LAUSR

Chronic kidney disease (CKD) patients are a growing population worldwide, affected by a high cardiovascular risk. The cause of this increase is certainly multifactorial; one of the possible culprits that have been invoked may lie in the marked derangement in the complex sulfur metabolism peculiar to these patients, leading to altered levels of several compounds in this pathway (Fig. 1). Homocysteine is probably the most studied among these; however, despite the huge amount of evidence that homocysteine, and/or one of its precursors/metabolites, is toxic [1, 2], the negative interventional trials brought the scientific community to consider it as the epitome of something that does not come through [3]. It is possibile that the negative results of the trials in CKD patients, conducted by the way in countries where folate fortification is mandatory, can be ascribed to the presence in the intervention of cianocobalamin [4]. Vitamin B12 is necessary for correct homocysteine remethylation, but cianocobalamin in CKD can accumulate and be detrimental. Another reason could be related to the possible adverse effects of high-dose folic acid, for example due to the presence of circulating UnMetabolized Folic Acid [UMFA, 5]. Slowly, however, new evidence is arising. In the China Stroke Prevention Primary Prevention Trial (CSPPT), it has been shown that low-dose folic acid (0.8 mg/day) is able to reduce the incidence of primary stroke in hypertensive patients [6]. In addition, a pre-specified CSPPT substudy demonstrates that low-dose folic acid is effective in slowing down the progression of CKD. Patients with moderate CKD (eGFR between 30–60 ml/min) benefit the most. The common methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism influences homocysteine levels and the renal outcome response [7]. Thus, if data are confirmed also in other populations, low-dose folic acid could constitute another tool to contrast CKD progression in our still scarce therapeutic armamentarium. The cross-sectional study by Cohen et al. [8] conveys a wealth of information in a very large cohort of subjects (n = 17,010) on the homocysteine issue [8]. Patients were referred for screening by their employers, and were 67% men. Israel is a country, like China, where no folic acid fortification is implemented. The association between homocysteine concentrations and CKD was looked upon and is confirmed at all levels of renal disease, while also adjusting for confounders which can affect CKD, such as age, smoking status, body mass index, hypertension and diabetes mellitus. The association is present in both men and women. Subjects with homocysteine > 15 μM were more likely to have an eGFR < 60 ml/min, and to have proteinuria. At a GFR < 60 ml/min, homocysteine was progressively higher in stages 3a, 3b, and 4 of CKD, with quite a large discrepancy between stage 3a and 3b, particularly in women. This could be of interest, given the fact that stage 3b is the one were cardiovascular disease hits the most, and it is therefore most likely to benefit from low-dose folic acid. This is the first study carried out in such an elevated number of patients, outside China, in a country with no folate fortification policy. While it does not prove cause and effect relationships (homocysteine and CKD, homocysteine and CKD progression, homocysteine and atherosclerosis, etc.), Spence et al. have shown for example that homocysteine accounts for a significant part of the effect of renal impairment on atherosclerosis [9]. This paper by Cohen et al. therefore paves the way for future studies on this topic. A detailed scheme of the metabolic interconnections of homocysteine with sulfur amino acids, folate cycle, B vitamins, and one carbon (C1) metabolism is provided in Fig. 1. Methionine is converted into S-adenosylmetionine (SAM; AdoMet), the universal methyl donor for several tens of SAM-dependent methyltransferases (MTs) in humans. Methyl acceptors include small molecules (guanidino * Alessandra F. Perna [email protected]