Abstract: TH-OR51
Autophagy-Related Gene Expression in Diabetes and CKD
Session Information
- Diabetic Kidney Disease - Clinical: Novel Insights into Precision Medicine
October 24, 2024 | Location: Room 33, Convention Center
Abstract Time: 05:20 PM - 05:30 PM
Category: Diabetic Kidney Disease
- 702 Diabetic Kidney Disease: Clinical
Authors
- Limonte, Christine P., University of Washington, Seattle, Washington, United States
- Eddy, Sean, University of Michigan, Ann Arbor, Michigan, United States
- Gharib, Sina, University of Washington, Seattle, Washington, United States
- Alpers, Charles E., University of Washington, Seattle, Washington, United States
- Barisoni, Laura, Duke University, Durham, North Carolina, United States
- Menon, Rajasree, University of Michigan, Ann Arbor, Michigan, United States
- Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States
- Rosas, Sylvia E., Joslin Diabetes and Endocrinology Research Center, Boston, Massachusetts, United States
- Poggio, Emilio D., Cleveland Clinic, Cleveland, Ohio, United States
- De Boer, Ian, University of Washington, Seattle, Washington, United States
Group or Team Name
- Kidney Precision Medicine Project (KPMP).
Background
Autophagy impairment is implicated in diabetic nephropathy pathophysiology. We examined autophagy-related gene (ARG) expression in human kidney biopsies from the Kidney Precision Medicine Project (KPMP).
Methods
KPMP is performing research kidney biopsies in adults with CKD. Single cell RNA sequencing has been performed in a subset of kidney biopsy samples using the 10xChromium v3 assay. We assessed differential expression of proximal tubular epithelial cell (PTEC) ARGs (n=604 genes identified from literature) in subjects with diabetes and CKD (n=32) versus controls (n=25). We used k-means consensus clustering to group subjects with diabetes and CKD by PTEC ARG expression patterns.
Results
326 ARGs were differentially expressed between subjects with diabetes and CKD and controls. Subjects with diabetes and CKD were clustered into 3 groups based on PTEC ARG expression (Table). Adjudicated diagnoses differed across clusters, with Clusters 1, 2, and 3 including 35%, 56%, and 0% people with a primary diagnosis of diabetic nephropathy, respectively. While eGFRs were similar across clusters, Cluster 2 members had more albuminuria and higher HbA1cs. Cluster 2 members had more severe structural tubulointerstitial pathology and the greatest proportion of injured PTECs.
Conclusion
PTEC ARG expression patterns may be able to distinguish between clinically relevant phenotypes of diabetes and CKD with distinct profiles of glycemic exposure, tubulointerstitial pathology, and cellular injury.
| Cluster 1 (n=17) | Cluster 2 (n=9) | Cluster 3 (n=6) | |
| Adjudicated diagnosis, N (%) | |||
| Diabetic nephropathy | 6 (35%) | 5 (56%) | 0 (0%) |
| Hypertensive nephrosclerosis | 4 (24%) | 1 (11%) | 2 (33%) |
| Cannot be determined | 4 (24%) | 1 (11%) | 2 (33%) |
| Other | 1 (6%) | 1 (11%) | 2 (33%) |
| HbA1c category, N (%) | |||
| <6.5% | 5 (29%) | 1 (11%) | 1 (17%) |
| 6.5 to <7.5% | 5 (29%) | 1 (11%) | 4 (67%) |
| 7.5 to <8.5% | 3 (18%) | 2 (22%) | 0 (0%) |
| >8.5% | 2 (12%) | 4 (44%) | 0 (0%) |
| eGFR Cr-Cys, ml/min/1.73m2, mean (SD) | 45 (19) | 47 (17) | 54 (34) |
| UACR, mg/g Cr, median [Q1, Q3] | 230 [2, 1374] | 710 [87, 4995] | 676 [19, 1560] |
| Interstitial fibrosis, %, mean (SD) | 24 (17) | 33 (17) | 20 (16) |
| Tubular atrophy %, mean (SD) | 20 (15) | 31 (17) | 18 (18) |
| Interstitial mononuclear white blood cells, %, mean (SD) | 16 (13) | 27 (16) | 10 (6) |
| Adaptive/maladaptive/repairing PTEC, N (% total cells) | 5128 (45%) | 7166 (83%) | 2560 (59%) |
Funding
- NIDDK Support