Homocysteine in uraemia—a puzzling and conflicting story

Mohamed E. Suliman1, Peter Bárány1, Kamyar Kalantar-Zadeh2, Bengt Lindholm1 and Peter Stenvinkel1

1 Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Karolinska University Hospital at Huddinge, Stockholm, Sweden and 2 Division of Nephrology and Hypertension, Harbor-UCLA Medical Center, Torrance, CA 90509, USA

Correspondence and offprint requests to: Peter Stenvinkel, MD, PhD, Department of Renal Medicine, K56, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden. Email: peter.stenvinkel{at}klinvet.ki.se



   Introduction
 Top
 Introduction
 Is homocysteine a vascular...
 Homocysteine is associated with...
 Diabetes mellitus (DM) may...
 Homocysteine—another case...
 Do patients reaching dialysis...
 Conclusion
 References
 
Homocysteine (Hcy) is a non-protein sulfur-containing amino acid that consists of various forms: a protein-bound fraction (70–80%), a free oxidized form (20–30%) and a free reduced form (~1%), which recently has attracted considerable interest as it may, by several mechanisms (Table 1) mediate premature atherosclerosis and cardiovascular disease (CVD). Indeed, in the general population, the results have shown that even mildly elevated plasma total homocysteine (tHcy) levels are associated with an increased cardiovascular risk [1–3]. However, not all prospective cohort studies are consistent with this finding [2] and, so far, the result of a large vitamin intervention study is not promising [4].


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Table 1. Proposed effects by which homocysteine may promote vascular disease

 
The normal range of tHcy is 3–15 µmol/l, and many factors may influence this level [5]. Beside nutritional deficiencies of B vitamins and genetic factors (C677T mutation of methylenetetrahydrofolate reductase; MTHFR), renal failure is one of the most frequent clinical causes of hyperhomocysteinaemia. Patients with end-stage renal disease (ESRD) usually have 2–3 times higher levels of tHcy and the prevalence of hyperhomocysteinaemia in this patient group is >90% [6–8]. Although several processes may explain the close correlation between kidney function and the plasma tHcy concentration, the exact mechanism(s) by which renal failure leads to hyperhomocysteinaemia are not completely understood. However, it has been reported that the fractional extraction of Hcy across the kidney is related to renal plasma flow [9].



   Is homocysteine a vascular risk factor in ESRD?
 Top
 Introduction
 Is homocysteine a vascular...
 Homocysteine is associated with...
 Diabetes mellitus (DM) may...
 Homocysteine—another case...
 Do patients reaching dialysis...
 Conclusion
 References
 
In contrast to the well documented association between tHcy and CVD in the general population, the association between tHcy and risk for atherothrombotic disease is not a consistent finding in ESRD (Table 2). Whereas some cross-sectional studies report higher levels of tHcy in ESRD patients with CVD [10–15], others report no difference in tHcy levels [16] or even paradoxically lower tHcy levels in CVD patients [6,7,17–19] (Table 2). Likewise, prospective studies revealed either a graded increase in relative risk with the rise of tHcy [20–25] or a worse outcome in patients with lower tHcy [7,19,26,27], whereas other studies did not find a difference between low and high tHcy levels [28,29]. Clearly, some of the studies investigating the association between high tHcy and poor outcome in ESRD patients are subject to some restrictions (see below). For example, in the study by Mallamaci et al. [22] patients with cardiovascular congestion were not included.


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Table 2. Plasma total homocysteine in relation to cardiovascular disease and survival in chronic kidney disease patients

 
Among many suggested mechanisms that may explain the relationship between hyperhomocysteinaemia and CVD (Table 1) in ESRD patients, endothelial dysfunction (a common phenomenon in this patient group) may be one of the most important. Indeed prolonged exposure of endothelial cells to Hcy impairs the production of nitric oxide and endothelium-dependent vasodilation [30]. The concept of Hcy-mediated endothelial dysfunction has been confirmed in a group of healthy adults with a high Hcy level [31]. However, recent small size studies with short intervention periods show no benefit of Hcy-lowering therapy on either endothelial dysfunction [32] or cardiovascular events [26] in ESRD patients. Moreover, in contrast to two positive clinical trials [33,34], a recent large intervention study in the general population failed to find an effect of Hcy-lowering therapy on vascular outcomes during a 2 year follow-up [4]. Although large-scale Hcy-lowering trials in the non-renal population are currently underway [35], it may be difficult (if a benefit is demonstrated) to distinguish whether this is due to reduction of Hcy level per se or caused by the documented direct beneficial action of folic acid on endothelial function [35].

In patients with homocystinuria due to cystathione ß-synthase deficiency, Yap et al. [36] showed that Hcy-lowering treatment regimens, including folic acid, significantly reduced cardiovascular risk despite a high post-treatment Hcy level. This study suggests that the observed decline in cardiovascular events may either be due to cause(s) other than a reduction in tHcy level or may disprove the concept that mild hyperhomocysteinaemia is a cardiovascular risk factor [35,36]. It is also possible that the reduced form of Hcy, rather than tHcy, may be the Hcy fraction that exerts the toxic effects on blood vessels. Indeed, Hoffer et al. [37] reported that the level of reduced Hcy increases in parallel to the level of tHcy in both renal patients and healthy subjects. To the best of our knowledge, there are no studies that have evaluated the putative association between the reduced form of Hcy level and cardiovascular events, although it has been shown recently that increased levels of the reduced form of Hcy, rather than other forms, were associated with endothelial dysfunction after oral methionine and oral Hcy loading in healthy subjects [38]. Another interesting mechanism by which Hcy may promote vascular injury was proposed recently by Ingrosso et al. [39]. They suggested that high Hcy levels in ESRD induce toxicity by an increase in total DNA hypomethylation, linked to a defect in the expression of genes regulated by methylation, and that folic acid supplementation restores DNA methylation, thereby correcting the abnormal gene expression.



   Homocysteine is associated with nutritional and inflammatory biomarkers
 Top
 Introduction
 Is homocysteine a vascular...
 Homocysteine is associated with...
 Diabetes mellitus (DM) may...
 Homocysteine—another case...
 Do patients reaching dialysis...
 Conclusion
 References
 
The fact that a high tHcy level does not show up as a risk factor for CVD in some studies of uraemic patients may appear puzzling. However, a number of factors or reasons may explain the observed discrepancies (Table 3). No doubt, discrepancies in the studies evaluating the relationship between plasma tHcy and outcome in ESRD patients can be partially attributed to differences in study design and population, i.e. selection bias. Indeed, some study sample sizes were relatively small with heterogeneous study populations. Moreover, most studies did not account for confounding risk factors, such as differences in type of dialysis, duration of dialysis, residual renal function, race, gender, genetic variations and prevalence of co-morbidities. Among the confounding factors that seem to influence the tHcy level the most in ESRD patients are hypoalbuminaemia, malnutrition and inflammation (inter-related factors that may initiate or aggravate atherosclerosis in ESRD). Circulating tHcy exists mainly as the protein-bound form, with albumin being the main Hcy-binding protein, and this is reflected by a positive correlation between plasma tHcy and serum albumin, as has been reported in ESRD patients [7,27]. In a longitudinal follow-up study in ESRD patients for 12 months during dialysis treatment, we confirm a strong correlation between baseline levels of tHcy and serum albumin, and between changes in tHcy levels and changes in serum albumin levels (Figure 1).


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Table 3. Putative causes and/or reasons that may explain why plasma total homocysteine (tHcy) does not show up as a cardiovascular risk factor in all studies of ESRD patients

 


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Fig. 1. The relationship between plasma total homocysteine (tHcy) and serum albumin in ESRD patients starting dialysis treatment (top) and the relationship between the changes ({Delta}) in the concentrations of tHcy and serum albumin during the first 12 months of dialysis therapy (bottom).

 
Another important finding in some of the studies with a reverse association in ESRD patients is the documented strong correlation between tHcy and serum creatinine, even stronger than that seen with serum albumin [27]. Although this finding may reinforce a strong nutritional component of tHcy, the correlation between tHcy and serum creatinine concentration could also be the result of the metabolic association between serum creatinine and tHcy. Indeed, the formation of creatine, the precursor of creatinine, depends on methyl donation by S-adenosylmethionine to become S-adenosyl-Hcy, leading to the formation of Hcy. Recent studies have shown that patients with signs of malnutrition have a lower plasma tHcy level than patients with normal nutritional status [6,7,27]. The impact of nutrition is also supported by the observation that the tHcy level increased in malnourished peritoneal dialysis patients after exposure to amino acid-based peritoneal dialysis solution [40]. Thus, there is a strong nutritional component driving the relationship between tHcy and outcome in ESRD. As inflammation and wasting are inter-related in ESRD [41], it could be hypothesized that inflammation may also contribute to the relationship between elevated tHcy and outcome in ESRD patients. Although recent findings by our group [42] showing that inflamed [C-reactive protein (CRP) ≥10 mg/l] ESRD patients had lower tHcy than non-inflamed patients support this hypothesis, no such relationship was reported in another study [27].



   Diabetes mellitus (DM) may also influence the association between tHcy and outcome
 Top
 Introduction
 Is homocysteine a vascular...
 Homocysteine is associated with...
 Diabetes mellitus (DM) may...
 Homocysteine—another case...
 Do patients reaching dialysis...
 Conclusion
 References
 
As studies in ESRD patients [6,27,43] and in diabetic patients without overt nephropathy [44] showed lower plasma tHcy levels in diabetic patients than in non-diabetics, the presence of DM may also influence the association between tHcy and outcome. Although the mechanism(s) responsible for the reduction of tHcy levels in patients with DM is unknown, it has been suggested that the demethylation pathway may be disturbed in diabetic patients [43]. Nonetheless, in a recent study [6], we found lower serum albumin and higher prevalence of malnutrition in diabetic patients than in non-diabetic patients, which might have influenced the plasma tHcy levels. Hence, since the prevalence of DM is high in ESRD, its presence further complicates the observed relationship.



   Homocysteine—another case of reverse epidemiology in ESRD
 Top
 Introduction
 Is homocysteine a vascular...
 Homocysteine is associated with...
 Diabetes mellitus (DM) may...
 Homocysteine—another case...
 Do patients reaching dialysis...
 Conclusion
 References
 
Clearly, fundamental differences in the study designs, such as the lack of information about prevalence of malnutrition and inflammation in studies with positive association, may make direct comparisons between different studies difficult. However, the reverse association in ESRD patients compared with the general population is not unique for tHcy. Well-established cardiovascular risk factors in the general population, such as serum cholesterol, blood pressure and body size, all have inverse associations with mortality in ESRD [45,46]. As clinical studies so far have failed to find an association between advanced glycation end-products and clinical outcome in ESRD [47,48], this may be yet another example of this phenomenon. However, the presence of a reverse association does not as such indicate that the vascular pathophysiology is different in ESRD, but may suggest that confounding factors are responsible for the paradoxical relationship. Indeed, the study by Liu et al. [49] showed that the presence of inflammation and malnutrition in ESRD alters the association between cholesterol and mortality in dialysis patients.



   Do patients reaching dialysis treatment constitute a group of survivors?
 Top
 Introduction
 Is homocysteine a vascular...
 Homocysteine is associated with...
 Diabetes mellitus (DM) may...
 Homocysteine—another case...
 Do patients reaching dialysis...
 Conclusion
 References
 
Another possible explanation for the observed relationship is the naturally occurring survival bias, a form of a selection bias. A recent study by Keith et al. [50] showed in 27 998 renal patients that death was far more common than reaching dialysis at all stages of kidney disease. Hence, chronic kidney disease patients reaching dialysis may be considered as a selected population of exceptional individuals surviving years of a hostile uraemic milieu [46]. Clearly, this intriguing hypothesis needs to be investigated further. It must also be appreciated that publication bias may have played a role, especially since studies that have shown the reverse epidemiology of tHcy in ESRD invariably have a recent origin. Previous findings with reverse association might not have been reported, since the investigators of such findings considered them erroneous. However, as more and more studies have now indicated the risk factor paradox, an increasing number of such ‘reversed’ findings, pertaining not only to tHcy but also to other risk factors in ESRD patients, have emerged recently [46].



   Conclusion
 Top
 Introduction
 Is homocysteine a vascular...
 Homocysteine is associated with...
 Diabetes mellitus (DM) may...
 Homocysteine—another case...
 Do patients reaching dialysis...
 Conclusion
 References
 
Considering the facts that even a mild increase in the tHcy level appears to be a vascular risk factor in the general population and the high prevalence of hyperhomocysteinaemia in ESRD, the paradoxical reverse association between tHcy and clinical outcome in ESRD patients does not, as such, refute a possible role for Hcy in the vascular pathogenesis. Clearly, as the absence of evidence is not the evidence of absence, hyperhomocysteinaemia may still represent one of many, factors in uraemia, which contributes to an increased vascular risk. However, since hyperhomocysteinaemia is an inherent feature of uraemia (and therefore an increased risk due to this complication) and is a more or less constant consequence of uraemia, the impact (if any) of incremental changes in the tHcy level above the ‘normal’ uraemic hyperhomocysteinaemia may not be as important as many other non-conventional risk factors, such as wasting, inflammation and vascular calcification. As the role of Hcy in promoting vascular injury in ESRD patients is presently unclear, provision of folic acid/multivitamin supplementation to ESRD patients is, in our opinion, not strongly supported by published data. However, it could be argued that the treatment still could be proposed in these patients, since folic acid supplementation has no apparent side effects and is inexpensive. Interestingly, the active debate about Hcy as an independent risk factor for CVD has generated new fascinating aspects of Hcy as a risk factor, not only for vascular disease, but also for other complications. For example, recent studies reported that tHcy may be an independent risk factor for bone fractures in older non-renal patients [51,52]. Therefore, it may be worthwhile to withhold any interventional trial until the clarification of the complex effects of the uraemic milieu on Hcy toxicity in ESRD patients. Furthermore, the current debate has highlighted the issue of ‘reverse epidemiology’ and should now encourage the nephrological community to identify the complex effects of the uraemic milieu on traditional risk factors.



   Acknowledgments
 
Conflict of interest. B.L. is an employee of Baxter Corp.



   References
 Top
 Introduction
 Is homocysteine a vascular...
 Homocysteine is associated with...
 Diabetes mellitus (DM) may...
 Homocysteine—another case...
 Do patients reaching dialysis...
 Conclusion
 References
 

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