The five types of glomerulonephritis classified by pathogenesis, activity and chronicity (GN-AC)

ABSTRACT

Glomerulonephritis (GN) is a diverse group of immune-mediated disorders. Currently, GN is classified largely by histological patterns that are difficult to understand and teach, and most importantly, do not indicate treatment choices. Indeed, altered systemic immunity is the primary pathogenic process and the key therapeutic target in GN. Here, we apply a conceptual framework of immune-mediated disorders to GN guided by immunopathogenesis and hence immunophenotyping: (i) infection-related GN require pathogen identification and control; (ii) autoimmunity-related GN, defined by presence of autoantibodies and (iii) alloimmunity-related GN in transplant recipients both require the suppression of adaptive immunity in lymphoid organs and bone marrow; (iv) autoinflammation-related GN, e.g. inborn errors of immunity diagnosed by genetic testing, requires suppression of single cytokine or complement pathways; and (v) Monoclonal gammopathy-related GN requires B or plasma cell clone-directed therapy. A new GN classification should include disease category, immunological activity to tailor the use of the increasing number of immunomodulatory drugs, and chronicity to trigger standard chronic kidney disease care including the evolving spectrum of cardio-renoprotective drugs. Certain biomarkers allow diagnosis and the assessment of immunological activity and disease chronicity without kidney biopsy. The use of these five GN categories and a therapy-focused GN classification is likely to overcome some of the existing hurdles in GN research, management and teaching by reflecting disease pathogenesis and guiding the therapeutic approach.

INTRODUCTION

Since glomeruli function as high flow filters that produce a substantial ultrafiltrate, they are vulnerable to inflammatory injury from a variety of causes, resulting in a diverse range of causes of glomerulonephritis (GN). Understanding, treating, studying and teaching GN is difficult, not only due to the diversity of diseases themselves, but also because there is no simple logical classification to underpin the long list of disease entities that comprise the GNs.

Currently, GN is categorized based largely on histopathological lesion patterns, with primary and secondary forms and a myriad of differential diagnoses for each entity [1]. There are historical reasons why we group GN in this manner, specifically the development of kidney biopsy and the capacity of light microscopy to describe patterns of glomerular injury, based largely on changes in cell number, deposits and matrix proteins in different parts of the glomerulus. The introduction of immunohistochemistry for immunoglobulins and complement, and electron microscopy extended this paradigm [2]. However, the evolution of immunophenotyping and the advent of genetics have demonstrated that the same histological lesions can develop from different disorders that require completely different treatments. Terms such as membranoproliferative GN (MPGN), focal segmental glomerulosclerosis (FSGS) and complement factor 3 GN (C3GN) are examples of the focus on lesional patterns that remain in use when describing and defining glomerular diseases, despite their diverse origins and requirement of different treatments [3]. Classifying diseases caused by different processes primarily according to pathology was useful when using generic therapies such as glucocorticoids, which although effective in some conditions, in other diseases either need to be combined with additional immunomodulatory therapies or are not indicated. In addition, nomenclature and classification systems tend to drive kidney-focused research, e.g. using each emerging -omic technology to repeatedly characterize kidney injury, inflammation, fibrosis and atrophy at an increasingly granular level within the kidney itself [4], while answers to the origin and persistence of immune-mediated GN can only be found outside the kidney.

Kidney biopsy confirms the GN diagnosis, helps to define immunological activity and informs the degree of irreversible damage [5]. However, a kidney-focused approach has impeded conceptual advances regarding disease categories. In addition, this approach has had limited impact on the understanding of how to control the aberrant immune mechanisms that induce and maintain GN by producing nephritogenic humoral and cellular immune effectors from outside the kidney.

To overcome some of these hurdles, we propose first to acknowledge that GN are primarily immune-mediated disorders and to categorize GN accordingly. In addition, we propose to classify them by immunological activity (A) and chronicity (C) in a simple “GN-AC” matrix (Table 1). We discuss how approaching GN from an immunological perspective and positioning immunophenotyping at the center of the diagnostic approach has multiple important implications for GN management, treatment, education and research.

Table 1:

Proposed GN-AC classification and reporting system for GN.

Classification criteria	Reporting	Therapy
GN: GN defined by immunophenotyping	Infection: specify type of infection	Infection control
	Autoimmunity: specify autoantigen (e.g. PLA2R, MPO, PR3, …) or systemic disorder (e.g. SLE)	Immunotherapy (activity)
	Alloimmunity: specify type of graft	Immunosuppression
	Autoinflammation: specify inborn error of immunity	Specific pathway blockade
	Monoclonal gammopathy: specify type of paraprotein and either B or plasma cell clone	Clone-directed
A: Activity	0: Absent	Observation
(immunological)	1: Low (serum biomarkers and/or no nephrotic syndrome and/or little active injury on biopsy)	Observation/specific therapy
	2: Moderate (serum biomarkers and/or moderate active injury on biopsy)	Specific therapy
	3: High (serum biomarkers and/or nephrotic syndrome and/or high active injury on biopsy)	Intense specific therapy
C: Chronicity	0: Absent (less than 3 months)
	1: Early CKD (G1/A1–2) and/or few fibrosis on biopsy	Observation
	2: Advanced CKD (G2–4/A1–3) and/or significant fibrosis on kidney biopsy	Observation/CKD therapy
	3: Kidney failure (G5, G5-D), kidney atrophy	CKD therapy

MPO: myeloperoxidase; PR3: proteinase 3; SLE: systemic lupus erythematosus.

GN-AC MATRIX STEP 1: THE TYPE OF GN

Defining GN by general categories of immune-mediated disorders

Immune-mediated disorders can be dissected into five categories defined by the key underlying immune mechanisms, i.e. infection, autoimmunity, alloimmunity, autoinflammation or monoclonal gammopathy.

Infection-related GNs

Infection-related GNs arise from host defense against an acute, subacute or persistent infection somewhere in the body with three main immunologic mechanisms (Fig. 1). (i) Post-streptococcal GN arises from the capacity of group A β-hemolytic streptococci antigens to activate complement directly or by inducing production of anti-factor B antibodies, mimicking a transient complementopathy. (ii) Other infection-related GN are caused by deposition of circulating immune complexes in the glomerulus related to: (a) primary or secondary (acquired or iatrogenic) immunodeficiencies that predispose to the severity or persistence of infection [6]; (b) colonization of implanted device such as catheters; or (c) host defense-escape mechanisms of certain pathogens, such as Schistosoma. Host defense against pathogens involves innate and adaptive immunity and can mimic an autoimmune disease, including transient positivity to anti-nuclear antibodies, cryoglobulines and other autoimmunity markers [7]. (iii) Cytotoxic effects of pathogens that can infect podocytes such as human immunodeficiency virus, Epstein–Barr virus, arbovirus, parvovirus B19 or severe acute respiratory syndrome coronavirus 2 causing a podocytopathy, particularly in carriers of a high-risk APOL1 genotype. In rare cases, persistent infections can also cause AA amyloidosis.

Figure 1:

The major entities of glomerulonephritis. The GNs can be classified into five major groups according to the respective pathogenesis that leads to glomerular injury and inflammation. It is the underlying pathogenesis that determines the most appropriate type of (immuno-)therapy. Immunophenotyping is the diagnostic approach to dissect the GNs and includes many different types of exams. Kidney biopsy may be needed or not in this context.

Therapeutic approach. Even if the immune response contributes locally to glomerular injury, the primary therapeutic target in infection-related GNs is the infection itself [8, 9]. Infection-related GN may spontaneously resume once host defense is able to eliminate the pathogen [10], while it persists when the pathogen keeps releasing antigens that maintain the respective immune response [7]. Without controlling the infection, the use of immunosuppressants is questionable and may even be counterproductive due to their capacity to impair host defense against the infectious agent [11]. For example, a diagnosis of endocarditis-related GN mandates the cure of endocarditis and not the use of glucocorticoids to control glomerular inflammation. Improvements in socioeconomic conditions at a population level has reduced the incidence and impact of these diseases.

Autoimmunity-related GNs

Autoimmunity-related GNs arise from adaptive immunity against a single or several of a wide spectrum of self-antigens (Fig. 2). Even if the clinical presentations and histological lesions patterns differ depending on the localization of the self-antigens, the mechanisms of the underlying adaptive immune response share some common features [12]. Autoimmunity arises from a loss of tolerance to which genetic and environmental factors contribute. Once tolerance is lost, cellular and humoral autoimmunity develops so that multiple adaptive and innate components may mediate injury [13]. Sometimes autoimmunity is transient, explaining spontaneous remissions of some cases of anti–phospholipase A2 receptor (PLA₂R) autoimmune GN [14]. Once long-term immune memory has formed, it manifests as clones of autoreactive memory T and B cells in the lymphoid organs and as long-lived plasma cells in their bone marrow niches which is similar to immune memory after infection or vaccination [15]. Tissue-resident T memory cells have been described in many autoimmune diseases including the kidney, and intrarenal tertiary lymphoid organs with T and B cells may be present [16, 17]. Re-exposure or persistent exposure to antigen in an immunologically “dangerous” context triggers antigen-specific immunological activity, which presents as either persistent or relapsing disease activity, depending on many levels of regulation [18]. Autoimmunity is always oligo- or polyclonal but can center on one or only a few antigenic epitopes [19–21]. Measurement of serum autoantibodies to some nephritogenic autoantigens predict immunological disease activity well, e.g. in anti–glomerular basement membrane (GBM) disease or in anti-PLA₂R autoimmune GN. However, in other conditions, while autoantibodies are relevant to disease, serum titers do not predict activity well enough to predict outcome or meaningfully guide therapy. This may at least in part be due to the multiple autoantigens involved in lupus nephritis, the multiple B cells epitopes detected in anti-MPO antibody assays in people with MPO-ANCA-associated GN [22] or antibodies targeting different forms of immunoglobulin A (IgA) in IgA nephropathy [23].

Figure 2:

Autoantigens in autoimmune glomerulonephritis. Autoimmune GN can involve different classes of autoantigens, which make them look different under the microscope and present differently clinically. However, the involved innate and adaptive immunity is similar. Therefore, they share key elements of pathophysiology implying the same set of immunotherapies to control immunological activity, if present. DC: dendritic cell; Th: T helper cell; IC-GN: immune complex GN; TMA: thrombotic microangiopathy.

Therapeutic approach. Treatments that restore tolerance by selectively eliminating the causative autoreactive lymphocyte clones or by selectively modulating their activity are not yet available. Therefore, we remain with therapies targeting the various elements of adaptive immunity that are common to many autoimmune GNs. Drugs used in this context include azathioprine, mycophenolate mofetil, calcineurin inhibitors, B cell–depleting agents and belimumab. More recently, plasma cells have become a therapeutic target, with trials using proteasome inhibitors or anti-CD38 IgG [15]. In addition, glucocorticoids are effective in this regard and suppress inflammation in the kidney. This dual effect of glucocorticoids is not shared by the newer immune modulators, which may explain why steroids are still in use despite their significant metabolic toxicities. Complement C5aR inhibition can at least partially replace glucocorticoids in active ANCA-associated vasculitis (with rituximab) [24] and may have a role in other highly active autoimmune GNs. An ultimate cure for autoimmune-GNs would selectively eliminate or silence all T and B cell clones responding to the antigenic epitope. Therefore, a “clone-directed therapy” is a conceptually promising approach also for autoimmune GNs, as is the use of tolerogenic platforms that aim to selectively modulate the activity of these clones [25].

Alloimmunity-related GNs

Alloimmunity-related GNs develop in patients that have received an allograft of a solid organ, bone marrow or cells (Fig. 1). The adaptive immune response is in some ways conceptually like that of autoimmunity, although in classical alloimmunity there is no response against the self, and there is also more evidence in alloimmunity for a key role for CD8⁺ T cells via donor-specific alloantigenic peptides being presented in the context of major histocompatibility complex class I molecules. While alloreactive CD8⁺ T effector cells are important, donor-specific antibodies are also crucial, especially in glomerular lesions [26]. Immunity is directed against numerous HLA and non-HLA antigens [27]. As the spectrum of donor antigens is wide, alloimmunity is polyclonal and biomarkers that would allow a precise monitoring of the activity of alloimmunity are difficult to define.

Therapeutic approach. Allo- and autoimmunity involve similar elements of the adaptive immune system; therefore, similar drugs are currently used to control alloimmunity in general and alloimmunity-related GNs [28]. The precise alloantigens or their epitopes triggering GN are difficult to define, which is a hurdle for the development of any antigen-specific therapy. Whether complement inhibitors could improve the outcome of alloimmunity-related GNs is currently unknown.

Autoinflammation-related GNs

Autoinflammation-related GNs develop from inborn errors of immunity and therefore require genetic testing to establish the diagnosis (Fig. 1) [29]. For example, genetic variants leading to overactivation of interleukin (IL)-1, tumor necrosis factor (TNF) or type I interferon signaling pathways can be sufficient to cause systemic and tissue inflammation causing organ damage [30, 31]. Genetic complementopathies leading to C3GN belong to this category and environmental co-factors may impose a second hit to trigger kidney injury [32]. Combinations with autoimmune forms of C3GN occur [33].

Therapeutic approach. Inborn errors of innate immunity leading to GN do not require the use of unspecific immunosuppressants because the adaptive immune system is not involved and there is often a single dysregulated pathway mediating disease. Innate glomerular inflammation should be controllable by selective blockade of the affected cytokine pathway, e.g. anti-IL-1, anti-TNF or anti-type I interferon, respectively [34]. Inborn errors of the alternative complement pathway belong to this category and such forms of, e.g. C3GN, should be treatable with a specific complement inhibitor, unless a mutated protein favors secondary autoimmunity [33]. Such a C3GN would be categorized with and managed within the autoimmune GN framework and benefit from immunosuppressants to suppress adaptive immunity.

Monoclonal gammopathy–related GNs

Monoclonal gammopathy–related GNs arise from a single B cell or plasma cell clone that produces a nephrotoxic immunoglobulin or immunoglobulin component (Fig. 1) [35]. Such monoclonal gammopathies of renal significance (MGRS) exemplify the management principle that targeting the primary problem, in this case the pathogenic clone in the bone marrow, is essential. Targeting the kidney with anti-inflammatory or anti-fibrotic drugs is of little use without targeting the disease-inducing clone in the bone marrow [35]. In an analogous manner, auto- and alloimmunity-related GNs involve autoreactive clones that as well as infiltrating the kidney, themselves produce nephritogenic antibodies in secondary lymphoid organs and bone marrow, arguing against a solely kidney-focused approach to immunotherapy of the GNs [36].

Therapeutic approach. “Clone-directed therapy” with drugs targeting B cells or plasma cells producing the nephrotoxic immunoglobulin or immunoglobulin component following the treatment algorithms for multiple myeloma is the standard approach for MGRS including GN [37].

Diagnostic categorization of a GN requires multidimensional immunophenotyping

The pathogenesis-based GN categories require thorough immunophenotyping to accurately allocate patients to the correct disease category (Fig. 3). Kidney biopsy can contribute significantly to immunophenotyping. For example, immune complex GN with either IgA, IgM or even full-house Ig deposits in the presence of C4d and in the absence of a serum autoantibody (or even in presence of transient positivity to autoantibodies) strongly supports an infection-related GN [7]. Also, the presence of certain podocyte antigens in the presence of a respective autoantibody in the serum implies autoimmune membranous GN, a more suitable term than “primary membranous GN” [14]. Monotypic immunoglobulin deposits in the glomerulus identify a monoclonal gammopathy–related GN [35]. However, kidney biopsy is unable to dissect an autoimmune, autoinflammatory or monoclonal cause of C3GN, hence these different entities are still often managed erroneously as a single entity [33]. In general, kidney biopsy cannot identify autoinflammatory GNs, thus immunophenotyping may extend to genetic testing whenever infections, autoantibodies, a transplant or a monoclonal gammopathy are absent [29]. Immunophenotyping may also include microbiology and serological studies to diagnose or exclude infections, an extended search for autoantibodies, serum complement studies, a bone marrow aspirate and flow cytometry studies of blood, bone marrow and urine. For example, ANCA-associated vasculitis can be diagnosed without a kidney biopsy in the presence of serum ANCA, haematuria and proteinuria, and impaired kidney function [38]. A similar concept applies to anti-GBM disease and has been proposed for anti-PLA₂R-associated nephrotic syndrome [39]. A similar paradigm may apply to the podocytopathies that are not always considered GNs, as they lack proliferative lesions [40]. However, patients with minimal change disease or FSGS need work-up for adaptive, infectious or genetic causes, as well as searching for anti-nephrin antibodies to identify cases of autoimmune podocytopathies [41].

Figure 3:

Multilevel diagnostic algorithm of GN. The accurate diagnosis and stratification of GN requires multilevel immunophenotyping to allow classification and staging according to the GN-AC matrix. The GN-AC classification defines the type and intensity of immunotherapy. Where non-invasive diagnostic markers for defining the type of GN, immunological activity and disease chronicity are available, kidney biopsy may become dispensable. MGUS: monoclonal gammopathy of unknown significance; PCR: polymerase chain reaction; MPO: myeloperoxidase; PR3: proteinase 3; SLE: systemic lupus erythematosus.

The lesion-based diagnostic approach as a barrier to understanding and management of GN

Some examples may illustrate better the limitations of the current approach.

MPGN is perhaps the best example of how using descriptive terms can hamper progress by causing confusion. The broad differential diagnosis of MPGN encompassing completely different disorders with different therapies disqualifies the use of this term to define a disease entity. The lesion pattern of MPGN can be replaced easily by more specific histopathological descriptions such as immune complex GN (infection or autoimmune), MGRS (monotypic deposits) or C3GN (absence or low Ig levels in presence of C3) [2].

C3GN is another descriptive term that may encompass a genetic disease, autoimmunity or a monoclonal gammopathy as the underlying disease requiring different treatments [33]. Even though the upcoming complement inhibitors may show effects on all forms of C3GN, a detailed diagnostic work-up of the C3GNs for the sake of correct categorization may still be needed to define adjunct and duration of treatment, e.g. monoclonal gammopathy–related C3GN may require additional therapeutics.

Lupus nephritis remains categorized by World Health Organization or International Society of Nephrology/Renal Pathology Society classes that do not accurately reflect the extent of the disease, do not clearly predict long-term outcomes and do not define clinical management [42]. Re-biopsy studies comparing classes in first and second biopsies are often distracting, while activity and chronicity indices are likely to guide lupus nephritis management more reliably. In this context, class VI lupus nephritis is redundant as it implies a high chronicity index and does not address the question as to whether immunosuppressive therapy is still useful.

IgA nephropathy is classified by the Oxford/MEST-C classification which is validated to predict outcomes [43] from the time of biopsy, but which does not inform the use of immunotherapy. Until reliable serum markers of immunological activity become broadly available, the National Institutes of Health (NIH) activity and chronicity indices used in lupus nephritis could be applied to IgA nephropathy, as both proliferative autoimmune GNs share many of their effector immune mechanisms of kidney injury.

In membranous nephropathy, the discovery of the many different autoantigens in membranous GN has revolutionized our understanding of the diseases that cause this histological pattern of injury and is making “primary” and “secondary” labels redundant [44]. What is needed is a concerted effort to develop a panel of immunoassays for serum autoantibodies directed against these autoantigens [44].

GN-AC MATRIX STEP 2: ACTIVITY AND CHRONICITY

Immunological disease activity determines immunosuppressive immunotherapy in autoimmune GNs

We have learned from AL amyloidosis how important it is to base treatment decisions on reliable biomarkers of immunological activity. In this condition, free-light chain assays have entirely replaced the unreliable proteinuria or M-spike in electrophoresis measurements for tailoring therapy [45]. In some autoimmune GNs with proven nephritogenic autoantibodies, serum titers provide highly relevant information about the immunological activity of the disease process within lymphoid organs. For example, anti-GBM IgG and anti-PLA₂R IgG levels can be used as biomarkers just as light chain levels can in a monoclonal gammopathy–related GN [38, 39]. Data from anti-PLA₂R autoimmune GN has alerted us to the fact that proteinuria levels do not adequately reflect immunological disease activity, especially upon significant podocyte injury [14]. The same principle applies to other forms of GN, including lupus nephritis, indicating the potential value of re-biopsy [46], e.g. protocol biopsy to assess immunological response to treatment whenever autoantibody tests are either not yet commercially available or are unreliable in predicting immunological GN activity.

However, lupus nephritis trials continue to enrol patients based on histopathological classes and proteinuria levels rather than based eligibility on the NIH index of immunological disease activity, which would enrich an active lupus nephritis population in order to enable testing of the efficacy of add-on immunomodulatory agents. Similarly, IgA nephropathy trials testing immunotherapies are recruiting patients based on historical diagnostic biopsies and certain levels of proteinuria, assuming proteinuria represents immunological disease activity, which is frequently not the case. Obesity, a high salt or high-protein diet, low nephron number, glomerular scarring, diabetes mellitus and vasodilator therapy are common causes of proteinuria in patients with inactive GN [47]. All these further factors always need to be first controlled before interpreting proteinuria as a marker of immunological activity.

Non-immune drivers of kidney injury and CKD progression in GN as a therapeutic opportunity

All five forms of GNs can cause irreversible kidney damage via nephron loss. Nephron loss implies an increased workload for the remaining nephrons, which can be compensated to some extent by the so-called renal reserve [48]. Compensation means increased shear stress for the single podocyte at the filtration barrier and increased metabolic workload for the single epithelial cell in the proximal tubule [48]. The more nephrons that are lost due to immunologically active persistent or relapsing GN, the greater the workload for the remaining glomeruli, leading, for example to the detachment and death of increasing numbers of podocytes and tubular cells [47]. Numerous cofactors enhance the workload of remnant nephrons and accelerate this process such as poor nephron endowment at birth or a reduced number of nephrons due to previous kidney injury, obesity, high salt or protein diets, diabetes mellitus and pregnancy [47, 48]. The consequence is an increasingly hypocellular kidney, glomerulosclerosis, tubular atrophy and interstitial fibrosis, clinically presenting as a progressive loss of glomerular filtration rate, often with proteinuria. Reducing the workload of the remaining nephrons, e.g. with inhibitors of the renin–angiotensin system and the sodium-glucose transporter-2, is the main therapeutic strategy to prevent chronic kidney disease (CKD) progression beyond immunotherapy in all forms of GN [47–49]. While this strategy is now established in the chronic phase of GN, it might well also apply to the acute phase, because reducing filtration pressure should help to limit glomerular barotrauma in a moment when the injured glomerular filtration barrier is particularly sensitive to an increased filtration pressure.

PRACTICAL IMPLICATIONS OF THE GN-AC MATRIX AND RESEARCH PERSPECTIVES

The proposed GN-AC matrix has several practical implications. First, non-invasive diagnostic tools become equally important to kidney biopsy to define the type of GN. Thus, we need research efforts into biomarkers that dissect pathogenesis-based GN categories in a sensitive and specific manner, such as free-light chain assays for the monoclonal gammopathies. This could be novel diagnostic tests for pathogen detection, serum autoantibodies and gene panels to identify causative inborn errors of immunity. Secondly, the increasing numbers of (costly) immunomodulatory drugs require disease categories that align with their potential use that are not provided by disease categories defined by unspecific lesion patterns. Thirdly, unspecific histological lesion patterns become less relevant in guiding GN management, and overemphasizing them in this context is confusing. Fourthly, determining immunological disease activity is key in guiding the intensity of immunotherapy and may replace proteinuria-based treatment indications and inclusion criteria of clinical trials. Fifthly, patients with GN benefit from CKD care, especially when signs of chronicity and CKD progression in absence of immunological disease activity are present. Dissecting GN activity from chronicity with non-invasive biomarkers to monitor GN will be an important step forward in GN management. Finally, a simple and intuitive GN classification matrix will reduce confusion inside and outside nephrology, and improve teaching and advocacy.

SUMMARY

The last decade has witnessed unprecedented progress in the treatment of GNs because of an increasing understanding of the causative mechanism and the interacting innate and adaptive immune system. The latter implies a full pipeline of novel (and costly) immunomodulatory drugs that warrant careful use where they are effective and no use where they are not. The GN-AC classification system overcomes some of these hurdles. Where non-invasive biomarkers of the GN-AC criteria become available, kidney biopsy may become dispensable, e.g. in autoimmune GN of the PLA₂R type or in multiple myeloma–related GN. Research on the immunopathogenesis of the GNs may benefit from a less kidney-focused perspective because pathogenesis and therapeutic targets localize outside the kidney. As an exception, the upcoming complement inhibitors are an exciting tool to control glomerular injury locally. Furthermore, an increasing number of drugs targeting non-immune mechanisms of GN chronicity will improve patient outcomes across all GN disease entities. Therefore, the GN-AC matrix proposed here may help to put the focus on clinically relevant aspects and bypass some of the existing hurdles in GN teaching, research and management.

FUNDING

H.-J.A. received funding from the Deutsche Forschungsgemeinschaft (AN372/27-1, 30-1 and TRR332: INST211/1067-1/A07) and the Volkswagen Foundation (97-744). H.-J.A. and P.R. received support from the EU ERA-PerMed rogram (Per-NEPH, 01KU2204). P.R. is supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 101 019 891, SIMPOSION). A.R.K. is funded by Australian National Health and Medical Research Council (NHMRC) Investigator and Grant (2 008 921).

AUTHORS’ CONTRIBUTIONS

P.R. and H.-J.A. drafted the first version of the manuscript and all authors edited the text and approved the final version.

DATA AVAILABILITY STATEMENT

No new data were generated or analysed in support of this research.

CONFLICT OF INTEREST STATEMENT

H.-J.A. received consultancy or lecture fees from Boehringer, Bayer, GSK, AstraZeneca, Novartis, Otsuka, Janssen, Kezar, Lilly and PreviPharma. A.R.K. has received lecture fees from Vifor Pharma and research funding via consultancy and grants from Vifor, Visterra, Toleranzia, Variant Bio and CSL Limited. N.L. has received research funding from Omeros and has stocks in AbbVie and Checkpoint Therapeutics. P.R. has nothing to disclose.