Proximal tubule dysfunction is associated with podocyte damage biomarkers nephrin and vascular endothelial growth factor in type 2 diabetes mellitus patients: a cross-sectional study.
BACKGROUND
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. 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.


METHODS
Two 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.


RESULTS
Urinary 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).


CONCLUSIONS
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. 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.
"Victor Babes" University of Medicine and Pharmacy, Dept. of Nephrology, Timisoara, Romania; County Emergency Hospital, Timisoara, Romania.
Ligia
L
Petrica
"Victor Babes" University of Medicine and Pharmacy, Dept. of Diabetes and Metabolic Diseases, Timisoara, Romania; County Emergency Hospital, Timisoara, Romania.
Adrian
A
Vlad
"Victor Babes" University of Medicine and Pharmacy, Dept. of Nephrology, Timisoara, Romania; County Emergency Hospital, Timisoara, Romania.
Gheorghe
G
Gluhovschi
"Victor Babes" University of Medicine and Pharmacy, Dept. of Nephrology, Timisoara, Romania; County Emergency Hospital, Timisoara, Romania.
Florica
F
Gadalean
"Victor Babes" University of Medicine and Pharmacy, Department of Pharmacology, Timisoara, Romania; County Emergency Hospital, Timisoara, Romania.
Victor
V
Dumitrascu
"Victor Babes" University of Medicine and Pharmacy, Dept. of Nephrology, Timisoara, Romania; County Emergency Hospital, Timisoara, Romania.
Cristina
C
Gluhovschi
"Victor Babes" University of Medicine and Pharmacy, Dept. of Nephrology, Timisoara, Romania; County Emergency Hospital, Timisoara, Romania.
Silvia
S
Velciov
"Victor Babes" University of Medicine and Pharmacy, Dept. of Nephrology, Timisoara, Romania; County Emergency Hospital, Timisoara, Romania.
Flaviu
F
Bob
"Victor Babes" University of Medicine and Pharmacy, Department of Pharmacology, Timisoara, Romania; County Emergency Hospital, Timisoara, Romania.
Daliborca
D
Vlad
"Victor Babes" University of Medicine and Pharmacy, Dept. of Cellular Biology, Timisoara, Romania; County Emergency Hospital, Timisoara, Romania.
Roxana
R
Popescu
County Emergency Hospital, Timisoara, Romania.
Oana
O
Milas
"Victor Babes" University of Medicine and Pharmacy, Dept. of Public Health Medicine, Timisoara, Romania.
Sorin
S
Ursoniu
D000419:Albuminuria / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism*; D003404:Creatinine / Q000652:urine; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004797:Enzyme-Linked Immunosorbent Assay; D005198:Fanconi Syndrome / Q000175:diagnosis* / Q000209:etiology / Q000473:pathology*; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D008562:Membrane Glycoproteins / Q000652:urine; D008565:Membrane Proteins / Q000652:urine; D050199:Podocytes / Q000378:metabolism*; D011991:Receptors, Virus; D042461:Vascular Endothelial Growth Factor A / Q000652:urine
D015415:Biomarkers; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011991:Receptors, Virus; D042461:Vascular Endothelial Growth Factor A; C113267:nephrin; D003404:Creatinine