Transcriptomic Profiling Reveals Left Ventricle and Kidney Pathology Resulting from Peritoneal Dialysis
Authors: Kriegel Alison J. , Nasci Victoria L. , Liu Pengyuan 
Published: May 2022

Approximately 50% of deaths in ESRD patients are attributed to cardiovascular (CV) related pathology. Only 2.5% of ESRD patients receive a kidney transplant, while the rest rely on dialysis for survival. Peritoneal dialysis (PD) therapy has been increasingly utilized in recent years, yet there is a paucity in data characterizing the effects of PD on CV function. The goal of this study was to assess molecular changes in response to PD to understand how PD could impact prevalence of CV mortality in ESRD. We hypothesized that PD would not improve CKD‐related CV pathology despite providing support during renal insufficiency. To determine how PD effects renal and left ventricle (LV) structural and functional, organ morphology, and gene expression, 10‐week‐old male rats underwent 5/6Nx or Sham operation. Peritoneal catheters were implanted 6 weeks post‐surgery. PD was initiated 3 days later in half of the 5/6Nx and sham animals (15ml [Baxter PD‐2 2.5%] 1‐hour dwell 3x/day x 8 days) for n=6‐7 per surgical and treatment group. Echocardiography, blood collection, and urine collection were performed at baseline, 6, and 7‐weeks post‐surgery. Acute carotid blood pressure was measured week 7. Results were analyzed by two‐way ANOVA and significance determined at p<0.05. Sequencing of RNA isolated from kidney and LV was performed (n=6 per surgical group and treatment). Statistical analysis of transcriptomic results compared transcript levels from rats that received PD and those that did not. Differential gene expression was determined using the R package DESeq2. The Benjamini‐Hochberg method was used to control FDR in differential expression analysis to provide an adjusted p‐value. Transcripts with an adjusted p‐value (q‐value) <0.05 were identified as differentially expressed genes (DEGs) for subsequent pathway analysis, regardless of fold change. The list of DEGs was entered into Ingenuity Pathway Analysis (IPA) for subsequent analysis. PD had no effect on LV parameters or blood pressure in Sham or 5/6Nx rats. Blood urea nitrogen, serum creatine, SDMA and cholesterol were significantly higher in 5/6Nx rats compared to sham rats and PD attenuated that increase. Serum triglycerides were also increased in 5/6Nx compared to sham, but augmented further with PD. RNA sequencing yielded >50 million reads (100 bp in length) per sample. The mapping rate for this dataset was >96% for all samples. Transcripts were considered differentially expressed with an adjusted p‐value <0.05. This identified numerous DEGs resulting from PD in sham LV, 5/6Nx LV, sham kidney and 5/6Nx kidney tissues (853, 162, 637, and 33 DEGs, respectively). IPA analysis predicted gene changes consistent with increased inflammatory responses in both the LV and kidney tissues from sham controls receiving PD, suggesting that dialysis alone may induce multi‐organ inflammatory signaling. The DEG pattern of enrichment in LV tissue from sham rats receiving PD indicated that the “Phagosome Formation“ pathway was activated, while the “EIF2 Signaling” pathway was highly enriched and activated in kidney tissue from sham rats receiving PD. In summary, our transcriptomic analysis identified a pro‐immune/inflammatory state resulting from PD alone, even in sham‐operated controls with normal renal function. The transcriptomic data align with our physiological measurements indicating PD did not diminish or improve cardiac function in sham or 5/6Nx rats, rather PD may augment inflammatory signaling to increase risk factors for CVD and cardiac mortality.