TRANSCRIPTOMIC PROFILES IN KIDNEY BIOPSIES FROM CKDu-PATIENTS IN CENTRAL AMERICA AND SRI LANKA

Chronic kidney disease of unknown cause (CKDu) predominantly affects young adults in rural areas in Central America and Sri Lanka. Clinical observations have revealed both phenotypic similarities and notable differences between affected populations, leading to an ongoing debate within the scientific community about whether the endemic forms represent a single disease entity with a shared etiology. Possible etiologies that have been proposed include environmental toxins and work-related heat stress. To advance understanding of the pathophysiological mechanisms underlying the disease, we performed RNA sequencing of kidney tissue from previous biopsy studies of CKDu patients in Central America and Sri Lanka. The resulting transcriptomic profiles were compared between the two different geographical CKDu regions, as well as in relation to healthy control biopsies (living kidney donor) and disease controls (IgA-nephropathy). 

Kidney biopsies preserved in RNAlater™, collected from patients with CKDu in El Salvador (n=7), Nicaragua (n=11,) and Sri Lanka (n=10) were microdissected into glomerular and tubulointerstitial fractions and RNA-sequencing was performed using Illumina Novaseq 6000. As healthy control and disease control material, kidney tissue from Swedish living kidney donors (n=11) and IgA-nephropathy patients (n=71) was used. All biopsies were processed and analyzed in the same way. Differential gene expression analysis was performed using DESeq2 and subsequent pathway enrichment analyses were conducted based on Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database.

A total of 15 024 unique genes were found in the dataset. The number of differentially expressed genes (DEGs) between biopsies from Sri Lanka and Central America was low, especially in the tubulointerstitial fraction (Figure 1), indicating a similar gene expression pattern in the two regions. Comparing CKDu with living donors, CKDu showed 901 upregulated and 407 DEGs in the glomerular fraction while 997 upregulated and 245 downregulated DEGs in the tubuliointerstitium (Figure 2A-B). When compared with IgA-nephropathy, 122 upregulated and 489 downregulated DEGs were found in the glomerular fraction and 305 upregulated and 257 downregulated DEGs in the tubulointerstitium (Figure 2C-D). GO enrichment analyses revealed that the predominant biological processes altered in CKDu relative to both control groups were mitochondria related, including oxidative phosphorylation, aerobic respiration, and ATP synthesis. Additionally, KEGG pathway analysis showed up-regulation of oxidative phosphorylation, ribosomal function, and thermogenesis in CKDu patients compared to both control groups. 

The study demonstrates that CKDu patients from Sri Lanka and Central America exhibit similar kidney gene expression and reveals an upregulation of mitochondrial processes, including oxidative phosphorylation and thermogenesis in CKDu compared to both healthy and disease controls. These findings suggest shared pathophysiological mechanisms between the two regions, supporting the hypothesis that CKDu represents a single disease entity. Moreover, the transcriptomic pathway analyses highlight dysregulation of cellular metabolism and thermogenesis as potential key factors in the CKDu-specific pathogenesis. 

Some of this data has been presented in an abstract at ASN Kidney Week 2022.