irbesartan Diabetic Nephropathy Trial included age, sex, body mass index (BMI), systolic blood pressure (BP), serum creatinine, plasma low- and high-density cholesterol, triacylglycerol, serum albumin, hemoglobin A1C, 24 h urinary protein excretion, plasma total homocysteine (tHcy), folate, B12, pyridoxal 5′-phosphate (PLP, active form of Vitamin B6), and plasma CRP levels. Results: In univariate analyses CRP was positively associated with female sex (r=0.08; P=0.04), BMI (r=0.34; P<0.01), serum creatinine (r=0.21; P<0.01), hemoglobin A1C (r=0.08; 0.04), and inversely associated with PLP (r=−0.17; P<0.01) and folate (r=−0.09; P=0.02). A stepwise multiple regression model found CRP directly correlated with BMI (P<0.01) and serum creatinine (P<0.01), and inversely correlated with PLP (P<0.01). The final model explained 16% of the total variance of CRP. Conclusions: These results extend previous findings of an inverse relationship between Vitamin B6 and CRP. The lack of association between CRP and certain established or emerging cardiovascular risk factors offers novel information regarding cardiovascular risk in this population. [Copyright &y& Elsevier]

Distribution of plasma folate forms in hemodialysis patients receiving high daily doses of L-folinic or folic acid. Background. We have previously reported that a daily oral high dose of l-folinic acid for the treatment of hyperhomocysteinemia in hemodialysis patients does not provide significantly greater reduction in fasting total homocysteine (tHcy) levels than an equimolar dose of folic acid. The present study uses the affinity/HPLC method to analyze the distribution of plasma folate forms in patients who received l-folinic acid versus those who received folic acid. This was done to investigate claims that renal insufficiency is associated with impaired folate interconversion, a stance that is supportive of the premise that tHcy lowering in these patients is more efficacious with folinic acid and other reduced folates, than folic acid. Methods. Forty-eight chronic and stable hemodialysis patients were block-randomized, based on their screening predialysis tHcy levels, sex, and dialysis center, into two groups treated for 12 weeks with oral folic acid at 15 mg/day or an equimolar amount (20 mg/day) of oral l-folinic acid. All 48 subjects also received 50 mg/day of oral vitamin B6 and 1 mg/day of oral vitamin B12 . Folate distribution was determined in plasma of 46 participants (Folinic acid group, N = 22; Folic acid group, N = 24) by using the affinity/HPLC method, with electrochemical (coulometric) detection. Results. Both groups had similar baseline geometric means of plasma total folate and similar folate forms distribution. Following treatment, both groups demonstrated similar marked elevation in plasma total folate (geometric mean of the increase: Folinic acid group, +337 ng/mL; Folic acid group, +312 ng/mL; P = 0.796). In the folinic acid-treated group, practically all of the increase in total folate was due to 5-methyltetrahydrofolate. In the folic acid-treated group 5-methyltetrahydrofolate accounted for 35% of the increase in... [ABSTRACT FROM AUTHOR]

Compares the efficacy the L-folinic acid and folic acid for the treatment of hyperhomocysteinemia in hemodialysis patients. Success of block randomization; Percentage of total homocysteine; Normalization in total homocysteine levels.