Diabetic Nephropathy - Pathology

Homocysteine (secundary pathology) - updated: 15 March 2008

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

Toxic effects of hyperhomocysteinemia in chronic renal failure and in uremia: cardiovascular and metabolic consequences

Semin Nephrol. 2006 Jan;26(1):20-3

Perna AF, Capasso R, Acanfora F, Satta E, Lombardi C, Ingrosso D, Violetti E, Romano MM, De Santo NG.

Hyperhomocysteinemia, highly prevalent in well-nourished patients with chronic renal failure and in uremia, causes toxic effects that can be envisioned in terms of cardiovascular risk increase. However, its effects on cellular metabolism and on gene expression, not to mention receptor regulation, only recently are being evaluated. For example, it has been shown that hypomethylation induced by hyperhomocysteinemia can alter erythrocyte membrane protein repair and gene expression. In addition, increased plasma protein L-isoaspartyl content, related to hyperhomocysteinemia and uremic toxicity, determines specific effects on protein function, with a reduced binding of homocysteine to albumin. We propose that uremia is a state in which proteins present a widespread derangement of structure-function relationships.

Publication Types:

• Review

Causes of hyperhomocysteinemia in patients with chronic kidney diseases

Semin Nephrol. 2006 Jan;26(1):3-7

Garibotto G, Sofia A, Valli A, Tarroni A, Di Martino M, Cappelli V, Aloisi F, Procopio V.

Plasma homocysteine (Hcy) levels are increased significantly in patients with moderate renal failure and increase markedly in patients with end-stage renal disease. An increase in plasma Hcy level theoretically could be caused by an increased production rate (ie, transmethylation), a decreased rate of removal by transsulfuration or remethylation, or a decrease in the excretion of Hcy. Current evidence indicates that the major mechanism for hyperhomocysteinemia in renal failure is a decrease in Hcy removal from the body. However, it is debated whether this effect is the result of a decrease in the renal metabolic clearance or a result of extrarenal metabolic changes. The human kidney plays a major role in the removal of several aminothiols or Hcy-related compounds from the circulation (eg, cysteine-glycine, glutathione, AdoMet, and AdoHcy). However, the glomerular filtration of Hcy seems to be restricted because of protein binding. Besides glomerular filtration, the normal kidney can remove Hcy by plasma flow and peritubular uptake. Although in the low normal range in absolute terms, the flow through the transsulfuration pathway is reduced if related to Hcy levels in uremia; in addition, the remethylation pathway also is impaired. Besides the potential effect of the reduced renal mass on Hcy removal, available evidence suggests the occurrence of a generalized down-regulation of the methionine cycle and catabolism in uremia. AdoHcy, sulfate, and dimethylglycine currently are being investigated as retained solutes that can inhibit 1 or more pathways of Hcy metabolism. In addition, the high Hcy levels decrease in malnourished end-stage renal disease patients and change according to nutrient intake and several other nutritional parameters, indicating that circulating Hcy levels become an expression of nutritional status

Publication Types:

• Review

Homocysteine and renal disease

Semin Thromb Hemost. 2000;26(3):313-24

van Guldener C, Robinson K.

Hyperhomocysteinemia refers to an elevated circulating level of the sulfur-containing amino acid homocysteine and has been shown to be a risk factor for vascular disease in the general population. In patients with renal failure, hyperhomocysteinemia is a common feature. The underlying pathophysiological mechanism for this phenomenon is unknown. Proposed mechanisms include reduced renal elimination of homocysteine and impaired nonrenal disposal, possibly because of inhibition of crucial enzymes in the methionine-homocysteine metabolism by the uremic milieu. Absolute or relative deficiencies of folate, vitamin B6, or vitamin B12 may also play a role. Several case-control and prospective studies have now indicated that hyperhomocystenemia is an independent risk factor for atherothrombotic disease in patients with predialysis and end-stage renal disease. In renal patients, plasma homocysteine concentration can be reduced by administration of folic acid in doses ranging from 1 to 15 mg per day. In more than 50% of the cases, however, the homocysteine concentration remains above 15 micromol/L. The effects of vitamin B12 or vitamin B6 are unclear. Large intervention trials are now needed to establish whether homocysteine-lowering therapy will reduce atherothrombotic events in patients with renal failure. These studies are now planned or are ongoing.

Publication Types:

• Review

Homocysteine and diabetic macroangiopathy

Nippon Rinsho. 2006 Nov;64(11):2153-8

Araki A.

Moderate hyperhomocysteinemia is one of risk factors for arteriosclerotic disease. In diabetic patients, hyperhomocysteinemia is an independent risk factor for macroangiopathy and mortality. Homocysteinemia is also associated with diabetic microangiopathy, silent stroke, and cognitive impairment. However, excluding those with nephropathy or microangiopathy, plasma homocysteine is lower in diabetic patients than non-diabetic controls. Oral treatment with folic acid, vitamin B12 and B6 reduces plasma homocysteine concentration about by 30%. The vitamin treatment for reduction of hyperhomocysteinemia improves endothelial dysfunction and retards carotid atherosclerosis. Few randomized control trials have showed a positive effect of the vitamin treatment on prevention from stroke and ischemic heart disease. Further prospective intervention studies are necessary to address the issue whether lowering homocysteine does prevent the development and progression of diabetic macroangiopathy.

Publication Types:

• Review

Publication Types:

• Review