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Kidney Week

Abstract: FR-OR34

Metabolomic and Transcriptomic Reveal Signature of Citrate Homeostasis in Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Maity, Soumya, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
  • Limonte, Christine P., University of Washington, Seattle, Washington, United States
  • Valo, Erkka A., Folkhalsanin tutkimuskeskus, Helsinki, Uusimaa, Finland
  • Zhang, Guanshi, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
  • Lee, Hak Joo, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
  • Pennathur, Subramaniam, University of Michigan, Ann Arbor, Michigan, United States
  • Snell-Bergeon, Janet, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Costacou, Tina, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Rossing, Peter, Steno Diabetes Center Copenhagen, Herlev, Capital Region, Denmark
  • Groop, Per-Henrik, Helsingin yliopisto, Helsinki, Uusimaa, Finland
  • Roy, Sourav, The University of Texas at El Paso, El Paso, Texas, United States
  • Sharma, Kumar, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Group or Team Name

  • KPMP Consortium.
Background

Kidneys are highly metabolic organs, and the TCA cycle primarily fulfills the enormous energy required to maintain their normal function. In our previous cross-sectional study, low urinary citrate was associated with chronic kidney disease progression in Type 2 Diabetic patients. In this study, we performed a longitudinal targeted urinary metabolomic screening in 4 cohorts of Type 1 Diabetic (T1D) patients and single-cell RNAseq analysis of separate kidney biopsies to explore potential metabolic reprogramming in diabetic kidney disease (DKD).

Methods

Metabolomic markers for DKD progression were investigated in a case-control study of four geographically and ethnically distinct cohorts (EDC, CACTI, STENO, and FinDiane) of type 1 diabetic patients. Cases were identified among patients with yearly eGFR decline ≥3 ml/min/1.73m2, while controls had yearly eGFR decline <1 ml/min/1.73m2. 42 urinary metabolites were measured using ZipChip mass spectrometry over 1750 participants. Comparative transcriptomics analysis was conducted in 11 kidney resident cells using Kidney Precision Medicine Project (KPMP) single-cell RNAseq data sets. Spatial metabolomic analysis in kidney biopsies was performed using MALDI-MSI.

Results

Glycolic acid and three TCA cycle metabolites, citrate, succinate, and fumarate, were significantly decreased in the cases compared to the control. Among them, citrate and glycolic acid were significantly associated with rapid eGFR decline and albuminuria. Single-cell RNAseq analysis demonstrates increased fatty acid uptake, impaired β-oxidation, improved glycolysis, partially maintained TCA cycle, and mitochondrial citrate accumulation in proximal tubules of DKD patients. Spatial metabolomic analysis reveals citrate accumulation in kidney biopsies of T1D patients compared to healthy control. Proximal tubule-specific upregulation of ACLY indicates the entry of accumulated citrate in de novo lipogenesis. The downregulation of both apical and basolateral membrane citrate transporters SLC13A2 and SLC13A3 implies dysregulation of tubular citrate flux in DKD.

Conclusion

Low urinary citrate could be a potential marker for CKD progression in T1D patients, and intracellular citrate homeostasis could be associated with DKD progression.

Funding

  • NIDDK Support