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Clinical Chemistry 51: 891-897, 2005. First published March 17, 2005; 10.1373/clinchem.2004.044453
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(Clinical Chemistry. 2005;51:891-897.)
© 2005 American Association for Clinical Chemistry, Inc.

General Clinical Chemistry

Disturbed Homocysteine and Methionine Cycle Intermediates S-Adenosylhomocysteine and S-Adenosylmethionine Are Related to Degree of Renal Insufficiency in Type 2 Diabetes

Wolfgang Herrmann1,a, Heike Schorr1, Rima Obeid1, Julia Makowski2, Brian Fowler3 and Martin K. Kuhlmann2,4

1 Department of Clinical Chemistry, Central Laboratory, and 2 Department of Nephrology and Hypertension, Saarland University Hospital, Homburg, Germany.
3 Metabolic Unit, University Children’s Hospital, Basel, Switzerland.
4 Renal Research Institute, New York, NY.

aAddress correspondence to this author at: Zentrallabor der Universitätskliniken des Saarlandes, Gebäude 57, 66421 Homburg, Germany. Fax 49-6841-1630703; e-mail kchwher{at}uniklinik-saarland.de.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Diabetic nephropathy is a common complication in patients with type 2 diabetes that may increase atherothrombotic risk. Hyperhomocysteinemia (HHcy) further increases the risk in those patients. We studied concentrations of total homocysteine (tHcy) and its related metabolites S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy) in relation to B-vitamin status and renal function in patients with type 2 diabetes who developed diabetic nephropathy.

Methods: The study included 93 patients with renal failure and type 2 diabetes. Chronic kidney disease was classified into four subgroups according to the National Kidney Foundation based on glomerular filtration rate plus pathologic abnormalities or markers of kidney damage.

Results: Serum or plasma concentrations of the metabolites increased significantly with worsening of renal function, whereas serum concentrations of the B vitamins (folate, vitamins B12 and B6) did not differ appreciably between the groups. Moreover, plasma concentrations of AdoHcy and AdoMet were markedly increased in patients with kidney failure compared with those in stage 2 (median AdoHcy, 112.7 vs 10.5 nmol/L; median AdoMet, 162.0 vs 80.0 nmol/L). The AdoMet/AdoHcy ratio was more than 80% lower in patients with renal failure compared with stage 2. Vitamin B12 was a significant determinant of concentrations of AdoMet, tHcy, methylmalonic acid (MMA), and cystathionine.

Conclusions: Increased plasma concentrations of tHcy and methionine cycle intermediates (AdoMet, AdoHcy) are related to disturbed renal function in patients with type 2 diabetes. Vitamin B12 and/or folate are significant predictors of tHcy, cystathionine, MMA, and AdoMet. The effect of therapeutic doses of the B vitamins on AdoMet, AdoHcy, and their ratio should be tested in renal patients.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Impaired renal function, a major complication in patients with type 2 diabetes mellitus, increases the risk for atherothrombotic diseases (1). Increased total homocysteine (tHcy;1 i.e., 15–80 µmol/L) is very common in renal patients (2)(3)(4). Hyperhomocysteinemia (HHcy) is an additional factor that increases the risk of vascular diseases in general and in renal patients in particular (3)(4). Furthermore, persons with type 2 diabetes are more susceptible to the harmful effects of HHcy than are nondiabetic individuals (5). Diabetic patients with HHcy have a higher mean intima-media thickness (5) and a higher susceptibility for fatal and nonfatal coronary events (6) than do normohomocysteinemic patients.

The kidney plays an important role in Hcy metabolism (7). Variations in renal function, even within the physiologic range, are an important determinant of interindividual differences in plasma concentrations of tHcy (7). Glomerular filtration rate (GFR) is a rate-limiting factor for the renal clearance of Hcy (8). The urinary excretion of Hcy has been found to be negligible in healthy persons (9). Furthermore, the fractional extraction of Hcy across the human kidney varies according to renal blood flow (10). These findings imply major alterations in the metabolism of this aminothiol in patients with end stage renal disease. Moderate HHcy in rats was associated with marked glomerular damage and sclerosis (11), renal tubulointerstitial injury, increased urinary albumin excretion, and decreased renal blood flow, GFR, and sodium and water excretion (12). In line with these data, treatment with folic acid and vitamin B6 lowered not only plasma tHcy, but also urinary albumin excretion in humans (13).

Hcy is produced from the hydrolysis of S-adenosylhomocysteine (AdoHcy) in a reversible reaction catalyzed by AdoHcy hydrolase. This reaction proceeds in the forward direction as long as the product, Hcy, is efficiently removed via the remethylation or the transsulfuration pathways. However, the conversion of Hcy into AdoHcy is favored under conditions of HHcy, which is the case in renal insufficiency. Previous studies underlined that AdoHcy is profoundly increased in plasma and erythrocytes of renal patients (14)(15). Furthermore, many transmethylation reactions are inhibited by AdoHcy through its competition with the natural substrate, S-adenosylmethionine (AdoMet), for binding domains in transmethylase enzymes (15)(16)(17)(18). The AdoMet/AdoHcy ratio is a more important determinant of cellular methylation potential than the is absolute amount of AdoMet (18)(19)(20)(21).

Serum concentrations of cystathionine and methylmalonic acid (MMA) are also increased in renal patients (22). The pathogenesis of HHcy and the disturbed methylation potential are not fully understood. Folate and vitamins B12 and B6 are important regulators in the metabolism of Hcy. Evaluating some cardiovascular risk factors, such as Hcy and related metabolites in patients with diabetes who have mild to moderate decreased GFR values may allow better management and reduce further complications. We aimed at investigating tHcy and it related metabolites, AdoMet, AdoHcy, cystathionine, cysteine, and MMA, in addition to vitamin B12, holo-transcobalamin (holoTC), vitamin B6, and folate in patients with overt diabetic nephropathy and various stages of chronic kidney disease.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
patients
Patients (n = 93) were recruited from the Department of Medicine, Division of Nephrology of the University Hospital of Saarland, Germany. Inclusion criteria included age >17 years, established diabetic nephropathy as primary cause of renal disease, and type 2 diabetes for at least 6 years. Exclusion criteria included cancer, stroke, thrombosis or myocardial infarction within the previous 3 months, and the consumption of any vitamin supplements within the previous 4 weeks. No patient had received antifolate or antiepilepsy medications or medications known to affect Hcy metabolism. All patients were clinically stable at the time of recruitment. Chronic kidney disease was classified according to the National Kidney Foundation into stages based on GFR plus pathologic abnormalities or markers of kidney damage (23). Stage 2 included patients with kidney damage and mildly decreased GFR (60–89 mL/min); stage 3 included patients with moderately decreased GFR (30–59 mL/min); stage 4 included patients with severely decreased GFR (15–29 mL/min); and stage 5 included patients with kidney failure (GFR <15 mL/min or dialysis). GFR was estimated from serum creatinine concentration, age, and gender by use of the well-validated MDRD equation. The study was approved by the Medical Ethical Committee of the University of Saarland, and all patients gave informed consent for the study.

blood collection and laboratory procedures
Blood from dialysis patients was obtained at the start of a regular dialysis treatment and in nondialysis patients during their visit in our outpatient clinics. Blood samples without anticoagulant and with EDTA were immediately chilled on ice and centrifuged within 1 h for 10 min at 2000g and 4 °C. Serum aliquots were stored at –70 °C for further analysis. EDTA-plasma samples (1 mL) were immediately deproteinized by addition of 0.625 mL of 100 mL/L perchloric acid. Deproteinized plasma samples were kept at –70 °C until analysis. The concentrations of AdoHcy and AdoMet were measured in deproteinized plasma by reversed-phase chromatography with fluorescence detection according to the method described by Loehrer et al. (14). Briefly, etheno derivatives of both metabolites were separated on a Hypergrom ODS column [200 x 4 mm (i.d.); 3 µm bead size] with a guard column [20 x 4 mm (i.d.)] filled with the same packing material. Serum concentrations of tHcy, cystathionine, and MMA were measured by gas chromatography–mass spectrometry as described elsewhere (24).

The concentrations of vitamin B12 and folate were determined in serum by a chemiluminescence immunoassay (ADVIA Centaur System; Bayer). Serum vitamin B6 (pyridoxal 5-phosphate) was measured by HPLC with fluorescence detection, using reagents from Immundiagnostik. HoloTC, the biologically active bound form of vitamin B12, was measured in serum by a RIA method as described previously (Axis-Shield) (25). Other analytes were measured by routine methods at our laboratory.

Data analyses were performed with the software package SPSS (Ver. 11.0; SPSS). Continuous variables were examined for distribution by the Kolmogorov–Smirnov test. All continuous variables were skewed and were therefore log-transformed before application of tests that assume a gaussian distribution. Differences in continuous variables between the groups were examined by ANOVA and post hoc Tamhane tests. Backward stepwise multivariate regression analysis was conducted to predict factors that influenced serum concentrations of the metabolites. A P value <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The main characteristics of the study population are listed in Table 1 according to the stage of renal dysfunction. As would be expected, patients in stage 5 had the worst renal function as indicated by a lower mean GFR and higher serum creatinine and urea. In addition, hematologic changes were common in patients in stage 5, such as lower hemoglobin and hematocrit and higher mean corpuscular volume (Table 1 ). Patients in stage 5 had significantly higher concentrations of C-reactive protein and lower albumin than those in stage 2. The concentrations of hemoglobin A1c did not differ significantly among the groups.


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  		Table 1. Main characteristics of the study patients.1

Concentrations of tHcy and the related metabolites showed a clear increase in relation to decreasing renal function (Table 2 ). AdoHcy and AdoMet were markedly increased in renal patients. The size of the increase was apparently related to the degree of HHcy and the degree of disturbance of renal function (Table 2 ). Differences in serum concentrations of MMA among the five groups were also significant. Increased concentrations of tHcy, cystathionine, and MMA were very common in our patients. In contrast, low concentrations of the vitamins were less prevalent: 2% had B12 <156 pmol/L, and 12% had B6 <17.4 nmol/L. Median serum concentrations of cystathionine and cysteine were significantly lower in the patients in stage 2 than in patients in stage 5 (cystathionine, 334 vs 2399 nmol/L; cysteine, 335 vs 448 µmol/L; Table 2 ). The increase in AdoHcy was more pronounced than those of tHcy and AdoMet (Table 2 ). Furthermore, the mean AdoMet/AdoHcy ratio markedly decreased with worsening renal function (Fig. 1 ). Additionally, the cystathionine/cysteine ratio substantially increased from stage 2 through stage 5 (Fig. 1 ).


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  		Table 2. Concentrations of the metabolites and the vitamins.1



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  		Figure 1. Geometric mean [95% confidence interval (CI; error bars)] of AdoMet/AdoHcy ratio (•) and cystathionine/cysteine ratio ({circ}) in diabetic patients with different degrees of chronic renal failure.

*, P <0.05 compared with stage 2 (ANOVA).

The cystathionine/cysteine ratio correlated directly with concentrations of AdoMet (r = 0.45; P <0.001) and tHcy (r = 0.57; P <0.001) and inversely with B6 (r = –0.31; P = 0.003; Fig. 2 ). These correlations remained significant after adjustment for age, sex, and serum albumin. Other important correlations between the metabolic markers and the vitamins are reported in Table 3 . Correlations between serum concentrations of tHcy and concentrations of MMA and cystathionine were strong, as was the correlation between AdoHcy and AdoMet (r = 0.52; P <0.001). The last correlation remained significant after adjustment for all possible confounding variables (creatinine, age, sex, hemoglobin, and albumin; r = 0.50; P <0.001). Moreover, we found a positive correlation between vitamin B12 and AdoMet (r = 0.27; P = 0.009), but not between vitamin B12 and AdoHcy or the ratio AdoMet/AdoHcy. We also found significant correlations between tHcy and both AdoHcy and AdoMet (r = 0.35 and 0.26, respectively). The correlation between B6 and folate was strong in our patients (r = 0.66; P <0.001). Hemoglobin A1c did not correlate to any of the metabolites or the vitamins.



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  		Figure 2. Scatter plots of the cystathionine/cysteine ratio plotted vs AdoMet (A), tHcy (B), and B6 (C) concentrations.

Spearman correlation coefficients are shown. Values on the x and y axes are in logarithmic format. For simplicity, stages 4 and 5 were combined. {square}, stage 4 plus 5; x, stage 3; {circ}, stage 2.


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  		Table 3. Correlations between serum concentrations of the metabolites and the vitamins.1

Multivariate backward regression analyses were applied to identify predictors of each of the metabolites (Table 4 ). Concentrations of tHcy were determined independently by serum concentrations of folate, vitamin B12, cysteine, and creatinine. AdoMet was determined by creatinine, vitamin B12, and AdoHcy, whereas creatinine was the only analyte that influenced AdoHcy. Furthermore, both creatinine and vitamin B12 were significant factors that determined serum concentrations of MMA and cystathionine (Table 4 ).


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  		Table 4. Backward stepwise regression analysis.1


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The current study represents the first comprehensive investigation of metabolic disturbances associated with HHcy in patients with diabetic nephropathy and various stages of chronic kidney disease. The study provides important information on the interrelationships between crucial metabolites of methionine and vitamin status in relation to renal function. In patients with diabetes and mildly decreased GFR (stage 2), serum concentrations of tHcy and the metabolites were comparable to those usually found in healthy individuals. This indicates that probably advanced renal injury, but not diabetes itself, is associated with disturbed Hcy metabolism. In line with this suggestion, hemoglobin A1c, an indicator of long-term diabetes control, was comparable among the groups and did not correlate to any of the markers investigated. Our results extend observations of other studies that showed normal tHcy and AdoHcy in patients with diabetes without overt diabetic nephropathy (no albuminuria and normal serum creatinine) (26).

Numerous studies, including ours, have revealed a high incidence of HHcy in renal patients (2)(22)(27). These studies have also suggested that AdoHcy mediates the harmful effects of Hcy in the vascular system (28)(29)(30). Our study shows a relationship between HHcy, AdoHcy, and the degree of impaired renal function (Table 2Up ). On the other hand, we observed no appreciable differences in serum concentrations of the vitamin with decreasing renal function.

Several possible causes of HHcy can be considered in renal patients. The role of the kidney in Hcy metabolism is supported by the finding that Hcy concentrations increased in living kidney donors after uninephrectomy and remained high 6 months thereafter, despite folate and vitamin B12 remaining unchanged (31). It is unlikely that altered Hcy metabolism is attributable to a decrease in the net filtration of Hcy from the diseased kidney because this is minimal in healthy persons (32). On the other hand, a lower rate of plasma Hcy clearance was observed in HHcy in renal patients compared with healthy persons, which suggests a role for the kidney in the elimination of this aminothiol (33). The remethylation of Hcy to methionine is lower in hemodialysis patients (34). In addition, Hcy remethylation was shown to be impaired in dialysis patients despite serum concentrations of vitamin B12 and folate being well above those found in the general population (4). In keeping with this, vitamin intervention studies show a significant decrease in tHcy after administration of supraphysiologic doses of the B vitamins intravenously (2)(22). We therefore propose that the requirement for B vitamins in renal patients may be much higher than that in the general population. In support of this idea, mononuclear cells isolated from renal patients showed a diminished ability to internalize vitamin B12 (35).

One notable finding in our study is the marked increase in serum concentrations of cystathionine and the cystathionine/cysteine ratio. Vitamin B6 is a cofactor for two enzymes in the transsulfuration pathway, cystathionine ß-synthase and cystathionase, and is also a cofactor in the serine hydroxymethyltransferase reaction, which catalyzes the formation of 5,10-methylenetetrahydrofolate. The strong correlation between B6 and folate suggests that the availability of folate depends on B6. Increased cystathionine may be partly attributed to reduced urinary excretion. The negative correlation between B6 and the cystathionine/cysteine ratio suggests that the reaction mediated by cystathionase could be impaired in renal patients. Additionally, an increased cystathionine/cysteine ratio was closely related to higher Hcy, which indicates increased production of cystathionine from Hcy. AdoMet has been shown to enhance the activity of cystathionine ß-synthase (36). This may explain why a higher AdoMet was associated with a higher cystathionine/cysteine ratio in our patients (Fig. 2Up ).

In line with previous studies (37), low serum concentrations of vitamin B12 (<156 pmol/L) or holoTC (<35 pmol/L) were rare (2% and 3%, respectively) despite markedly increased MMA in 70% of the patients. However, the vitamin B12 concentration was a stronger determinant of tHcy, cystathionine, and MMA than was folate (Table 4Up ). Furthermore, therapeutic doses of vitamin B12 have been shown to lower tHcy and MMA concentrations in dialysis patients (2)(36). The active form of vitamin B12, holoTC, may be increased in patients with renal involvement (38) (Table 2Up ). The reason for holoTC accumulation in renal patients remains unclear, but it is probably related to a generalized peripheral resistance to the vitamin. An altered conformation of the transcobalamin–B12 complex that may influence the interaction of transcobalamin with its cellular receptor has also been suggested (37).

In agreement with previous reports, plasma concentrations of AdoHcy were markedly increased in our patients with chronic HHcy (14)(26)(39). In erythrocytes, however, a transient increase in plasma tHcy after methionine loading in humans did not lead to increases in AdoHcy or AdoMet (39). Plasma concentrations of AdoHcy were decreased after vitamin B12 treatment (40). Moreover, treatment of dialysis patients with methyltetrahydrofolate led to an appreciable increase in AdoMet and in the AdoMet/AdoHcy ratio (41). In contrast to a previous study on persons with normal renal function (42), vitamin B12 was a significant determinant of plasma AdoMet in our patients (Table 4Up ), which suggest that higher B12 status may increase AdoMet by increasing Hcy remethylation to methionine (40).

A striking finding in this study is the clear increase in the AdoHcy concentration, which exceeded that of AdoMet and was strongly related to decreasing renal function. AdoMet and AdoHcy concentrations have been reported to be ~100- and 30-fold higher, respectively, in urine than in serum (43). In addition to a lower urinary excretion of these metabolites, AdoMet is increasingly consumed in renal patients in the formation of creatine released from the muscles (a precursor of creatinine). The accumulation of AdoMet may well be explained by the suppression of transmethylation reactions by AdoHcy. AdoHcy is a potent inhibitor of intracellular methylation reactions, and the AdoHcy/AdoMet ratio represents the methylation potential in the cell (44).

In conclusion, concentrations of tHcy, cystathionine, and MMA in patients with diabetic nephropathy were related to the degree of renal insufficiency as well as to folate, vitamin B12, and vitamin B6 status. Higher concentrations of these vitamins were associated with a better metabolic profile. Functional vitamin B12 deficiency causes impaired folate utilization and thus a relative shortage of AdoMet. On the other hand, HHcy induces a marked increase in plasma concentrations of AdoHcy. The magnitude of the increase of AdoHcy in plasma was severalfold higher than that of tHcy or AdoMet in patients with kidney failure. The strong decrease in the AdoHcy/AdoMet ratio points to a lower methylation potential. Further studies should investigate the effect of pharmacologic doses of folate and vitamins B6 and B12 on AdoMet, AdoHcy, and their ratio.


   Footnotes
 
1 Nonstandard abbreviations: tHcy, total homocysteine; HHcy, hyperhomocysteinemia; GFR, glomerular filtration rate; AdoHcy, S-adenosylhomocysteine; AdoMet, S-adenosylmethionine; MMA, methylmalonic acid; and holoTC, holo-transcobalamin.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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