|Year : 2002 | Volume
| Issue : 3 | Page : 336-343
|Hyperhomocysteinemia and its Role in Chronic Renal Failure
Samir G Mallat, Mabel Aoun
Department of Nephrology, Hotel Dieu Hospital, St. Joseph University, Beirut, Lebanon
Click here for correspondence address and email
|How to cite this article:|
Mallat SG, Aoun M. Hyperhomocysteinemia and its Role in Chronic Renal Failure. Saudi J Kidney Dis Transpl 2002;13:336-43
| Introduction|| |
Homocysteine (Hcy) is an endogenous sulfur-containing intermediate of the essential aminoacid methionine. 
The first step in the synthesis of Hcy is the formation of S-adenosylmethionine (Ado Met), an important methyl donor. AdoMet is then converted to S-Adenosylhomocysteine (AdoHcy), which is further hydrolyzed to yield Hcy and adenosine.  Homocysteine may then enter either transsulfuration or remethylation pathways [Figure - 1]. If methionine stores are adequate, Hcy is converted to cystathionine then cysteine in a series of reactions catalyzed by vitamin B6-dependent enzymes (cystathionine betasynthase and gamma cystathionase). If methionine is required, homocysteine is converted to methionine-by-methionine synthase using vitamin B12 as a cofactor and 5-methyltetrahydrofolate as a substrate or by betaine/Hcy methyl-transferase in the presence of betaine; this latter reaction is confined to the human liver and kidneys.
| Homocysteine: from normal to high levels|| |
The average fasting plasma total homocysteine levels for healthy human subjects range between 6 and 12 µmol/l. Hyperhomocysteinemia is considered moderate with levels between 12 and 30 µmol/L, intermediate between 31 and 100 µmol/L and severe above 100 µmol/L. 
Seventy-five percent of the total plasma homocysteine is bound via a disulfide bond to protein, primarily albumin, while the remaining 25% exists in unbound form. Hyperhomocysteinemia appears when production is accelerated or clearance is decreased.
Folate and vitamin B 12 deficiencies may lead to hyperhomocysteinemia by impairing the remethylation pathway, while vitamin B6 deficiency tends to induce hyperhomocysteinemia by impairing trans-sulfuration that is evident after a methionine load. The methionine-load test consists of administering 100 mg/kg of methionine orally and measuring homocysteine level after two hours; this may uncover about 39% of hyperhomocysteinemia but the clinical value of this test remains uncertain. ,
| Causes of hyperhomocysteinemia|| |
Hyperhomocysteinemia is found in different situations [Table - 1]. Inherited enzymatic deficiencies were the first discovered cause of hyperhomocysteinemia.
Homozygous cystathionine beta-synthase gene deficiency leads to the syndrome of homocysteinuria, a condition in which fasting plasma homocysteine concentrations may reach 400 to 500 µmol/L and includes ectopia lentis, marfanoid features, mental retardation and atherothrombotic events. , Homozygous deficiency of genes encoding to 5,10-methylenetetrahydrofolate reductase and to methionine synthase can also lead to hyperhomocysteinemia.
Other reported associations are advanced age, male sex, nutritional deficiencies (folate, vitamins B 6 and B 12 ), hypothyroidism, malignancies, inflammatory bowel disease, psoriasis, connective tissue disorders such as lupus erythematosus, and finally medications such as nicotinic acid, L-dopa, methotrexate, theophylline, nitrous oxide, cholestyramine, colestipol, metformin, anticonvulsants, androgens.  Cyclosporine has been suggested as an independent risk factor of hyperhomocysteinemia in renal transplant patients,  but two other studies defied this hypothesis. ,
| Hyperhomocysteinemia and renal failure|| |
Hyperhomocysteinemia was first related to renal failure in 1977 by Cohen et al.  As with other amino acids, the healthy kidney has a high capability to filter, reabsorb and metabolize homocysteine. In addition to the filtered load, homocysteine uptake may also occur on the basolateral tubular cell surface,  which means that normal kidneys play a primordial role in homocysteine handling.
In chronic renal failure, hyperhomocysteinemia starts to appear when the glomerular filtration rate (GFR) decreases to less than 70 ml/min. GFR may be equated, for clinical purposes, with creatinine clearance which is normally estimated from serum and urinary creatinine levels. It is noteworthy, however, that creatine, the precursor molecule of creatinine, is derived from S-adeno-sylmethionine, which makes creatinine closely related to the metabolism of homocysteine. Nevertheless, many studies of highly accurate GFR measurements using markers other than creatinine (such as iohexol, 51-Cr-ethylenediaminetetraacetate and cysteine C) showed a net correlation between homocysteine levels and kidney function independently of creatinine. 
Total homocysteine, free homocysteine and bound homocysteine are all increased in renal failure.  There is 80 to 90% of uremic patients who are almost constantly hyperhomocysteinemic. , Levels are elevated in patients with end-stage renal disease (ESRD) on hemodialysis but lower and more stable in patients on peritoneal dialysis.  Homocysteine levels tend to decrease after a hemodialysis session and this effect seems to be sustained for the following eight hours. 
In renal transplants, hyperhomocysteinemia is also present. The mechanism might be related to renal impairment, folate resistance or immunosuppressive therapy such as cyclosporine-A. In a study by Bostom et al,  renal transplant recipients had high prevalence of fasting and postmethionine load hyperhomocysteinemia.
Several mechanisms have been incriminated in causing hyperhomocysteinemia in renal failure. Impaired renal excretion was the first hypothesis, but urinary excretion of homocysteine increases progressively with renal dysfunction. , Another controversial mechanism is impaired renal metabolism via the reduction of functioning renal mass; but van Guldener et al  conducted a study on 20 healthy subjects and found no difference in the homocysteine level between the renal vein and artery of normal kidneys and concluded that kidney tissue had little effect on homocysteine metabolism. The most acceptable current hypothesis is the altered extrarenal metabolism by uremic toxins. , This is supported by three observations considered by Perna et al  in their review of the metabolic consequences of hyperho-mocysteinemia in uremia: first, high doses of folate are not able to normalize homocysteine levels in uremic patients; second, renal transplant recipients respond to high doses of folate; third, highflux dialyzers that eliminate more efficaciously uremic toxins reduce homocysteine levels in the long-term.
In summary, although the exact mechanism of hyperhomocysteinemia in renal failure remains unclear, the most plausible explanation is a defective extra renal clearance of homocysteine.
| Homocysteine and atherogenesis|| |
1. In the general population:
Hcy plays a major role in the pathogenesis of atherosclerosis. ,,,,,,, Mechanisms of vascular injury induced by hyperhomocysteinemia are multiple but the endothelial dysfunction seems to be primordial.
Hcy is incriminated in stimulating the proliferation of the smooth-muscle cell, increasing susceptibility to the oxidation of low density lipoprotiens (LDL), increasing platelet adherence and aggregation, activating the coagulation factors. ,, inhibiting protein C activation, and finally direct damage of the endothelium. , Hcy has been proposed to decrease the bioavailability of nitric oxide by reducing its synthesis or increasing its degradation through the generation of oxygen-derived free radicals such as superoxide anion and hydrogen peroxide. Hyperhomocysteinemia causes attenuation in both endothelium-dependent and endothelium-independent vasodilation by the derangement of nitric oxide synthesis and its subsequent signal transduction. 
Observations in many clinical and epidemiologic studies (about 80 studies) have suggested that hyperhomocysteinemia is an independent risk factor for atherosclerotic disease including coronary, carotid, cerebral, aortic, peripheral vessels and deep venous thrombosis. , However, many other prospective studies showed no association between hyperhomocysteinemia and the incidence of stroke, myocardial infarction or cardiovascular death.  Despite conflicting epidemiologic and clinical data, the hypothesis of atherosclerosis induced by hyperhomocysteinemia is still highly suspected and ongoing further studies are on their way to clarify the matter. 
2. In renal failure:
Uremic patients have a high mortality rate of 9% per year attributable mainly to cardiovascular disease, which is 30 times the risk in the general population. This risk cannot be explained only by the conventional cardiovascular risk factors including hyperparathyroidism in renal failure. Hyperhomocysteinemia seems to be one of the risk factors in the uremic state.  In a report of Perna et al,  Hcy was exposed as a uremic toxin involved in protein membranes damage through the inhibition of methylation reactions via the direct effect of increased concentrations of S-adenosylhomocysteine (AdoHcy). In addition to the hypomethylation reaction caused by hyperhomocysteinemia, causes of atherosclerosis in renal failure induced by the moderate elevated levels of homocysteine resemble those seen in the general population, especially the endothelial dysfunction. ,
In addition to the retrospective casecontrol studies, three prospective studies showed association between hyperhomocysteinemia and cardiovascular disease in ESRD. The first one, conducted by Bostom et al  on 73 dialysis-dependent patients for a median follow-up of 17 months, showed an increased risk for cardiovascular disease related to hyperhomocysteinemia. Another study, conducted by Jungers et al  in pre-dialysis ESRD patients, showed similar results. The last prospective study, conducted by Moustapha et al  in 167 dialysis-dependent patients, showed 76 cardiovascular complications (22 events of arteriovenous fistula thrombosis, 16 of coronary artery disease, 14 of stroke, 14 of peripheral vascular disease and five of deep venous thrombosis), and 12 cardiovascular deaths among the hyperhomocysteinemic patients. Furthermore, it showed that the relative risk for the occurrence of cardiovascular events or death increased 1% for each one µmol/L increase in Hcy concentration. In another prospective study on 84 hemodialysis patients with either fistula or prosthetic graft, a high incidence of fistula thrombosis was associated with hyperhomocysteinemia. Thus, there was a 4% increase in the risk of access thrombosis for each one µmol/L increase Hcy.  The relation between hyperhomocysteinemia and cardiovascular events has also been demonstrated in renal transplant recipients. 
| Treatment of hyperhomocysteinemia in renal failure|| |
On the basis of data suggesting that homocysteine is a major cause of cardiovascular disease in renal failure, many measures have been advocated to reduce the total plasma Hcy level in renal failure.
Folic acid was the first element in the therapeutic protocol of hyperhomocysteinemia. About 18 intervention trials have been conducted using folic acid, vitamin B 6 and/or B12 in peritoneal and hemodialysis patients to prove reduction of hyperhomocysteinemia in addition to five other trials on transplant recipients. , Several studies also assessed predialysis renal failure. ,,
However, in contrast to the response of elevated levels of Hcy in the general population, hyperhomocysteinemia in ESRD patients seemed quite refractory to standard folate-B-vitamin containing supplementation.
In hemodialysis patients, treatment with folic acid at a dose ranging between 1 mg and 30 mg combined or not to vitamins B6 and B12 showed a relative reduction of homocysteine levels of about 15 to 35% with levels greater then 12 µmol/L in 90% of them. In a recent review on folate metabolism, De Vriese et al, suggested that folate metabolism was disturbed in uremia and might be responsible for the inefficiency of folate to normalize homocysteine in patients with renal failure.  However, Bostom et al and Yango et al found normal folate metabolism in renal failure. ,
In renal transplant recipients, high doses of folate succeeded in a larger reduction of total homocysteine levels. In a trial by Beaulieu et al, homocysteine level less than 12 micromoles was attainable in the majority of the renal transplant patients by using a combination of folic acid (2.4 mg), vitamin B6 (50 mg) and vitamin B12 (0.4 mg).  In predialysis renal failure, even high-dose folic acid failed to normalize hyperhomocysteinemia. 
The failure of folate to normalize homocysteine levels has incited to use alternative therapies for management of hyperhomocysteinemia such as methyl-tetrahydrofolate (MTHF) and folinic acid instead of folic acid. ,, MTHF and folinic acid are the reduced forms of folic acid and seem to be metabolically more active than folate. Folinic acid is the immediate precursor of 5-10methylenetetrahydrofolate, which produces MTHF. MTHF is necessary for the conversion of homocysteine to methionine. It has been demonstrated that using folinic acid or MTHF instead of folate reduced homocysteine levels by 70%. , However, two trials showed equal efficacy of folinic acid and methyltetrahydrofolate versus folic acid. , Accordingly, this alternative regimen is yet to be confirmed by other large and controlled studies.
Modification of the dialysis prescription in order to improve homocysteine clearance has been suggested. However, the use of highflux dialyzers in a randomized controlled trial by Andrew et al  did not show significant reduction of homocysteine levels after three months of the study. Despite that, another study was promising with the long-term use of the highflux dialyzers.  On the other hand, a recently published study by Friedman and al,  concluded that total homocysteine level was lower among patients undergoing nocturnal hemodialysis (NHD) compared to standard hemodialysis.
Finally, treatment with folate, though reducing homocysteine levels did not show any improvement in endothelial function in ESRD patients in many experimental trials. ,, In addition, it is still not known whether reduction of plasma homocysteine by vitamin therapy will reduce cardiovascular morbidity and mortality in ESRD patients. Recently, a large randomized placebocontrolled trial studying the effect of homocysteine-lowering therapy on cardiovascular end points in 4000 stable renal transplant recipients has been initiated in the USA.
We conclude that the current data on hyperhomocysteinemia in renal failure can be summarized as the following:
The pathogenesis of hyperhomocysteinemia in renal failure is not yet clear with a great tendency to the hypothesis of altered extrarenal clearance by uremic toxins.
Hyperhomocysteinemia may be a cause of endothelial dysfunction in patients with kidney disease, a state that might be responsible of atherogenesis.
The moderately elevated homocysteine level in ESRD patients seems to be an independent cardiovascular risk factor for morbidity and mortality.
Hyperhomocysteinemia may be a risk factor for thrombosis of dialysis access in hemodialyzed patients.
Treatment with folate, with or without vitamin B 6 and B 12 , reduces, but fails to normalize plasma homocysteine level in a large proportion of ESRD patients either in predialysis stage, on hemodialysis, peritoneal dialysis or even after transplantation.
The alternative therapies using the reduced forms of folic acid, folinic acid and MTHF, still need further evaluation.
Studies on evaluating the effect of reducing hyperhomocysteinemia on the cardio vascular disease in ESRD patients are still unavailable.
Whether screening for hyperhomocysteinemia in renal failure patients and administering folate and vitamin B6 should be done routinely to prevent cardiovascular mortality and morbidity is still unresolved. Further large and controlled trials are needed.
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Samir G Mallat
Nephrology Department, Hotel Dieu de France, St. Joseph University, Beirut
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