Ascertaining the mechanistic etiology of COVID-associated glomerulonephritis: a systematic review

Abstract

Background: Since its first reported case in December 2019, COVID-19 disease, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), evolved into a major pandemic throughout the world. Although COVID-19 is most often characterized as a respiratory pathology, there are also extensive reports of renal complications, such as glomerulonephritis (GN). However, the precise nature of COVID-associated glomerulonephritis (COVID-GN) has yet to be fully understood. This review seeks to elucidate COVID-GN pathophysiology by conducting an exhaustive systematic review.

Methods: Herein, we compare the different GN subtypes associated with COVID-19 in the literature. We also review the cytokines, antibodies, and genes most implicated in COVID-GN.

Results: The GN subtype with the highest number of cases associated with COVID-19 infection was focal segmental glomerulosclerosis, specifically the collapsing morphology. Meanwhile, the highest number of cases associated with COVID-19 vaccination was IgA nephropathy. The most prevalent mechanism in the literature for COVID-GN involves a cytokine storm, which may be accompanied by immune complex deposition.

Discussion: Both infection and vaccination from SARS-CoV-2 can induce robust CD4+ T cell responses promoted by an IL-6 amplifier loop of inflammation. This immune response is likely further enhanced by interactions with complement systems and the renin-angiotensin-aldosterone system (RAAS). SARS-CoV-2-mediated pathways of both direct cytotoxicity and stimulation of polyclonal immunoglobulin may converge to cause glomerular inflammation and injury. Further investigation of these inflammatory pathways may provide insight into COVID-19 pathophysiology, treatment, and long-term outcomes.

Keywords: COVID-19; COVID-19 associated nephropathy; cytokines; glomerulonephritis; glomerulopathies; immune complex; immunology; vaccines.

FIGURE 1

(A) Tallied cases of glomerulonephritis (GNs) associated with coronavirus disease 2019 (COVID-19) infection. The highest number of reports was de novo FSGS with 196 cases. The lowest frequency was relapsed MCD with 0 reported cases. (B) Tallied cases of GNs associated with COVID-19 vaccination. The highest number of reports was relapsed IgAN with 141 cases. The lowest frequency was acute and relapsed C3GN and relapsed anti- GBM with 0 reported cases. FSGS, focal segmental glomerulosclerosis; MCD, minimal change disease; IgAN, IgA nephropathy; MN, membranous nephropathy; AAV-GN, ANCA, associated vasculitis and glomerulonephritis; LN, lupus nephritis; anti-GBM, anti-glomerular basement membrane nephritis; C3GN, C3 glomerulonephritis.

FIGURE 2

Pathophysiologic summary of coronavirus disease (COVID)-associated glomerulonephritis (GNs). Green boxes represent primarily adaptive immune processes, yellow boxes represent primarily innate immune responses, blue boxes are neutral, red boxes indicate GN subtypes. Mechanisms that are more well-established in the literature are represented by solid arrows, whereas mechanisms that are less well-understood are represented by dashed arrows. IFN-y, interferon gamma; NF-kB, nuclear factor kappa B; TNF-a, tumor necrosis factor a; EGFR, epidermal-like growth factor receptor; STAT3, signal transducer and activator of transcription 3; ORF7a, open reading frame 7a; IL-6, interleukin 6; IL-6Ra, interleukin 6 receptor alpha; TLR, toll-like receptor; ACE-2, angiotensin-converting enzyme 2; ADAM 17, disintegrin and metalloproteinase 17; MHC, major histocompatibility complex; HLA-DR, human leukocyte antigen-DR; THSD7A, thrombospondin type-1 domain- containing 7A; NELL1, nerve epidermal growth factor- like antigen 1; Gd-lgA1, galactose-deficient lgA1; MPO, myeloperoxidase; PR3, proteinase 3.

FIGURE 3

Proposed mechanism of the IL-6 amplifier pathway in the setting of coronavirus disease 2019 (COVID-19). Ang II, angiotensin II; ACE-2, angiotensin-converting enzyme 2; ATR1, angiotensin II type 1 receptor; ADAM17, disintegrin and metalloproteinase 17; TNF-a, tumor necrosis factor alpha; EGFR, epidermal-like growth factor receptor; NF-kB, nuclear factor kappa B; STAT3, signal transducer and activator of transcription 3; IL-6, interleukin 6; IL-6Ra, interleukin 6 receptor alpha; IFN-1, type 1 interferon; IFN-y, interferon gamma; TLR, toll-like receptor; NET, neutrophil extracellular traps; MPO, myeloperoxidase; PR3, proteinase 3; Gd-IgA1, galactose-deficient IgA1.

FIGURE 4

Proposed mechanism of MHC-II contribution to coronavirus disease (COVID)-associated AAV-GN. MON, monocyte; Mo, macrophage; CYT, pro-inflammatory cytokines; CD4 T, CD4+ T cell; CD8 T, CD8+ T cell; MHC II, major histocompatibility complex class II; TCR, T cell receptor; AAV-GN, ANCA- associated vasculitis and glomerulonephritis; HLA-DR, human leukocyte antigen receptor; MPO, myeloperoxidase; PR3, proteinase 3.