Heightened innate immune response to COVID-19 infection in CKD: Implications to poorer outcome during CKD

Background: Meta-analyses reveal show a significant association of chronic kidney disease (CKD) with severe COVID-19. The double stranded RNA virus SARS-CoV-2 can evoke a damaging inflammatory response. To understand the mechanism for the greater severity of the disease in patients with CKD, we studied an animal model of CKD exposed to polyinosinic-polycytidylic acid [poly(I:C), a synthetic analog of double-stranded RNA that recapitulates the innate immune response provoked by SARS-CoV-2]. Methods: C57Bl6j mice were injected with 2 doses of cisplatin at 15 mg / kg or vehicle control subcutaneously, 2 weeks apart. After CKD established, control and CKD mice were subsequently injected with poly(I:C) at 30 mg/kg intravenously and monitored for body weight loss and mortality. Bone marrow cells were isolated 2 weeks post poly(I:C) treatment and grown in serum-free medium supplemented with macrophage colony stimulation factor for 7 days to obtain bone marrow derived macrophages (BMDM). These cells were stimulated with 10 ug / ml poly (I:C), followed by measurement of proinflammatory cytokines. Single cell RNA sequencing was used to compare transcriptome between normal and CKD kidneys. Results: CKD animals had elevated plasma creatinine (0.14 ± 0.02 mg / dL, n=8, control mice 0.09 ± 0.01 mg / dL, n=5, p<0.05) and elevated plasma levels kidney injury marker 1 (KIM-1;133.6 ± 29.9 pg /ml, vs undetectable, n=5, p<0.05). Poly (I:C) treatment induced a greater body weight loss in CKD animals (9.9± 2.9 %, n=8 vs control mice 6.8 ± 2.0 %, n=5, p<0.0005) and greater mortality of CKD mice (46% mortality within 24h in CDK mice vs no mortality in control mice). BMDMs from CKD mice produced greater levels of IL-6 than control BMDM upon poly (I:C) stimulation at both the mRNA and protein levels. In addition, Single cell RNA sequencing revealed that there is 3-fold higher relative number of macrophages in CKD kidneys. Conclusions: Our results show that CKD mice are more sensitive to foreign double strand RNA insult. BMDM isolated from cisplatin-induced CKD demonstrated a greater innate immune response during CKD. We propose that the inherent hyperinflammatory nature of CKD drives a greater innate immune response in this model of viral injury and may be responsible, at least partially, for the poor outcomes in CKD patients with Covid-19 infection.