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Annals of Clinical & Laboratory Science 32:279-286 (2002)
© 2002 Association of Clinical Scientists

Association Between Homocysteinemia and Renal Function in Patients with Type 2 Diabetes Mellitus

Bilgin Ozmen1, Dilek Ozmen2, Nevbahar Turgan2, Sara Habif2, Isil Mutaf2 and Oya Bayindir2
1 Department of Endocrinology, Celal Bayar University School of Medicine, Manisa, Turkey
2 Department of Clinical Biochemistry, Ege University School of Medicine, Izmir, Turkey

Address correspondence to Dilek Ozmen, M.D., Department of Clinical Biochemistry, Ege University School of Medicine, 35100, Bornova, Izmir, Turkey; tel and fax 90 232 339 2144; email: dozmen{at}med.ege.edu.tr.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Homocysteinemia is an independent risk factor for cardiovascular disease, but information on its association with type 2 diabetes and mild renal dysfunction is limited. Plasma total homocysteine (tHcy) concentration is partly determined by renal plasma clearance. Serum cystatin C (Cys C) concentration has been introduced as a marker of renal function, specifically as an indicator of glomerular filtration rate (GFR). The aim of this study was to explore the relationships among tHcy, creatinine clearance (Ccr), serum Cys C, and microalbuminuria in a population with type 2 diabetes. Fasting plasma tHcy, serum homocysteine-related vitamins (folate and vitamin B12), serum Cys C, serum creatinine, urine microalbumin, and creatinine clearance were determined in 75 type 2 diabetic patients and 40 healthy control subjects. The patients were assigned to two groups based on urinary albumin excretion (UAE): normoalbuminuric (NAU, UAE <30 mg/24 hr, n = 35) and microalbuminuric (MAU, UAE 30–300 mg/24 hr, n = 40). Ccr was calculated using the Cockroft-Gault formula. Plasma Hcy levels were determined by HPLC with fluorescence detection and serum Cys C by automated particle enhanced immunoturbidimetry. Plasma tHcy levels were significantly higher in normoalbuminuric and microalbuminuric patients than in controls (10.64 ± 0.53, 13.29 ± 0.78, 6.91 ± 0.37 mmol/L, respectively). Serum Cys C levels in microalbuminuric diabetics were higher than in normoalbuminurics and controls (1.36 ± 0.06, 1.12 ± 0.04, 1.10 ± 0.06 mg/L, respectively). Positive correlations were noted between tHcy and Cys C levels in normoalbuminuric and microalbuminuric diabetics (r = 0.72, r = 0.64, respectively ). Homocysteine and creatinine concentrations were correlated in both diabetic groups (r = 0.89, r = 0.93, NAU and MAU, respectively ). Elevated plasma total homocysteine concentrations in type 2 diabetics suggest an association between homocysteinemia and deterioration of renal function, evidenced by increased serum creatinine and Cys C, Ccr, and microalbuminuria. These findings implicate homocysteinemia in the relationship between diabetic nephropathy and cardiovascular complications of diabetes.

(received 8 February 2002; accepted 25 March 2002)

Keywords: diabetes mellitus type 2, homocysteine, cystatin C, microalbuminuria, renal function


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Homocysteine (Hcy) is the transmethylation product of the essential sulphur-containing amino acid methionine [1,2]. Experiments have shown that high concentrations of homocysteine may cause vascular damage [3]. Epidemiological research suggests an association between elevated total homocysteine (tHcy) levels and cardiovascular disease (CVD), which is the most common cause of mortality in patients with type 2 diabetes mellitus [2]. The association between homocysteinemia and atherosclerotic vascular disease is especially strong in patients with type 2 diabetes, compared to nondiabetic subjects. Increased plasma tHcy levels are reported to be associated with hypertension, hyperlipidemia, smoking, hyperuricemia, and impaired adrenal function [4–8]. Plasma tHcy concentration is strongly related to renal function [9]. A study in rats identified the kidney as a major site for removal and metabolism of Hcy [10]. Two mechanisms appear to be involved. The main source of Hcy is adenosylmethionine-dependent methylation of guanidoacetate to form creatine and its anhydride creatinine [11]. Second, renal function plays a central role for clearance of both creatinine and Hcy [12,13].

Plasma tHcy concentrations in diabetic patients can be affected by both glomerular hyper- and hypo-filtration, which can respectively decrease and increase the tHcy concentrations [14,15]. However, reduced glomerular filtration rate (GFR) accompanies microalbuminuria (MAU) in the late phase of diabetic nephropathy, and reduction of GFR causes elevation of plasma Hcy levels [16,17]. These data provide a potential link between microalbuminuria, diabetic nephropathy and cardiovascular disease [18–20].

Despite some disadvantages, in clinical practice serum creatinine and creatinine clearance determinations are routinely used for the estimation of GFR in diabetic patients. Recently, serum cystatin C (Cys C) concentration has been introduced as a new marker of renal function, specifically as an indicator of the GFR. Cys C comprises one non-glycosylated polypeptide chain with 120 amino acid residues (mol wt 13 kDa) [21]. Investigations have indicated that serum Cys C is superior to serum creatinine for the detection of early decreases of GFR [21–24]. In contrast to serum creatinine, Cys C is not related to muscle mass or the formation of creatinine; it only reflects the GFR [22,25].

GFR is proposed as an independent determinant of plasma tHcy and a rate limiting parameter for renal clearance of homocysteine and cysteine in diabetic patients without overt nephropathy [13,14]. Based on these considerations, this study was designed to assess the association between plasma tHcy and serum Cys C for the evaluation of renal function in type 2 diabetic patients.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
This study included 75 patients (30 men, 45 women, age 40–65 yr) with type 2 diabetes mellitus, with or without microalbuminuria, who received care at the Department of Endocrinology of Celal Bayar University Hospital. Their diagnosis of diabetes mellitus was based on a previous history of diabetes or the American Diabetes Association (ADA) criteria [26] questionnaire, which includes age, duration of diabetes, use of medication for diabetes, vitamin supplementation, smoking habits, and ethanol intake. The control group consisted of 40 healthy subjects (18 men, 22 women, age 40–69 yr) who were screened by a physician for signs of diabetes mellitus and who did not show any clinical evidence of the disease. The subjects were all informed about the protocol and their written consent was obtained.

The diabetic patients were divided into two groups based on their urinary albumin excretion (UAE). Group 1 included 35 patients with normoalbuminuria (NAU), (UAE <30 mg/24 hr); Group 2 included 40 patients with microalbuminuria (MAU), (UAE 30–300 mg/24 hr).

HbA1C, creatinine, homocysteine, folate, vitamin B12 and cystatin C concentrations were determined in blood or serum samples after an overnight fast. Urine albumin excretion was measured in 24 hr urine specimens. Among the diabetic patients, 42 were treated with sulphonylurea drugs, 10 with combinations of sulphonylurea and alpha-glucosidase inhibitors, and 23 with insulin.

Serum creatinine concentrations were analyzed by standard laboratory methods with an automatic analyzer (Technicon Dax-48, Bayer Diagnostics, Toshiba, Japan). HbA1c and urine albumin excretion were measured by immunoturbidimetric assay kits (Roche Diagnostic GMBH, Germany) with a Hitachi 704 analyzer (Tokyo, Japan). Creatinine clearance in males was calculated by the Cockroft-Gault formula [27]: (140-age) x weightkg/72 x serum creatininemg/100ml. For females, the value obtained by this equation was multiplied by 0.85.

Serum cystatin C levels were determined by a latex particle enhanced immunoturbidimetric assay (DAKO, Glostrop, Denmark). Folate and vitamin B12 in serum were measured by a chemiluminescent immunoassay (Access, Sanofi Diagnostics Pasteur, Marnes La Coquette, France); the reference intervals were >6.8 nmol/L for folate and 133 to 675 pmol/L for vitamin B12.

For homocysteine analyses, blood was collected in EDTA-containing tubes; the plasma was separated within 15–20 min and stored at -20°C. Total homocysteine (tHcy) in plasma was measured by HPLC and fluorescence detection [28]. A Shimadzu LC 10A HPLC system (Shimadzu Corp., Kyoto, Japan) was used, consisting of a Shimadzu LC-10AD pump, a Shimadzu SIL-10AXL autoinjector with a 20 µL loop, and a Shimadzu RF-10AXL fluorescence detector. The system was controlled through a Shimadzu CBM-10A communication module and a personal computer. The column was EC 150/4.6 Nucleosil 100–5 C18 5 mm (Macherey-Nagel, Duren, Germany). Tri-n-butyl-phosphine (TBP) in dimethly formamide (DMF) was applied for reduction of disulfide-bound homocysteine and ammonium 7-fluorobenzo-2-oxa-1,3-diazide-4-sulphonate (SBDF) served as a derivatization agent. Cysteamine hydrochloride was added as an internal standard.

Results are reported as mean ± SE. Differences in mean values of the three groups were evaluated by the t-test (p <0.05 was considered significant). Correlations were tested by the Pearson rank correlation test. The Statistical Package for Social Sciences (SPSS Version 7.5, SPSS Inc., Chicago, IL, USA) was used.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Laboratory findings of patients and control subjects are listed in Table 1Go. There were no significant differences in age or sex between the two diabetic groups and the controls. Plasma homocysteine, serum cystatin C, and serum creatinine concentrations showed significant differences between the two diabetic groups. Creatinine clearance values were lower in both diabetic groups (p < 0.01 for both values), compared to controls. Serum folate and vitamin B12 concentrations are not included in Table 1Go, since these parameters were used only to exclude deficiencies of these vitamins that could affect tHcy levels. All subjects had folate concentrations >6.8 nmol/L and vitamin B12 concentrations between 133 and 675 pmol/L.


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  		Table 1. Summary of the data (mean ± SE) for diabetic patients and healthy controls
 
Mean plasma homocysteine concentrations were significantly higher in normo- and microalbuminuric diabetic patients than in the controls (10.64 ± 0.53 and 13.29 ± 0.78 vs 6.91 ± 0.37 µmol/L, respectively, p < 0.01)

The mean serum cystatin C concentration in microalbuminuric patients was higher than in normoalbuminuric patients and controls (1.36 ± 0.06 , 1.12 ± 0.04, and 1.10 ± 0.06 mg/L, respectively, p <0.01) The difference between normoalbuminuric diabetics and controls was insignificant.

Serum creatinine levels in microalbuminuric patients were higher than in normoalbuminuric patients and controls (113.15 ± 4.42, 92.82 ± 3.54, and 82.21 ± 2.86 µmol/L, respectively, p <0,01) There were no significant differences in serum creatinine levels between normoalbuminuric diabetics and control subjects.

Mean creatinine clearance values in normo- and microalbuminuric groups were higher than in controls (60.50 ± 5.19 and 59.87 ± 3.49, versus 91.43 ± 0.06 ml/min, respectively, p < 0,01).

In normoalbuminuric diabetics, positive correlations were observed between plasma homocysteine and serum cystatin C concentrations (r = 0.72, p <0.01, Fig. 1aGo), between plasma homocysteine and serum creatinine levels (r = 0.89, p <0.01) (Fig. 1bGo), and between plasma homocysteine and age (r = 0.48, p <0.01) (Table 2Go).




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  		Fig. 1a (left panel) and Fig. 1b (right panel) show the graphs and regression equations for comparisons between plasma homocysteine and serum cystatin C (1a) and plasma homocysteine and serum creatinine (1b) concentrations in normoalbuminuric diabetic patients.

 

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  		Table 2. Pearson’s correlation coefficient (r) and p values for determinants of plasma homocysteine concentrations in diabetic patients
 
In microalbuminuric diabetic patients, there were positive correlations between plasma homocysteine and serum cystatin C levels (r = 0.64, p <0.01) (Fig. 2aGo), homocysteine and serum creatinine levels (r = 0.93, p <0.01) (Fig. 2bGo), and homocysteine and age (r = 0.58, p <0.01) (Table 2Go).




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  		Fig. 2a (left panel) and Fig. 2b (right panel show the graphs and regression equations for the comparisons between plasma homocysteine and serum cystatin C (2a) and plasma homocysteine and serum creatinine (2b) concentrations in microalbuminuric diabetic patients

 
No significant correlations were observed between any of the parameters in healthy controls.


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Growing interest is being focused on the association of homocysteinemia with diabetes mellitus. However, consensus on how type 2 diabetes affects plasma homocysteine concentrations has not been achieved [2]. Homocysteinemia has been established as a risk factor for cardiovascular disease and occurs with high prevalence in patients with type 2 diabetes: 31% of type 2 diabetic patients have homocysteine concentrations above >15 mmol/L [29]. Only a few studies found no significant differences in fasting plasma tHcy levels between type 2 diabetic patients without microalbuminuria and healthy control subjects [30]. A large amount of evidence supports increased plasma tHcy levels in type 2 diabetes [2,4,15,18,20,29,31,32]. Buysschaert et al [29] reported increased plasma tHcy levels in type 2 diabetics with advanced nephropathy, compared to control subjects and diabetics without nephropathy.

The relationship between homocysteinemia and microalbuminuria is more problematic. Some authors found an association between plasma tHcy and microalbuminuria in diabetes [2,18,30,33,34], while others did not [32,35]. In our study, plasma homocysteine concentrations were significantly higher in microalbuminuric patients than in normoalbuminuric patients or controls. Chico et al [18], Emoto et al [2], and Lanfredini et al [30] found strong association between homocysteinemia and deteriorated renal function. According to previous reports, homocysteine is ultrafiltrated through the glomeruli, almost completely reabsorbed in the tubuli, and degraded in kidney tissue by transmethylation and transsulfuration [36]. Decreased renal clearance of homocysteine results in homocysteinemia [10–12], but the exact mechanism is unknown [37].

Recently, serum cystatin C has been introduced as a more sensitive marker for mildly impaired GFR, compared to creatinine and GFR, and also as an independent determinant of plasma tHcy concentrations [21,22]. Norlund et al [17] suggested that the increase of plasma homocysteine concentrations with advancing age may be due to age-related decline in renal function. It has also been shown that cystatin C shows a higher predictive value for tHcy concentrations than age or serum creatinine [17].

Our data indicate that serum cystatin C levels in patients with microalbuminuria were significantly higher than in patients with normoalbuminuria or control subjects. Additionally, we found that plasma homocysteine concentrations correlated better with serum creatinine than with serum cystatin C. Our data are in agreement with the study of Abdella et al [31], who also showed that plasma homocysteine concentrations correlated better with serum creatinine than with cystatin C, presumably because of the relationship between creatine-creatinine synthesis and homocysteine production.

Contradicting these data, Bostom et al [38] and Aras et al [39] reported that serum cystatin C was a much better predictor of fasting total homocysteine concentrations in renal transplant recipients with normal renal function. In patients with coronary artery disease and normal renal function (serum creatinine concentrations < 123.8 µmol/L), serum cystatin C was reported to be an independent predictor of fasting tHcy concentrations [40].

Although kidney function plays an important role in the metabolism of homocysteine, it is not clear whether homocysteinemia is associated with or can precede microalbuminuria [5,41]. Homocysteinemia is believed to increase the risk of atherothrombic disease directly by impairing endothelial function, stimulating vascular smooth muscle cell proliferation, and altering extracellular matrix properties [42]. High plasma homocysteine levels may also exert an atherothrombic effect by inducing oxidative stress, which may impair endothelial function. Oxidative stress is thought to be increased in type 2 diabetes [43]. Thus, homocysteinemia may contribute to the development of renal impairment and subsequent microalbuminuria in diabetic patients through increased oxidative stress [5].

In summary, the present study shows that plasma homocysteine concentrations are elevated in type 2 diabetic patients with and without microalbuminuria. Microalbuminuric type 2 diabetic patients have higher plasma homocysteine levels than normoalbuminuric patients and controls. Elevated plasma homocysteine concentrations in type 2 diabetic patients suggest an association between homocysteinemia and impaired renal function, as evidenced by increased serum creatinine and cystatin C levels. These findings suggest that homocysteinemia may partly explain the link between diabetic nephropathy and cardiovascular complications of diabetes.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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