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Review
. 2024 Jul;31(4):290-298.
doi: 10.1053/j.akdh.2024.03.008.

Collapsing Glomerulopathy

Abbal Koirala  1 , Shreeram Akilesh  2 , J Ashley Jefferson  3
Affiliations
Review

Collapsing Glomerulopathy

Abbal Koirala et al. Adv Kidney Dis Health. 2024 Jul.

Abstract

Collapsing glomerulopathy (CG) is a pattern of kidney injury characterized by segmental or global collapse of the glomerular tuft associated with overlying epithelial cell hyperplasia. Although CG may be idiopathic, a wide range of etiologies have been identified that can lead to this pattern of injury. Recent advances have highlighted the role of inflammatory and interferon signaling pathways and upregulation of apolipoprotein L1 (APOL1) within podocytes in those carrying a high-risk APOL1 genotype. In this review, we describe the etiology, pathogenesis, pathology, and clinical course of CG, focusing on nonviral etiologies. We also describe current treatments and explore potential therapeutic options targeting interferon/APOL1 pathways in CG.

Keywords: APOL1; Collapsing glomerulopathy; Focal segmental glomerulosclerosis; Interferon; Nephrotic syndrome; Podocyte.

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Figures

Figure 1:
Figure 1:. Kidney Pathology:
Panel A shows the collapse of the glomerular capillary tuft with hypertrophy/hyperplasia of overlying glomerular epithelial cells (arrowed). Panel B shows extensive interstitial infiltrates with dilated tubules containing eosinophilic proteinaceous casts (tubular microcystic changes).
Figure 1:
Figure 1:. Kidney Pathology:
Panel A shows the collapse of the glomerular capillary tuft with hypertrophy/hyperplasia of overlying glomerular epithelial cells (arrowed). Panel B shows extensive interstitial infiltrates with dilated tubules containing eosinophilic proteinaceous casts (tubular microcystic changes).
Figure 2:
Figure 2:. Mechanisms and potential therapies for APOL1-associated CG.
Inflammatory cytokines (IFN-α,β,γ, and IL-1, IL-6, TNF-α), often triggered by infection/inflammation, bind to their podocyte cell surface receptors and initiate downstream signaling cascades through JAK-STAT pathways resulting in upregulated transcription of the APOL1 gene. Potential therapeutic candidates inhibiting these pathways are shown in red. Antisense oligonucleotide (IONIS) blocks the translation of APOL1 mRNA to APOL1 protein. Upregulation of APOL1 mRNA leads to the insertion of APOL1 protein channels at the podocyte cell surface, promoting increased intracellular sodium influx leading to cell swelling and death. APOL1 variants induce ER stress, reduction of ubiquitin levels, and prolonging the retention of intracellular proteins, including APOL1 itself, leading to cell death. Calcium release through ER leads to mitochondrial injury and downstream injurious pathways (STING, NLRP3, gasdermin D). Increased APOL1 activity may be inhibited at the level of mRNA (antisense oligonucleotides), protein pore inhibitors (inaxaplin), or downstream pathways (Created in Biorender).
See this image and copyright information in PMC

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