| Abstract |
Background: Diabetes mellitus (DM) is a chronic illness characterized by impaired
metabolism of carbohydrates, fat and protein secondary to a deficiency in secretion
and/or action of insulin. Diabetic kidney disease is a major complication of DM with
significant associated morbidity and mortality. A significant proportion of these
patients are going to develop end-stage renal disease. Albuminuria has traditionally
been used for the diagnosis and classification of diabetic kidney disease. At the same
time, it is well-known that podocyte injury plays a crucial role in the pathogenesis
and progression of diabetic kidney disease. We aimed to examine whether there is
evidence suggestive of glomerular damage in patients with DM prior to the detection
of albuminuria. Therefore, we investigated whether patients with DM and
normoalbuminuria present podocyte markers in urine suggestive of early podocyte
injury.
Methods:We studied 80 patients with type 2 DM who were examined at the Diabetes
Clinic of the University Hospital of Heraklion, Crete, from January to June 2011.
Exclusion criteria were (1) history of renal disease, (2) history of micro or
macroalbuminuria, (3) presence of urinary infection, (4) known duration of DM <1
year and (5) use of nephrotoxic medication. We also studied 50 non-diabetic
controls, some of whom were followed up in the metabolic clinic for hypertension
(HTN) and/or hyperlipidemia without known renal disease. Exclusion criteria for
control subjects were (1) history of DM, impaired glucose tolerance or impaired
fasting glucose, (2) history of renal disease, (3) history of micro/macroalbuminuria,
(4) presence of urinary infection and (5) use of nephrotoxic medication. All the
subjects were categorized according to their urinary podocyte marker profile into 2
groups, those with only synaptopodin mRNA presence (synaptopodin only group)
17
and those with nephrin and/or podocin mRNA presence in addition to synaptopodin
in their urine (nephrin and/or podocin group).
Results: Nine diabetic patients and 11 controls were found to have an increased
UAE (urine albumin to creatine ratio (ACR) >20 mg/g measured on enrollment) and,
therefore, were not included in analysis. Among 71 patients with type 2 DM and 39
non-diabetic controls, all with normal UAE, synaptopodin mRNA was detected in
the urine of all the diabetics and controls. The presence of nephrin and/or podocin
mRNA in urine was more frequent among DM patients compared to controls (53.5
vs. 30.8%, respectively; p = 0.022). Binary logistic regression analysis revealed that
the only significant predictor of the presence of nephrin and/or podocin mRNA in
urine was the presence of DM (OR 2.59, 95% CI 1.14–5.91, p = 0.024, adjusted for
all risk factors). A strong correlation between nephrin and podocin urinary mRNA
levels was noted (r = +0.796, p < 0.001).
Conclusion: Overall, this study, including the largest population studied so far,
demonstrated the presence of podocyte markers in the urine of normoalbuminuric
diabetic patients. Nephrin and podocin mRNA is more prevalent in diabetic patients
with normal UAE compared to controls, and this may reflect early podocyte injury.
DM was the only significant determinant of their presence in urine of this population.
Synaptopodin mRNA was uniformly detected in all the subjects independent of their
DM status and, thus, synaptopodin is unsuitable for the diagnosis of podocyte
injury. Therefore, it appears of particular importance to prospectively evaluate
diabetic patients with urinary nephrin and/or podocin mRNA and normal UAE to
clarify whether they are at increased risk of developing diabetic nephropathy, the
relation to prognosis and if early treatment, for example, with angiotensin-converting
enzyme inhibitors may retard the development of renal injury.
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