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Review
. 2022 Mar 24;23(7):3525.
doi: 10.3390/ijms23073525.

New Insights into the Treatment of Glomerular Diseases: When Mechanisms Become Vivid

Da-Wei Lin  1 , Cheng-Chih Chang  2 , Yung-Chien Hsu  3   4 , Chun-Liang Lin  3   4   5   6   7
Affiliations
Review

New Insights into the Treatment of Glomerular Diseases: When Mechanisms Become Vivid

Da-Wei Lin et al. Int J Mol Sci. .

Abstract

Treatment for glomerular diseases has been extrapolated from the experience of other autoimmune disorders while the underlying pathogenic mechanisms were still not well understood. As the classification of glomerular diseases was based on patterns of juries instead of mechanisms, treatments were typically the art of try and error. With the advancement of molecular biology, the role of the immune agent in glomerular diseases is becoming more evident. The four-hit theory based on the discovery of gd-IgA1 gives a more transparent outline of the pathogenesis of IgA nephropathy (IgAN), and dysregulation of Treg plays a crucial role in the pathogenesis of minimal change disease (MCD). An epoch-making breakthrough is the discovery of PLA2R antibodies in the primary membranous nephropathy (pMN). This is the first biomarker applied for precision medicine in kidney disease. Understanding the immune system's role in glomerular diseases allows the use of various immunosuppressants or other novel treatments, such as complement inhibitors, to treat glomerular diseases more reasonable. In this era of advocating personalized medicine, it is inevitable to develop precision medicine with mechanism-based novel biomarkers and novel therapies in kidney disease.

Keywords: IgA nephropathy; immunosuppressant; membranous nephropathy; minimal change disease; precision medicine.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pathogenesis of minimal change disease. Overexpressed CD80 and NEPH1 interact via extracellular domain. Interaction of CD80 and CD28 leads to increase expression of phosphor SRC, which causes dephosphorylation of synaptopodin. Increased expression of c-mip by Th17 results in dephosphorylation of nephrin. These activities and circulating permeability factors, including anti-nephrin autoantibodies, impair slit diaphragm integrity and destabilization of the actin-cytoskeleton. GBM: glomerular basement membrane; CNI: calcineurin inhibitor; MMF: mycophenolate mofetil; MPA: mycophenolic acid; SMPDL-3b: Sphingomyelin Phosphodiesterase Acid Like 3B; ASMase: Acid sphingomyelinase; c-mip: c-maf inducing protein; CTLA-4: cytotoxic T-lymphocyte-associated protein 4.
Figure 2
Figure 2
Pathogenesis of IgA nephropathy with 4 hits theory. Hit 1: synthesis of gd-IgA1; Hit 2: anti-gd-IgA1 antibody production; Hit 3: Circulating IgA immune complex formation; Hit 4: Circulating IgA immune complex deposition to the glomeruli. TLRs: Toll like receptors; BAFF: B-cell activating factor; APRIL: a proliferation-inducing ligand; gd-IgA1: galactose-deficient IgA1; C1GALT1: Core 1 Synthase, Glycoprotein-N-Acetylgalactosamine 3-β-Galactosyltransferase 1; GALNT2: Polypeptide N-Acetylgalactosaminyltransferase 2; ST6GALNAC2: ST6 N-Acetylgalactosaminide α-2,6-Sialyltransferase 2; anti-gd-IgA1 Ab: anti-gd-IgA1 antibody; CNI: calcineurin inhibitor; MMF: mycophenolate mofetil; MPA: mycophenolate acid. Blue dash lines denote undergoing novel treatment in IgA nephropathy.
Figure 3
Figure 3
Pathogenesis of idiopathic membranous nephropathy with 3 hits theory. Hit 1: Synthesis of autoantibodies against PLA2R/THSD7A; Hit 2: IgG4 predominant autoimmunization against PLA2R/THSD7A by class shift; Hit 3: Increased expression of C3a1 and C5a1 alone with MAC. PLA2R: Phospholipase-A2-Receptor; THSD7A: Thrombospondin type I domain-containing 7A; MBL: mannose-binding lectin; MASP-1/2: mannose-associated serine protease 1 and mannose-associated serine protease 2; MAC: membrane attack complex; CNI: calcineurin inhibitor; MMF: mycophenolate mofetil; MPA: mycophenolate acid; blue dash lines imply possible novel treatments.
Figure 4
Figure 4
A paradigm of precision medicine in the field of glomerular diseases.
See this image and copyright information in PMC

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