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American Journal of Kidney Diseases

Advances in Understanding of Pathogenesis and Treatment of Immune-Mediated Kidney Disease: A Review

  • Sam Kant
    Affiliations
    Division of Nephrology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland
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  • Andreas Kronbichler
    Affiliations
    Department of Internal Medicine IV (Nephrology and Hypertension), Medical University of Innsbruck, Innsbruck, Austria

    Department of Medicine, University of Cambridge, Cambridge, United Kingdom
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  • Purva Sharma
    Affiliations
    Division of Kidney Diseases and Hypertension, Zucker School of Medicine, Hofstra University/Northwell Health, Hempstead, New York
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  • Duvuru Geetha
    Correspondence
    Address for Correspondence: Duvuru Geetha, MD, MRCP (UK), 301 Mason Lord Dr, Johns Hopkins Bayview Medical Center, Baltimore, MD 21224.
    Affiliations
    Division of Nephrology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland
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Published:September 08, 2021DOI:https://doi.org/10.1053/j.ajkd.2021.07.019
      There continues to be rapid advancement in our understanding of the pathogenesis of immune-mediated kidney disease. This progress has culminated in the development of multiple therapeutic agents that have consistently improved renal and patient outcomes. The focus of this review is to discuss these recent advancements in immune-mediated kidney disease via the lens of direct and indirect immune-mediated mechanisms. In the direct immune-mediated disease, recently described antigens in anti–glomerular basement membrane (GBM) disease and membranous nephropathy are discussed, along with new therapeutic regimens in membranous nephropathy and focal segmental glomerulosclerosis. From an indirect immune-mediated disease standpoint, recent pivotal trials in antineutrophil cytoplasmic antibody vasculitis, lupus nephritis, and IgA nephropathy are examined from a real-world practice perspective. New molecular pathways in various disorders of alternate complement pathway are described, which in turn have led to development of various experimental therapies. In addition, pivotal and ongoing therapeutic trials in the aforementioned diseases are presented.

      Index Words

      Introduction

      The kidneys and immune system are inextricably linked. Through expression of various hormones and resident immune cells, the kidneys play a role in the maintenance of immune homeostasis. In addition, they aid in clearance of inflammatory cytokines and bacterial lipopolysaccharides, along with maintenance of peripheral tolerance to circulating antigens such as food proteins and hormones. At the confluence of this vital interaction, the immune system via both direct and indirect mechanisms can lead to development of a multitude of kidney diseases on a spectrum of acute to chronic kidney disease, including kidney failure. Advances in technology combining laser microdissection of glomeruli and mass spectrometry have led to the discovery of novel antigens implicated in the pathogenesis of kidney disease, and a number of controlled trials have refined existing therapy and investigated new targeted therapies. These advances have in turn led to revised diagnostic and treatment algorithms with an ultimate goal of personalized therapy. In this review, we focus on recent pathophysiological and therapeutic advances in immune-mediated kidney disease.

      Direct Immune-Mediated Kidney Disease

      In direct immune-mediated kidney diseases, specific antigens within the kidney are targets of an immune response. Differences in their underlying pathogenesis targeting different structures within the glomerulus explain the distinct clinical syndrome. In the next sections, we discuss 2 specific examples: damage to glomerular or alveolar basement membrane, and podocyte injury caused by antipodocyte antibodies and circulating factors.

      Damage to Glomerular or Alveolar Basement Membrane

      Anti–glomerular basement membrane (anti-GBM) disease is a representative disease of severe vascular damage induced by autoantibodies. In anti-GBM disease, patients develop autoantibodies directed against the noncollagenous (NC) domain 1 of the α3 or α5 chains of the type IV collagen. Anti-GBM disease might be considered a “conformeropathy” because the autoimmune process is elicited by a perturbation of the quaternary structure of the α345NC1 hexamer involving a conformational change in either the α3NC1 or α5NC1 subunits.
      • Pedchenko V.
      • Bondar O.
      • Fogo A.B.
      • et al.
      Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis.
      Novel autoantigens have also been identified in anti-GBM disease, including laminin-521 (LM521); autoantibodies to LM521 are associated with younger age, prevalence of smoking, hemoptysis, pulmonary hemorrhage, and gross hematuria. Presence of LM521 autoantibodies may potentially predict a poor outcome in anti-GBM disease; a combined kidney failure or death end point was found to occur more frequently in this subgroup.
      • Shen C.
      • Jia X.
      • Luo W.
      • et al.
      Laminin-521 is a novel target of autoantibodies associated with lung hemorrhage in anti-GBM disease.
      In anti-GBM disease, a rapid decline of anti-GBM antibodies should be targeted with a standard immunosuppressive regimen and plasma exchange. It is advisable not to start immunosuppression in kidney-limited disease with oliguric kidney failure requiring dialysis, especially if the kidney biopsy reveals 100% crescents. Kidney survival at 1 year is 95% in patients presenting with a serum creatinine level (Scr) of <5.7 mg/dL and 82% in those with a Scr ≥ 5.7 mg/dL but not requiring immediate dialysis; the kidney prognosis of those requiring dialysis at presentation is poor (<10% kidney survival) after standard treatment.
      • Levy J.B.
      • Turner A.N.
      • Rees A.J.
      • Pusey C.D.
      Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression.
      • McAdoo S.P.
      • Tanna A.
      • Hrušková Z.
      • et al.
      Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients.
      • Van Daalen E.
      • Jennette J.C.
      • McAdoo S.P.
      • et al.
      Predicting outcome in patients with anti-GBM glomerulonephritis.
      In an anti-GBM disease mouse model, the application of the IgG-degrading enzyme of Streptococcus pyogenes (IdeS) was reported to reduce proteinuria and lead to degradation of both circulating and kidney-bound anti-GBM antibodies.
      • Yang R.
      • Otten M.A.
      • Hellmark T.
      • et al.
      Successful treatment of experimental glomerulonephritis with IdeS and EndoS, IgG-degrading streptococcal enzymes.
      The ability of IdeS, a cysteine protease, to cleave IgG in the hinge region was first described in 2002.
      • Von Pawel-Rammingen U.
      • Johansson B.P.
      • Björck L.
      IdeS, a novel streptococcal cysteine proteinase with unique specificity for immunoglobulin G.
      Thus, IdeS was considered an option for the management of antibody-mediated diseases. It is being investigated (as imlifidase) in the management of highly sensitized kidney transplant recipients because it eliminates donor-specific antibodies and enables human leukocyte antigen–incompatible kidney transplantation.
      • Jordan S.C.
      • Lorant T.
      • Choi J.
      • et al.
      IgG endopeptidase in highly sensitized patients undergoing transplantation.
      In anti-GBM disease, the phase 2 GOOD-IDES01 trial recruited 15 patients with poor prognosis (Scr > 5.7 mg/dL) who received a single dose of imlifidase, capable of cleavage of IgGs within minutes, in combination with corticosteroids, cyclophosphamide, and plasma exchange when antibodies rebounded. Six hours after imlifidase administration, antibodies were either undetectable or within the reference range. At 6 months, 10 patients were dialysis independent, 1 died, and 4 had kidney failure requiring dialysis.

      Segelmark M, Uhlin F, Sonesson E. The immunoglobulin G degrading enzyme imlifidase for the treatment of anti-GBM disease: the GOOD-IDES 01 trial. Abstract PO2639. ASN Kidney Week 2020. https://www.asn-online.org/education/kidneyweek/2020/program-abstract.aspx?controlId=3479229

      The standard immunosuppressive regimen for anti-GBM disease includes corticosteroids (1 mg/kg/d up to a maximum 60 mg, with tapering to 20 mg by week 6 and gradual discontinuation by 6-9 months), cyclophosphamide (2-3 mg/kg/d given orally for 2-3 months), and plasma exchange (continued for 14 days or until antibody levels are fully suppressed).

      Podocyte Injury Caused by Antipodocyte Antibodies

      Phospholipase A2 receptor (PLA2R), detected in 70% to 80% of patients as the target antigen on podocytes of patients with membranous nephropathy (MN), has not only changed our understanding of this complex disease but led to revisiting the diagnostic and therapeutic algorithms.
      • Beck Jr., L.H.
      • Bonegio R.G.B.
      • Lambeau G.
      • et al.
      M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.
      Additional antigens were characterized—some associated with systemic autoimmunity (exostosin 1 and 2 [EXT1/2] and neural cell adhesion molecule 1 [NCAM1]) or malignancy (thrombospondin type 1 domain-containing protein 7A [THSD7A] and neural epidermal growth factor-like 1 protein [NELL-1]).
      • Caza T.N.
      • Hassen S.I.
      • Dvanajscak Z.
      • et al.
      NELL1 is a target antigen in malignancy-associated membranous nephropathy.
      • Hanset N.
      • Aydin S.
      • Demoulin N.
      • et al.
      Podocyte antigen staining to identify distinct phenotypes and outcomes in membranous nephropathy: a retrospective multicenter cohort study.
      • Ren S.
      • Wu C.
      • Zhang Y.
      • et al.
      An update on clinical significance of use of THSD7A in diagnosing idiopathic membranous nephropathy: a systematic review and meta-analysis of THSD7A in IMN.
      • Ronco P.
      • Plaisier E.
      • Debiec H.
      Advances in membranous nephropathy.
      • Ravindran A.
      • Casal Moura M.
      • Fervenza F.C.
      • et al.
      In patients with membranous lupus nephritis, exostosin-positivity and exostosin-negativity represent two different phenotypes.
      Genetic predisposition explains 25% to 32% of disease risk.
      • Xie J.
      • Liu L.
      • Mladkova N.
      • et al.
      The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis.
      Proteolysis of 2 essential podocyte structure proteins—synaptopodin and nephrin-like protein 1 (NEPH1)—in the presence of complement activation by patient sera with circulating anti-PLA2R antibodies or isolated IgG4 explains the podocyte injury seen in MN. Although IgG4 dominance was reported for THSD7A- or PLA2R-associated membranous nephropathy,
      • Beck Jr., L.H.
      • Bonegio R.G.B.
      • Lambeau G.
      • et al.
      M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.
      ,
      • Hara S.
      • Tsuji T.
      • Fukasawa Y.
      • et al.
      Clinicopathological characteristics of thrombospondin type 1 domain-containing 7A-associated membranous nephropathy.
      NELL-1-positive membranous nephropathy exhibits a dominant or codominant IgG1-subclass staining in most cases.
      • Caza T.N.
      • Hassen S.I.
      • Dvanajscak Z.
      • et al.
      NELL1 is a target antigen in malignancy-associated membranous nephropathy.
      In PLA2R-associated MN, spontaneous remission can occur. All patients with MN and proteinuria should receive supportive care (ie, renin-angiotensin-aldosterone system [RAAS] inhibitors and statins). Immunosuppressive therapy may be initiated in those with at least 1 risk factor for progressive disease or presenting with serious complications of nephrotic syndrome.
      The MENTOR trial recruited patients with MN and a creatinine clearance of at least 40 mL/min/1.73 m2.
      • Fervenza F.C.
      • Appel G.B.
      • Barbour S.J.
      • et al.
      Rituximab or cyclosporine in the treatment of membranous nephropathy.
      Patients received either 2 infusions of rituximab, which was repeated at month 6 in case of partial response, or cyclosporine, which was stopped after 14 months. The remission rates at 12 months were comparable, but significantly more patients in the rituximab group had sustained remission after 24 months. GEMRITUX found that rituximab was not superior to a nonimmunosuppressive antiproteinuric treatment at month 6 in terms of remission rate. During a follow-up period of 17 months, more patients in the rituximab arm achieved remission, indicating that the full effect of remission induction therapy can be expected after 6 months of follow-up observation.
      • Dahan K.
      • Debiec H.
      • Plaisier E.
      • et al.
      Rituximab for severe membranous nephropathy: a 6-month trial with extended follow-up.
      In the STARMEN trial, cyclical treatment with cyclophosphamide/corticosteroids induced an immunological response more frequently and showed higher remission rates at 24 months in comparison with a sequential treatment of tacrolimus followed by rituximab at month 6.
      • Fernández-Juárez G.
      • Rojas-Rivera J.
      • Avd Logt
      • et al.
      The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy.
      The MENTOR and STARMEN trials demonstrated that calcineurin inhibitor-based regimens achieve fewer complete remissions and are slow in achieving an immunologic response (albeit achieving faster remissions in the former trial). The RI-CYCLO trial randomized patients to rituximab or cyclical cyclophosphamide and found higher rates of complete remission at 12 months (16% vs 32%) in the latter group but similar overall remission (complete or partial) rates at month 12 or 24.

      Scolari F, Delbarba E, Santoro D, et al. Rituximab or cyclophosphamide in the treatment of membranous nephropathy: the RI-CYCLO randomized trial. J Am Soc Nephrol. 2021:ASN.2020071091. https://doi.org/10.1681/ASN.2020071091

      It is important to note that GEMRITUX, STARMEN, and RI-CYCLO had low sample sizes and were likely underpowered to detect significant differences among the treatment groups. Based on the findings of these trials, rituximab and cyclophosphamide are now comparable first-line options due to their similar rates of remission. The long-term benefit of rituximab in maintaining proteinuric or immunologic remission remains to be seen, given the short-term follow-up periods in the randomized trials.

      Podocyte Injury Caused by Circulating Factors

      In primary focal segmental glomerulosclerosis (FSGS), podocyte injury is caused by a circulating factor. Several candidates have been identified, such as soluble urokinase-type plasminogen activator receptor, cardiotrophin-like cytokine factor 1, or an anti-CD40 antibody, but confirmatory studies are largely missing.
      • Wen Y.
      • Shah S.
      • Campbell K.N.
      Molecular mechanisms of proteinuria in focal segmental glomerulosclerosis.
      The pathophysiological steps are incompletely understood, but a loss of decay-accelerating factor, a complement C3 convertase regulator, induces complement activation and initiates an autocrine proinflammatory signaling loop, leading to progressive glomerulosclerosis.
      • Angeletti A.
      • Cantarelli C.
      • Petrosyan A.
      • et al.
      Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis.
      The recommended initial treatment for FSGS comprises high-dose corticosteroids, with a duration based on treatment response. Calcineurin inhibitors are an alternative first-line treatment in FSGS, and they are considered as an option in individuals with steroid dependency or steroid resistance. In the latter scenario, many therapeutic approaches were tested recently, with a variable degree of success.
      Table 1 lists the ongoing clinical trials in anti-GBM disease and FSGS. Figure 1 demonstrates the newly discovered and previous antigens/antibodies in membranous nephropathy, FSGS, and anti-GBM disease.
      Table 1Ongoing Trials in IgAN, LN, MN, FSGS, Anti-GBM Disease, AAV, C3 Glomerulopathies, and aHUS
      TrialRegistration No.PhaseIntervention/Mechanism of ActionPrimary Outcome Measures
      IgA Nephropathy
      Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) Study (Low Dose)NCT015600523Experimental: Low-dose oral methylprednisolone (start at 0.4 mg/kg/d), reduction over 6-9 mo

      Comparator: Placebo
      • 1.
        Progressive kidney failure
      • 2.
        Primary outcome for low-dose cohort: change in proteinuria (BL to 6 and 12 mo); change in eGFR at 6 and 12 mo
      Effect and Safety of Sparsentan in the Treatment of Patients With IgA Nephropathy (PROTECT)NCT037628503Experimental: Sparsentan (angiotensin II and endothelin I receptor blocker; 200 mg initially, dose increase to 400 mg)

      Comparator: Irbesartan
      Change in 24-h UPCR (BL to wk 36)
      Efficacy and Safety of Nefecon in Patients With Primary IgA Nephropathy (NEFIGARD)NCT036439653Experimental: Nefecon (16 mg once daily for 9 mo)

      Comparator: Placebo
      • 1.
        Change in 24-h UPCR (BL to 9 mo after first dose of study drug)
      • 2.
        Change in eGFR
        Calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.
        (vs BL)
      Safety and Efficacy of OMS721 in Patients With IgA Nephropathy (ARTEMIS-IGAN)NCT036080333Experimental: OMS721 (human mAb targeting MASP-2)

      Comparator: Placebo
      Change (BL to 36 wk from start of treatment) in 24-h UPE in g/d
      Study of Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients (APPLAUSE-IgAN)NCT045788343Experimental: LNP023 (selective complement factor B inhibitor)

      Comparator: Placebo
      • 1.
        Ratio in UPCRs (9 mo vs BL)
      • 2.
        Annualized total eGFR slope over 24 mo
      Atrasentan in Patients With IgA Nephropathy (ALIGN)NCT045734783Experimental: Atrasentan (endothelin receptor antagonist selective for subtype A)

      Comparator: Placebo
      Change in proteinuria (up to wk 24 or ∼6 mo)
      Blisibimod Response in IgA Nephropathy Following At-Home Treatment by Subcutaneous Administration (BRIGHT-SC)NCT020626842/3Experimental: Blisibimod (selective antagonist of BAFF)

      Comparator: Placebo
      Proportion achieving reduction in proteinuria from BL (at 24 wk)
      Safety and Efficacy Study of VIS649 for IgA NephropathyNCT042879852Experimental: VIS649 (low, medium, and high dose; mAb targeting APRIL)

      Comparator: Placebo
      • 1.
        Safety assessment
      • 2.
        Effect on proteinuria of repeated doses of VIS649 added to SOC (ACEI/ARB) vs SOC
      Lupus Nephritis
      Safety and Efficacy of Two Doses of Anifrolumab Compared to Placebo in Adult Subjects With Active Proliferative Lupus Nephritis (TULIP-LN1)NCT025479222Experimental: Anifrolumab (lower and higher dose; mAb to IFN-α)

      Comparator: Placebo
      Relative difference in change in 24-h UPCR (BL to wk 52)
      Evaluate the Efficacy and Safety of Obinutuzumab in Patients With ISN/RPS 2003 Class III or IV Lupus Nephritis (REGENCY)NCT042214773Experimental: Obinutuzumab at wk 0, 2, 24, 26, 50, 52

      Comparator: Placebo
      Percentage of participants with complete renal response
      Safety, Efficacy and Tolerability of Secukinumab Versus Placebo, in Combination With SoC Therapy in Patients With Active Lupus Nephritis (SELUNE)NCT041817623Experimental: Secukinumab (mAb to IL-17A)

      Comparator: Placebo
      Proportion achieving complete renal response
      Study of Guselkumab in Participants With Active Lupus Nephritis (ORCHID-LN)NCT043768272Experimental: Guselkumab dose 1 or 2 (IV or SC; mAb to IL-23)

      Comparator: Placebo
      Percentage of participants with ≥50% decrease in proteinuria at wk 24
      Zanubrutinib in Participants With Active Proliferative Lupus NephritisNCT046434702Experimental: Zanubrutinib (low, medium, and high dose; Bruton tyrosine kinase inhibitor)

      Comparator: Placebo
      Proportion with complete renal response
      Safety, Pharmacokinetics, and Preliminary Efficacy Study of CFZ533 in Patients With Lupus NephritisNCT036105162Experimental: CFZ533 (anti-CD40 mAb antibody)

      Comparator: Placebo
      • 1.
        Safety as assessed by AEs
      • 2.
        Proteinuria (BL to wk 25)
      Investigational Study to Evaluate the Safety and Effectiveness of BMS-986165 With Background Treatment in Participants With Lupus NephritisNCT039431472Experimental: BMS-986165 (dose 1 and 2; oral selective tyrosine kinase 2 inhibitor)

      Comparator: Placebo
      • 1.
        Incidence of AEs (over 73 wk)
      • 2.
        Incidence of lab abnormalities (over 73 wk)
      • 3.
        Partial renal response (at wk 24)
      ANCA-Associated Vasculitis
      Rituximab and Belimumab Combination Therapy in PR3 Vasculitis (COMBIVAS)NCT039679252Experimental: Belimumab

      Comparator: Placebo
      Time to PR3-ANCA negativity
      Abatacept for the Treatment of Relapsing, Non-Severe, Granulomatosis With Polyangiitis (ABROGATE)NCT021088603Experimental: Abatacept (costimulatory blockade)

      Comparator: Placebo
      Treatment failure rate defined by relapse, disease worsening, or BVAS > 1 at 6 mo
      Study of IFX-1 to Replace Steroids in Patients With Granulomatosis With Polyangiitis and Microscopic Polyangiitis (IXCHANGE)NCT038958012Experimental: IFX-1 (anti-C5a mAb)

      Comparator: Placebo
      Proportion with clinical response (reduction in BVAS of ≥50% vs BL and no worsening in any body system)
      Safety and Efficacy Study of IFX-1 in Add-on to Standard of Care in GPA and MPANCT037123452Experimental: IFX-1 low-dose or high-dose

      Comparator: Placebo
      No. and % of participants with ≥1 treatment-emergent AE
      Membranous Nephropathy
      Belimumab With Rituximab for Primary Membranous Nephropathy (REBOOT)NCT039498552Experimental: RTX + Belimumab

      Comparator: RTX
      Proportion in complete remission at wk 104
      A Study Evaluating the Efficacy and Safety of Obinutuzumab in Participants With Primary Membranous NephropathyNCT046292483Experimental: Obinutuzumab (wk 0, 2, 24, 26)

      Comparator: Tacrolimus
      Percentage with complete remission at wk 104
      Rituximab Combined With Cyclosporine Versus Rituximab Alone in the Treatment of iMNNCT047437393Experimental: RTX (d 1 and d 181, repeated if CD19+ B cells present) + cyclosporine for 9 mo

      Comparator: RTX
      Complete remission or partial remission at 24 mo
      Rituximab Plus Cyclosporine in Idiopathic Membranous NephropathyNCT009779772Experimental: RTX, 2 infusions separated by 2 wk, repeated after 6 mo; cyclosporine for 6 mo, then tapered1. Safety (over 24 mo)

      2-5. Percentage with complete and partial remissions at: 6, 12, 18, 24 mo (each a separate outcome)
      Efficacy and Safety of LNP023 Compared with Rituximab in Subjects With Idiopathic Membranous NephropathyNCT041547872Experimental: LNP023 (selective factor B inhibitor)

      Comparator: Placebo
      Ratio of UPCRs (at 24 wk of treatment vs BL)
      Trial to Assess Safety and Efficacy of MOR202 in Anti-PLA2R+ Membranous Nephropathy (aMN) (M-PLACE)NCT041454401/2Experimental: MOR202 (anti-CD38 antibody)Safety and tolerability: incidence and severity of treatment-emergent AEs
      Efficacy, Safety and PK/PD of MOR202 in Anti-PLA2R + Membranous Nephropathy (aMN) (NewPLACE)NCT047330402Experimental: MOR202 (either 2 or 5 doses; anti-CD38 antibody)Efficacy: % change in anti-PLA2R Ab levels (BL to mo 3)
      Anti-GBM Disease
      An Open-Label Phase II Study to Evaluate the Efficacy and Safety of IdeS in Anti-GBM Disease (GOOD-IDES)NCT031570372Experimental: IdeS single doseProportion with independent kidney function at 6 mo
      Focal Segmental Glomerulosclerosis
      A Study to Evaluate PF-06730512 in Adults With Focal Segmental Glomerulosclerosis (PODO)NCT034486922Experimental: PF-06730512 cohort 1 and 2 (ROBO2/SLIT2 inhibition)Percentage change in UPCR (BL to wk 13)
      A Study of CCX140-B in Subjects With Primary FSGS and Nephrotic SyndromeNCT037039082Experimental: CCX140-B (CCR2 inhibitor)Changes in UPCR (BL to wk 12)
      A Study of CCX140-B in Subjects with FSGSNCT035367542Experimental: CCX140-B (3 different dosing regimens)

      Comparator: Placebo
      Changes in UPCR (BL to wk 12)
      Study of Oral CXA-10 in Primary Focal Segmental Glomerulosclerosis (FIRSTx)NCT034225102Experimental: 4 treatment regimens of CXA-10 (oral nitrated fatty acids)Overall reduction in proteinuria at 3 mo
      Study of Sparsentan in Patients With Primary Focal Segmental Glomerulosclerosis (DUPLEX)NCT034936853Experimental: Sparsentan, initial dose 400 mg, titrated up to 800 mg (angiotensin II and endothelin I receptor blocker)

      Comparator: Irbesartan
      Slope of eGFR (wk 6 to 108)

      Proportion with UPCR ≤ 1.5 g/g and > 40% reduction in UPCR (BL to wk 36)
      C3 Glomerulopathies
      Controlled Trial Evaluating Avacopan in C3 Glomerulopathy (ACCOLADE)NCT033014672Experimental: Avacopan (C5a receptor 1 antagonist)

      Comparator: Placebo
      Percentage change from BL in the C3G Histologic Index for disease activity
      A Proof of Concept Study for 6 Month Treatment in Patients With C3 GlomerulopathyNCT034594432Experimental: ACH-0144471 (small molecule factor D inhibitor)

      Comparator: Placebo
      1. Change (BL to end of 6 mo of treatment) in kidney biopsy score based on changes in both the activity index and C3 staining

      2-3. No. and % of participants with significant improvement in proteinuria (from BL to end of 6 mo of treatment)
      Study of Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy (APPEAR-C3G)NCT048176183Experimental: Iptacopan (selective complement factor B inhibitor)

      Comparator: Placebo
      Log-transformed ratio of UPCRs (6 mo vs BL)
      Study on Efficacy and Safety of LNP023 in C3 Glomerulopathy Patients Transplanted and Not TransplantedNCT038321142Experimental: LNP023 (selective complement factor B inhibitor)Change in UPCR (from BL)
      Evaluation of a Renin Inhibitor, Aliskiren, Compared to Enalapril, in C3 GlomerulopathyNCT041831012Experimental: Aliskiren (titrated up to 300 mg daily)

      Comparator: Enalapril (up to 20 mg)

      Crossover at 6 mo
      • 1.
        C3 levels in serum
      • 2.
        Complement deposition in kidneys
      Atypical Hemolytic Uremic Syndrome
      Safety and Efficacy Study of OMS721 in Patients with Atypical Hemolytic Uremic SyndromeNCT032059953Experimental: OMS721 (human mAb targeting MASP-2)Platelet count change (BL to wk 26)
      A Study Evaluating the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Crovalimab in Adult and Adolescent Participants With Atypical Hemolytic Uremic Syndrome (COMMUTE-a)NCT048612593Experimental: Crovalimab (C5 inhibitor)Percentage of participants with complete TMA response
      Efficacy and Safety of Iptacopan (LNP023) in Adult Patients With Atypical Hemolytic Uremic Syndrome Naïve to Complement Inhibitor Therapy (APPELHUS)NCT048894303Experimental: Iptacopan (selective complement factor B inhibitor)
      • 1.
        Percentage of participants with complete TMA response without the use of PE/PI and anti-C5 antibody (at wk 26)
      • 2.
        Long-term (52 wk) safety and efficacy evaluations
      rVA576 (Coversin) Long Term Safety and Efficacy Surveillance Study (CONSERVE)NCT038294493C5 inhibitorLong-term safety and efficacy: AEs, SAEs, standard lab tests, ECG results
      Only includes studies focusing on one particular disease subset, with a sample size of over 30 participants (except in selected trials; ie, NewPLACE, NCT03703908, NCT03459443), and indicated as phase 2 or 3 trials. Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; ACH-0144471, danicopan; AE, adverse event; aHUS, atypical hemolytic uremic syndrome; ANCA, antineutrophil cytoplasmatic antibody; anti-GBM, anti–glomerular basement membrane; APRIL, a proliferation-inducing ligand; ARB, angiotensin receptor blocker; AAV, ANCA-associated vasculitis; BAFF, B-cell activating factor; BL, baseline; BMS-986165, deucravacitinib; BVAS, Birmingham Vasculitis Activity Score; C3G, C3 glomerulopathy; CCR2, C-C chemokine receptor type 2; CFZ533, iscalimab; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; FSGS, focal segmental glomerulosclerosis; IdeS, IgG-degrading enzyme of Streptococcus pyogenes; IgAN, IgA nephropathy; IFN, interferon; IFX-1, vilobelimab; IL, interleukin; iMN, idiopathic membranous nephropathy; IV, intravenous; lab, laboratory; LN, lupus nephritis; LNP023, iptacopan; mAb, monoclonal antibody; MASP-2, mannan-binding lectin-associated serine protease 2; MOR202, felzartamab; OMS721, narsoplimab; PE/PI, plasma exchange/plasma infusion; PR3, proteinase 3; ROBO2, roundabout guidance receptor 2; RTX, rituximab; SAE, serious adverse event; SC, subcutaneous; SLIT2, slit guidance ligand 2; SOC, standard of care; TMA, thrombotic microangiopathy; UPCR, urinary protein-creatinine ratio; UPE, urinary protein excretion.
      a Calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.
      Figure thumbnail gr1
      Figure 1A representation of target antigens of direct immune-mediated kidney diseases—membranous nephropathy, focal segmental glomerulosclerosis (FSGS), and anti–glomerular base membrane disease—with associated antigens and antibodies. Created with BioRender.com. Abbreviations: anti-GBM, anti–glomerular base membrane; CCR2, C-C chemokine receptor type 2; INF-2, inverted formin 2; NELL1, neural EGF-like-1 protein; NEPH, nephrin-like protein; PLA2R, M-type phospholipase A2 receptor 1; PCDH7, protocadherin 7; Sema3B, semaphorin 3B; SuPAR, soluble urokinase plasminogen activator receptor; THSD7A, thrombospondin type 1 domain-containing 7A.

      Indirect Immune-Mediated Kidney Disease

      Kidney injury can be inadvertent consequence of systemic immune disorders. As shown in Figure 2, there are 3 major mechanisms are implicated in the indirect immune-mediated kidney injury: systemic autoantibody-induced glomerular damage, circulating immune complex deposition, and dysregulation of the alternate complement pathway. These processes usually occur in isolation, albeit a combination of these has been known to occur.
      Figure thumbnail gr2
      Figure 2A representation of various indirect immune-mediated kidney diseases—systemic antibody-induced vascular damage (ANCA vasculitis), immune complex deposition (lupus nephritis and IgA nephropathy), monoclonal immunoglobulin deposition and dysregulation of alternative complement pathway—with associated antigens and antibodies. Created with BioRender.com. Abbreviations: ANCA, antineutrophil cytoplasmic antibody; C3GN, C3 glomerulonephritis; CFHRs, complement factor H receptor proteins; GN, glomerulonephritis; Ig, immunoglobulin; LCPT, light chain cast nephropathy; MIDD, monoclonal immunoglobulin deposition disease; NET, neutrophil extracellular trap; PGNMID, proliferative glomerulonephritis with monoclonal IgG deposits; ROS, reactive oxygen species; SLE, systemic lupus erythematosus.

      Systemic Autoantibody-Induced Glomerular Damage

      Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), a systemic necrotizing vasculitis, is a representative model for the first type of injury. The pathogenesis of AAV lies at the confluence of genetic, epigenetic, and environmental factors. ANCAs cause excessive activation of neutrophils, leading to generation of inflammatory cytokines, reactive oxygen species, and lytic enzymes. This process also leads to the formation of neutrophil extracellular traps (NETs) and complement activation, which in combination with the aforementioned inflict significant vascular damage.
      • Kitching A.R.
      • Anders H.J.
      • Basu N.
      • et al.
      ANCA-associated vasculitis.
      A 2-phase approach of remission induction and remission maintenance is exercised in the management of AAV. Although remission rates and patient survival have improved drastically, a significant proportion of patients continue to progress to kidney failure, and therapy-related adverse events remain a major cause of early mortality and long-term morbidity. The focus of more recent randomized trials has been on safer, fast-acting therapies.
      The PEXIVAS trial clarified the role of plasma exchange (PLEX) and explored steroid reduction, and the ADVOCATE trial explored steroid avoidance in remission induction.
      • Walsh M.
      • Merkel P.A.
      • Peh C.
      • et al.
      Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis.
      • Jayne D.R.W.
      • Merkel P.A.
      • Schall T.J.
      • Bekker P.
      Avacopan for the treatment of ANCA-associated vasculitis.
      • Walsh M.
      • Catapano F.
      • Szpirt W.
      • et al.
      Plasma exchange for renal vasculitis and idiopathic rapidly progressive glomerulonephritis: a meta-analysis.
      The premise for using PLEX is to remove the circulating pathogenic antibodies, which are mediators of inflammation and tissue injury. PEXIVAS was a 2-by-2 factorial randomized trial that evaluated PLEX versus no PLEX and standard versus reduced dose oral glucocorticoids in patients with severe AAV.
      PLEX was not associated with a significant difference in the primary composite outcome of death from any cause or kidney failure or the secondary outcomes of sustained remission, serious adverse events, or serious infections at 1 year. There are important caveats associated with these findings. Because kidney biopsy was not an entry criterion, we cannot truly assess acuity of disease to actually ascertain who would benefit from PLEX. Additionally, the subgroup analysis of nonsevere (n = 130; hazard ratio [HR], 0.64 [95% CI, 0.33-1.24]) and severe pulmonary hemorrhage (n = 61; HR, 0.64 [95% CI, 0.28-1.64]) trended toward a possible benefit from PLEX.
      One of pivotal findings of PEXIVAS was that decreasing the cumulative dose of glucocorticoids to 60% of the standard dosing by 6 months was associated with a reduced risk of serious infections at 1 year and was noninferior to the standard dose regimen. This is especially pertinent because infections are the leading cause of early mortality, and it has already been established that glucocorticoids are associated with increased infectious risk and progressive organ damage in patients with AAV.
      • Robson J.
      • Doll H.
      • Suppiah R.
      • et al.
      Glucocorticoid treatment and damage in the anti-neutrophil cytoplasm antibody-associated vasculitides: long-term data from the European vasculitis study group trials.
      • McGregor J.G.
      • Hogan S.L.
      • Hu Y.
      • Jennette C.E.
      • Falk R.J.
      • Nachman P.H.
      Glucocorticoids and relapse and infection rates in anti-neutrophil cytoplasmic antibody disease.
      • Goupil R.
      • Brachemi S.
      • Nadeau-Fredette A.C.
      • et al.
      Lymphopenia and treatment-related infectious complications in ANCA-associated vasculitis.
      • Charlier C.
      • Henegar C.
      • Launay O.
      • et al.
      Risk factors for major infections in Wegener granulomatosis: analysis of 113 patients.
      Glucocorticoid avoidance has been a major goal in the management of AAV. Experimental and clinical evidence have suggested that activation of the alternative complement pathway is involved in the pathogenesis of AAV. In AAV, C5a and the C5a receptor (C5aR) have been implicated in the pathogenesis by their effect on neutrophils and vascular endothelial cells.
      • Furuta S.
      • Jayne D.R.W.
      Antineutrophil cytoplasm antibody-associated vasculitis: recent developments.
      ,
      • Halbwachs L.
      • Lesavre P.
      Endothelium-neutrophil interactions in ANCA-associated diseases.
      Most recently, the ADVOCATE trial (n = 331) compared the oral C5aR inhibitor avacopan at 30 mg twice daily (n = 166) with oral prednisone given on a tapering schedule for 20 weeks (n = 165) in patients with newly diagnosed or relapsing AAV after induction therapy.
      • Jayne D.R.W.
      • Merkel P.A.
      • Schall T.J.
      • Bekker P.
      Avacopan for the treatment of ANCA-associated vasculitis.
      Avacopan was noninferior to prednisone for remission at week 26 and was superior to prednisone in sustained remission at week 52. A significant reduction in steroid-related adverse effects was observed in the avacopan arm when compared with the prednisone arm, with an acceptable safety profile for avacopan.
      Maintenance immunosuppressive therapy is a requisite, given the relapsing nature of AAV. The options for maintenance therapy in AAV are rituximab, azathioprine, and mycophenolate mofetil. The MAINRITSAN trial showed that after remission induction with cyclophosphamide, rituximab was superior to azathioprine for relapse prevention.
      • Guillevin L.
      • Pagnoux C.
      • Karras A.
      • et al.
      Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis.
      A major limitation of MAINRITSAN was the protocol-defined taper of azathioprine beginning at month 12 in comparison with constant dosing of rituximab. MAINRITSAN 2 answered the question of frequency of rituximab dosing by demonstrating that the relapse rates were similar for tailored and scheduled rituximab.
      • Charles P.
      • Terrier B.
      • Perrodeau É.
      • et al.
      Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2).
      It should be pointed out, however, that the absence of ANCA and CD19 did not always guarantee remission in all patients in this trial. More recently, MAINRITSAN 3 showed that extending rituximab maintenance therapy by another 2 years was associated with a reduced relapse risk compared with standard maintenance therapy.
      • Charles P.
      • Perrodeau É.
      • Samson M.
      • et al.
      Long-term rituximab use to maintain remission of antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial.
      However, 74% of patients in the control group also remained relapse free, which argues that long-term rituximab should not be the standard of care in AAV and surrogate markers other than ANCA and CD19 need to be explored to guide the duration of rituximab therapy.
      The appropriate maintenance regime in patients treated with rituximab for remission induction was provided with further clarity in the RITAZAREM trial, which recruited patients with relapsed AAV whose remission was reinduced with rituximab and glucocorticoids; the participants were randomized to receive either rituximab or azathioprine as maintenance therapy. The results of the induction phase findings from the trial demonstrated that treatment with rituximab and glucocorticoids achieved a remission rate of 90%.
      • Smith R.M.
      • Jones R.B.
      • Specks U.
      • et al.
      Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis.
      The initial results of the maintenance phase, reported at the American College of Rheumatology and European Renal Association conference, demonstrated that rituximab is superior to azathioprine for preventing disease relapse in patients with relapsing AAV. At 20 months after randomization, 13% of the patients in the rituximab group had experienced a relapse compared with 38% patients in the azathioprine group.
      • Smith R.
      • Jayne D.
      • Merkel P.
      A randomized, controlled trial of rituximab versus azathioprine after induction of remission with rituximab for patients with ANCA-associated vasculitis and relapsing disease. Abstract LB004.
      ,
      • Smith R.
      • Jayne D.
      • Merkel P.
      A randomized, controlled trial of rituximab versus azathioprine after induction of remission with rituximab for patients with ANCA-associated vasculitis and relapsing disease. Abstract 806.
      The optimal duration of maintenance therapy remains uncertain. The REMAIN trial provided evidence that 3 to 4 years of therapy with azathioprine and prednisone decreases relapse risk and improves renal survival.
      • Karras A.
      • Pagnoux C.
      • Haubitz M.
      • et al.
      Randomised controlled trial of prolonged treatment in the remission phase of ANCA-associated vasculitis.
      Concerning the use of rituximab for remission maintenance, an assessment of relapse risk factors, consequences of relapse, and infection risk on an individual level should guide the duration of rituximab use.
      Standard induction therapy for AAV includes either cyclophosphamide (oral, 2 mg/kg/d for 3-6 months) or rituximab (375 mg/m2 every week for 4 weeks, or 2 doses of 1 g separated by 14 days) in combination with corticosteroids (1 mg/kg/d up to a maximum of 60 mg, with tapering to 20 mg by week 8 and gradual discontinuation by 6 months). The options for maintenance therapy include rituximab or azathioprine. A summary of the major trials for remission induction and remission maintenance in AAV are presented in Tables 2 and 3; Table 1 lists the currently ongoing trials.
      Table 2Trials Assessing Various Induction Regimens in ANCA-Associated Vasculitis
      StudyKey Inclusion/Exclusion CriteriaInterventionsPrimary OutcomeStrengthsLimitations
      CYCLOPS (AIM 2009)
      • De Groot K.
      • Harper L.
      • Jayne D.R.W.
      • et al.
      Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial.
      ; N = 149
      Inclusion: Newly diagnosed GPA/MPA/RLV with renal involvement (Scr >1.7-<5.7 mg/dL)IV
      For IV CYC, if aged 60-70 years, reduction by 2.5mg/kg; aged>70 years, reduction by 5mg/kg; 2.5mg/kg reduction for Scr>3.4-<5.7mg/dL, pulse dose reduction by 20% if leukocyte nadir of 2-3 ×109/L and 40% if nadir of 1-2 ×109/L. For oral CYC, if aged 60-70 years, reduction by 25%; aged>70 years, reduction by 50%; CYC withheld if leukocytes<4 ×109/L, resumed at a dose reduced by 25mg/d.
      : CYC 3 pulses 15 mg/kg (2 wk apart), then pulses every 3 wk until remission, then for another 3 mo

      Oral
      For IV CYC, if aged 60-70 years, reduction by 2.5mg/kg; aged>70 years, reduction by 5mg/kg; 2.5mg/kg reduction for Scr>3.4-<5.7mg/dL, pulse dose reduction by 20% if leukocyte nadir of 2-3 ×109/L and 40% if nadir of 1-2 ×109/L. For oral CYC, if aged 60-70 years, reduction by 25%; aged>70 years, reduction by 50%; CYC withheld if leukocytes<4 ×109/L, resumed at a dose reduced by 25mg/d.
      : CYC 2 mg/kg/d until remission, then 1.5 mg/kg/d for another 3 mo
      Time to remission
      • -
        High rate of disease remission with either treatment strategy (78.9%)
      • -
        IV CYC could replace oral CYC in this large trial, with a reduction of cumulative dose (8.2 vs 15.8 g)
      • -
        Open-label trial
      • -
        High number of withdrawals (>10%) and deaths (7.4%)
      • -
        Exclusion of patients with severe kidney disease
      RAVE (NEJM 2010)
      • Stone J.H.
      • Merkel P.A.
      • Spiera R.
      • et al.
      Rituximab versus cyclophosphamide for ANCA-associated vasculitis.
      ; N = 197
      Inclusion: Newly diagnosed or relapsing GPA/MPA; Scr ≤ 4.0 mg/dL

      Exclusion: mechanical ventilation because of alveolar hemorrhage
      RTX: 4 × 375 mg/m2 (weekly)

      CYC: 2 mg/kg for 3-6 mo (adjusted for kidney function), then AZA (2 mg/kg)
      Complete remission defined by BVAS/WG of 0 and completion of GC taper by mo 6
      • -
        First large RCT in AAV
      • -
        RTX noninferior to CYC/AZA at 6 & 18 mo (64% vs 53%; 39% vs 33%)
      • -
        RTX superior in relapsing PR3-AAV
      • -
        No information in patients with more severely decreased kidney function at BL
      • -
        Most relapsing patients failed to maintain remission after previous CYC use
      RITUXVAS
      • Jones R.B.
      • Cohen Tervaert J.W.
      • Hauser T.
      • et al.
      Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.
      (NEJM 2010); N = 44
      Inclusion: Newly diagnosed GPA/MPA/RLV with renal involvementRTX: 4 × 375 mg/m2 (wkly) + 2 pulses CYC (15 mg/kg)

      CYC: pulses (15 mg/kg) for 3-6 mo, then AZA
      Sustained remission at 12 mo and SAEs
      • -
        Included patients with severe presentation
      • -
        Equivalent sustained remission rates (76% vs 82%) and SAEs (42% vs 36%)
      • -
        Open-label trial
      • -
        Sample size (33 in RTX arm, 11 in comparator arm)
      • -
        RTX arm received 2 pulses CYC
      MEPEX (JASN 2007)
      • Jayne D.R.W.
      • Gaskin G.
      • Rasmussen N.
      • et al.
      Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis.
      ; N = 137
      Inclusion: Newly diagnosed GPA/MPA with renal involvement and Scr > 5.8 mg/dL

      Exclusion: life-threatening nonrenal manifestations
      Both groups: CYC 2.5 mg/kg/d (2 mg/kg/d for age >60), reduced to 1.5 mg at mo 3 (for 3 mo), then AZA (2 mg/kg)

      PLEX arm: 7 sessions (in 2 wk, 60 mL/kg)

      MP arm: 3 × 1,000 mg
      Dialysis independence at 3 mo
      • -
        Included patients with severely decreased kidney function
      • -
        PLEX superior for dialysis independence at 3 mo (69% vs 49%) and renal survival at 12 mo (59% vs 80%)
      • -
        Information about histopathology of kidney biopsies essential
      • -
        Open-label trial
      • -
        102 survivors (74.5%) at 12 mo
      • -
        High cumulative CYC exposure
      PEXIVAS (NEJM 2020)
      • Walsh M.
      • Merkel P.A.
      • Peh C.
      • et al.
      Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis.
      ; N = 704
      Inclusion: Newly diagnosed GPA/MPA with renal involvement and eGFR < 50 mL/min/1.73 m2

      Exclusion: “a comorbidity that, in the opinion of the investigator, absolutely mandates the use of PLEX”
      Both groups: Remission induction either CYC (oral/IV, dose adjustments) or RTX (4 × 375 mg/m2) and remission maintenance with AZA (2 mg/kg, CYC users only)

      2-by-2 factorial design:
      • 1:
        PLEX vs no PLEX (7 sessions within 14 d, 60 mL/kg)
      • 2:
        GC standard dose vs reduced dose
      Composite outcome of death from any cause or kidney failure
      • -
        Largest trial in AAV conducted so far
      • -
        Main outcomes show dose reduction in GCs is safe
      • -
        Outcomes:
        • 1.
          PLEX not superior (28.4% vs 31.0%)
        • 2.
          Reduced-dose GC noninferior (27.9% vs 25.5%) with fewer serious infections at 12 mo (IRR, 0.69)
      • -
        Open-label trial
      • -
        No screening log (of patients undergoing nonrandomized PLEX)
      • -
        No information about kidney histology
      • -
        Risk reduction for patients with nonsevere and severe alveolar hemorrhage (power in these subgroups?)
      • -
        Benefit of patients with severe kidney disease at BL?
      MYCYC (ARD 2019)
      • Jones R.B.
      • Hiemstra T.F.
      • Ballarin J.
      • et al.
      Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: a randomised, non-inferiority trial.
      ; N = 140
      Inclusion: Newly diagnosed GPA/MPA

      Exclusion: Life-threatening vasculitis, rapidly declining kidney function and eGFR < 15 mL/min/1.73 m2
      MMF: 2 g/d (increases to 3 g/d permitted for uncontrolled disease at 4 wk)

      CYC: IV arm according to CYCLOPS

      Maintenance: AZA
      Remission at 6 mo
      • -
        MMF as a potential option when CYC or RTX contraindicated
      • -
        MMF noninferior to CYC for remission induction (67% vs 61%)
      • -
        Higher relapse rate with MMF, especially in PR3-ANCA patients
      • -
        Open-label trial
      • -
        No mycophenolic acid trough levels
      • -
        High cumulative GC exposure
      ADVOCATE (NEJM 2021)
      • Jayne D.R.W.
      • Merkel P.A.
      • Schall T.J.
      • Bekker P.
      Avacopan for the treatment of ANCA-associated vasculitis.
      ; N = 331
      Inclusion: Newly diagnosed or relapsing GPA/MPA, eGFR ≥15 mL/min/1.73 m2

      Exclusion: invasive pulmonary ventilation support
      Both groups: Remission induction either CYC (oral/IV, dose adjustments) or RTX (4 × 375 mg/m2) and remission maintenance with AZA (start at 1 mg/kg; titrate up to 2 mg/kg, CYC users only)

      Intervention:
      • 1.
        Prednisone (60 mg, with tapering steps)
      • 2.
        Avacopan (30 mg, 2×/d)
      Remission at wk 26 and sustained remission at wk 52
      • -
        Largest RCT in AAV
      • -
        First trial to study steroid-free induction in a severe disease like AAV
      • -
        Main outcomes: Avacopan noninferior to GC for remission induction at wk 26 (72.3% vs 70.1%) and superior to GC for sustained remission at wk 52 (65.7% vs 54.9%)
      • -
        116 vs 166 SAEs, no difference in severe infections
      • -
        Active treatment with avacopan throughout trial, while prednisone withdrawn within the first 6 mo
      • -
        “Pill burden” (6 extra tablets per day)
      • -
        Use of additional non–study supplied GC in the avacopan arm
      • -
        No information in patients with severe presentation forms
      Abbreviations: AAV, ANCA-associated vasculitis; AIM, Annals of Internal Medicine; ANCA, antineutrophil cytoplasmatic antibody; AZA, azathioprine; BL, baseline; BVAS/WG, Birmingham Vasculitis Activity Score/Wegener granulomatosis; CYC, cyclophosphamide; eGFR, estimated glomerular filtration rate; GC, glucocorticoids; GPA, granulomatosis with polyangiitis; IRR, incidence rate ratio; IV, intravenous; JASN, Journal of the American Society of Nephrology; MMF, mycophenolate mofetil; MP, methylprednisolone; MPA, microscopic polyangiitis; NEJM, New England Journal of Medicine; PLEX, plasma exchange; PR3, proteinase 3; RCT, randomized controlled trial; RLV, renal-limited vasculitis; RTX, rituximab; SAE, serious adverse event; Scr, serum creatinine.
      a For IV CYC, if aged 60-70 years, reduction by 2.5 mg/kg; aged >70 years, reduction by 5 mg/kg; 2.5 mg/kg reduction for Scr >3.4-<5.7 mg/dL, pulse dose reduction by 20% if leukocyte nadir of 2-3 × 109/L and 40% if nadir of 1-2 × 109/L. For oral CYC, if aged 60-70 years, reduction by 25%; aged >70 years, reduction by 50%; CYC withheld if leukocytes < 4 × 109/L, resumed at a dose reduced by 25 mg/d.
      Table 3Trials Assessing Various Maintenance Regimens in ANCA-Associated Vasculitis
      StudyKey Inclusion/Exclusion CriteriaInterventionsPrimary OutcomeStrengthsLimitations
      CYCAZAREM (NEJM 2003)
      • Jayne D.
      • Rasmussen N.
      • Andrassy K.
      • et al.
      A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.
      ; N = 155
      Inclusion: New diagnosis of GPA/MPA, Scr < 5.7 mg/dL (n = 155), achieved remission with oral CYC for at least 3 mo (n = 144)144 patients entered remission:
      • -
        CYC (continued; 1.5 mg/kg)
      • -
        AZA (2 mg/kg)
      Relapse rate at 18 mo
      • -
        Long-term treatment with CYC has significant side effects, replacement possible with AZA
      • -
        Relapse rates similar at 18 mo (10 in CYC arm; 11 in AZA arm)
      • -
        Similar number of SAEs
      • -
        First study to show duration of CYC use can be reduced
      • -
        Open-label trial
      • -
        No information about patient characteristics at the time of remission therapy initiation (ANCA negativity, eGFR, etc)
      IMPROVE (JAMA 2010)
      • Hiemstra T.F.
      • Walsh M.
      • Mahr A.
      • et al.
      Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial.
      ; N = 156
      Inclusion: New diagnosis of GPA/MPA who achieved remission with oral CYCAZA: 2 mg/kg; reduced to 1.5 and 1 mg/kg after 12 and 18 mo, withdrawal at 42 mo

      MMF: 2,000 mg/d; reduced to 1,500 and 1,000 mg/d after 12 and 18 mo, withdrawal at 42 mo
      Relapse-free survival
      • -
        MMF tested because superior to AZA in the treatment of LN, but this study shows AZA seems to be superior in AAV
      • -
        Higher rates of relapse in patients treated with MMF (42/76 vs 30/80; major and minor relapses)
      • -
        Open-label trial
      • -
        No information about eGFR at switch to maintenance
      • -
        More patients in the MMF group ANCA positive at switch
      • -
        Renal relapses comparable (no details given)
      • -
        MPA level not measured
      MAINRITSAN (NEJM 2014)
      • Guillevin L.
      • Pagnoux C.
      • Karras A.
      • et al.
      Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis.
      ; N = 115
      Inclusion: Newly diagnosed or relapsing GPA/MPA who achieved remission with pulse CYCRTX: 2 × 500 mg (14 d apart), 1 dose at mo 6, 12, 18

      AZA: 2 mg/kg for 12 mo, then 1.5 mg/kg for 6 mo and 1 mg/kg for 4 mo
      Rate of major relapses at mo 28
      • -
        RTX superior to AZA in remission maintenance: major relapses, 5% vs 29%; minor relapses, 11% vs 16%
      • -
        SAEs similar (19% vs 14%), especially in PR3-ANCA patients
      • -
        Open-label trial
      • -
        No standardized GC tapering
      • -
        Findings despite non-balanced BL characteristics (more GPA patients and better kidney function in RTX arm)
      MAINRITSAN 2 (ARD 2018)
      • Charles P.
      • Terrier B.
      • Perrodeau É.
      • et al.
      Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2).
      ; N = 162
      Newly diagnosed or relapsing GPA/MPA who achieved remission with CYC, MTX, or RTX“Fixed”-dose RTX: 500 mg on d 0 and d 14 and mo 6, 12, and 18

      “Tailored”-dose RTX: 500 mg at randomization then B cells and ANCA checked 3-monthly, further RTX if CD19 count > 0 and ANCA titers reappeared or doubled
      Number of relapses at mo 28
      • -
        Large trial comparing 2 RTX regimens; tailored dose noninferior to a fixed dose
      • -
        14/81 patients with relapse in the tailored vs 8/81 in the fixed dose (17.3% vs 9.9%); major relapses: 6 vs 3
      • -
        Fewer SAEs in tailored arm (37 vs 53), but balanced frequency of infections (18 each)
      • -
        Fewer infusions in the tailored arm
      • -
        Open-label trial
      • -
        No standardized GC tapering
      • -
        Tailored dose would need more monitoring visits (if applied in clinical routine)
      • -
        Long-term consequences (eg, hypogammaglobulinemia) with unclear association of RTX doses
      • -
        More relapses in the tailored arm
      MAINRITSAN 3 (AIM 2020)
      • Charles P.
      • Perrodeau É.
      • Samson M.
      • et al.
      Long-term rituximab use to maintain remission of antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial.
      ; N = 97
      Inclusion: GPA/MPA patients in sustained remission after completing MAINRITSAN 2Randomization at mo 28:
      • -
        RTX arm: 500-mg infusion at mo 0, 6, 12, 18
      • -
        Placebo arm
      Relapse-free survival at mo 28
      • -
        RTX after long-term remission (28 mo) superior to no treatment
      • -
        Relapse-free survival: 96% vs 74%, major relapse-free survival: 100% vs 87%
      • -
        SAEs: 24% vs 30%
      • -
        Open-label trial
      • -
        More patients with GPA at inclusion in placebo arm
      • -
        Uncertainty about ideal treatment duration of RTX remains
      RITAZAREM (unpublished)
      • Smith R.
      • Jayne D.
      • Merkel P.
      A randomized, controlled trial of rituximab versus azathioprine after induction of remission with rituximab for patients with ANCA-associated vasculitis and relapsing disease. Abstract 806.
      ; N = 170
      Inclusion: Relapsed GPA/MPA (reinduced with RTX)RTX: 1,000 mg every 4 mo (5 doses)

      AZA: 2 mg/kg
      Time to relapse
      • -
        RTX superior to AZA in patients with relapsing disease (HR, 0.36)
      • -
        Fewer SAEs in RTX arm
      • -
        Hypogammaglobulinemia comparable to AZA (after RTX induction)
      • -
        Open-label trial
      • -
        Full report awaited
      • -
        High cumulative dose of RTX
      REMAIN (ARD 2017)
      • Karras A.
      • Pagnoux C.
      • Haubitz M.
      • et al.
      Randomised controlled trial of prolonged treatment in the remission phase of ANCA-associated vasculitis.
      ; N = 110
      Inclusion: GPA/MPA/RLV patients in stable remission on AZA/GC; kidney involvement and/or other threatened loss of function of a vital organ; 18-24 mo from diagnosisContinuation arm: Prednisone tapering until mo 24, AZA 1 mg/kg until end of trial

      Withdrawal arm: Prednisone withdrawal by mo 5; AZA, 0.75 mg/kg, withdrawal by mo 3
      Relapse risk from randomization to 48 mo from diagnosis
      • -
        Long-term treatment with AZA/GCs reduces the risk of relapse (13/59 vs 32/51)
      • -
        Open-label trial
      • -
        Long-term GC and AZA exposure (with potential long-term sequelae)
      • -
        7 patients (6%) lost to follow-up
      Abbreviations: AAV, ANCA-associated vasculitis; AIM, Annals of Internal Medicine; ANCA, anti-neutrophil cytoplasmatic antibody; ARD, Annals of the Rheumatic Diseases; AZA, azathioprine; BL, baseline; CYC, cyclophosphamide; eGFR, estimated glomerular filtration rate; GC, glucocorticoids; GPA, granulomatosis with polyangiitis; HR, hazard ratio; LN, lupus nephritis; MMF, mycophenolate mofetil; MPA, microscopic polyangiitis; MTX, methotrexate; NEJM, New England Journal of Medicine; PR3, proteinase 3; RLV, renal-limited vasculitis; RTX, rituximab; SAE, serious adverse event; Scr, serum creatinine.

      Circulating Immune Complex Deposition

      Immune complexes have a predilection for deposition in glomeruli given the size- and charge-dependent filtration process. Immune complex deposition leads to glomerular inflammation by engagement of humoral and cell-mediated mechanisms. This inflammation is further compounded by activation of the complement pathways. Pertinent to this pathway, lupus nephritis (LN) and IgA nephropathy warrant discussion.

      Lupus Nephritis

      Patients with systemic lupus erythematosus (SLE) have genetic variants that interfere with immune tolerance to nuclear autoantigens, leading to immune complex formation. Other mechanisms of kidney injury include activation of Toll-like receptors and formation of de novo perivascular lymphoid organs inside the kidney by infiltrating leukocytes.
      The first-line therapeutic agents in lupus nephritis remain nonselective immunosuppressants such as steroids, cyclophosphamide, mycophenolate mofetil, and azathioprine, but there has been rapid development of newer agents targeting specific cell types.
      • Appel G.B.
      • Contreras G.
      • Wofsy D.
      • et al.
      Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.
      • Houssiau F.A.
      • Vasconcelos C.
      • D’Cruz D.
      • et al.
      Immunosuppressive therapy in lupus nephritis: the Euro-Lupus nephritis trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.
      • Dooley M.A.
      • Jayne D.
      • Ginzler E.M.
      • et al.
      Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis.
      • Houssiau F.A.
      • D’Cruz D.
      • Sangle S.
      • et al.
      Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN nephritis trial.
      Hydroxychloroquine is recommended for all patients with SLE, including patients with LN.
      • Hahn B.H.
      • McMahon M.A.
      • Wilkinson A.
      • et al.
      American college of rheumatology guidelines for screening, treatment, and management of lupus nephritis.
      ,
      • Pons-Estel G.J.
      • Alarcón G.S.
      • McGwin G.
      • et al.
      Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort.
      Recognizing that B cells are not only sources of autoantibody production but also contribute to autoimmunity and inflammation through other mechanisms, B cell–targeted therapy has been at the forefront of recent trials.

      Belimumab

      Belimumab, a monoclonal antibody directed against B-lymphocyte stimulator (also known as B-cell activating factor [BAFF]), was studied in 2 randomized controlled trials in LN. BLISS-LN was a multicenter randomized trial of adult patients with biopsy-proven active LN that compared intravenous belimumab to placebo, in addition to standard therapy.
      • Furie R.
      • Rovin B.H.
      • Houssiau F.
      • et al.
      Two-year, randomized, controlled trial of belimumab in lupus nephritis.
      The trial showed that more patients in the belimumab group had a primary efficacy renal response (43% vs 32%) and complete renal response (30% vs 20%). This led to its US Food and Drug Administration approval in December 2020 for use in LN. Limitations of this trial were low enrollment of Black patients and lack of random assignment of induction agents.
      Of note, in the mycophenolate subgroup, the proportion of participants with a complete renal response was higher in the belimumab arm than in the placebo arm. By contrast, in the cyclophosphamide-azathioprine subgroup, the proportions of participants achieving a response were equivalent in the belimumab and placebo arms. Although fraught with the inherent disadvantages of a subgroup analysis, some of the potential reasons for this difference could be that the patients in the cyclophosphamide group had higher severity of illness or that azathioprine was not as effective in this population. The CALIBRATE trial, a phase 2, randomized controlled trial of cyclophosphamide plus rituximab followed by belimumab in patients with active LN demonstrated that this regimen was safely tolerated in patients with refractory disease.
      • Atisha-Fregoso Y.
      • Malkiel S.
      • Harris K.M.
      • et al.
      Phase II randomized trial of rituximab plus cyclophosphamide followed by belimumab for the treatment of lupus nephritis.

      Obinutuzumab

      Obinutuzumab, as a type II monoclonal antibody, differs from rituximab in epitope specificity, pharmacokinetics, and ability to induce cytotoxicity and apoptosis; it has superior B-cell depletion compared with rituximab.
      • Reddy V.
      • Klein C.
      • Isenberg D.A.
      • et al.
      Obinutuzumab induces superior B-cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples.
      The NOBILITY study was a phase 2, randomized trial in patients with class III/IV LN that compared obinutuzumab with placebo, in addition to mycophenolate mofetil and steroids.
      • Furie R.
      • Cascino M.D.
      • Garg J.P.
      • et al.
      B-cell depletion and response in a randomized, controlled trial of obinutuzumab for proliferative lupus nephritis. Abstract O35.
      The obinutuzumab group had a higher complete kidney response at week 52 and did not confer a higher risk of serious adverse events or serious infections.

      Voclosporin

      Voclosporin, a novel calcineurin inhibitor, was studied in the AURA-LV trial.
      • Rovin B.H.
      • Solomons N.
      • Pendergraft W.F.
      • et al.
      A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis.
      This was a phase 2 randomized controlled trial in patients with active LN, of 2 doses of voclosporin versus placebo in combination with mycophenolate mofetil and rapidly tapered dose of steroids for induction of remission in LN. There was a higher complete remission rate of patients in both the high- and low-dose groups compared with placebo, but also a higher risk of death in the low-dose voclosporin group. The phase 3 AURORA trial demonstrated superior renal response at 52 weeks compared with placebo (40.8% vs 22.5%).
      • Rovin B.H.
      • Teng Y.K.O.
      • Ginzler E.M.
      • et al.
      Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.
      There was no difference in adverse effect profile between the 2 groups. Voclosporin obtained FDA approval in January 2021. The landmark LN trials are summarized in Table 4.
      Table 4Summary of Major Trials in Lupus Nephritis
      StudyKey Inclusion/Exclusion CriteriaInterventionsPrimary OutcomeStrengthsLimitations
      Euro-Lupus Nephritis Trial (ARM 2002)
      • Houssiau F.A.
      • Vasconcelos C.
      • D’Cruz D.
      • et al.
      Immunosuppressive therapy in lupus nephritis: the Euro-Lupus nephritis trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.
      ; N = 90
      Patients with proliferative LN (class III-V) and proteinuria ≥ 500 mg/dBoth groups: 3 × 750 mg MP, then oral prednisolone (0.5 mg or 1 mg/kg)
      • -
        High-dose CYC: 6 monthly pulses, then 2 quarterly pulses; initial 0.5 g/m2, increased by 250 mg (max 1,500 mg) based on WBC nadir on d 14
      • -
        Low-dose CYC: 6 fortnightly CYC at a fixed dose of 500 mg
      Treatment failure, defined as 1 of the following 3: absence of a primary response after 6 mo of therapy, occurrence of a GC-resistant flare, or Scr doubling
      • -
        Shows low-dose CYC can safely replace high-dose CYC in induction therapy for proliferative LN (3 vs 8.5 g cumulative dose; treatment failure of 16% vs 20%)
      • -
        Long follow-up: of 41.3 & 41 months
      • -
        Open-label trial
      • -
        Only 28% had nephrosis at BL
      • -
        White patients only
      • -
        Low sample size
      ALMS (JASN 2009)
      • Dooley M.A.
      • Jayne D.
      • Ginzler E.M.
      • et al.
      Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis.
      ; N = 370
      Patients with proliferative LN (class III-V) and proteinuria of ≥2 g/d (kidney biopsy within 6 mo of randomization)Both groups: Prednisone at a max starting dose of 60 mg/d
      • -
        MMF: 1 g in wk 1, 2 g in wk 2, to a target dose of 3 g/d in wk 3 (reduction to 2 g/d permitted)
      • -
        CYC: monthly pulses of 0.5-1 g/m2 (modified NIH protocol)
      Superiority of MMF to IV CYC, namely, the proportion with a response (decrease in 24-h UPCR to <3 in patients with BL nephrotic-range (UPCR ≥ 3), or by ≥50% in those with BL UPCR <3, and stabilized or improved Scr at 24 wk
      • -
        Large sample size
      • -
        Inclusion of racially/ethnically diverse patients
      • -
        MMF as effective as CYC (56.2% vs 53.0%)
      • -
        Group including Hispanic and “other” patients had better response to MMF vs CYC
      • -
        Open-label trial
      • -
        High number of patients prematurely withdrew
      • -
        Assessing efficacy after 24 wk too early
      • -
        Not FDA approved (negative trial)
      ALMS Maintenance (NEJM 2011)
      • Dooley M.A.
      • Jayne D.
      • Ginzler E.M.
      • et al.
      Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis.
      ; N = 227
      Patients who met response criteria in the ALMS induction trial (see above), 36-mo follow-up
      • -
        MMF: 1 g, 2×/d
      • -
        AZA: 2 mg/kg
      Time to treatment failure, defined as death, kidney failure, sustained doubling of Scr, renal flare (proteinuric or nephritic), or rescue therapy for LN
      • -
        Large RCT
      • -
        MMF superior to AZA for maintenance of remission (16.4% vs 32.4%); renal flare occurred in 12.9% vs 23.4%
      • -
        Only 55.9% completed the 36 mo of treatment (adverse events and LN flares)
      • -
        High number of AEs leading to withdrawal (25.2% vs 39.6%)
      MAINTAIN Nephritis (ARD 2010)
      • Houssiau F.A.
      • D’Cruz D.
      • Sangle S.
      • et al.
      Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN nephritis trial.
      ; N = 105
      Patients with proliferative LN (class III-V) and proteinuria ≥ 500 mg/d (biopsy performed less than 1 mo before entry in the protocol)Both groups: induction with low-dose CYC

      At wk 12, patients randomized to AZA 2 mg/kg/d or MMF 2 g/d
      Time to renal flare (superiority trial of MMF over AZA)
      • -
        Nominally fewer renal flares in MMF group (19% vs 25%; NS)
      • -
        Open-label trial
      • -
        Predominantly White patients
      • -
        Only 39% of patients had nephrotic-range proteinuria at BL
      • -
        High dropout rate (23.5%)
      • -
        Not powered to prove superiority of MMF
      • -
        Higher BL proteinuria in MMF group
      LUNAR (ARD 2012)
      • Rovin B.H.
      • Furie R.
      • Latinis K.
      • et al.
      Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment With Rituximab study.
      ; N = 144
      Patients with class III or IV (eventually combined with V) LN (kidney biopsy within 12 mo)

      - Exclusion: >50% glomerular sclerosis or interstitial fibrosis; eGFR < 25 mL/min/1.73 m2
      Both groups: MMF (started at a dose of 1.5 g/d, increased to 3 g/d by wk 4); MP at d 1 and repeated 1× within 3 d, oral prednisone 0.75 mg/kg with tapering
      • -
        RTX: 1,000 mg on d 1, 15, 168, 182
      • -
        Placebo
      Renal response (defined as complete renal response, partial renal response, or no response) at wk 52 (superiority)
      • -
        Renal response rates: 56.9% vs 45.8% (RTX nonsuperior)
      • -
        Percentage of patients who discontinued therapy larger in placebo arm (25% vs 10%)
      • -
        RTX arm more likely to achieve complete or partial response in proteinuria at wk 78
      • -
        Rescue therapy more frequent in placebo arm
      • -
        Low sample size
      • -
        Background treatment with high doses of steroids and MMF
      • -
        Short follow-up to assess the primary end point
      • -
        RTX not approved in the management of LN
      NOBILITY (unpublished)
      • Furie R.
      • Cascino M.D.
      • Garg J.P.
      • et al.
      B-cell depletion and response in a randomized, controlled trial of obinutuzumab for proliferative lupus nephritis. Abstract O35.
      ; N = 125 (phase 2)
      Patients with class III or IV LN treatedBoth groups: MMF and steroids
      • -
        Obinutuzumab (wk 0, 2, 24, 26)
      • -
        Placebo
      Complete renal response at wk 52
      • -
        Nominally higher complete renal response rates at wk 52 for obinutuzumab (35% vs 23%; NS), with no increase in rate of AEs
      • -
        Significantly higher rates of complete renal response achieved at wk 76 and 104
      • -
        Needs confirmation in a phase 3 trial
      BLISS-LN (NEJM 2020)
      • Furie R.
      • Rovin B.H.
      • Houssiau F.
      • et al.
      Two-year, randomized, controlled trial of belimumab in lupus nephritis.
      ; N = 448
      Patients with proliferative LN (class III-V), biopsy within 6 mo
      • -
        Exclusion: eGFR < 30 mL/min/1.73 m2
      Both groups: CYC or MMF induction; AZA (2 mg/kg target dose), MMF (1-3 g/d)
      • -
        Belimumab: d 1, 15, 29, and every 28 d thereafter to wk 100
      • -
        Placebo
      Primary efficacy renal response at wk 104 (UPCR of 0.7 g/d, eGFR no worse than 20% below pre-flare value or ≥60 mL/min/1.73 m2, and no use of rescue therapy)
      The primary end point was changed during the conduct of the trial.
      • -
        Superiority of belimumab in achieving the primary efficacy renal response (43% vs 32%)
      • -
        Sustained complete renal response rate through wk 104 (significant in favor of belimumab)
      • -
        SAEs: 26% vs 30%
      • -
        Non-superior in terms of complete renal response after CYC induction
      • -
        Patients had only mildly decreased GFR
      • -
        No information about dosing of AZA or MMF
      • -
        No information about % receiving AZA or MMF
      • -
        Expense
      CALIBRATE (AR 2021)
      • Atisha-Fregoso Y.
      • Malkiel S.
      • Harris K.M.
      • et al.
      Phase II randomized trial of rituximab plus cyclophosphamide followed by belimumab for the treatment of lupus nephritis.
      ; N = 43 (phase 2)
      Patients with recurrent or refractory LN who had previously been treated with CYC or MMF; kidney biopsy within the 18 mo prior to enrollmentBoth groups: RTX 1,000 mg and CYC 750 mg at wk 0 and 2; prednisone 40 mg/d with tapering
      • -
        RCB (RTX and CYC, then belimumab)
      • -
        RC (RTX and CYC)
      Percentage of participants with ≥1 grade 3 or higher infectious AE by wk 24, 48, 96
      • -
        Adding belimumab to RTX and CYC safe (AE outcome: 9.5% vs 23%)
      • -
        Overall renal response: 52% vs 41%
      • -
        Open-label trial
      • -
        Low sample size
      • -
        Needs confirmation in phase 3 trial (difficult recruitment of this patient population)
      AURORA (Lancet 2021)
      • Arriens C.
      • Polyakova S.
      • Adzerikho I.
      • Randhawa S.
      • Solomons N.
      Op0277 aurora phase 3 study demonstrates voclosporin statistical superiority over standard of care in lupus nephritis (ln).
      ; N = 357
      Patients with proliferative LN (class III-V), kidney biopsy within 2 y of screening, UPCR ≥ 1.5 mg/mg (≥2 mg/mg if pure class V); required increase in UPCR in the 6 mo before screening in those with biopsy >6 mo before screening

      - Exclusion: eGFR ≤ 45 mL/min/1.73 m2
      Both groups: MP bolus d 1 and d 2 (0.5 g/d if body weight > 45 kg), prednisone 20-25 mg/d started on d 3, rapid taper; MMF 2 g/d (if starting, 1 g/d for the first wk, then increased)
      • -
        Voclosporin 23.7 mg (3 tablets)
      • -
        Placebo
      Complete renal response (UPCR ≤ 0.5 mg/mg, eGFR of 60 mL/min/1.73 m2 or no confirmed eGFR decrease of >20%, no rescue medication, no ≥10 mg/d prednisone equivalent for ≥3 d in series [≥7 d in total]), at 52 weeks
      • -
        Voclosporin superior in achieving primary end point (41% vs 23%)
      • -
        UPCR ≤ 0.5 mg/mg during trial achieved by 65% vs 44%
      • -
        SAEs in 21% in each arm
      • -
        If MMF was ≤2g/d, voclosporin was superior
      • -
        High number of patients discontinued (46/357); 21 (5.9%) withdrew consent
      • -
        Costs likely high; unclear benefit over tacrolimus
      • -
        No long-term data on renal safety of voclosporin
      Abbreviations: AE, adverse event; AR, Arthritis and Rheumatology; ARD, Annals of the Rheumatic Diseases; ARM, Arthritis and Rheumatism; AZA, azathioprine; BL, baseline; CYC, cyclophosphamide; eGFR, estimated glomerular filtration rate; FDA, US Food and Drug Administration; GC, glucocorticoids; GFR, glomerular filtration rate; IV, intravenous; JASN, Journal of the American Society of Nephrology; LN, lupus nephritis; MMF, mycophenolate mofetil; MP, methylprednisolone; NEJM, New England Journal of Medicine; NIH, National Institutes of Health; NS, not statistically significant; RC, rituximab/cyclophosphamide; RCB, rituximab/cyclophosphamide/belimumab; RCT, randomized controlled trial; RTX, rituximab; SAE, serious adverse event; Scr, serum creatinine; UPCR, urinary protein-creatinine ratio; WBC, white blood cell count.
      a The primary end point was changed during the conduct of the trial.

      IgA Nephropathy

      In IgA nephropathy, a multi-hit hypothesis has been suggested to explain its pathophysiology. There are elevated levels of serum Gd-IgA1 (galactose-deficient IgA1) in the circulation (hit 1). Circulating antiglycan autoantibodies target these immunoglobulins (hit 2), and form pathogenic IgA1-containing circulating immune complexes (hit 3). This leads with eventual deposition in the glomeruli, resulting in kidney injury (hit 4).
      • Novak J.
      • Rizk D.
      • Takahashi K.
      • et al.
      New insights into the pathogenesis of IgA nephropathy.
      The pathogenic immune complexes contains abnormally glycosylated polymeric IgA1, and its deposition triggers mesangial cell proliferation, extracellular matrix expansion, and cytokine release. Mucosal TLR-9 (Toll-like receptor 9) activation induces BAFF overexpression in dendritic cells, proliferation of B cells, and increased IgA synthesis. TLR also stimulates production of a proliferation-inducing ligand (APRIL) and interleukin 6 (IL-6), which lead to the formation of Gd-IgA1 complexes. Therefore, in lymphoid tissue of mucosa, BAFF and APRIL are important therapeutic targets. In addition, there is increasing evidence of the role of alternative and lectin complement pathway in the pathogenesis of this disease.
      Most mild cases of IgA nephropathy do not require immunosuppression, and conservative management (RAAS blockade) is deemed sufficient. The STOP-IgAN trial showed that the addition of immunosuppressive therapy to intensive supportive care was not associated with improved outcomes and had a higher incidence of adverse events.
      • Rauen T.
      • Eitner F.
      • Fitzner C.
      • et al.
      Intensive supportive care plus immunosuppression in IgA nephropathy.
      The TESTING trial evaluated the efficacy and safety of oral glucocorticoids versus supportive therapy alone and was terminated early because of an increased risk of serious adverse events in the steroid group.
      • Lv J.
      • Zhang H.
      • Wong M.G.
      • et al.
      Effect of oral methylprednisolone on clinical outcomes in patients with IgA nephropathy: the TESTING randomized clinical trial.
      The NEFIGAN trial was a randomized phase 2b trial of patients with biopsy-confirmed primary IgA nephropathy and persistent proteinuria.
      • Fellström B.C.
      • Prof Barratt J.
      • FRCP
      • Cook H.
      • PhD
      • et al.
      Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial.
      Patients were randomly allocated in a 1:1:1 ratio to 16 mg/d TRF (target release formulation)-budesonide, 8 mg/d TRF-budesonide, or placebo. The study showed that the higher dose of TRF-budesonide reduced proteinuria.
      In addition, sodium/glucose cotransporter 2 (SGLT2) inhibitor trials have shown benefit in patients with IgA nephropathy as adjunct to RAAS-inhibitor therapy.
      Patients with proteinuria of >1 g/d despite maximal RAAS blockade are at risk for progression, and a 6-month course of corticosteroids should be considered after a thorough discussion of the benefits and risks with the patient. In patients with concomitant rapidly progressive glomerulonephritis, a combination of cyclophosphamide and corticosteroids should be employed. Table 1 lists ongoing trials in LN and IgA nephropathy.

      Dysregulation of the Alternative Complement Pathway

      Genetic mutations (C3 mutation, factor H/I deficiency) and autoimmunity (C3 nephritic factor [NeF]) against regulatory components of the complement system can result in excessive activation of the alternative complement system. Disease manifestations include C3 glomerulopathies (C3 glomerulonephritis and dense-deposit disease) and atypical hemolytic uremic syndrome (aHUS).

      C3 Glomerulopathies

      Autoantibodies are increasingly recognized as being implicated in pathogenesis of C3 glomerulopathies, in addition to genetic mutations. The autoantibodies termed NeFs target neoepitopes in C3 or C5 convertases, resulting in prolongation of their half-lives.
      • Corvillo F.
      • Okrój M.
      • Nozal P.
      • Melgosa M.
      • Sánchez-Corral P.
      • López-Trascasa M.
      Nephritic factors: an overview of classification, diagnostic tools and clinical associations.
      Other autoantibodies include anti-factor H, anti-factor B, and anti-C3b. Three major NeFs have now been identified:
      • 1.
        Properdin-dependent C3NeFs responsible for the activation of C5 convertase. These are also called C5NeFs and are associated with C3 glomerulonephritis (C3GN).
      • 2.
        Properdin-independent C3NeFs, which activate C3 convertase and have been associated with dense deposit disease (DDD).
        • Donadelli R.
        • Pulieri P.
        • Piras R.
        • et al.
        Unraveling the molecular mechanisms underlying complement dysregulation by nephritic factors in C3G and IC-MPGN.
      • 3.
        NeFs against the classic/lectin pathway C3 convertase, known as C4NeFs.
      With regard to therapy, a combination of mycophenolate mofetil and steroids is the most widely studied efficacious regimen.
      • Rabasco C.
      • Cavero T.
      • Román E.
      • et al.
      Effectiveness of mycophenolate mofetil in C3 glomerulonephritis.
      A recent study demonstrated the ability of renin to cleave C3 molecules into C3a and C3b, accelerating the activation of the alternative complement pathway. The use of aliskiren (a direct renin inhibitor) led to a significant decrease in complement activation, resulting in less deposition of C3 and C5b-9 in DDD.
      • Békássy Z.D.
      • Kristoffersson A.
      • Rebetz J.
      • Tati R.
      • Olin A.I.
      • Karpman D.
      Aliskiren inhibits renin-mediated complement activation.
      These findings require further validation and represent a viable adjuvant therapy.
      The use of eculizumab in C3 glomerulopathies has not resulted in notable benefit, with the only main current clinical indication being crescentic rapidly progressive disease.
      • Le Quintrec M.
      • Lapeyraque A.
      • Lionet A.
      • et al.
      Patterns of clinical response to eculizumab in patients with C3 glomerulopathy.
      This is likely indicative of the fact that other upstream components of the complement pathway may be involved in pathogenesis.

      Atypical Hemolytic Uremic Syndrome

      There has been considerable advancement in our understanding of pathogenesis and development of efficacious therapy in aHUS over the past decade. Therapeutic options beyond eculizumab now exist. Ravulizumab is a long-acting C5 inhibitor engineered from eculizumab that has a longer elimination half-life (leading to an extended dosing interval from 2 to 8 weeks). It has demonstrated favorable outcomes in aHUS and is now approved for use in aHUS in the United States and European Union.
      • Rondeau E.
      • Scully M.
      • Ariceta G.
      • et al.
      The long-acting C5 inhibitor, ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment.

      Article Information

      Authors’ Full Names and Academic Degrees

      Sam Kant, MD, Andreas Kronbichler, MD, PhD, Purva Sharma, MD, and Duvuru Geetha, MD, MRCP (UK).

      Support

      None.

      Financial Disclosure

      Dr Geetha is a consultant to ChemoCentryx and Aurinia. Dr Kronbichler has received personal fees from Novartis, Terumo BCT, Miltenyi Biotech, Vifor Pharma, and Alexion. The other authors declare that they have no relevant financial interests.

      Peer Review

      Received March 11, 2021. Evaluated by 2 external peer reviewers, with direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form July 25, 2021.

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