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Abstract: FR-PO434

Gene Expression Profiles of Hyperfiltration in Early Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Stefansson, Vidar T. N., UiT The Arctic University of Norway, Tromso, Norway
  • Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States
  • Mariani, Laura H., University of Michigan, Ann Arbor, Michigan, United States
  • Melsom, Toralf, UiT The Arctic University of Norway, Tromso, Norway
  • Eriksen, Bjorn Odvar, UiT The Arctic University of Norway, Tromso, Norway
  • Nelson, Robert G., National Institutes of Health, Phoenix, Arizona, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
Background

Hyperfiltration (HF) is a state of high glomerular filtration rate (GFR) seen in early diabetic kidney disease. Prolonged HF damages glomeruli, eventually leading to a vicious cycle of fibrosis and an increased filtration load for remaining glomeruli. Previous definitions of HF based on GFR cut-points have not convincingly captured microstructural and gene expression signatures in individuals. We used novel methods of capturing individual HF to elicit morphometric and gene expression profiles from kidney biopsies.

Methods

111 Pima Indians with type 2 diabetes had a research kidney biopsy between 2002-2007 and 9-29 iothalamate GFR and albumin-creatinine ratio (ACR) measurements between 1989 and 2017. Those with mean GFR <60ml/min/1.73m2 or ACR >300mg/g around the time of biopsy were excluded. Subjects who had their highest ever recorded GFR measurement within two years of biopsy were categorized as having HF. Eigengene-based weighted gene co-expression network analysis modules were constructed from glomerular transcriptomes. Pathway analyses and downstream targets were identified.

Results

The interquartile range of GFR among HF subjects was 138.1-203.5. One module uniquely associated with HF. Individual genes of interest included KDR, ICAM2 and PECAM1. Main pathways included Hepatic Fibrosis and the Th2 Pathway. Downstream targets included angiogenesis and endothelial cell proliferation.

Conclusion

A new method of capturing individual HF in early diabetic kidney disease correlated with clinical and morphological data and yielded novel findings in gene expression analyses. These pathways may be potential targets for further research on diagnosis and treatment of HF.

Summary statistics at the time of biopsy
 GFR peak >2 years prior to biopsyGFR peak within 2 years of biopsyGFR peak >2 years after biopsyp-value (*=quadratic trend)
Number of subjects273227 
Age, years (standard deviation (SD))47.8 (10.0)44.8 (10.9)45.0 (8.5)0.30
Sex, % male30%16%30%0.15*
BMI, kg/m2 (SD)35.0 (7.1)37.7 (9.4)35.9 (8.0)0.23*
Diabetes duration, years (SD)17.3 (7.3)15.2 (5.1)12.8 (3.7)0.004
GFR, ml/min (SD)134.2 (40.7)171.4 (43.1)156.5 (38.6)0.006*
ACR, mg/g (SD)40.2 (44.7)65.0 (62.4)39.2 (48.5)0.04*
Hemoglobin A1C, % (SD)9.3 (1.7)9.8 (1.8)8.7 (1.9)0.04*
Blood pressure, mm Hg (SD)121.9/77.2 (11.0/5.6)121.9/76.4 (10.2/5.3)118.5/76.4 (9.1/6.2)0.23/0.57
Glomerular volume, x106 µm3 (SD)2.21 (0.66)2.63 (0.70)2.18 (0.74)0.01*
Podocyte numerical density, PCx105/glom (SD)1.48 (0.68)1.16 (0.68)1.57 (0.83)0.04*

Funding

  • NIDDK Support