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Abstract: TH-OR13

Alternative Splicing in CKD

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms


  • Mohandes, Samer, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Alternative splicing (AS) is a process that can lead to variable genotype expression. The primary forms are exon skipping, intron inclusion, alternative 5’ and 3’ splice sites. The role of alternative splicing of VEGF has been shown to play an important role in chronic kidney disease (CKD) development, however a comprehensive assessment of AS events in CKD has not been undertaken yet.


Human kidney tissue (n=410) was collected from nephrectomies of healthy subjects and patients with diabetic or hypertensive CKD. Clinical demographics information was collected via honest broker and histopathology was analyzed in an unbiased manner. RNA was extracted from the tubular compartment and sequenced. RNA-seq reads were aligned to the human genome using STAR v 2.7.3. Outliers identified by Mahalanobis distance. Aligned BAM files were sorted and indexed using Samtools v1.17 and junctions were extracted using Regtools v 1.0. Differential splicing for was analyzed separately using leafcutter v 0.2.7 and adjusted for age, sex, race and RNA quality indices (RNA integrity number, 5’-3’bias, %ribosomal genes, total reads).


When comparing healthy samples to those with eGFR of less than 60 cc/min/1.73m2 (CKD stage 3-5), we identified 31 intron cluster alternative splicing events at an adjusted p-value of 0.05. 26 of these were previously annotated. Pathway analysis using gene ontology (GO) terms showed enrichment for cell death and metabolic pathway. When comparing samples with less than 10% fibrosis to those with greater than 10% fibrosis, we identified 239 alternative differential splicing clusters. 233 of these were previously annotated. Pathway analysis using GO terms demonstrated these genes were enriched in the metabolic and immune pathways.


Large number of differential splicing events were observed in CKD compared to controls with enrichment in the metabolic and immune pathway genes.

(CKD vs control)
No. of Significant Differentially Spliced GenesTop GenesTop pathway enrichment by GO terms
GFR <60 ml/min/1.73m2146 vs 26431RAB11FIP3
Regulation of cell death
Negative regulation of cell death
Generation of precursor metabolites and energy
Cell death
Homeostatic process
Interstitial Fibrosis
170 vs 240239RPS24
Small molecule metabolic process
Organic acid metabolic process
Positive regulation of immune system
Positive regulation of leukocyte migration
Organonitrogen compound