Abstract
BackgroundThere is an ongoing debate as to whether early diabetic nephropathy in Type 2 diabetes mellitus may be attributed to the glomerulus or to the proximal tubule. Urinary excretion of nephrin and vascular endothelial growth factor may increase even in the normoalbuminuria stage. In the course of diabetic nephropathy, the proximal tubule may be involved in the uptake of urinary nephrin and vascular endothelial growth factor.Materials and MethodsTwo groups of consecutive Type 2 diabetes mellitus outpatients (38 normo-, 32 microalbuminuric) and 21 healthy subjects were enrolled in a cross-sectional study and evaluated concerning the relation of proximal tubule dysfunction with the podocyte biomarkers excretion, assessed by ELISA methods. The impact of advanced glycation end-products on this relation was also queried.ResultsUrinary alpha1-microglobulin and kidney injury molecule-1 correlated with urinary albumin:creatinine ratio (R2 = 0.269; p<0.001; R2 = 0.125; p<0.001), nephrinuria (R2 = 0.529; p<0.001; R2 = 0.203; p<0.001), urinary vascular endothelial growth factor (R2 = 0.709; p<0.001; R2 = 0.360; p<0.001), urinary advanced glycation end-products (R2 = 0.578; p<0.001; R2 = 0.405; p<0.001), serum cystatin C (R2 = 0.130; p<0.001; R2 = 0.128; p<0.001), and glomerular filtration rate (R2 = 0.167; p<0.001; R2 = 0.166; p<0.001); nephrinuria and urinary vascular endothelial growth factor correlated with urinary albumin:creatinine ratio (R2 = 0.498; p<0.001; R2 = 0.227; p<0.001), urinary advanced glycation end-products (R2 = 0.251; p<0.001; R2 = 0.308; p<0.001), serum cystatin C (R2 = 0.157; p<0.001; R2 = 0.226; p<0.001), and glomerular filtration rate (R2 = 0.087; p = 0.007; R2 = 0.218; p<0.001).ConclusionsIn Type 2 diabetes mellitus there is an association of proximal tubule dysfunction with podocyte damage biomarkers, even in the normoalbuminuria stage. This observation suggests a potential role of the proximal tubule in urinary nephrin and urinary vascular endothelial growth factor processing in early diabetic nephropathy, a fact which could be related to advanced glycation end-products intervention. Podocyte damage and proximal tubule dysfunction biomarkers could be validated as a practical approach to the diagnosis of early diabetic nephropathy by further studies on larger cohorts.
Highlights
Due to the increasing epidemic of diabetes mellitus (DM) worldwide, diabetic kidney disease is the leading cause of endstage renal disease and may be attributed up to 40% of cases referred to renal replacement therapies, both in developed and emerging countries [1,2].There is an ongoing debate as to whether early diabetic nephropathy (DN) in Type 2 DM may be attributed to the glomerulus or to the proximal tubule (PT)
In Type 2 diabetes mellitus there is an association of proximal tubule dysfunction with podocyte damage biomarkers, even in the normoalbuminuria stage
This observation suggests a potential role of the proximal tubule in urinary nephrin and urinary vascular endothelial growth factor processing in early diabetic nephropathy, a fact which could be related to advanced glycation end-products intervention
Summary
There is an ongoing debate as to whether early diabetic nephropathy (DN) in Type 2 DM may be attributed to the glomerulus or to the proximal tubule (PT). The classical concept concerning mechanisms of albuminuria in DN relies on defects in the glomerular filtration barrier [4,5] According to this hypothesis, it is considered that albuminuria is determined by the severity of the glomerular lesions, but this correlation is not strict in preceding the onset of albuminuria, a fact demonstrated on iterated renal biopsies in patients with Type 2 DM [6]. There is an ongoing debate as to whether early diabetic nephropathy in Type 2 diabetes mellitus may be attributed to the glomerulus or to the proximal tubule. In the course of diabetic nephropathy, the proximal tubule may be involved in the uptake of urinary nephrin and vascular endothelial growth factor
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