Membranous Nephropathy: Core Curriculum 2021

The understanding and management of membranous nephropathy, a common cause nephrotic syndrome that is more frequently encountered in adults than children, has rapidly evolved over the past decade. Identification target antigens allowed for precise molecular diagnoses, ability to monitor circulating autoantibodies added new vantage point terms disease monitoring decisions about immunosuppression. Although immunosuppression with alkylating agents combined corticosteroids, or calcineurin inhibitor–based regimens, been historical mainstay treatment, observational now randomized controlled trials B-cell–depleting agent rituximab have moved this forefront therapy primary nephropathy. In Core Curriculum, we discuss typical features secondary disease; highlight such as phospholipase A2 receptor, thrombospondin type 1 domain-containing 7A, neural epidermal growth factor-like 1, semaphorin-3B; describe relationship between immunologic clinical courses review modern supportive care immunosuppressive treatment based on these composite parameters. FEATURE EDITOR:Asghar RastegarADVISORY BOARD:Ursula C. BrewsterMichael ChoiAnn O'HareManoocher SoleimaniThe Curriculum aims give trainees nephrology strong knowledge base core topics specialty by providing an overview topic citing key references, including foundational literature led current approaches. EDITOR: Asghar Rastegar ADVISORY BOARD: Ursula Brewster Michael Choi Ann O'Hare Manoocher Soleimani Membranous nephropathy (MN) adult seen less commonly children. field advanced significantly decade, introduction tools diagnose, classify, activity. This intended update reader recent progress provide general guide disease. Case: A 46-year-old Asian woman referred gradual 10-pound weight gain new-onset leg edema, well protein (3+) trace blood urine analysis. She denies infections, joint pains, rashes. Physical examination significant pressure 145/85 mm Hg, normal findings heart lung examinations, but pitting edema (2+). Laboratory testing shows serum creatinine level 1.03 mg/dL, albumin 3.1 g/dL, total cholesterol 278 urinary protein-creatinine ratio 6.7 g/g. up date her age-appropriate cancer screening, antinuclear antibody, hepatitis serologic findings, complement levels are within ranges. You initiate renin-angiotensin system inhibition, diuretics sodium restriction, statin.Question 1: Which additional test would be most helpful at point?a)Kidney biopsyb)Duplex ultrasonography renal vesselsc)Titer receptor (PLA2R) antibodiesd)Antiphospholipid antibody testFor answer question, see following text. statin. Question For MN represents spectrum diseases sharing histopathologic pattern, namely presence immunoglobulin complement-containing immune deposits subepithelial position (see Kidney Pathology). Historically, classified idiopathic basis pathologic clues. identification autoantigens MN, starting description 2009 antibodies against M-type PLA2R, was turning our methods diagnosis monitoring. nomenclature classification evolving increasing number being identified phenotypes become apparent. We will use term “primary” those subtypes which there humoral autoimmune response podocyte antigen absence etiologies “Secondary” refers cases arise setting systemic processes infection, malignancy, drug exposure underlying disorder expected lead resolution MN. subtype should specified (eg, PLA2R-associated MN) when feasible, learning certain may blur distinction (Box 1; Fig 1).Box 1Common Causes Primary, Secondary, Alloimmune MNPrimary MNa•PLA2R-associated•THSD7A-associated•NELL-1–associated•Sema3B-associated•UncharacterizedSecondary MN•Autoimmune/collagen-vascular disease: SLE mixed connective tissue (includes EXT1/EXT2-associated), Sjogren’s, thyroiditis, sarcoidosis, dermatitis herpetiformis•Infection: HBV HCV, malaria, congenital syphilis, leprosy•Drugs, toxins, other adulterants: NSAIDs, gold salts, penicillamine, mercury, cationic bovine (infant formula)•Malignancy: solid-organ carcinomas (lung, breast, colon, kidney), NHL, leukemia; rarely associated THSD7A expression tumor; NELL-1–associated linked malignancyAlloimmune MN•Antenatal alloimmune caused anti-NEP antibodies•De novo kidney allograft•Graft-vs-host diseaseAbbreviations: EXT1/EXT2, Exostosin 1/Exostosin 2; HBV, B virus; C nephropathy; NELL-1, NEP, neutral endopeptidase; non-Hodgkin lymphoma; NSAID, nonsteroidal anti-inflammatory drug; receptor; Sema3B, SLE, lupus erythematosus; THSD7A, 7A.aPrimary reflects process targets intrinsic text). included here even though source not yet clear. Several under investigation listed uncharacterized. Primary MNa•PLA2R-associated•THSD7A-associated•NELL-1–associated•Sema3B-associated•Uncharacterized Secondary malignancy Abbreviations: 7A. aPrimary PLA2R 180-kDa transmembrane glycoprotein expressed human podocyte, where its function Autoantibodies responsible many 80% patients (reflecting approximately 55% all found biopsy). discovery assay diagnosis, obviating biopsy situations. Data highly suggestive causal anti-PLA2R (henceforth simply anti-PLA2R) pathogenesis, further studies needed ascertain relationship. Thrombospondin 7A (THSD7A) next 250-kDa multidomain basal surface immediately beneath slit diaphragm. account 1%-3% Western countries. also overexpressed malignancies incite reaction tumor glomerular leading exact mechanism how anti-THSD7A state known, mouse model, rabbit observed 90-kDa secreted (NELL-1) addition prevalent antibodies. NELL-1 through mass spectrometric approach enrichment peptides from candidate laser-capture microdissected glomeruli uncharacterized evidence THSD7A. 16% PLA2R-negative without any identifiable associations, representing approximate 2.5% prevalence across entire (Fig 1). Unlike PLA2R- THSD7A-associated (Ig) G1-predominant. suggests connection malignancy. Further study microdissection spectrometry (LCM-MS) revealed another antigen, semaphorin-3B (Sema3B), autoantibodies. Anti-Sema3B were predominantly IgG1 detected immunoblot only reducing conditions, suggesting existence potentially cryptic epitope. Of note, infants present segmental pattern tuft occasionally tubular basement membrane well. Detection complex (class V nephritis; MN). Circulating 2 (EXT1/EXT2) identified, staining identify disorders. As 30% diagnoses represent likely autoimmune/collagen vascular infections; drugs, adulterants; mechanisms defined It assumed (endogenous exogenous), complexes, monoclonal immunoglobulins “planted” side (GBM) virtue size and/or charge thereby formation position. Finally, (antenatal de posttransplantation inconsistencies host donor systems phenotype detect established paradigm purposes conceptualize pathophysiology. same principles apply recently discovered There currently tests approved US Food Drug Administration assess amount enzyme-linked immunosorbent reports titer IgG useful initial detection change time. Values <14 RU/mL considered negative manufacturer, some shown 2-14 range very low titers can verified assays. indirect immunofluorescence (IF) uses cells transfected recombinant sensitive low-titer anti-PLA2R, IF yields semiquantitative 1:10, 1:100, 1:300). These stains accumulated question (c), it noninvasive establish baseline titer. (a) if result negative. no signs warrant immediate antiphospholipid (d) need duplex (b) look vein thrombosis. ?Beck LH Jr, Bonegio RG, Lambeau G, et al. N Engl J Med. 2009;361(1):11-21. ?ESSENTIAL READING?Tomas NM, Beck Meyer-Schwesinger C, type-1 2014;371(24):2277-2287.?Sethi S, Madden BJ, Debiec H, 1/exostosin 2-associated Am Soc Nephrol. 2019;30(6):1123-1136.?Sethi B, Neural Int. 2020;97(1):163-174.?Sethi Semaphorin 3B-associated distinct pediatric patients. 2020;98(5):1253-1264. one causes White, nondiabetic adults. Despite generalization, races ethnicities. incidence case per 100,000 persons year. typically male patients, although described THSD7A- predominance. median age onset early 50s, wide distribution presentation ranging children elderly. population, quite rare, forms virus (HBV) infection considered. young Sema3B- albumin–associated presentations standpoint similar often involve syndrome: heavy proteinuria, hypoalbuminemia, anasarca, hyperlipidemia, lipiduria. tend develop slowly overlooked months, unlike explosive minimal earliest stages, indolent course. Conceptually, due progressive resultant injury Pathophysiology). Proteinuria ongoing months years subclinical before diagnosis. degree proteinuria variable, subnephrotic 20 g/d. Eighty percent syndrome, remainder diagnosed earlier course after incidental finding proteinuria. Urinary sediment usually lipiduria oval fat bodies fatty casts 2). Microscopic hematuria uncommon 1+ (unless thrombosis present, significant). Red cell seen, casts, their pleiomorphic circular droplets, sometimes mistaken casts. Blood 70% filtration rate (GFR) preserved If GFR becomes reduced, consider coexisting thrombosis, concomitant interstitial nephritis crescentic glomerulonephritis, iatrogenic effect overdiuresis inhibitors renin angiotensin pathway. Hyperlipidemia nephrotic-range Venous thromboembolic events reason why patient presents attention Anticoagulation). Clinical clues help distinguish obtained careful history, laboratory studies, histologic biopsy. cases, offending predate years, whereas, (malignancy lupus), induced presenting feature One vexing issues variable few parameters predict ultimate Even potential undergo spontaneous remission, treated avoid adverse consequences prolonged state. On average, third exhibit remission (slightly <8 g/d), take 15-20 achieve partial 25-40 reach complete remission. Any whether therapy, beneficial survival. contrast, remain failure. Ten-year follow-up data independent demonstrate 35%-40% reaching failure conservatively, compared 8%-11% agent/corticosteroid regimen. Because slow time frame resolves, experience (>50% decrease <3.5 g/d) they (<0.3 g/d). Therefore, long-term (?5 years) given trial determine full remissions. Relapses occur 25%-30% Rates relapse higher reflect incompletely-suppressed activity withdrawn. cessation eventual dissipate. class (“membranous”) nephritis, prognosis depends alone combination nephritis. general, isolated excellent prognosis, reported 10-year survival rates 72%-98%. ?Donadio JV Torres VE, Velosa JA, Idiopathic nephropathy: natural history untreated 1988;33(3):708-715.?Schieppati A, Mosconi L, Perna Prognosis 1993;329(2):85-89.?Hladunewich MA, Troyanov Calafati J, non-nephrotic patient. Clin 2009;4(9):1417-1322.?Polanco N, Gutiérrez E, Covarsí Spontaneous 2010;21(4):697-704. READING?van den Brand van Dijk PR, Long-term outcomes using restrictive strategy. 2014;25(1):150-158. characteristic light microscopy, IF, electron microscopy 3. changes complexes immunoglobulin, components form (ie, subepithelial) injury, includes simplification, loss diaphragms foot processes, production matrix material around deposits. pronounced depending during performed. Keep mind “membranous nephropathy” merely descriptor particular lesion histopathology does itself refer single Early disease, noted rigid-appearing capillary walls Jones silver stain highlights extracellular elements GBM With close observation, areas translucency (“craters”) might persist grow size, increased deposited injured results spike-like projections stain. progresses, encircles deposits, resulting lace-like splitting laddering appearance GBM. longstanding chronic damage sclerosis, fibrosis, atrophy found. inferior prognosis. Coexisting conditions crescent tubulointerstitial require testing. generally detecting routine pathologist frozen sections IgG, IgA, IgM, C3, C1q. C3 nearly always positive, appearing fine granular, peripheral loop pattern. or, fixed tissues, immunohistochemistry important adjunctive aid Less frequent emerging Sema3B assayed manner. antigens, accumulate identical C3. lesions global affect portions tuft, (such NELL-1-associated lesions. Features etiology include moderate reactants beyond “full-house” (IgG/IgA/IgM C3/C1q) EXT1/EXT2 granular capillary-loop conditions. Another entity membranous-like glomerulopathy masked IgG? light-chain pronase digestion required expose Many diseases. Staining subclasses assist determination etiology. mixture IgG4 tends predominant codominant IgG1, IgG2, IgG3 predominate. clear IgG1-predominant diseases, proportion Ehrenreich-Churg stage electron-dense assessed microscopy. find stages deposits: (small discrete podocyte), (deposits separated each newly formed material), 3 completely encircled matrix), 4 (electron-lucent; resorption complexes). Podocyte show effacement diaphragms, apical microvillous change. subendothelial mesangial tubuloreticular structures endothelium, ?Larsen CP, Messias NC, Silva FG, Walker PD. Determination versus utilizing biopsies. Mod Pathol. 2013;26(5):709-715.?Huang CC, Lehman Albawardi subclass biopsies glomerulonephritis indicates switch progression. 2013;26(6):799-805.?Fogo AB, Lusco Najafian Alpers CE. AJKD atlas pathology: Dis. 2015;66(3):E15-E17. Like heritable component link leukocyte (HLA) locus chromosome 6, associations HLA II White population DR3. European genome-wide association 556 indeed demonstrated single-nucleotide variation HLA-DQA1 locus. second peak mapped intronic region PLA2R1. Homozygosity both risk alleles conferred odds 80, showing interaction alleles. Larger cohorts international populations, especially China, loci DRB1 DRB3. allelic variants positions peptide-binding groove molecule. suggested genetic enhance discourage antigenic derived system. large confirmed previous PLA2R1 genes, East populations mapping DRB1. closely