Why is homocysteine elevated in renal failure and what can be expected from homocysteine-lowering?

Extract

Patients with chronic kidney disease, especially end-stage renal disease (ESRD), exhibit many abnormalities in protein and amino acid metabolism. One of these alterations involves an increased plasma concentration of the sulphur-containing amino acid homocysteine. Hyperhomocysteinaemia has attracted a lot of attention in renal patients, not only because of its close relationship with renal function, but also because it has been implicated as an independent cardiovascular risk factor in these patients [ 1–3 ], although some recent studies have found no significant or even an inverse association between plasma homocysteine level and cardiovascular events and mortality in ESRD patients [ 4–6 ]. These discordant findings may have been caused by strong confounders which are associated with low homocysteine levels and increased mortality, such as protein energy malnutrition and/or inflammation [ 7 ].

Homocysteine and renal function

Plasma homocysteine is strongly correlated with (estimates of) glomerular filtration rate (GFR). Hyperhomocysteinaemia, defined as a plasma total homocysteine level of 12 µmol/l, occurs already at a GFR of about 60 ml/min and when ESRD has been reached, the prevalence of hyperhomocysteinaemia is 85–100%. The association between plasma homocysteine and GFR seems linear and is present even in the hyperfiltrating range [ 8 , 9 ]. The precise mechanism by which GFR is related to plasma homocysteine concentration is not definitively established. There is a reasonably good clinical evidence that hyperhomocysteinaemia does not cause renal insufficiency [ 10–12 ], although a recent study has linked higher homocysteine levels to a greater decline of GFR [ 13 ]. The association between hyperhomocysteinaemia and renal dysfunction may therefore be causal, i.e. renal failure causes elevated plasma homocysteine levels, but the relationship may also be due to other confounding factors, which on the one hand lead to renal dysfunction and on the other hand cause hyperhomocysteinaemia by different mechanisms. Two, not mutually exclusive hypotheses for the first possibility are: (i) homocysteine disposal in the kidneys themselves is disturbed and (ii) extrarenal homocysteine metabolism is impaired. Factors that cause renal dysfunction and hyperhomocysteinaemia by different mechanisms have not been identified.