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A Proposal for a Serology-Based Approach toMembranous Nephropathy

An S. De Vriese,* Richard J. Glassock,† Karl A. Nath,‡ Sanjeev Sethi,§ andFernando C. Fervenza‡

*Division of Nephrology, AZ Sint-Jan Brugge-Oostende, Brugge, Belgium; †Department of Medicine, Geffen School ofMedicine, University of California, Los Angeles, California; and ‡Division of Nephrology and Hypertension and§Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota

ABSTRACTPrimarymembranous nephropathy (MN) is an autoimmunediseasemainly caused byautoantibodies against the recently discovered podocyte antigens: the M-typephospholipase A2 receptor 1 (PLA2R) and thrombospondin type 1 domain-contain-ing 7A (THSD7A). Assays for quantitative assessment of anti-PLA2R antibodies arecommercially available, but a semiquantitative test to detect anti-THSD7A anti-bodies has been only recently developed. The presence or absence of anti-PLA2Rand anti-THSD7A antibodies adds important information to clinical and immuno-pathologic data in discriminating between primary and secondary MN. Levels ofanti-PLA2R antibodies and possibly, anti-THSD7A antibodies tightly correlate withdisease activity. Low baseline and decreasing anti-PLA2R antibody levels stronglypredict spontaneous remission, thus favoring conservative therapy. Conversely,high baseline or increasing anti-PLA2R antibody levels associate with nephrotic syn-drome and progressive loss of kidney function, thereby encouraging prompt initi-ation of immunosuppressive therapy. Serum anti-PLA2R antibody profiles reliablypredict response to therapy, and levels at completion of therapy may forecast long-term outcome. Re-emergence of or increase in antibody titers precedes a clinicalrelapse. Persistence or reappearance of anti-PLA2R antibodies after kidney trans-plant predicts development of recurrent disease.We propose that an individualizedserology-based approach to MN, used to complement and refine the traditionalproteinuria-driven approach, will improve the outcome in this disease.

J Am Soc Nephrol 28: ccc–ccc, 2016. doi: 10.1681/ASN.2016070776

Membranousnephropathy(MN)is amor-phologic pattern of injury characterized bythickening of the glomerular capillary wallbecause of subepithelial deposition of im-mune complexes and complement com-ponents and attendant new basementmembrane synthesis (Figure 1). MN iscaused by an array of conditions with dif-fering etiologies and pathogeneses.

Primary MN, responsible for approx-imately 80%of cases, is an organ-specificautoimmune disease, in which circulat-ing autoantibodies bind to an autoantigen

on the surface of the podocytes. Twomajor target antigens are now firmly rec-ognized: the M-type phospholipase A2receptor 1 (PLA2R)1 and the thrombo-spondin type 1 domain-containing 7A(THSD7A).2,3 Together, PLA2R-associatedMN and THSD7A-associated MN ac-count for the large majority (about80% ormore) of primaryMN. Althoughthe presence of anti-PLA2R antibodies(Abs) and anti-THSD7A Abs was ini-tially considered to be mutually exclu-sive, patients with dual positivity have

recently been described.4 The remainingcases of primary MN may either becaused by autoantibodies against as yetunidentified intrinsic antigens or reflectmisclassified PLA2R-associated MN,THSD7A-associated MN, or secondaryMN. Thus, the term idiopathic MNmayno longer be appropriate.

In approximately 20% of cases inadults, the MN lesion is secondary tovarious disorders, including infection(hepatitis B), systemic disease (SLE andsarcoidosis), drugs (nonsteroidal anti-inflammatory drugs), thyroiditis, andma-lignancy. Foreign antigens may travelthrough the glomerular basement mem-brane (GBM), become planted under thepodocytes, and subsequently, be bound bycirculating Abs.5 Alternatively, circulatingimmune complexes may dissociate andreform in the subepithelial space.6,7

Traditionally, the differential diagno-sis andmanagementofMNison thebasisof the integration of clinical and biopsyfindings.8 In this article, we will explorehow the discovery of the target podocyte

Published online ahead of print. Publication dateavailable at www.jasn.org.

Correspondence: Dr. An S. De Vriese, Division ofNephrology and Infectious Diseases, AZ Sint-JanBrugge, Ruddershove 10, B-8000 Brugge, Belgium,or Dr. Fernando C. Fervenza, Division of Nephrol-ogy and Hypertension, Mayo Clinic, 200 1st Street SW,Rochester, MN 55905. Email: [email protected] [email protected]

Copyright © 2016 by the American Society ofNephrology

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mailto:[email protected]

mailto:[email protected]

antigens and the development of com-mercial assays for PLA2R and THSD7AAbs may guide diagnosis and manage-ment and complement traditional algo-rithms.9 The following questions will beaddressed. (1) Can PLA2R and THSD7AAbs be used to diagnose MN andthereby, avoid the need for a kidney bi-opsy? (2) Can PLA2R and THSD7A Absadequately discriminate between pri-mary and secondary MN and thus, ob-viate the need to search for the presenceof a secondary underlying condition? (3)Can quantification of PLA2R andTHSD7A Abs guide prognosticationand the decision to start, tailor, or with-draw immunosuppressive treatmentfor primary MN? (4) Can PLA2Rand THSD7A Ab levels aid the predic-tion, detection, and treatment of post-transplant recurrence? Evidence for theclinical usefulness of determining plasmaPLA2R Ab levels has mushroomed overthe past 2 years andwill be themain focusof this review. Because the discovery ofTHSD7A was more recent, only limiteddata address the role of THSD7A Ab indiagnosis, prognosis, and managementofMN. For each question, wewill presentthe available evidence, followed by anopinion-based proposal to integratethis evidence in the clinical approach tothe patient.

AUTOANTIBODY ASSAYS ANDANTIGEN STAINING

Western blotting, as used in the seminalstudies revealing the PLA2R Ab1 andTHSD7A Ab,2 is unsuitable for routineclinical use. The first commercially avail-able assay for PLA2R Ab was a cell-basedassay using indirect immunofluores-cence (CBA-IFA; Euroimmun, Luebeck,Germany). Its semiquantitative naturemakes it less suitable for monitoringdisease progression and therapeuticresponse. A subsequently developedELISA (Euroimmun) is not as sensitiveas Western blotting and CBA-IFA butquantitates plasma levels of PLA2R Aband is currently used routinely in manyclinical laboratories. The most recent di-agnostic acquisition is a laser bead im-munoassay (ALBIA; Mitogen AdvancedDiagnostics Laboratory, Calgary, Can-ada), providing a sensitive and quantita-tive assay of PLA2R Ab. In addition, thetechnology is designed to simulta-neously measure multiple targets in asingle sample and thus, can probe forthe presence of other conditions (SLE,ANCA-associated vasculitis, anti-GBMdisease, etc.).10

In clinical practice, the ELISA test isthe most suitable for follow-up PLA2RAbmeasurements, whereas the CBA-IFA

is a more sensitive technique for the de-tection of very low PLA2R Ab levels, inthe diagnosis of PLA2R-associated MN,when lowPLA2RAb levels are suspected,or when the ELISA is not conclusive. Themanufacturer’s definition for PLA2R Abpositivity of the commercial ELISA assayis.14 RU/ml. However, it has been sug-gested that any titer .2 RU/ml may beconsidered positive; this threshold im-proves sensitivity but will obviously leadto false positives.11 A semiquantitative in-direct immunofluorescence test to detectTHSD7AAbwas recently developed12 butis not yet commercially available.

PLA2R-associatedMNand THSD7A-associated MN may also be diagnosedby showing the antigen in the immunedeposits, using immunofluorescenceor immunoperoxidase methods onpronase-digested sections of paraffin-embedded biopsy material, and using apolyclonal anti-PLA2R or THSD7A Ab.Most patients with primaryMNand pos-itive PLA2R Ab have an intense granularPLA2R staining along the glomerularcapillary walls (Figure 1E). This patternof staining has been called enhancedPLA2R staining.13 In normal kidneys orother glomerular diseases, the antigen isonly weakly detectable on the podocytesurface. A negative PLA2R stainingshows no staining or only a minimalblush representing the intrinsic PLA2Rstaining of the epithelial cells (Figure 2).Generally, a strong association betweenglomerular PLA2R staining and circulat-ing PLA2R Ab is found,14–16 in particularwhen the Ab levels are measured in closeproximity to the time of biopsy.13 Like-wise, granular staining for THSD7A isenhanced in biopsies of patients withMNand positive THSD7AAb.2,4,12 How-ever, its distinction from the linearTHSD7A staining pattern in normal kid-neys or other glomerular diseases re-quires an experienced renal pathologist.

SEROLOGY-BASED DIAGNOSIS

Traditional ApproachThe kidney biopsy is the gold standardin recognizing the pattern of injury le-sion of MN. However, standard light,

Figure 1. Primary PLA2R–associated MN. (A) Light microscopy shows thickened GBMswithout mesangial or endocapillary hypercellularity (periodic acid-Schiff stain). Originalmagnification, 340. (B–E) Immunofluorescence microscopy reveals granular staining for (B)IgG, (C) C3, and (E) PLA2R, with negative staining for (D) C1q. Original magnification,340. (F)Electron microscopy shows subepithelial deposits separated from each other by basementmembrane spikes. No subendothelial or mesangial electron dense deposits are present.Tubuloreticular structures are absent in endothelial cells. Original magnification,34800.

2 Journal of the American Society of Nephrology J Am Soc Nephrol 28: ccc–ccc, 2016


immunofluorescence,andelectronmicro-scopic examination may not be sufficientto establish the true nature of the disorder.The main challenge in the diagnosis ofMN is the differentiation between pri-mary and secondary MN, in particularmalignancy-associated MN in elderlypatients. The concurrence of MN andsecondary disease does not necessarilyprove causality but may be coincidental.Conversely, the absence of a secondarycause at diagnosis does not rule out itsdevelopment later in the disease course.It is current common practice to excludesecondary causes of the lesion of MN onthe basis of a detailed medical history,physical examination, laboratory analy-sis, and imaging. There is no consensuson how aggressive the search should be,especially as regards an occult malig-nancy. A careful evaluation of the immu-nopathologic characteristics of the bi-opsy specimen may provide additionaldiscriminative information.17 Subepi-thelial, intramembranous, and mesan-gial deposits suggest secondary MN(Figure 3); an exclusive subepithelial lo-cation of the deposits is more typical forprimary MN (Figure 1). C1q depositionis rarely seen in primary MN but may beseen in other secondary causes, particu-larly in SLE. IgG subclass staining mayfurther help to classify MN. IgG1, IgG2,and IgG3 generally dominate in the de-posits of secondary MN, whereas a pre-ponderance of IgG4 is characteristic forprimary MN, reflecting the fact that

PLA2R Ab and THSD7A Ab are mainlyof the IgG4 subclass.

Diagnostic Value of PLA2R AbThe specificityofPLA2RAb for the lesionof MN nears 100%.18 PLA2R Abs havenot been detected in either patients withother kidney or systemic diseases orhealthy individuals. This has led to thesuggestion that a kidney biopsy in pa-tients with positive PLA2R Ab may notbe required, especially when there arerelative contraindications to perform abiopsy.17 Approximately 50%–80% ofpatients with primary MN test positivefor PLA2R Ab.19 The large variabilityamong published studies reflects, inpart, the type of test used (Westernblot, CBA-IFA, and ALBIA aremore sen-sitive than ELISA) or the ethnic origin ofthe study population (the prevalence ofPLA2R Ab is lower in Japanese cohorts).However, the most influential contribu-tor to the observed variability is the tim-ing of measurement in relation to thedisease course. There are three scenariosaccounting for the inability to detectPLA2R Ab in patients with primaryMN. In the first scenario, serum samplesmay be collected when the patient hasalready entered immunologic remissioneither spontaneously or by virtue of im-munosuppressive therapy. Proteinuriamay persist because of the time lag be-tween immunologic and clinical remis-sion or because of irreversible podocytedamage in the absence of active

disease.20 In these patients, PLA2R Abmay be low or undetectable, but glomer-ular PLA2R staining may serve as a foot-print of PLA2R-associated MN. As anexample, only 22% of serum samplesobtained long after the histologic diag-nosis were PLA2R Ab positive, whereas59% of the corresponding biopsies werepositive on PLA2R staining.15 In the sec-ond scenario, serum PLA2R Ab may befalsely negative early in the diseasecourse, and seroconversion may occurlater on.21,22 This phenomenon hasbeen explained by “kidney as a sink”21:PLA2R Abs enter the circulation, bind tothe target antigens on the podocytes, andare rapidly cleared from the blood. Onlywhen the rate of production exceeds thebuffering capacity of the kidney do pa-tients exhibit seropositivity. Serial as-sessment of PLA2R Ab for at least 3months should, therefore, be performedin patients with positive glomerularPLA2R staining who are initially sero-negative but have persistent disease ac-tivity. These two mechanisms explainwhy up to 30% of patients with PLA2R-associated MN may be seronegative;they can be properly categorized byperforming a PLA2R staining on the kid-ney biopsy.14,15,22 The inverse (i.e., posi-tive PLA2R Ab and negative glomerularPLA2R staining) is distinctly uncom-mon14 ,15 ,22 and in al l l ikelihood,reflects a technical artifact. A third sce-nario is when a non-PLA2R Ab mecha-nism (THSD7A or other not yet definedAb) is involved.

A clinically highly relevant question iswhether a positive PLA2R serology reli-ably excludes secondary MN and obvi-ates further diagnostic workup. Nopatients with positive PLA2R Ab1,23–26

or glomerular PLA2R13 were reportedin a number of studies of well definedgroups of secondary MN. In particular,class 5 SLE seems to be almost uniformlyPLA2R negative, consistent with thepathophysiology of immune complexdeposition in SLE. Others studies foundsmall numbers of positive patients invarious groups of secondary MN.15,27–33

The question thus arises whether thesepatients represent true secondary MNor rather, PLA2R-associated MN with

Figure 2. PLA2R staining. A–C show a biopsy ofMNwith positive PLA2R staining, andD–Fshow a biopsy of MNwith negative PLA2R staining. (A and D) IgG, (B and E) C3, and (C andF) PLA2R. Original magnification, 340.

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coincident secondary disease. The latterpossibility is supported by the followingfindings in such studies. First, in somepatients, the glomerular histologic fea-tures of secondary MN were absent, andthe predominant IgG subclass wasIgG4.27,30,32 Second, patients are de-scribed who entered remission withouttreatment of the secondary disease,32

and conversely, other patients exhibitedpersistent or recurrent proteinuria,despite successful treatment of the sec-ondary disease.27 However, in certainsubgroups of secondary MN, positiveglomerular PLA2R staining has beenobserved in a substantial number ofpatients. In a study of 39 patients withhepatitis B-related MN, 25 (64%) had apositive PLA2R staining, overlapping

with hepatitis B antigen deposits.31 Fur-thermore, the immunopathologic char-acteristics were typical for secondaryMN. Similarly high proportions of pos-itive PLA2R staining were seen in hepa-titis C (seven of 11; 64%)28 and activesarcoidosis (three of four; 75%28 andfive of nine; 55%34), thus suggestingthat these disorders may induce an im-mune response to PLA2R.

Diagnostic Value of THSD7A AbThus far, the THSD7A Ab has not beendetected in healthy controls or patientswith other renal and systemic dis-eases,2,32 yielding a 100% specificity forthe lesion ofMN. The percentages of pri-mary MN that are THSD7A associatedrange from 3% in Europe and the United

States to 9% in Japan (Table 1). Notably,in a large number of patients withTHSD7A-associated MN (eight of 38;21%), a malignant tumor was detectedwithin a median time of 3 months fromdiagnosis of MN.12,35 Analysis of endo-metrial carcinoma12 and gallbladder car-cinoma35 cells revealed elevatedTHSD7A protein expression. Remark-ably, the initiation of chemotherapy re-sulted in a decline THSD7A Ab followedby a decrease in proteinuria.35 Thesefindings have led to the thesis that theimmune system may recognize tumorTHSD7A as a foreign antigen leading tothe production of THSD7AAb, the latterthen binding to podocyte THSD7A insitu. If confirmed, the concept of pri-mary versus secondary MN may requirerevision.

It is presently unclear whether pa-tients with dual PLA2R and THSD7AAb positivity, as recently described,4

behave phenotypical ly as PLA2R-associated MN, THSD7A-associatedMN, or an entirely distinct form of MN.

A Proposed Diagnostic AlgorithmIn patients inwhomMN is suspected, wepropose a serology-based diagnostic ap-proach (Figure 4). When PLA2R Abs aredetected in plasma and there is no evi-dence for secondary disease, one mayconsider to not perform a kidney biopsy,provided that patients have normal oronly mildly decreased kidney function.In patients with impaired kidney func-tion, a biopsy may aid in excluding acrescentic form of MN36 or superim-posed disease and assessing the degreeof chronic damage.

SEROLOGY-BASED ASSESSMENTOF PROGNOSIS

Traditional ApproachThe natural course of MN is unpredict-able. A sizeable proportion (20%–30%)of patients, even those with nephroticsyndrome at presentation, achievesspontaneous long-term remission.Others have chronic, persistent low-grade proteinuria and preserved renalfunction. Both groups do not require

Figure 3. Early secondaryMNdue to an autoimmune disease. Electronmicroscopy shows(A) subepithelial deposits along the capillary walls, (B) subepithelial and subendothelialdeposits along the capillary walls, (C) subepithelial andmesangial electron dense deposits,and (D) tubuloreticular inclusions in the endothelial cells. Thin black arrows point to sub-epithelial deposits, white arrows point to subendothelial deposits in B and mesangialdeposits in C, and thick black arrows point to tubuloreticular inclusions. Original magni-fication, 36800 in A; 39300 in B; 39300 in C; 318,500.



immunosuppression (IS). A third groupconsists of patients with persistent high-grade proteinuria at high risk for pro-gression to ESRD. Clinical predictors ofpoor renal outcome are persistent high-grade proteinuria (.8 g/24 h) over the

course of 6 months, rapid rate of declineof renal function over this 6-month in-terval, and elevated serum creatinine atthe time of diagnosis.37 Scientific guide-lines recommend initiation of IS in suchpatients.8 However, the prolonged

observation period required to assessthe risk of progression may either delaytreatment beyond the point at whichsuch treatment may prove effective orincur significant residual kidney dam-age. Conversely, patients may be judgedto be at high risk and exposed to po-tentially toxic IS but still develop aspontaneous remission.38 The intrinsicweakness of the “wait and see” clinicalapproach is that indices such as protein-uria and serum creatinine may notpromptly or reliably reflect disease activ-ity in MN for the following reasons: (1) aprolonged delay (extending over severalmonths) may exist between changes inimmunologic and clinical activity, and(2) proteinuria and elevated serum creat-inine do not discriminate betweenimmunologically active disease and irre-versible structural damage to podocytesand the basement membrane.

Prognostic Value of PLA2R AbAlthough some studies found an associ-ation between the degree of proteinuriaand PLA2R Ab titer at a defined timepoint,30,33,39,40 others found only aweak or no association.13,22,41 Such var-iability in association likely reflects thetime lag between immunologic and clin-ical activity, and indeed, a latency periodas long as 8 months has been observedbetween the presence of PLA2R Ab inserum and the first clinical manifesta-tions of MN.42 Low baseline PLA2R Ablevels predict subsequent spontaneousremission,40,43 whereas high baselinePLA2R Ab levels are associated with de-velopment of nephrotic syndrome inpatients with initial non-nephrotic pro-teinuria44 and with progressive loss of

Table 1. Prevalence of THSD7A-associated MN in different cohorts

Ref. Origin Positive THSD7A Ab Positive THSD7A Staining

Tomas et al.2 Europe/Boston 15 of 483 Prevalent primary MN (3.1%),two of 67 prevalent secondary MN (3.0%)

Five of five THSD7A Ab positive,zero of 50 THSD7A Ab negative

Iwakura et al.32 Japan Five of 55 incident primary MN (9.1%),zero of 37 incident secondary MN (0%)

Hoxha et al.12 Hamburg/Boston Nine of 345 incident primary MN (2.6%),29 of 931 prevalent primary MN (3.1%)

18 of 18 THSD7A Ab positive,one THSD7A Ab negative

Larsen et al.4 United States Nine of 258 incident MNa (3.5%; two ofnine dual positive for THSD7A/PLA2R)

aAll native kidney biopsies with MN, except membranous lupus nephritis (International Society of Nephrology/Renal Pathological Society class 5).

Figure 4. Diagnostic algorithm. The diagnostic evaluation starts with a quantification ofPLA2R Ab (ELISA; potentially superseded by ALBIA in the near future) and a screening forsecondary disease, including antinuclear Abs, viral hepatitis serology, thyroiditis autoim-munity, chest x-ray (or computed tomography inpatients at high risk formalignancy), andanevaluation for sarcoidosis in selected patients. The presence of PLA2R Ab and the absenceof evidence for secondary disease confirm the diagnosis of a PLA2R Ab–associated MN,even without additional pathologic evidence. In patients with negative PLA2R Ab, stainingfor the PLA2R antigen on the biopsy identifies additional patients as PLA2R-associatedMN. When both PLA2R Ab and antigen are negative, traditional immunopathologiccharacteristics, as delineated above, along with measurement of THSD7A Ab should beused to categorize MN as either primary or secondary. Patients without clear evidence ofsecondary diseasebutwith immunopathologic characteristics suggestive of secondaryMNmay have an occult neoplasm and should be comprehensively screened for cancer. In viewof the high prevalence of malignancy in THSD7A-associated MN, these patients shouldalso undergo a thorough evaluation for occult malignancy. This algorithmwill likely changewith the availability of new information. Recent data12 indicate that a substantial proportionof THSD7A-associated MN was IgG4 negative on biopsy, irrespective of whether a ma-lignancy was present, suggesting that all patients who are PLA2R Ab/antigen negative,independent of the dominant IgG subtype in their renal biopsy, may need to be tested forTHSD7A. We recognize that the diagnostic tools in this algorithm, in particular the mea-surement of THSD7AAb and the specialized immunopathology studies,may not bewidelyor routinely available at present.



kidney function.44–46 Serial measure-ments of PLA2R Ab levels provide evenbetter prognostic information. Decreas-ing levels strongly predict remission ofproteinuria.39,47,48 A recent study sug-gested that PLA2R Ab epitope-specificassays with analysis of the epitope profileand intramolecular epitope spreadingmay be developed and refined as a prog-nostic test.49 Serum Ab activity re-stricted to the cysteine-rich epitope ofthe PLA2R molecule is associatedwith a high rate of spontaneous remis-sion, whereas epitope spreading duringfollow-up associates with worsening ofthe disease.49 The prognostic utility ofPLA2R Ab assays will most likely im-prove as epitope-specific assays aredeveloped for clinical use, akin to whatoccurred in anti-GBM disease.

Prognostic Value of THSD7A AbLimited data suggest that THSD7A Ablevels are associated with disease activityin THSD7A-associated MN,2,12 but con-firmation in larger cohorts with serial Abmeasurements is required.

A Proposed Prognostic AlgorithmIn patients with PLA2R-associated MN,we propose a serology-based assessmentof prognosis (Figure 5). The fate ofpatients who are Ab negative is morecontroversial, likely reflecting the het-erogeneous nature of this subgroup, asdetailed in the previous section. A highproportion of patients who are PLA2Rand THSD7A Ab negative developsspontaneous remission,50 thereby avoid-ing the need for IS: delaying such therapymay thus be warranted.

SEROLOGY-BASED MONITORINGOF TREATMENT

Traditional ApproachA comprehensive discussion of IS regi-mens for MN51 is beyond the scope ofthis perspective. Generally, patients aregiven a specified course of IS for a fixedperiod of time, regardless of the responseto treatment. Response to therapy is tra-ditionally assessed using standard labo-ratory parameters (Table 2) and highly

unpredictable. If a patient responds toIS, a drop in proteinuria usually occurswithin a few months. However, com-plete or partial remissionmay be delayedfor up to 18 months or longer after com-pletion of IS. The latter course is charac-teristic of extensive immune damagethat requires prolonged podocyte re-modeling to restore the architectureand function of the glomerular filtrationbarrier. Certain patients may not re-spond to the initial type of IS therapybut may respond to an alternative IS reg-imen. More than 20% of patients treatedwith various IS regimens and followedfor 10 years never achieve remission,with 75% of these patients progressingto ESRD.52 One third of patients whorespond to IS eventually relapse, whichunfavorably affects long-term progno-sis.52 Notably, none of the clinical vari-ables at presentation predict a relapse.52

In addition, refractory or relapsing im-mune injury is difficult to distinguishclinically from incomplete filtration bar-rier repair or the development of glo-merulosclerosis. A repeat kidney biopsymay be helpful in deciding whether to

restart IS because of the presence of freshimmune deposits or conversely, eschewIS because of widespread chronic and ir-reversible histologic damage.

Therapeutic Monitoring with PLA2RAbWhether baseline PLA2R Ab titer pre-dicts the response to IS is controversial.Patients with low PLA2R Ab before thestart of IS have a higher probability ofremission and attain remission of pro-teinuria sooner than patients with highPLA2R Ab, as observed in some stud-ies22,44,53 but not in others.54,55 In con-trast, the plasma profiles of PLA2R Abreliably predict outcome. A decline inPLA2R Ab levels consistently heralds adecline in proteinuria.22,33,44,47,53–56 Al-though the rate of Ab reduction variesamong studies, the general pattern thatemerges is that Abs decrease dramati-cally in the first 3 months of treatmentand disappear over 6–9months followedby a remission of proteinuria over 12–24months. Importantly, PLA2R Ab levelsat the completion of therapy mayforecast the nature of the long-term

Figure 5. Prognostic algorithm. Although the temporal relationship between PLA2R Ablevels and disease activity is well established, a time lag of several months between im-munologic and clinical response should be taken into account. Measurement of PLA2R Abmay obviate the need for a “wait and see” period of 6 months, as recommended by theKidney Disease Improving Global Outcomes guidelines, and allow more rapid treatmentdecisions. Serial PLA2R Ab measurements may guide the decision to start IS. Patients withinitial high PLA2R Ab titers should be followed monthly, whereas those with moderate tolow PLA2RAbs should be re-evaluated bimonthly. This recommendation does not apply topatients with rapidly declining renal function, in whom prompt initiation of IS may bewarranted. PLA2R Ab ELISA (Euroimmun): low =14–86 U/ml; moderate =87–204 U/ml; andhigh $204 U/ml.53 SCreat, serum creatinine.



outcome.54 Patients with undetectablelevels after therapy have a high likeli-hood of remaining in remission for 5years.54 Conversely, patients with,50% reduction in Ab titers are likelyto have resistant disease. None of thepatients with positive Ab after comple-tion of treatment remained in remis-sion at 2 years.54 Re-emergence ofor an increase in Ab titers precedes aclinical relapse by approximately 3months.53

In patients with similar baseline clin-ical characteristics and Ab levels, the rel-ative Ab reduction was greater in thosetreated with the combination of tacroli-mus and rituximab compared with thosetreated with cyclophosphamide,55 anda greater reduction was also observedin patients treated with cyclophospha-mide compared with those treated withmycophenolate mofetil.54 In contrast,in other studies, the decline of Ablevels was not affected by the type of IS(alkylating agents, calcineurin inhibi-tors, and different dosing regimens ofrituximab).44,47,56

The recognition that patients withtherapy-resistant disease have high Ablevels may engender interest in plasmaexchange as a rescue therapy in these pa-tients, as recently supported in a pilotstudy.57

A Proposed Therapeutic AlgorithmIn subjects with detectable PLA2R Ab,serial measurement of Ab titer servesas a guide to IS therapy (Figure 6).

SEROLOGY-BASED MONITORINGOF POST-TRANSPLANTRECURRENCE

Traditional ApproachMN frequently recurs after kidney trans-plantation. In studies using system-atic protocol biopsies, which enablediagnosis of MN at a subclinical stage,recurrence rates of up to 50% havebeen described.58,59 Some patients de-velop de novo MN after transplantation,with a histologic pattern indistinguish-able from recurrent MN. Although the

etiology of de novo MN is uncertain, itmay reflect an alloimmune diseasecaused by donor-specific anti-HLAAbs.60,61

The risk of recurrence is highest dur-ing the first year after transplantation,with cases detected as early as 1week aftersurgery.62 A second wave of recurrenceoccurs after 4–5 years, possibly due totapering of transplant IS. About onethird of patients with recurrent MNhave no progression and do not requireadditional IS.58 The remainder exhibitsadvancing disease with a high risk ofgraft loss. In several recent series,58,62,63

treatment with rituximab achieved a highrate of clinical response, even attendedby histologic resolution. Clinical param-eters do not predict which patients willdevelop recurrent disease. In addition,histologic findings correlate poorlywith clinical manifestations,58 possiblyreflecting the superimposed effect ofmaintenance IS, and should not beused alone to guide therapy.

Recurrence Monitoring with PLA2RAbAlthough several case series reported thathigh PLA2RAb titers at the time of trans-plantation strongly predicted subse-quent recurrence,62–64 others foundonly a low positive predictive value.60,65

There are several possible explanationsfor the inconsistent recurrence in pa-tients with positive PLA2R Ab at thetime of transplantation. The inductiontherapy and transplant IS may be suffi-cient to induce immunologic remission.Furthermore, the PLA2R epitopes of thetransplant may differ from those of thenative kidney andmay not be recognizedby the Ab. Finally, a subclinical recur-rence with low-grade proteinuria maybe masked by treatment with angioten-sin converting enzyme inhibitors or cal-cineurin inhibitors. Conversely, severalseries show a high recurrence rate in pa-tients with negative PLA2R Ab at thetime of transplantation.58,64 Obviously,some of these patients may have non-PLA2R–associated MN. Performing aPLA2R antigen staining on archived na-tive biopsies addresses this possibility.Additionally, recurrences detected by

Table 2. Traditional assessment of treatment response

Complete remission Proteinuria ,0.3 g/24 hPartial remission Proteinuria .50% reduction from baseline and $0.3 and ,3.5 g/24 hNo remission Proteinuria ,50% decrease from baseline level or $3.5 g/24 hRelapse Recurrence of proteinuria $3.5 g/24 hESRD eGFR,15 ml/min per 1.73 m2 or requirement of RRT

Figure6. Therapeutic algorithm.Patientswith apromptand robust immunologic responsemay receive shorter than usual courses of IS. It is important to recognize that, for not onlyrituximab67 but also, cyclophosphamide,68 the stoppage of such therapies leaves sus-tained effects on B cell depletion for a variable period of time. A conversion to an alter-native therapy should be considered in thosewho do not show a significant reduction in Abtiters. Patients with high baseline PLA2R Ab may require a longer duration of therapy toachieve immunologic remission and may need to be treated with more intensive andprolonged IS, possibly including plasma exchange.



protocol biopsies in the absence of overtproteinuria may reflect low levels of Abthat are below the threshold of detectionby serologic tests.

In patients with confirmed PLA2R-associated MN, serial monitoring of theAb titer is informative, because persistenceor reappearance of PLA2R Ab is tightlyassociated with recurrent disease.62,64,65

Finally, PLA2R Ab staining and PLA2Rantigen staining are useful in differentiat-ing recurrentMN from de novoMNwhenthe etiology of the native kidney disease isunknown, because they are invariablynegative in de novoMN.60,61,66

Recurrence Monitoring withTHSD7A AbPreliminary data suggest that, in patientswith THSD7A-associated MN, highTHSD7A Ab titers at the time of trans-plantation are associated with recurrentdisease.3

A Proposed Post-TransplantAlgorithmMN in the native kidney should be cate-gorized as PLA2R or non-PLA2R associ-ated, if necessary by performing PLA2Rantigen staining on archived native biop-sies. In patients with PLA2R-associatedMN and high pretransplant Ab levels,preemptive rituximab therapy beforetransplantation may be considered. Indeceased donor transplantation withhigh Ab levels at the time of transplan-tation, aggressive induction therapy andmore intense maintenance IS may berequired. Serial PLA2R Ab levels (bi-monthly in the first year after transplan-tation, yearly thereafter, and wheneverproteinuria increases) may guide the de-cision to administer rituximab.

CONCLUSION

Traditionally, the approach to MN is onthe basis of conventional indices of renaldisease, namely proteinuria and serumcreatinine. However, proteinuria doesnot always accurately reflect disease ac-tivity. A change in proteinuria typicallylags several months behind a change inimmunologic activity. Additionally, pro-

teinuria may reflect irreversible damage tothe glomerular filtration barrier in the ab-sence of active disease. The discovery ofPLA2R and THSD7A as target antigensprovidesnewdiagnostic tools that comple-ment and refine existing ones. A growingbody of evidence has documented, andconvincingly so, that PLA2RAb titer tightlycorrelates with disease activity. BecauseTHSD7Awas only recently discovered asa target antigen in MN, there is relativelylimited evidence supporting the associa-tion of THSD7A Ab with disease activity.However, there is an emerging sense thatthe association is analogous to what is de-scribed for PLA2R Ab and disease activity.

A change from a proteinuria-basedapproach to a serology-based approachoffers two major advantages. First, ther-apeutic decisions may be made moreswiftly, because Ab levels provide aprompt and reliable readout on immu-nologic status. Second, therapeutic deci-sions can be mademore accurately whenproteinuria and Ab levels are discordant.Specifically, persistent proteinuria in theface of low Ab levels may be more easilyidentified as resulting fromchronic dam-age, whereas highAb levels in the absenceof clinical symptomsmay portend an im-pending relapse.

We propose that a serology-based in-dividualized approach toMNwill increasediagnostic and prognostic accuracy, limitunnecessary exposure to IS, optimize effi-cacyof treatment, andminimize theriskorseverity of recurrent disease in allotrans-plants. A randomized, controlled trialcomparing the serology-based with thetraditional approach is required to verifythat our proposals are valid, safe, effective,and applicable in clinical practice.

DISCLOSURESNone.

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