Using a cross-sectional design, we observed in a relatively small cohort of young patients with type1 diabetes several associations between lower urine levels of π-GST:crea ratio and adverse changes in carotid artery structure and cutaneous microvascular function. Female gender and exposure to tobacco smoke appear to strengthen this association. This is in keeping with some previous studies showing that girls with type1 diabetes are more prone to atherosclerosis development , and that exposure to tobacco smoke further increases cardiovascular risk among type1 diabetes patients .
The development of renal disease in type1 diabetes is often subtle especially in younger patients. The test recommended by the American Diabetes Association for diagnosing and monitoring diabetes nephropathy is the urinary albumin:creatinine ratio; however, this test performs poorly, with relatively low sensitivity and low specificity (7).
In view of the previous studies suggesting that vascular and kidney disease in type1 diabetes progress hand in hand [24, 25], the association of π-GST, a novel marker of kidney disease, with increased carotid artery intima-media thickness and cutaneous microvascular dysfunction in the present study is perhaps not surprising. These two adverse vascular changes have been shown to develop early after the onset of type1 diabetes . Abnormalities in peripheral arterial function and structure have been documented in both pediatric and adult cohorts with renal disease [3, 27], suggesting a complex “cross-talk” between the vascular system and the kidney .
With the exception of this study, to the best of our knowledge, there are no further reports on π-GST:crea ratio in a pediatric population. In adult diabetic patients, urinary π-GST:crea ratio was found to rise with increasing albuminuria . A similar trend was observed in adult patients with overt renal disease . The cohort included in the present study is much younger and free of albuminuria, and was earlier found to have lower levels of π-GST:crea ratio than in healthy controls . Whether age, diabetes duration, and/or stage of kidney injury could influence the urine levels of π-GST remains to be assessed in future studies. Maybe, since the origin of π-GST is renal, there is a bimodal response of kidney π-GST:crea ratio to diabetic kidney injury with an early decrease followed by increase as microalbuminuria occurs.
We noted a weak correlation of π-GST:crea ratio with the inflammatory marker CRP. Smoke exposure, diabetes duration, and poor diabetes control (HbA1c), may all be involved in the onset and progression of endothelial damage in type1 diabetes, with release of inflammatory mediators [4, 29]. Intuitively sustained injury to the vessel wall could provide a potential substrate for injury to renal tubules . This could in turn, over time, lead to increase in π-GST excretion. Alternatively, these two processes could be unrelated to each other, although, at least based on our findings suggesting some association between π-GST and IMT, a common mechanism seemingly related to the diabetes milieu (e.g., inflammation, oxidative stress, and hyperglycemia) is likely to trigger both. Oxidative stress due to acutely induced hyperglycemia resulted in increased urine GST expression in a mouse model . Recurrence of such events could in time lead to enzymatic exhaustion. Diabetic subjects with decreased π-GST activity are less likely to cope with oxidative stress and, therefore, could more easily develop generalized vascular injury and endothelial dysfunction .
Tamm-Horsfall protein appears to rise with increasing diabetes duration, whereas urine albumin excretion, a more conventional marker for the development of nephropathy, remains normal . This may explain why in this study THP was not associated with diabetic, inflammatory or vascular markers.
Study limitations: π GST was measured in urine, not in the blood or the cytosolic of renal cells, making thus difficult the interpretation of the precise meaning of our findings. This issue needs to be addressed in future studies.