In the study by Pavia et al. (1) and the subsequent commentary by Cotellessa et al. (2), the problem of homocysteine levels in patients with type 1 diabetes was raised. The authors found no differences in plasma total homocysteine (tHcy) concentration between diabetic children and/or adolescents and age-matched control subjects. They also did not observe any association between tHcy levels and either duration or metabolic control of the disease or its complications. The 91 patients analyzed had a duration of type 1 diabetes ranging from 1 to 15 years, and in ∼50% of them, the duration of the disease was >5 years. Patients did not have microalbuminuria and had serum creatinine within the normal range.
Pavia et al. (1) pointed out that hyperhomocysteinemia is already present in the early stages of renal failure (3). However, no change in renal function, measured as the serum creatinine concentration, was found in their patients.
In our opinion, there are two points that should be emphasized in this context. First, serum creatinine concentration is not an accurate measure of glomerular filtration rate (GFR), especially in the range of 50–140% of normal. Therefore, mildly disturbed renal function is underestimated when assessed only on the basis of serum creatinine concentration. Although not perfect, the Cockroft-Gault formula should at least be used to measure creatinine clearance as a surrogate of GFR (4). The second and probably more important point is that renal abnormalities may already be present at very early stages of type 1 diabetes. Indeed, at the onset of the disease, a state of hypertrophy and hyperfunction (with hyperfiltration) of the kidneys is often observed. GFR may be as much as 40% above normal. The next stage is the appearance of microalbuminuria, a phenomenon that is thought to be an early marker of diabetic nephropathy. This is of special interest because GFR is the strongest independent predictor of plasma tHcy concentration. The study performed by Wollesen et al. (5) clearly showed that in diabetic patients with a normal serum creatinine concentration (<115 μmol/l) and GFRs in the lower range, the concentration of tHcy was higher than in subjects who had GFRs in the upper range. Hyperfiltration or GFRs above the normal values for their age and sex were found in >80% of patients. The authors found a strong inverse linear correlation between plasma tHcy and GFR in the range of 47–165 ml · min–1 · 1.73 m–2. In this study, GFR determined plasma levels of tHcy independently of age, serum folic acid and B-group vitamin concentrations, serum creatinine concentration, and urine-albumin excretion rate.
Thus, because no patients suffered from overt nephropathy in the population of patients studied by Pavia et al. (1), a relative hyperfiltration is the most plausible cause of their results, which showed low tHcy concentrations in this group of diabetic patients. Although they found a correlation between tHcy and creatinine concentration, measuring only creatinine concentration is not sufficient for assessing GFR (with special regard to hyperfiltration) in this specific population. We agree that hyperhomocysteinemia is not the cause of vascular complications in diabetic patients, at least in those without overt nephropathy.
Article Information
S.B. is the recipient of a Marie Curie Training Site Fellowship.
References
Address correspondence to Szymon Brzosko, Angela Valenti Laboratory of Genetic and Environmental Risk Factors for Thrombotic Disease, Department of Vascular Medicine and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro, Italy. E-mail: [email protected].
