|
 
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| REVIEW ARTICLE |
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| Year : 2021 | Volume
: 8
| Issue : 1 | Page : 5 |
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New insights into the immunity and podocyte in glomerular health and disease: From pathogenesis to therapy in proteinuric kidney disease
Paulina X Medina Rangel, Anupama Priyadarshini, Xuefei Tian
Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| Date of Submission | 02-May-2021 |
| Date of Decision | 30-May-2021 |
| Date of Acceptance | 11-Jun-2021 |
| Date of Web Publication | 08-Sep-2021 |
Correspondence Address:
Dr. Xuefei Tian
300 Cedar St., TAC S370, New Haven, Connecticut 06519
USA
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/imna.imna_26_21
Evidence has been furnished that immune cells, and immune-podocytes interactions have increasingly become the focus of proteinuric kidney diseases, which affect millions of patients worldwide. Podocytes are highly specialized, terminally differentiated epithelial cells that wrap around the glomerulus to maintain the integrity of the glomerular filtration barrier. More recent studies demonstrate that podocytes express many elements of the innate and adaptive immune system including the complement components and receptors, through which podocytes can be involved in immune-mediated glomerular injuries and as a therapeutic target to alleviate the podocyte injury and progression to chronic kidney disease. The present review will shed light on recent findings, which have furthered our understanding of the immune mechanisms involved in podocyte injury, as well as the therapeutic implications in the treatment of immune-mediated glomerular injury.
Keywords: Complement, immunity, podocyte, proteinuria
How to cite this article:
Medina Rangel PX, Priyadarshini A, Tian X. New insights into the immunity and podocyte in glomerular health and disease: From pathogenesis to therapy in proteinuric kidney disease. Integr Med Nephrol Androl 2021;8:5 |
How to cite this URL:
Medina Rangel PX, Priyadarshini A, Tian X. New insights into the immunity and podocyte in glomerular health and disease: From pathogenesis to therapy in proteinuric kidney disease. Integr Med Nephrol Androl [serial online] 2021 [cited 2023 Mar 26];8:5. Available from: https://journal-imna.com//text.asp?2021/8/1/5/325664 |
| Introduction | |  |
The glomerulus is a highly specialized structural and functional unit of the kidney that allows the excretion of metabolic waste into urine and leaves the essential proteins in the plasma through the selective ultrafiltration of the glomerular filtration barrier (GFB). The GFB consists of a fenestrated endothelium lining the inner glomerular layer, podocytes lining the outermost glomerular layer, and a glomerular basement membrane (GBM) between them. This elegant three-layer sieve serves to selectively retain in blood high-molecular-weight molecules such as proteins and circulating cells, while water and small solutes (amino acids, mineral ions, and amino acids) freely traverse the GBM, resulting in a protein-free urinate filtrate. Injury at any component of the GFB can cause the loss of proteins in the blood such as albumin and its excretion in urine. Persistent proteinuria has been shown the independent risk factor for the development of end-stage kidney disease (ESKD)/kidney failure in proteinuric kidney disease patients.[1],[2] Glomerular diseases account for ~83% of all cases that progress to ESKD based on the United States Renal Data system released in November 2020 (https://adr.usrds.org/2020/). The pathophysiological mechanism mediated by the immune is the major cause, resulting in glomerular injury, characterized by proteinuria, hematuria, azotemia, and deposition of immune-complex or complements in the glomeruli. Evidence has been furnished that podocyte-directed injury plays a very critical role in immune-mediated glomerular diseases including membranous nephropathy (MN).[3]
Podocytes, also known as visceral epithelial cells, are highly specialized cells covering the outermost surface of the glomerulus. Podocytes are composed of a cell body and important processes that extend from their cell body named as primary, secondary, and tertiary processes (foot processes, [FP]), establishing an interdigitated structure that wraps around the glomerular capillaries and leaves slits between them, the slit diaphragm (SD). FPs have an actin-based cytoskeleton while several proteins (i.e., nephrin, podocin, NEPH1, and CD2AP) maintain the integrity of SD.[4] Besides its function of maintaining the integrity of GFB, podocytes also display properties of immune cells. Podocytes express various immunoglobulin receptors, complement components, cytokine receptors, and chemokines that allow them to be involved in various immune-mediated injuries, leading to the disorganization of the actin cytoskeleton, disruption of the SD structure and cell detachment from the GBM, and characteristics of proteinuric kidney diseases.[5],[6],[7],[8] Understanding the pivotal role of the podocytes in immune-mediated glomerular injuries is the discovery of new diagnostic approaches such as the examination of serum antiphospholipase A2 receptor (PLA2R) levels in patients with MN[9] and immune-targeted therapeutic drug, such as the application of the chimeric CD20-antibody rituximab (RTX) in patients with MN and minimal changes disease (MCD), especially in patients with refractory nephrotic syndrome (NS).[3],[10] This review aims to highlight the immunity and the role of podocytes in glomerular health and illness, as well as potential treatments for immune-mediated podocyte diseases.
| The Interaction Between The Immune System And Kidney | | |
The immune system is divided into innate and adaptive immunity, both implicated in the maintenance of homeostasis of kidney health.[11] Innate immunity refers to nonspecific and immediate defence mechanisms against foreign invaders. Kidneys participate in the production of vitamin D that plays a role in the regulation of innate immunity through the metabolism of proteins recognizing pathogenic molecules such as toll-like receptors (TLR). Kidney failure can weaken the immune system and patients with ESKD are more prone to get an infection.[12] The inflammasomes, protein complexes, that play a central role in the innate immune response and promote the development of adaptive immunity, have been widely studied in glomerular diseases as inflammation has been demonstrated to be as an essential factor in podocyte injury.[13] Recent studies have shown that inflammasomes, especially aberrant activation of NLRP3 (NACHT, LRR, and pyrin domain-containing protein 3), play a critical impact in podocyte injury and proteinuria mediated by many pathophysiological processes in the podocyte. The activation of NLRP3 in podocytes can be induced by injury factors including the K + efflux, production of reactive oxygen species, and lysosomal rupture.[14] The formation of activated NLRP3 in podocyte increases the production of interleukin (IL-1) β and IL-18 mediated by the caspase-1. The increased IL-1 β and IL-18 in podocytes suppress the expression of nephrin and podocin, two important proteins that maintain the integrity of GFB, resulting in proteinuria.[15],[16] NLRP3 inhibitors are currently being investigated as a potential therapeutic strategy for kidney disease.[17] However, the convincing evidence of inflammasomes in podocyte function is still lacking as there are no podocyte-specific conditional knockout mice available; the inflammasome exists in a variety of kidney-inherent cells and inflammatory cells, the pattern of paracrine cannot be completely excluded, and the role of inflammasomes in podocyte in glomerular diseases remains to be further explored.
Adaptative immunity relies on the immunological memory after an initial reaction to a precise pathogen, leading to a boosted protection in future invasions. In adaptative immunity, ubiquitous antigen-presenting cells (APCs) such as macrophages and dendritic cells (DCs) are responsible for antigen capture and presentation of antigenic molecules to immature T cells. Within the kidney, several APCs have been discovered and their role in immune-mediated diseases has been elucidated.
Kidneys are a target of systemic immune and autoimmune diseases. Renal autoimmune disorders occur when the immune system attacks kidney autoantigens such as the anti-PLA2R antibody against PLA2R expressed normally by podocytes to cause the PLA2R-positive MN. Frequently, the immune response begins in the glomerulus, causing glomerulonephritis. Yet, irreversible kidney injury occurs when the inflammation is persistent and involves the tubulointerstitium, leading to chronic kidney disease (CKD).[11] The interaction between T cells and kidney-immune cells can cause immune complex deposition and progress into glomerulosclerosis and renal interstitial fibrosis, the end stage of CKD.
Infections such as the common pyelonephritis, noninfectious causes such as ischemia, crystals, or toxins can secrete cytokines that promote inflammation and can cause immunopathology. Whether innate or adaptive immunity is implicated, or whether the kidney disorder is acute or chronic, inflammatory cytokines play an important role in immune-mediated injury.[18]
In immune-mediated glomerular disease, podocytes have been considered as passive antigenic targets; however, recent studies show that podocytes are indeed able to activate T-cell responses by acting as APCs.
| Podocytes As Antigen- Presenting Cells | | |
A line of evidence has recently demonstrated that podocytes can also act as kidney APCs as shown by their capabilities to process antigens and present them and form peptide major histocompatibility complex (MHC), which can initiate T-cell responses.[19] It has been demonstrated that podocytes express certain immune genes such as MHC Class II,[20] CD80 (also known as B7-1, a protein that activates T-cell by releasing T-cell attractive cytokines),[21] and FcRn receptor (protein in antigen-presenting lymphocytes), hence exhibiting features as immune cells.[22] Goldwich et al. demonstrated through in vitro studies that the podocyte expression of MHC I and II molecules was similar to those expressed in macrophages. Moreover, double staining revealed that T-cells are contiguous to podocytes in several inflammatory kidney disease models, both in rodents and humans. These findings suggest that podocytes may be directly involved in immune-mediated glomerular injuries and potentially in kidney transplant rejection, where T cell-mediated immunity is responsible for the renal injury.[19] Another study showed an active role of podocytes in the development of inflammatory glomerular diseases, in which inflammatory cytokines stimulate antigen presentation by podocytes.[23] These emerging evidence of podocyte's participation in the antigen-presentation and activating immune responses, provide a potential target for immunotherapies of inflammatory renal diseases and transplant rejection.
Interestingly, proteinuria can also trigger immune responses, resulting in a downstream renal tubular cell injury. Proteins in the filtrate, such as albumin, can activate the expression of cytokines and macrophage recruitment in the tubulointerstitium. The production of cytokines and extracellular matrix molecules by tubular cells can progress into kidney fibrosis.[24]
Herein, we describe the most common immune-mediated podocyte diseases, the mechanisms involved in the immune-mediated podocyte dysfunction, and potential therapeutic targets. In most of these pathologies, patients suffer from NS, characterized by massive proteinuria, hypoalbuminemia, hyperlipidemia, and edema.[25] NS is indeed a consequence of damage in the GFB.
| Immune-Mediated Podocyte Diseases | | |
Minimal change disease
MCD is the major cause of idiopathic NS, which accounts for 70%–90% of children patients with more than 1 year of age and approximately 15% of adult patients.[26] As the name indicates, this pathology is characterized by no visible abnormality when the kidney tissue is examined under conventional light microscopy; however, the diffuse foot process effacement is observed when analyzed by transmission electron microscopy. Clinical manifestation of MCD is the sudden onset of NS, leading to massive albuminuria (>3.5 g/day), edema, hypoalbuminemia, and in most cases hyperlipidemia.[27] Even if the exact cause of the pathology has not been fully elucidated, several studies suggesting the mechanism for MCD include the abnormal electronegative charges of GBM, circulating molecules, and T-cell disorder in the podocytes. Some of the suggested mechanisms are described below.
Myers et al. suggested that changes in the anionic properties of the GBM might be involved in the pathogenesis of MCD. The electronegative charges are normally sustained by sialic acids in the GBM.[28],[29] Furthermore, it was reported that reduced sialylation can interfere with the maturation of the podocytes.[30]
In the 1970s, Shalhoub suggested that MCD was the origin of an immune mechanism, although inflammation in the glomerulus or deposition of immunoglobulins had not been observed.[31] Yet, MCD is effectively treated with steroids and cyclophosphamide, indicating that the immune system may have an important role in pathogenesis.[32]
Reiser and Mundel suggested that MCD was a disorder initiated by the activation and misregulation of CD80 on the podocytes that led to the development and progression of proteinuria. As aforementioned, CD80, a molecule that activates T-cell, is commonly expressed on the surface of immune cells including B cells and DCs.[33] Expression of CD80 on podocytes may be triggered by immunological factors such as viral infections or allergies. According to Garin and colleagues, abnormal regulatory T cells (Treg) play a role in MCD. Even if Treg cells do not have direct access to podocytes, they secrete soluble molecules including IL-10 and Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) that suppress CD80 expression. Indeed, serum and urinary levels of CTLA-4 tend to be lower in MCD conditions.[34] Moreover, the expression of CD80 has been detected in the cultured immortalized human podocytes in vitro.[35] Levels of CD80 in urine are elevated and relevant to the diagnosis and prognosis in idiopathic NS patients,[36],[37],[38] making of CD80 a potentially useful biomarker.[39] However, there are some debating results on the involvement of CD80 in the MCD by not detecting CD80 in podocytes of all MCD patients and adriamycin-induced podocyte injury mice model.[40] The efficacy and safety of the antibody against CD80 such as abatacept, have not been thoroughly investigated in reliable clinical trials. Indeed, only MCD patients with CD80-positive staining kidney biopsy may be sensitive to treatment.[10],[41]
Other researchers have also suggested that MCD is mediated by cytokines.[42],[43],[44] Yap et al. observed an upregulation of the gene IL-13 in CD4+ and CD8+ T-cells from MCD patients and downregulation of monocyte proinflammatory IL-8 and IL-12. They demonstrated the presence of IL-13 receptors in podocyte cultures and glomeruli isolated from humans and rats. Upon IL-13 binding to its receptor, the expression of nephrin, podocin, and dystroglycan is significantly reduced, leading to proteinuria.[45] Ortega and Fornoni suggested that MCD could be considered a two-step disease, first stimulation of CD80 on podocytes by IL-13 or other circulating molecules, second silencing of CD80 by the insufficient release of soluble CTLA-4 (cytotoxic T-lymphocyte antigen-4).[46]
According to Bertelli et al., pathogenesis of MCD includes innate and acquired immunity and also oxidants.[47] They suggested that T-effector cells, Th17 cells, and Treg stimulate inflammatory signaling pathways. Low Treg concentrations are reported in MCD patients which seems to be associated with proteinuria.[48] Another group of researchers suggested an epigenetic role in the development of MCD by showing increased expression of the “nuclear factor related to kappa B binding protein” in the nuclei of the T cells of MCD patients.[49] Despite this much work on the pathomechanism of MCD, it cannot be clearly/certainly defined; however, it can be attributed to the interplay of these suggested mechanisms.
MCD is generally responsive to glucocorticoids, though, many MCD patients, particularly children with idiopathic NS, present frequent relapses or glucocorticoid dependence, along with common complications after long-term use of glucocorticoids such as Cushingoid habitus, infections, impaired glucose tolerance, reduced bone mineral density cataract, and osteonecrosis of the femoral head.[50],[51] Many other drugs such as cyclophosphamide, cyclosporin, tacrolimus, and mycophenolate mofetil have been used to treat MCD patients; unfortunately, these medications are not quite effective as expected in NS patients and also experience individually adverse effects. Hence, further understanding in the pathogenesis of MCD and the exploration of the glucocorticoid-sparing alternative medication or therapeutic strategies are needed and urgent.
Weins et al. recently confirmed that circulating autoantibodies against podocyte nephrin were present in a subset of MCD patients and correlated with disease activity. Antinephrin antibodies in podocytes were also detected in renal biopsy specimens of serum antinephrin autoantibody-positive MCD patients.[52] These findings broaden and deepen our understanding of the immune etiology of MCD since not only T-cells but also B-cells potentially participate in the pathogenesis of MCD. RTX, a chimeric monoclonal antibody with murine variable regions and a human immunoglobulin (IgG1) constant region against CD20, a membrane protein expressed on the surface of B-lymphocytes except for the pro-B and plasma cells, has been tried to cure the MCD, especially for the steroid-resistant NS or steroid-dependent NS patients and made encouraging and promising success reported by some clinical trials on the treatment of MCD patients.[53],[54],[55] The findings by Weins et al. provide new insight into the immune pathogenesis of MCD, the subset of anti-nephrin antibody-positive MCD could be a biomarker and prognostic factor for the treatment with RTX as a glucocorticoid-sparing alternative medication.
| Primary Membranous Nephropathy | | |
MN, a major cause of NS in adults, is an autoimmune disease caused by circulating antibodies that target antigens on the surface of podocytes. Nearly 75% of the cases, referred to as primary MN because only the kidneys are affected, are considered to have an autoimmune origin. The prevalent immunoglobulins observed within immune deposits are IgG, in particular IgG4. The remaining 25% of cases, designated as secondary MN, are considered to be caused by systemic diseases (conditions that affect the entire body, i.e., lupus erythematosus), malignancies, infections (i. e., hepatitis B), or exposure to certain medications or PM2.5 air pollution.[56] The presence of IgG and immunoglobulin A and M (IgA and IgM) is distinctive for secondary MN.
Even if some primary MN patients have spontaneous remission without treatment, one-third of patients develop ESKD. Primary MN biopsies are characterized by podocyte foot process effacement, thickening of the GBM, electron-dense subepithelial immune deposits, and granular positivity for IgG along the GBM by immunofluorescence.[57],[58]
One of the first attempts to elucidate the disease arises in 1959 when Heymann created an experimental nephrotic rat model, in which gp330, a podocyte protein, was later identified as the major antigen.[59],[60] For decades, Heymann's nephritis was a good experimental animal model for primary MN; however, the target protein gp330, also known as megalin, is not present in human glomeruli. It was until 2009 that Beck et al. established that MN is associated with PLA2R, a transmembrane glycoprotein expressed on the human foot process of podocytes.[61] PLA2R acts as the antigen for circulating autoantibodies in 70% of cases of primary MN, leading to the in situ formation of immune deposits, following by the activation of the complement system in podocytes, which culminates in proteinuria.[62]
In 3% of MN cases, the autoantibodies attack another podocyte protein, thrombospondin type 1 domain-containing protein 7A (THSD7A).[63] THSD7A-positive patients are more associated with cancer than PLA2R or double negative (no PLA2R and THSD7A detected) MN patients.[64] The detection of PLA2R or THSD7A in subepithelial deposits in biopsies, as well as the presence of anti-PLA2R or anti-THSD7A antibodies in patient serum, is used for the diagnosis and prognosis of the disease. In 2019, exostosin 1 and 2 (EXT1/2) and neural epidermal growth factor-like 1 protein were also suggested as potential podocyte antigens in MN.[65],[66]
The complement system is a part of the immune system that enhances the neutralization of pathogens by antibodies. In MN, the deposition of the immune complex at the podocyte membrane leads to the formation of membrane attack complex C5b-9. C5b-9 is an assembly of proteins that forms at the surface of pathogens and disrupts the cell membrane, causing cell lysis and death. Hence, insertion of the C5b-9 complex into podocytes causes fatal damage by the activation of several downstream signaling pathways. Several studies have demonstrated the co-localization of C5b-9 and immune deposits in biopsy specimens. Furthermore, C5b-9 has also been detected in the urine of MN patients and its concentration in urine correlates with the progression of the disease.[57],[58]
The complement system can be activated by three pathways: the classical complement pathway, the alternative pathway, and the lectin pathway. In all pathways, C3-convertase cleaves the complement component 3 protein, known as C3. Similar to C5b-9, C3 has been detected in almost all glomeruli of primary MN patients and plays an important role in glomerular injury.[57],[58]
The classical pathway is triggered when C1q, a molecule from the C1-complex, binds to an antigen-IgG or antigen-IgM complex. Depending on the staining technique used, C1q positivity has been observed in 17%–80% of renal biopsies of MN patients. Wiech et al. reported 82% positive staining for C1q in patients with PLA2R-antibody. Hanset et al. showed glomerular C1q deposition in all cases with positive EXT1/2.[64] Interestingly, IgG4, the predominant immunoglobulin in primary MN, is immunologically inert as is not able to activate the classical pathway through C1q, raising the question if IgG4 autoantibodies and/or the classical pathway play a central role in primary MN.
On the other hand, the lectin pathway can be activated upon binding of mannose-binding lectin (MBL) to glycan residues on the surface of pathogens. MBL depositions have been identified in glomeruli of MN patients, suggesting that the lectin pathway may be involved in kidney damage. Very recently, Kistler et al. suggested that altered glycosylation might render IgG4 antibodies capable of activating the complement system and be primarily responsible for triggering the lectin pathway in PLA2R-associated MN. They identified synaptopodin and Neph1 as the targets of complement-induced podocyte injury, leading to foot process effacement. Interestingly, primary MN can also develop in people with MBL deficiency, suggesting that the alternative pathway becomes active in these patients.[67]
MN has also been associated with C4d, another biomarker of the complement system. C4d, a product released by the complement system through classical or lectin pathway activation, has been reported in 100% of cases of primary MN.[68] Interestingly, C4d staining has become the principal technique for evaluating whether antibodies participate in the antibody-mediated rejection process following kidney transplant.[69]
These findings suggest that the different pathways that activate the complement system play an important role in disease development. Understanding the factors that make an activation system pathway the dominant provides new insights into the treatment and prognosis of MN patients. Ongoing clinical trials for MN comprise the blockage of the complement initiation pathways. Inhibition of the alternative pathway has been demonstrated to have therapeutic effects in MN.[70],[71]
The discovery and identification of PLA2R antigen on podocytes greatly promoted the diagnosis and treatment of MN patients. Adult patients with podocytopathy and serum positive-anti PLA2R antibody could be diagnosed without the invasive renal biopsy procedure due to the specificity of the anti PLA2R antibody in the pathogenesis of MN. In the meantime, the regular monitoring of the serum anti-PLA2R antibody levels in MN patients can be viewed as an important surrogate for the observation of the changes of disease course and the response to the treatment. Since the MN was first described by the pathologist Elexious T. in 1946,[72] the treatment strategies have been evolving and optimized, especially after the discovery and identification of PLA2R in 2009 and further understanding of the immunological pathogenesis of MN. The efficacy and safety of RTX in the treatment of MN patients have been investigated in the GEMRITUX clinical trial in 2017 and the MENTOR clinical trial in 2019.[73],[74] The beneficial evidence of RTX obtained from clinical investigation makes it the critical treatment medicine in primary MN patients, as recommended by the KDIGO clinical practice guideline on glomerular diseases in 2020. However, the results from the recent clinical trial of RI-CYCLO showed that RTX-treatment had no more benefit for MN patients with proteinuria >3.5 g/d compared to the cyclic corticosteroid-cyclophosphamide treatment and along with more adverse effects.[75] The efficacy and safety of RTX in the treatment of MN patients need to be further explored.
| Lupus Nephritis | | |
Lupus nephritis (LN) is the common and severe kidney involvement manifestation of systemic lupus erythematosus induced by an autoimmune disorder. The deposition of immune complexes in kidneys causes inflammation, activation of the complement system, and release of cytokines that lead to the development and progression of glomerulonephritis. The currently used histopathological classification of LN, enacted by the International Society of Nephrology/Renal Pathology Society, has 6 classes defined as Class I-VI.[76]
The Class V of LN, also known as membranous lupus nephritis (MLN), is one of the major causes of secondary MN worldwide. The symptoms of MLN are generally proteinuria, hypoalbuminemia, and dyslipidemia, with normal or slightly elevated levels of serum creatinine. Microscopic hematuria is also frequently present. The presentation of MLN kidney in histology and electron microscopy often shows mesangial hypercellularity, mesangial, and/or subepithelial immune complex deposition. Positive staining for IgG, IgM, IgA, and C1q in MLN makes it simpler to differentiate it from primary MN. In addition, the predominant immunoglobulins in MLN are IgG1 and IgG3, whereas IgG4 is typical of primary MN.[77] The presence of C1q and MBL suggests that the classic and the lectin pathway play a role in the pathogenesis of MLN. Furthermore, EXT1/2 was detected in patients experiencing MLN or another autoimmune disease, suggesting that EXT1/2 may become a biomarker to differentiate primary forms from secondary MN.[57]
Patients with diffuse proliferative glomerulonephritis, the Class of LN, present severe symptoms of LN including NS, hypertension, elevated serum creatinine, and active urinary sediment with erythrocytes and cellular casts that require aggressive treatment to alleviate the progressive decline of kidney function and decrease mortality.[78]
The renin-angiotensin-aldosterone system (RAAS) blockers, steroids, and immunosuppressive agents are the main therapeutic strategies for the treatment of LN, especially for patients with active lesions in the kidneys.[77],[79] As the increasing understanding of underlying mechanisms of immune disorder in the development and progression of LN, the use of RTX and belimumab (monoclonal antibody against the cytokine B-cell activating factor) has recently gained attraction, particularly for the recurrent or refractory LN patients. In recent clinical trials, belimumab combined with standard therapy showed a better renal response in LN patients than those who received only the standard therapy.[80] Hence, belimumab becomes a potentially promising therapeutic option in the treatment of active LN.
| Immunoglobulin A Nephropathy With Podocyte Injury | | |
Immunoglobulin A nephropathy (IgAN) is the most common type of glomerulonephritis in humans with approximately 20%–40% of patients progressing to kidney failure within 10–20 years, especially for those patients with high-risk factors including persistent proteinuria ≥1 g/d, hypertension, and severe kidney pathological lesions.[81],[82] It is primarily an immune-mediated disorder along with the genetic and environmental factors contributing to the development and progression of the disease.[83] Patients with IgAN show deposition of IgG autoantibodies against galactose-deficient IgA1 (Gd-IgA1)[84],[85] in the mesangium, leading to complement activation and the release of cytokines and chemokines IgAN are distinguished by mesangial proliferation, glomerulosclerosis, and atrophying tubulointerstitial fibrosis.[84],[86]
The pathogenesis of IgAN is a multievent process that is also influenced by genetic and environmental factors.[84],[87] The presence of circulating and glomerular immune complexes which comprise Gd-IgA1, an IgG autoantibody is found in the IgAN patients. The appearance of aberrantly glycosylated IgA1 is an inherited trait with a polygenetic background initiated by mucosal infection.[82],[88] Increased Gd-IgA1 production has been reported during certain bacterial infections.[89] The levels of circulating Gd-IgA1 also depend on environmental factors.[86],[90] The deposition of these immune complexes leads to glomerular inflammation and mesangial proliferation.[86] Furthermore, the activation of the complement and RAAS leads to loss of kidney function due to progressive glomerulosclerosis and tubulointerstitial fibrosis. The alternative route of complement activation and the lectin pathway has been implicated in the pathogenesis of IgAN.[91],[92]
Recent studies indicated that podocyte injuries in IgAN patients were associated with increased proteinuria levels and disease progression, denuded GBM was observed in renal biopsies of IgAN patients due to podocyte detachment and loss, which favors the proteinuria and glomerular sclerosis.[93],[94] Persistent proteinuria and glomerular sclerosis are believed to the independent risk factors for the progression of ESKD in IgAN patients.[81],[95] The increased number of urinary podocytes and severe proteinuria in IgAN patients were observed by some studies. The increased podocyte loss detected in urine was associated with kidney histological abnormalities.[96],[97] As such, focusing on understanding the mechanism of podocyte injury may be important for assessing the risk of progression and improving prognosis in IgAN patients.
How are the podocytes damaged in the IgAN? The possible mechanisms are as follow:
- The effects of mesangial cells regulated by the Gd-IgA1/IgG antibody immune complex on podocytes. When human podocytes were incubated with supernatants from the cultured human mesangial cells after treatment with Gd-IgA or isolated sera from the IgAN patients, a significantly reduced expression of nephrin and disorganized cytoskeleton actin in podocytes mediated by platelet-activating factor was observed, disrupting the podocyte function and the integrity of GFB.[98] Besides, the cultured human mesangial cells could release the angiotensin II (Ang II) after incubation with pIgA isolated from IgAN patients.[99] The medium from mesangial cells incubated with IgA1 from IgA patients could reduce the adhesion ability of podocytes which could be partially rescued by the Ang II receptor blocker valsartan.[100] This study showed that the Ang II could damage podocytes mediated by the increased intracellular calcium concentration[101]
- The effects of immune cells and peripheral blood mononuclear cells (PBMC) on podocytes. It has been demonstrated that the activation of B cells plays a role in the development of IgAN.[102] Various cytokines produced during infections or/and other antigenic challenges have been associated with IgAN pathogenesis. The expression of TLR -4 (TLR-4) in PBMC of IgAN patients was increased, along with a significant positive correlation with the proteinuria.[103],[104] TLR4 could upregulate the CD80 expression on the podocyte surface and the activation of NF-Κb.[104],[105] Constitutional activation of the NF-κB p65 pathway in murine podocytes has been implicated to induce glomerulosclerosis, proteinuria, and progressive kidney failure, which favors the podocyte damage.[106],[107] Renal biopsies from IgAN patients show the increased NF-κB expression in the kidney cells including the mesangial cells and podocytes which was correlated with the progression of kidney histological injury.[108] CD80 expression is associated with kidney histological damage, T-cell activation, and proteinuria in IgAN patients[109]
- The effects of the Gd-IgA1/IgG antibody immune complex on the integrin expression of podocytes. Gd-IgA1 from the sera of IgAN patients could decrease the adhesion ability of cultured podocytes by the upregulation of integrin-linked kinase.[100] The use of corticosteroid and immunosuppressive in combination with RAAS blockers in IgAN patients are the common therapies considering podocytes as the target for treatment, especially for high-risk patients with persistent proteinuria ≥1 g/d. Along with the advances in understanding the underlying mechanism of IgAN and the released results from some critical clinical trials such as STOP-IgA, TESTING, and NEFIGAN, as well as the KDIGO clinical practice guideline on glomerular diseases in 2020.[110],[111],[112],[113] New therapeutic approaches to decrease the proteinuria and protection of kidney function may be proposed such as Narsoplimab (a human monoclonal antibody targeting mannan-binding lectin-associated serine protease-2 against the lectin pathway in the complement activation, NCT03608033), Atrasentan (a selective and potent inhibitor of the endothelin A receptor, NCT04573920), and Sparsentan (a dual selective antagonist of the angiotensin II type 1 receptor and the endothelin type A receptor, NCT 03762850), etc.
| Concluding Remarks | | |
We review the recent studies on immune-mediated podocyte injury in glomerular diseases such as MCD, MN, LN, and IgAN. Modulating the immune system using glucocorticoids and cytotoxic agents has been the mainstay of therapies. The recent efforts to curtain immune-mediated podocyte injury in glomerular disease have led to exciting advances in further understanding the immunological mechanisms and development of novel immune cell-targeted biological agents such as RTX and belimumab [Table 1]. This can lead to newly customized treatment strategies and forego the use of prolonged immunosuppressants such as glucocorticoids in patients with immune-mediated podocyte injuries, hoping to reduce the common complications such as severe infections, which is the major cause of death to these patients. | Table 1: Summary for pathogenesis, kidney histological characterizations, and treatment of common immune-mediated podocytes injury glomerular diseases
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Authors contribution
P. X. M. R and A. P contributed equally to this work
Financial support and sponsorship
None.
Conflicts of Interest
Xuefei Tian is an Editorial Board Member of the journal. The article was subject to the journal's standard procedures, with peer review handled independently of this editor and his research groups.
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