The Immune System and Idiopathic Nephrotic Syndrome

Abstract

Idiopathic nephrotic syndrome often responds to immunosuppressive treatment. Nevertheless, this syndrome—and the drugs used to treat it—remain important causes of patient morbidity. Idiopathic nephrotic syndrome is usually caused by minimal change disease or FSGS, diseases that primarily affect the podocytes. In spite of decades of research, the underlying causes of both diseases remain incompletely understood. There is, however, a large body of observational and experimental data linking the immune system with both minimal change disease and FSGS, including associations with systemic infections and hematologic malignancies. Perhaps most compellingly, many different immunomodulatory drugs are effective for treating idiopathic nephrotic syndrome, including biologic agents that have well-defined immune targets. In fact, the unexpected efficacy of targeted therapeutic agents has provided important new insights into the pathogenesis of these diseases. Given the large number of drugs that are available to deplete or block specific cells and molecules within the immune system, a better understanding of the immunologic causes of idiopathic nephrotic syndrome may lead to better diagnostic and therapeutic approaches.

Introduction

Idiopathic nephrotic syndrome refers to nephrotic syndrome that occurs in the absence of an identifiable systemic cause. Although most pediatric patients with nephrotic syndrome are not biopsied, those who are usually have minimal change disease or FSGS patterns of injury. Both diseases are considered “podocytopathies” (1), and the histology does not usually show the typical hallmarks of an inflammatory disease. The glomeruli are not hypercellular, for example, and deposits of immune complexes and/or complement are generally absent or sparse. Indeed, the only changes apparent in most minimal change disease glomeruli are effacement of the podocyte foot processes (2). As early as the 1970s, however, idiopathic nephrotic syndrome was theorized to have an immune basis (3,4). Shalhoub (4) proposed that “lipoid nephrosis” (now known as minimal change disease) is a T cell–mediated disease. This hypothesis was on the basis of the favorable response to treatment with glucocorticoids, the association of the disease with T cell malignancies and atopy, and the lack of glomerular immune complexes (arguing against it being a B cell–mediated disease) (3,4). Similar associations were observed in FSGS.

Since Shalhoub (4) first published this theory, additional tools for interrogating or modulating the immune system have been utilized to analyze blood, urine, biopsy samples, and the genome of affected patients (5). Perhaps most compellingly, idiopathic nephrotic syndrome frequently responds to treatment with biologic agents that have well-defined immune targets, such as B cell–depleting drugs (6–8). It is also noteworthy that the drugs used to treat idiopathic nephrotic syndrome are also effective in autoimmune kidney diseases, such as membranous nephropathy. This suggests that these glomerular diseases have common mechanisms of injury, even if the histologic findings are different. Nevertheless, the molecular causes of idiopathic nephrotic syndrome remain incompletely understood.

What Is an Immune-Mediated Disease?

The immune system is composed of adaptive immune cells (e.g., T cells and B cells), innate immune cells (e.g., neutrophils and macrophages), and a large number of soluble molecules (cytokines, chemokines, antibodies, and complement proteins). The term “autoimmune” is usually used to describe diseases in which the adaptive immune system inappropriately targets self-tissue. Kidney biopsies are typically immunostained for Ig (IgG, IgM, and IgA) and complement proteins (C1q and C3), and these analyses are well suited to detect immune-complex glomerular diseases. When these immune proteins are detected in idiopathic nephrotic syndrome tissue, however, their significance is not always clear. Subsets of patients have minimal change disease or FSGS patterns by light microscopy, but they also have prominent glomerular deposits of IgM (“IgM nephropathy”) or C1q (“C1q nephropathy”) (9,10). Detection of these proteins does not currently influence the treatment decisions, and outcomes of IgM and C1q nephropathy are similar to those of minimal change disease and FSGS (11).

More broadly, one can define an “immune-mediated” disease as one in which immune cells or molecules are drivers of tissue injury, and standard pathology methods do not detect many of these processes. Inflammation is not usually seen in minimal change disease and FSGS kidneys by light microscopy, for example, yet immunostaining of FSGS biopsies for T cell, B cell, and macrophages markers reveals increased numbers of these cells compared with control samples (12). Immune cells also produce soluble cytokines that can act remotely (13). Levels of these molecules can be measured in serum and urine, but it is difficult to detect their effects on target tissues. Newer “-omics” methods, such as RNA sequencing, can detect the downstream effects of these molecules, and molecular studies of patients with idiopathic nephrotic syndrome have identified transcriptional signatures characteristic of cytokine responses (14,15).

Clinical Associations that Implicate the Immune System in Idiopathic Nephrotic Syndrome

Primary versus Secondary Disease

Secondary causes of minimal change disease and FSGS include malignancies, certain medications, viruses, and “adaptive” causes, such as obesity or low nephron number (16). The distinction between the primary and secondary forms of disease is on the basis of detecting certain histologic features and the absence of an obvious secondary cause (17). It is worth noting, however, that flares of idiopathic nephrotic syndrome are often “triggered” by systemic disease, such as viral infections (Table 1). Similarly, secondary causes of nephrotic syndrome may affect podocytes through the same immune pathways as idiopathic nephrotic syndrome. Lupus podocytopathy, for example, manifests as diffuse podocyte effacement without immune-complex deposition and is usually treated similar to minimal change disease (18). Thus, even though lupus podocytopathy is a secondary cause of nephrotic syndrome, it may be mechanistically closer to minimal change disease than it is to other forms of lupus nephritis.

Table 1.

Examples of genetic and secondary causes of idiopathic nephrotic syndrome with associated pathologic findings

Nephrotic Syndrome	Examples	Immune Mediated	Biopsy Findings	APOL1 Association
Genetic causes	NPHS1, NPHS2, ACTN4, ANLN	No	FSGS, MCD
Secondary
Infectious	Viral: HIV, parvovirus B19, EBV, CMV, RSV, influenza, SARS-CoV-2; bacterial: Mycoplasma pneumonia	Likely for CMV and EBV	Collapsing FSGS (HIV, parvovirus B19, EBV, CMV, COVID-19), MCD (examples: RSV, COVID-19)	HIVAN and COVAN
Medications	IFN, CNIs, anthracyclines, lithium, heroin, gold, pamidronate, NSAIDs, anabolic steroids, sirolimus; immunizations: influenza, Pfizer-BioNTech COVID-19, Moderna COVID-19	Likely	FSGS (IFN, CNI), MCD (NSAIDs, vaccines)	Associated with IFN-induced FSGS
Malignancy	Hodgkin disease, non-Hodgkin lymphoma, solid organ tumor (renal cell, colon, and ovarian cancer)	Likely	FSGS (NHL, GVHD, renal cell); MCD (Hodgkin lymphoma, ovarian cancer)
Adaptive	Obesity, hypertension, nephropenia (congenital or acquired)	No	FSGS	Associated with FSGS
Allergens	Pollen, dander, dust, food allergy	Likely	MCD
Systemic diseases	SLE, GVHD, HLH, IPEX	Likely	MCD (SLE, IPEX), MCD or FSGS with C1q deposits, MCD or FSGS (HLH)

MCD, minimal change disease; EBV, Epstein–Barr virus; CMV, cytomegalovirus; RSV, respiratory syncytial virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; COVID-19, coronavirus disease 2019; HIVAN, HIV-associated nephropathy; COVAN, COVID-19 associated nephropathy; CNI, calcineurin inhibitor; NSAID, nonsteroidal anti-inflammatory drug; NHL, non-Hodgkin's lymphoma; GVHD, graft versus host disease; HLH, hemophagocytic lymphistiocytosis; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X linked.

Minimal change disease and FSGS have similar responses to immunosuppressive drugs, raising the question as to whether they have shared pathophysiology. Both conditions are often categorized as “steroid sensitive” or “steroid resistant” (19). Presumably, this clinical response identifies patients whose disease is immune mediated. Several newer techniques have been used to evaluate the different immune signature between those “responders” and “nonresponders.” Flow cytometry has been used to analyze subsets of B cells following treatment of pediatric patients who are steroid sensitive and steroid resistant (20–23). Lymphocyte subsets have also been examined in detail using time-of-flight mass cytometry in patients treated with anti-CD20 antibodies (24). Time-of-flight mass cytometry analysis revealed that anti-CD20 treatment depleted B cells, but frequent relapsers had higher numbers of class-switched memory B cells (including B-regulatory cells) after treatment (24). Recently, urinary single-cell RNA analysis showed higher numbers of urinary immune cells in patients with FSGS (predominantly adults) compared with those with minimal change disease (14). The number of immune cells was also higher in urine from patients with active disease compared with patients in remission. Another single-cell RNA sequencing study of patients with FSGS identified distinct patterns of disease on the basis of the transcriptional patterns in endothelial cells (25). Conversely, whole-exome sequencing of samples from steroid-resistant nephrotic syndrome tends to identify pathologic variants in the genes of podocyte proteins (26), potentially identifying patients in whom the immune system is not the main driver of injury. Future studies will likely provide additional diagnostic methods of distinguishing immune subtypes of these diseases.

Infections and Idiopathic Nephrotic Syndrome

The link between viral infections and idiopathic nephrotic syndrome was part of the original justification of Shalhoub (4) for suspecting a role for T cells. It was observed that measles infections, which dampen T cell immunity, are associated with remission of disease. Viral infections are also common triggers of both FSGS and minimal change disease (27) (Table 1). In HIV-associated nephropathy, which is associated with collapsing FSGS (cFSGS), the virus directly infects podocytes, leading to cytoskeleton damage and upregulation of intracellular mediators that contribute to podocyte dedifferentiation (28,29). Cytomegalovirus, Epstein–Barr virus, and, more recently, severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019) are also associated with cFSGS (28,30). Similarly, upper respiratory infections with several viruses, including respiratory syncytial virus, influenza, parainfluenza, and coronavirus disease 2019, are associated with relapses of minimal change disease (31,32). Direct viral infection of the kidney is not seen in cytomegalovirus or Epstein–Barr virus, suggesting that these infections cause disease via systemic immune activation by the virus.

Variants in the gene for APOL1 are strongly linked with higher risk of FSGS in patients with HIV-associated nephropathy (28). APOL1 protein is expressed by podocytes, and it is believed that the risk variants exacerbate inflammatory signaling within the podocyte (33). Consistent with this, APOL1 risk variants have been linked with the development of cFSGS following treatment with therapeutic IFN (34). Interestingly, a recent study showed that endothelial APOL1 affects the inflammatory response to sepsis (35), suggesting that this protein also influences inflammatory responses of other cell types, perhaps indirectly affecting podocytes.

Cancer and Idiopathic Nephrotic Syndrome

Hematologic malignancies are associated with idiopathic nephrotic syndrome, most notably Hodgkin lymphoma. In this disease, IL-13 produced by dysregulated Th2 cells is believed to propagate nephrotic syndrome, an effect replicated in rat models (36). Nephrotic syndrome is also associated with other cancer-related conditions, including graft versus host disease after hematopoietic stem cell transplant. In this setting, glomerular disease is believed to be the result of B and T cell activation, which induces local damage by monocytes (37). Case reports also suggest that FSGS and minimal change disease can occur as paraneoplastic syndromes related to renal cell carcinoma or ovarian cancer (38,39). Hemophagocytic lymphohistiocytosis is a rare syndrome of immune overactivation that is associated with infections and malignancies. Hemophagocytic lymphohistiocytosis can cause multiple organ dysfunction via increased production of IFN-γ, IL-1β, and IL-18, and it has been linked with cases of minimal change disease and FSGS (40,41).

Medications and Idiopathic Nephrotic Syndrome

Several classes of medication have been linked to FSGS, including calcineurin inhibitors (CNIs), anthracyclines, and lithium. Some medications, like pamidronate, probably act directly on the podocyte. Others, such as lithium and IFN-α, -β, or -γ, may cause disease through systemic effects on the immune system (42–46). Nonsteroidal anti-inflammatory drugs have been specifically associated with minimal change disease, and this seems to be a variant of acute interstitial nephritis caused by an immune response to the drug (44).

Evidence of Specific Immunologic Factors in Idiopathic Nephrotic Syndrome

T Cells

The initial focus of Shalhoub (4) on a role of T cells in nephrotic syndrome was supported by the improvement of some patients following treatment with steroids or cyclophosphamide and the apparent lack of autoantibodies or immune complexes. Several studies have reported altered numbers or phenotypes of T cell subsets. The relative number of CD4 to CD8 T cells may decrease with disease, although this has not been consistent across all studies (47,48). The Th17 subset of CD4 T cells is increased in some adult patients with idiopathic nephrotic syndrome, whereas the number of T-regulatory cells (Tregs) is decreased compared with controls and with disease recurrence (49–51). Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome is a rare condition associated with the defective production of Tregs. A patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome who developed minimal change disease was reported, further implicating Tregs in the disease (52).

Many observations indicate that idiopathic nephrotic syndrome is caused by soluble factors in plasma. Idiopathic FSGS rapidly recurs in 40%–60% of transplant recipients (53). In one fascinating report, rapid retransplantation of an affected kidney led to the resolution of FSGS (54). There are also reports of transient nephrotic syndrome in fetuses, presumably due to transplacental passage of causative factors (55,56). Importantly, injection of patient serum into rats can cause proteinuria (57). These observations have prompted researchers to search for a circulating “permeability factor” (58), and much of the focus has been on T cell products. Indeed, supernatant from a T cell hybridoma induced proteinuria when injected into rats, confirming that T cells produce molecules that can affect glomerular permeability (59). Several possible effectors have been identified. IL-13 is produced by Th2 CD4 T cells and has been implicated in the development of minimal change disease (60), although IL-13 levels do not always correlate to disease activity (61). IL-17 is a cytokine produced by the Th17 subset, and levels of IL-17 correlate with glomerulosclerosis in patients with FSGS (62). IL-1 and TNF-α levels are also increased in some patients with idiopathic nephrotic syndrome, providing further evidence of T cell activation (63). A causative role for IL-1 was corroborated by a recent case series, demonstrating the benefit in adults with advanced nephrotic syndrome who were treated with anakinra (an IL-1 receptor antagonist, which blocks the effects of IL-1α and IL-1β) (64). Studies have also shown that FSGS is associated with activation of TNF-α pathways in podocytes (65), although the response to TNF-α blockade is inconsistent (66). In spite of extensive research, however, it is still not known whether specific pathogenic T cell populations or products cause idiopathic nephrotic syndrome.

Role of B Cells

Although the initial focus was on T cells, a growing body of evidence implicates B cells in the pathogenesis of idiopathic nephrotic syndrome. Even though glomerular immune complexes are not prominent, Ig is sometimes seen within the glomeruli by immunofluorescence (67). Furthermore, B cells have other immune functions beyond the production of antibodies (Figure 1). They are antigen-presenting cells that strongly affect the T cell response to antigens. They can also produce a range of pro- and anti-inflammatory cytokines (68). The number of circulating B cells as a percentage of lymphocytes is higher in children with nephrotic syndrome compared with control patients (22). Importantly, this difference is present in samples collected prior to treatment with immunomodulatory drugs. Also of note, B cell numbers are not altered in patients with genetically induced disease, indicating that this is not a nonspecific consequence of nephrotic syndrome. Additionally, a B cell activation marker (sCD23) was found to be higher in patients with relapsed idiopathic nephrotic syndrome than in patients in remission or in healthy controls (69).

Figure 1.

Multiple functions of B cells in the immune response. Autoimmune B cells may be the primary cause of nephrotic syndrome in some patients through the production of antibodies that target podocyte antigens, such as annexin A2, nephrin, and UCHL1. Production of natural antibodies reactive in injury epitopes may also be a secondary factor in disease progression. Complement activation within the glomerulus generates C3a, which ligates the C3a receptor on podocytes and causes morphologic changes. B cells also have other immune functions that may contribute to disease. They are antigen-presenting cells and modulate T cell immunity. They also produce cytokines and other soluble factors that can affect podocytes. c-mip, c-Maf–inducing protein; NF-κβ, nuclear factor-κappa-β; RelA, REL-associated protein; TCR, T-cell receptor; TLR, Toll-like receptor; UCHL1, ubiquitin carboxyl-terminal hydrolase L1.

Autoantibodies in Idiopathic Nephrotic Syndrome.

IgG in the serum of some patients with idiopathic nephrotic syndrome binds to podocytes, and studies have discovered several podocyte proteins that are the targets of autoantibodies. In one study, mass spectrometry identified annexin A2 as a possible autoantigen (70). The authors analyzed samples from 596 incident patients and detected antiannexin A2 antibodies in 18% of the patients (70). They also eluted IgG from three of the kidney biopsies and showed that it bound to annexin A2, confirming that antiannexin A2 antibody was present within the glomeruli. A recent study also found antinephrin IgG in the serum of 29% of patients with idiopathic nephrotic syndrome (71). Antibody levels fell in response to treatment and became undetectable in those patients who had a complete response to treatment. Yet another possible podocyte autoantigen is UCLH1. Anti-UCLH1 antibody titers were higher in pediatric patients with idiopathic nephrotic syndrome compared with those with other diseases, and antibody levels increased during relapse (72). Experiments demonstrated that the anti-UCLH1 antibodies directly altered podocyte morphology in vitro, and they induced proteinuria when injected into mice. Interestingly, anti-UCLH1 levels were higher in pediatric patients with minimal change than they were in adult patients.

In a study of patients with FSGS who underwent kidney transplantation, investigators found that increased levels of anti-CD40 IgG predicted disease recurrence post-transplantation, and they detected CD40 expression on podocytes of the affected kidneys (73). Passive transfer of the antibodies into mice was associated with increased albuminuria. Case reports have also found autoantibodies to other targets in patients with transplants and FSGS, including the angiotensin 2 receptor (74). Thus, although idiopathic nephrotic syndrome is not regarded as an immune-complex disease, a substantial percentage of patients have IgG antibodies reactive with podocyte antigens.

In addition to being a primary cause of injury, antibodies can also bind to antigens that are generated after tissue injury. It has been known for decades that IgM and complement C3 are deposited in the glomeruli of some patients with sclerotic glomeruli (67,75–77). Although it is commonly believed that these proteins are passively trapped in areas of tissue damage, IgM in the glomeruli colocalizes with activated complement fragments in both human (78) and murine (79,80) disease. IgM only activates complement when bound to a cognate ligand, so this indicates that the IgM is bound to a target antigen within the glomerulus. Experiments also showed that natural IgM binds to cardiolipin displayed on injured glomerular endothelial cells (79,80). Detection of glomerular IgM and complement deposits does not consistently associate with a worse prognosis in patients with idiopathic nephrotic syndrome (31,76,81,82). Nevertheless, this may be a mechanism of secondary injury to the glomerulus.

After antibodies bind to glomerular structures, complement activation can mediate glomerular injury. A recent study in mice revealed that injured podocytes downregulate expression of decay accelerating factor (DAF; or CD55), a complement regulatory protein (83). Decreased expression of DAF by the podocyte increases glomerular complement activation and might potentiate antibody-mediated injury. The authors also found that C3a generated during complement activation binds to C3a receptor expressed on podocytes, resulting in cytoskeletal rearrangement in the cells. Examination of samples from patients with FSGS also found decreased DAF expression within the glomeruli and increased glomerular complement activation. Interestingly, a study using a model of diabetic nephropathy also found that C3a generated in the glomerulus alters podocyte morphology and causes proteinuria (84). Thus, C3a may link various different primary glomerular insults with downstream changes in podocytes and proteinuria.

B Cell–Targeted Therapies.

Perhaps the most compelling evidence supporting a role for the immune system in idiopathic nephrotic syndrome comes from studies showing that B cell–depleting drugs are effective in some patients. After an early report of a patient who incidentally entered remission after treatment with rituximab (85), several subsequent randomized trials have supported this finding (7,86,87). Several studies in pediatric patients have shown that disease typically does not recur until after B cells have reconstituted, and recovery of the class-switched memory B cell population may predict relapse (21–23). This raises the possibility that drugs targeting specific subsets of B cells may be effective for treating disease and that B cell markers may be useful for monitoring patients.

In head-to-head trials, rituximab appears more effective at preventing relapses compared with treatment with CNIs (88) or mycophenolate mofetil (86), drugs that affect T cell immunity. Ofamtumumab is a humanized anti-CD20 antibody with higher binding affinity than rituximab. Ofamtumumab and rituximab appeared to be equally effective in a recent trial of pediatric and young adult patients (7). The depletion of B cells by these medications also alters T cell populations, as T and B cell responses are strongly intertwined. Th17 cells decrease after B cell depletion (89), whereas the number of Tregs increases (21,90). Thus, even drugs that specifically target B cells, like rituximab and ofatumumab, may improve nephrotic syndrome through their indirect effects on T cell immunity (91).

Other Soluble Immune Molecules

Other immune-derived molecules may also function as permeability factors. An elegant study identified soluble urokinase plasminogen activator receptor (suPAR) as a possible driver of FSGS (92). However, further studies showed that isolated suPAR does not cause proteinuria, and suPAR levels are also increased in nonproteinuric kidney disease (93,94). Thus, it does not seem to be a specific cause of disease. Similarly, cardiotropin-like cytokine 1 was identified as a possible permeability factor, but this finding has not been confirmed by subsequent studies (95).

Toll-like receptors (TLRs) are innate immune receptors that can detect bacterial and viral constituents. Podocytes express several TLRs, and signaling through these receptors can directly change podocyte morphology and induce expression of chemokines (96–99). TLRs could, therefore, link infection-associated molecules and nephrotic syndrome flares. In addition, TLR signaling increases podocyte expression of CD80, a T cell costimulatory molecule (98,99). TLRs, therefore, could also modulate the interaction between podocytes and T cells. CD80 has been detected in urine and biopsy samples of patients with idiopathic nephrotic syndrome (100,101), raising the possibility that it might be a biomarker of immune activation of podocytes. Furthermore, CTLA4-Ig is a fusion protein that blocks costimulation of T cells by CD80, and it was reported to reduce proteinuria in five patients with FSGS (101). Nevertheless, the detection of CD80 in FSGS biopsies has not been reproduced by other laboratories (102), and treatment with CTLA4-Ig is not effective in all patients (103).

Off-Target Effects of Immunomodulatory Drugs

The efficacy of immunomodulatory drugs in idiopathic nephrotic syndrome is important to our understanding of these diseases. Clinical associations, such as changes to cytokine levels or immune cell numbers in the circulation, might be downstream consequences of disease or its treatments, whereas a clinical response to immunosuppressive drugs provides evidence that the immune system plays a causal role in disease. However, even drugs with specific mechanisms of action can have off-target effects. One important study showed that CNIs can directly stabilize podocytes, independent of their effects on the immune system (104). Another study showed anti-CD20 antibodies bound sphingomyelin phosphodiesterase acid–like 3b on podocytes, stabilizing the cells (105), although no follow-up studies have confirmed this effect. In spite of these potentially beneficial off-target effects, it is striking that so many immunosuppressive drugs with distinct mechanisms of action are effective in idiopathic nephrotic syndrome, including glucocorticoids, CNIs, mycophenolate mofetil, cyclophosphamide, and rituximab/ofatumumab (106). The immunologic effects of these medications and the newer therapeutic options currently being evaluated are summarized in Table 2.

Table 2.

Current and future treatment options for idiopathic nephrotic syndrome and their mechanisms of action on the immune system

Medication Class	Medication Name	Site(s) of Action	Mechanism of Action	Indication	Population
Glucocorticoids	Prednisone; methylprednisolone	Glucocorticoid receptor in T and B cells as well as inflammatory cells; may also directly act on podocytes, parietal epithelial cells	Global reduction in cytokines, chemokines, inflammatory cells; stabilization of cytoskeleton and increased podocyte survival	MCD, FSGS	Pediatric, adult
Alkylating agents	Cyclophosphamide	T cells	Decreases Tregs and secretion of IFN-γ and IL-12; increases IL-4, IL-10 secretion	Frequently relapsing/steroid-dependent MCD, frequently relapsing FSGS	Pediatric, adult
Purine analogs	Mycophenolate mofetil	T cells, B cells	Interrupts purine synthesis in activated T and B cells, causing lymphocyte depletion	Frequently relapsing/steroid-dependent MCD; steroid-sparing idiopathic NS	Pediatric, adult
Calcineurin inhibitors	Tacrolimus; cyclosporin	T cells; podocyte cytoskeleton	Binds and inhibits calcineurin, leading to decreased T cell activation; stabilizes podocyte cytoskeleton	Steroid-sparing idiopathic NS; frequently relapsing/steroid-dependent MCD, steroid-resistant FSGS	Pediatric, adult
mAbs	Rituximab	B cells; podocyte basement membrane	Binds to CD20 on B cells; depletes B cells, reducing autoantibody formation; indirectly affects T cells; may stabilize podocytes via binding of SMPDL-3b	Frequently relapsing/steroid-dependent MCD; initial treatment in MCD; recurrent FSGS	Pediatric, adult
mAbs	Ofatumumab	B cells	Binds to CD20 on B cells; depletes B cells, reducing autoantibody formation; indirectly affects T cells	Steroid-dependent NS	Pediatric
mAbs	Belimumab	B cell–activating factor	Binds to B cell–activating factor, preventing B cell survival and differentiation into plasma cells	Frequently relapsing NS	Pediatric
mAbs	Obinutuzumab and daratumumab	Obinutuzumab: B cells; daratumumab: plasma cells	Obinutuzumab: binds to CD20 on naïve and memory B cells; daratumumab: binds to CD38 on plasma cells	Steroid-dependent NS	Pediatric
mAbs	Bleselumab	B cells	Binds to CD40, preventing CD40–CD154 interactions between B cells, T cells, and antigen-presenting cells	Recurrent FSGS	Adult
mAbs	Adalimumab	Immune system; locally at the level of kidney parenchyma	Inhibits TNF-α, which may reduce kidney fibrosis, glomerular permeability	Treatment-resistant MCD; FSGS	Adult
Melanocortin peptide	ACTH	Immune system; adrenal cortex; podocyte	Steroidal effects via the MCR2 receptor at the adrenal gland; nonsteroidal effects via MCR1 affecting the immune system and locally at the podocyte	Steroid-dependent/steroid-resistant FSGS; recurrent FSGS	Pediatric, adult
Leukotriene receptor antagonist	Montelukast	Th2 cells	Suppresses Th2 cytokine production (IL-4, IL-13), reducing podocyte permeability and cytoskeletal changes in vitro	Undergoing evaluation for use in frequently relapsing NS	Pediatric
IL receptor blocker	Anakinra (case series)	IL-1 receptor	Targets and inactivates IL-1R1, preventing IL-1β and IL-1R1 signaling	Treatment-resistant/ frequently relapsing FSGS and MCD	Pediatric, adult
Cytokines	Proleukin	IL-2	Increases Tregs, which secrete CTLA4 to bind CD80 and prevents activation of T cells	Undergoing evaluation for use in treatment-resistant NS	Pediatric
Chemokine receptor inhibitor	DMX-200/repargeranium currently in clinical trials, ClinicalTrials.gov identifier NCT05183646	CCR2 receptor	Antagonizes chemokine receptors expressed in podocytes, reducing proteinuria	FSGS	Adult
Chemokine receptor inhibitor	Propergeranium ClinicalTrials.gov identifier NCT03649152	CCR2 receptor	Antagonizes chemokine receptors expressed in podocytes, reducing proteinuria	FSGS	Adult

Recurrent FSGS indicates FSGS that has recurred following kidney transplant. MCD, minimal change disease; Treg, T-regulatory cell; NS, nephrotic syndrome; SMPDL-3b, sphingomyelin phosphodiesterase acid–like 3b; ACTH, adrenocorticotrophic hormone; MCR2, melanocortin receptor 2; MCR1, melanocortin receptor 1; Th2, T helper 2; CTLA4, cytotoxic T-lymphocyte associated protein 4; CCR2, CC chemokine receptor 2.

Overall, there is overwhelming evidence that idiopathic nephrotic syndrome is immune mediated, at least in some patients. Several new treatments have become available, most notably B cell–targeted drugs. Unfortunately, none of the available drugs lead to remission in all patients, and we do not have accurate methods for predicting which patients will respond to treatment. Patients with identical clinical and biopsy findings can have widely different responses to treatment. Consequently, some patients with idiopathic nephrotic syndrome are exposed to an array of potentially harmful medications without deriving any clinical benefit. It is important, therefore, that we identify “druggable” targets in nephrotic syndrome and equally important to develop reliable biomarkers for patients in whom the target is activated. New methods of detecting particular immune signatures in affected patients are needed. Once accomplished, classifying patients as having primary or secondary disease will become less important than stratifying patients as “likely to respond” or “unlikely to respond” to the available treatments.

Disclosures

J.M. Thurman receives royalties from Alexion Pharmaceuticals, Inc. and is a consultant for Q32 Bio, Inc., a company developing complement inhibitors. He holds stock in, receives research funding from, and will receive royalty income from Q32 Bio, Inc. The remaining author has nothing to disclose.

Funding

None.

Author Contributions

R.E. Campbell and J.M. Thurman conceptualized the study, wrote the original draft, and reviewed and edited the manuscript.