Diabetic Nephropathy - Prevention

B-complex - updated: 15 March 2008

The role of homocysteine in kidney disease

In kidney disease, homocysteine levels in the blood increase because the kidneys do not properly filter homocysteine. Elevated levels of homocysteine are commonly seen in renal patients, sometimes three or four times higher than normal levels. Homocysteine is consistently elevated to very high levels in patients who require dialysis. Plasma homocysteine concentrations often decrease after dialysis. Therefore, to further help lower homocysteine levels, dialysis patients often require high levels of nutrients, including folic acid, vitamin B12, TMG, and vitamin B6

For some time, physicians have recognized the danger of homocysteine and they recommend use of vitamin supplements to lower homocysteine levels. The "normal range" used by commercial laboratories is 5-15 micromoles/L of blood. However, epidemiological data reveal that homocysteine levels above 6.3 result in a steep, progressive risk of heart attack, with each three-unit increase equaling a 35% increase in risk for heart attack. There may be no safe "normal range" for homocysteine. A survey in Cardiologia reported that the average American's level of homocysteine is 10.

The kidney and homocysteine metabolism

J Am Soc Nephrol. 2001 Oct;12(10):2181-9

Friedman AN, Bostom AG, Selhub J, Levey AS, Rosenberg IH.

Homocysteine (Hcy) is an intermediate of methionine metabolism that, at elevated levels, is an independent risk factor for vascular disease and atherothrombosis. Patients with renal disease, who exhibit unusually high rates of cardiovascular morbidity and death, tend to be hyperhomocysteinemic, particularly as renal function declines. This observation and the inverse relationship between Hcy levels and GFR implicate the kidney as an important participant in Hcy handling. The normal kidney plays a major role in plasma amino acid clearance and metabolism. The existence in the kidney of specific Hcy uptake mechanisms and Hcy-metabolizing enzymes suggests that this role extends to Hcy. Dietary protein intake may affect renal Hcy handling and should be considered when measuring Hcy plasma flux and renal clearance. The underlying cause of hyperhomocysteinemia in renal disease is not entirely understood but seems to involve reduced clearance of plasma Hcy. This reduction may be attributable to defective renal clearance and/or extrarenal clearance and metabolism, the latter possibly resulting from retained uremic inhibitory substances. Although the currently available evidence is not conclusive, it seems more likely that a reduction in renal Hcy clearance and metabolism is the cause of the hyperhomocysteinemic state. Efforts to resolve this important issue will advance the search for effective Hcy-lowering therapies in patients with renal disease.

Publication Types:

• Review

Plasma homocysteine and microvascular and macrovascular complications in type 1 diabetes: a cross-sectional nested case-control study

J Intern Med. 2005 Nov;258(5):450-

Soedamah-Muthu SS, Chaturvedi N, Teerlink T, Idzior-Walus B, Fuller JH, Stehouwer CD; Eurodiab ProspectivE Complications Study Group.

OBJECTIVES. To examine the independent relationship between plasma total homocysteine (tHcy) and microvascular and macrovascular complications. DESIGN. We performed a cross-sectional nested case-control study from the EURODIAB Prospective Complications Study. SETTING. A hospital-based multicentre study at 24 centres in 13 European countries. SUBJECTS. A total of 533 type 1 diabetic patients, diagnosed at <36 years of age. Cases (n=359) were defined as those with one or more complications of diabetes and control subjects (n=174) were all those with no evidence of any complication. Main outcome measures. Retinopathy, albumin excretion rate (AER), glomerular filtration rate (GFR) estimated by Cockcroft-Gault formula, hypertension and cardiovascular disease (CVD) were assessed. RESULTS. In unadjusted models, tHcy (per 5 micromol L(-1)) was significantly associated with nonproliferative retinopathy (OR=1.45, 95% CI: 1.10-1.91), proliferative retinopathy (OR=1.74, 95% CI: 1.34-2.27), macroalbuminuria (OR=1.90, 95% CI: 1.49-2.42), hypertension (OR=2.23, 95% CI: 1.69-2.93) and CVD (OR=1.59, 95% CI: 1.18-2.14). In multivariate models, tHcy was significantly related to macroalbuminuria (OR=1.66, 95% CI: 1.24-2.24) and hypertension (OR=1.57, 95% CI: 1.19-2.07), independent of age, sex, diabetes duration, GFR, microvascular and macrovascular complications and cardiovascular risk factors. There was a significant relationship between tHcy and decreased GFR, independent of established risk factors. The relationship between tHcy and retinopathy was not independent of albuminuria or GFR. The initial positive relationship with CVD was explained by cardiovascular risk factors. CONCLUSION. In this large study of European type 1 diabetic subjects, increased concentrations of tHcy were independently related to macroalbuminuria, renal function and hypertension, which suggests that tHcy might play an important role in the pathogenesis of vascular complications in type 1 diabetes.

Publication Types:

• cross-sectional nested case-control study

Vitamin supplements and cardiovascular risk: review of the randomized trials of homocysteine-lowering vitamin supplemen

Semin Thromb Hemost. 2000;26(3):341-8

Clarke R, Armitage J.

Epidemiological studies have shown that higher blood homocysteine levels appear to be associated with higher risks of coronary, cerebral, and peripheral vascular disease and are inversely related to blood levels of folate and of vitamin B12 and vitamin B6. However, observational studies cannot exclude the possibility that elevated homocysteine levels may be associated with some other factor, rather than being causally related to vascular disease. Large-scale clinical trials of sufficient dose and duration of treatment are required to test this hypothesis, but there was substantial uncertainty about the optimal vitamin regimen to test in such trials. A meta-analysis of 12 randomized trials of vitamin supplements to lower homocysteine levels was carried out to determine the optimal dose of folic acid required to lower homocysteine levels and to assess whether vitamin B12 or vitamin B6 had additive effects. This meta-analysis demonstrated that reductions in blood homocysteine levels were greater at higher pretreatment blood homocysteine levels and at lower pretreatment folate concentrations. After standardization for a pretreatment homocysteine concentration of 12 micromol/L and folate concentration of 12 nmol/L (approximate average concentrations for western populations), dietary folic acid reduced homocysteine levels by 25% (95% confidence interval [CI]: 23 to 28%) with similar effects in a daily dosage range of 0.5 to 5 mg. Vitamin B12 (mean 0.5 mg) produced an additional reduction in blood homocysteine of 7%, whereas vitamin B6 (mean 16.5 mg) did not have any significant effect. Hence, in typical populations, daily supplementation with both 0.5 to 5 mg folic acid and about 0.5 mg vitamin B12 would be expected to reduce homocysteine levels by one quarter to one third (from about 12 micromol/L to about 8 to 9 micromol/L). Large-scale randomized trials of such regimens are now required to determine whether lowering homocysteine levels by folic acid and vitamin B12, with or without added vitamin B6, reduces the risk of vascular disease.

Publication Types:

• Review

Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women

JAMA. 1998 Feb 4;279(5):359-6

Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA, Manson JE, Hennekens C, Stampfer MJ.

CONTEXT: Hyperhomocysteinemia is caused by genetic and lifestyle influences, including low intakes of folate and vitamin B6. However, prospective data relating intake of these vitamins to risk of coronary heart disease (CHD) are not available. OBJECTIVE: To examine intakes of folate and vitamin B6 in relation to the incidence of nonfatal myocardial infarction (MI) and fatal CHD. DESIGN: Prospective cohort study. SETTING AND PATIENTS: In 1980, a total of 80082 women from the Nurses' Health Study with no previous history of cardiovascular disease, cancer, hypercholesterolemia, or diabetes completed a detailed food frequency questionnaire from which we derived usual intake of folate and vitamin B6. MAIN OUTCOME MEASURE: Nonfatal MI and fatal CHD confirmed by World Health Organization criteria. RESULTS: During 14 years of follow-up, we documented 658 incident cases of nonfatal MI and 281 cases of fatal CHD. After controlling for cardiovascular risk factors, including smoking and hypertension and intake of alcohol, fiber, vitamin E, and saturated, polyunsaturated, and trans fat, the relative risks (RRs) of CHD between extreme quintiles were 0.69 (95% confidence interval [CI], 0.55-0.87) for folate (median intake, 696 microg/d vs 158 microg/d) and 0.67 (95% CI, 0.53-0.85) for vitamin B6 (median intake, 4.6 mg/d vs 1.1 mg/d). Controlling for the same variables, the RR was 0.55 (95% CI, 0.41-0.74) among women in the highest quintile of both folate and vitamin B6 intake compared with the opposite extreme. Risk of CHD was reduced among women who regularly used multiple vitamins (RR=0.76; 95% CI, 0.65-0.90), the major source of folate and vitamin B6, and after excluding multiple vitamin users, among those with higher dietary intakes of folate and vitamin B6. In a subgroup analysis, compared with nondrinkers, the inverse association between a high-folate diet and CHD was strongest among women who consumed up to 1 alcoholic beverage per day (RR =0.69; 95% CI, 0.49-0.97) or more than 1 drink per day (RR=0.27; 95% CI, 0.13-0.58). CONCLUSION: These results suggest that intake of folate and vitamin B6 above the current recommended dietary allowance may be important in the primary prevention of CHD among women.

Publication Types:

• Prospective cohort study

Homocysteine and cardiovascular disease: a review of the evidence

Diab Vasc Dis Res. 2007 Jun;4(2):143-50

Wierzbicki AS.

Elevated homocysteine (HCY) levels can be caused by a number of factors, including folate and B-vitamin deficiency, pre-existing atherosclerotic disease, diabetes and various drugs. Epidemiological evidence, as well as data from retrospective and prospective studies, supports an association between elevated HCY levels and increased risk of cardiovascular disease (CVD). However, whether lowering HCY levels by administration of folate and vitamins B6 and B12 is associated with any significant decrease in vascular risk remains the subject of ongoing debate. Although the major studies that have reported to date show that vitamin supplementation was associated with a decrease in HCY levels, this failed to have any significant effect on cardiovascular risk. Furthermore, although some lipid-modifying treatments have been shown to increase HCY levels, there is no evidence that this attenuates or compromises the beneficial effects of such treatments on cardiovascular risk. Taken together, these data suggest that HCY is a marker, rather than a cause, of CVD and therefore do not provide support for routine screening for and treatment of elevated HCY to prevent CVD. Data from ongoing clinical trials are awaited to clarify this issue.

Publication Types:

• Review

Publication Types:

• Review