drug-induced glomerular disease: immune...

Drug-Induced Glomerular Disease:Immune-Mediated Injury

Jonathan J. Hogan,* Glen S. Markowitz,† and Jai Radhakrishnan‡

AbstractDrug-induced autoimmune disease was initially described decades ago, with reports of vasculitis and a lupus-likesyndrome in patients taking hydralazine, procainamide, and sulfadiazine. Over the years, multiple other agentshave been linked to immune-mediated glomerular disease, often with associated autoantibody formation.Certain clinical and laboratory features may distinguish these entities from their idiopathic counterparts, andmaking this distinction is important in the diagnosis and management of these patients. Here, drug-induced,ANCA-associated vasculitis, drug-induced lupus, and drug-associated membranous nephropathy are reviewed.

Clin J Am Soc Nephrol 10: 1300–1310, 2015. doi: 10.2215/CJN.01910215

IntroductionExposure to certain drugs can elicit an immune re-sponse that results in the generation of autoantibodiesand clinical autoimmune disease, including immunecomplex or pauci-immune GN. Awareness of theseassociations by clinicians is important in discerningdrug-associated syndromes from their primarycounterparts, a distinction that may affect prognosisand treatment. These entities may also lend insight intothe underlying pathogenesis of primary autoimmuneglomerular disease. Here, we review drug-induced,ANCA-associated vasculitis (AAV), drug-induced lu-pus (DIL), and drug-associated membranous nephrop-athy (MN).

Drug-Induced AAVHistory and Clinical Presentation

Reports emerged linking drugs to vasculitis as earlyas the 1940s. This hypothesis was strengthened afterthe discovery of ANCAs and their target antigensproteinase 3 (PR3) and myeloperoxidase (MPO) in the1980s, with case series of patients who were ANCApositive and exposed to medications, such as hydral-azine and propylthiouracil (PTU); some developedvasculitis (1–4).

Choi et al. (5) conducted the largest retrospectiveanalysis of drug-associated AAV in 250 patients withMPO-positive AAV. The 30 patients with the highestanti-MPO antibody titers were reviewed for the use of11 candidate medications; 60% (18 of 30) of patientshad been exposed to one of these medications (hydral-azine, n510; PTU, n53; penicillamine, n52; allopuri-nol, n52; sulfasalazine, n51), and nine of 10 patientswith hydralazine AAV had evidence of renal involve-ment, with five exhibiting pauci-immune necrotizingGN on kidney biopsy. Four of the remaining eight pa-tients also had renal involvement (one patient each forPTU, penicillamine, allopurinol, and sulfasalazine).

Lung involvement (manifesting as pulmonary hemor-rhage/hemoptysis, hemothorax, radiographic infil-trates or nodules, or lung biopsy–proven AAV) wasmore common in 12 patients without detectable drugexposure (83% versus 38% with hydralazine/PTU ex-posure; P,0.05), but the frequencies of other clinicalmanifestations, death, and dialysis dependence werenot different between groups.The presence of additional autoantibodies in pa-

tients with drug-associated AAV was also noted; nineof 10 patients on hydralazine, all three patients on PTU,and four of five patients on penicillamine/allopurinol/sulfasalazine also had detectable antibodies to elastaseor lactoferrin (other antigens for perinuclear ANCA[p-ANCA]). No patientwas positive for anti-PR3ANCA.Both patients with culprit drug exposure (16 of 18) andnonexposure (eight of 12)were often antinuclear antibody(ANA) positive, but positivity for antidouble–strandedDNA antibodies (dsDNAs) was uncommon (four of 30).On the basis of this report and others, drug-associatedAAV should be considered in patients with a history ofdrug exposure, high-titer anti-MPO antibodies, and thepresence of other autoantibodies. Table 1 lists drugsmost commonly associated with AAV.

Renal HistologyKidney biopsies from patients with drug AAV ex-

hibit necrotizing and crescentic GN (Figure 1) that ispauci-immune by immunofluorescence. Although twostudies found less severe histologic findings in Chinesepatients with PTU AAV versus primary AAV (6,7),these differences have not otherwise been reported.The histologic classification scheme used in idiopathicAAV to predict clinical prognosis (8) has not beenvalidated in drug-associated AAV.

TreatmentNo trials have been conducted in the treatment of drug-

associated AAV. In mild cases, stopping the offending

*Department ofMedicine, Division ofNephrology, Hospitalof the University ofPennsylvania,Philadelphia,Pennsylvania; and†Department ofPathology and‡Division ofNephrology,Department ofMedicine, ColumbiaUniversity MedicalCenter, New York,New York

Correspondence:Dr. Jonathan J. Hogan,Hospital of theUniversity ofPennsylvania,Division ofNephrology,3400 Spruce Street,1 Founders,Philadelphia,PA 19104. Email:[email protected]

www.cjasn.org Vol 10 July, 20151300 Copyright © 2015 by the American Society of Nephrology

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drug may lead to resolution of AAV. However, in severecases, particularly with pulmonary or renal involvement,aggressive treatment with immunosuppression regimensused in idiopathic AAV (9,10) (corticosteroids with cyclo-phosphamide or rituximab and plasma exchange for pul-monary hemorrhage and rapidly progressive GN) shouldbe considered. Importantly, patients should be educatedabout future drug avoidance, with the culprit drug addedas an allergen in the patient’s medical record. Other con-troversial aspects in managing drug-associated AAV in-clude using a shorter duration of induction therapy andforegoing maintenance immunosuppression.

Drugs Associated with AAVCocaine- and Levamisole-Associated Vasculitis. Multiple

reports describe the development of vasculitis in cocaineusers, including cutaneous vasculitis, cerebral vasculitis(11), and cocaine-induced midline destructive lesions (12).Recently, the adulterant levamisole has been implicatedas a culprit in cocaine-associated AAV.Levamisole has been used in humans for pediatric ne-

phrotic syndrome (NS), colon cancer, inflammatory boweldisease, and rheumatoid arthritis (RA). Reports exist de-scribing cutaneous vasculitis (13,14) and the presence ofautoantibodies, including ANCAs (15,16), in patients ex-posed to levamisole. Levamisole was withdrawn from themarket in the United States in 2000 because of cases oftreatment-associated agranulocytosis.

Levamisole has been detected with increased frequencyin the illicit cocaine supply entering the United States andEurope over the last decade (17,18), with a 2011 Drug En-forcement Agency report noting contamination in 82% ofthe United States supply. Levamisole shares similar phys-ical properties (appearance, smell, and taste) with cocaine,and it may mimic or potentiate the euphoric effects of co-caine through sympathetic nervous system stimulation.One hypothesis is that the availability of levamisole inSouth America is because of its veterinary use as an anti-helminth agent.There is a temporal association between the rise in the

number of patients with cocaine AAV and the detection oflevamisole in the United States cocaine supply. In 2009,cases emerged of cocaine users who presented with agran-ulocytosis (19) followed by AAV with characteristic skinfindings of small- (palpable purpura) and medium-vessel(retiform purpura) vasculitis (Figure 2). Neutropenia oc-curred in some patients with cocaine AAV, and levamisolewas detected in some patients (20).McGrath et al. (21) describe the largest case series of

levamisole-associated AAV. Of 327 patients with newlypositive ANCA titers between 2009 and 2010, 30 had evi-dence of active cocaine use by report or toxicology. Onpresentation, 83% had arthralgias, 61% had skin manifes-tations, 44% had ear/nose/throat involvement, 44% hadevidence of renal involvement (defined by abnormal urinedipstick or urine microscopy), 28% were neutropenic, and

Table 1. Drugs commonly implicated in ANCA-associated vasculitis

Drug Evidence Renal Involvement Comments

Cocaine andlevamisole

Multiple case series andcase reports

44%a Skin manifestations in 61%a

Neutropenia in 28%a

Hydralazine Case series and casereports

80%–90%b Combined pulmonary-renalsyndrome is rare (15 patientsto date)

Lupus-like syndrome is commonAntithyroidmedications

PTU: multiple case seriesand case reports

May be common Animal models also supportassociation with PTU

Carbimazole andmethimazole: casereports

Minocycline Small case series andcase reports

No reported cases of renalinvolvement with small-vessel vasculitis

Conflicting data on ANCAseroconversion with minocyclineuse (45,46)

PAN with p-ANCApositivity and renalinvolvement reported

Allopurinol Case reports Reported Pulmonary-renal syndrome rarelyreported

Penicillamine Case reports Reported No seroconversion noted in analysisof scleroderma trial (46)

Sulfasalazine Case reports Reported Pulmonary-renal syndrome alsoreported

No seroconversion noted in analysisof the CSSRD Trial (46)

PTU, propylthiouracil; PAN, polyarteritis nodosa; p-ANCA, perinuclear ANCA; CSSRD, Cooperative Systematic Studies of theRheumatic Diseases.aData from the largest case series of cocaine- and levamisole-associated, ANCA-associated vasculitis (21).bData from the largest series of hydralazine-associated, ANCA-associated vasculitis (5,38).

Clin J Am Soc Nephrol 10: 1300–1310, July, 2015 Drug-Induced, Immune-Mediated GN, Hogan et al. 1301

17% had pulmonary hemorrhage. No patient had pulmonary-renal syndrome. Two patients had severe AKI, one ofwhom underwent a kidney biopsy showing pauci-immunecrescentic GN. Both of these patients were left with signif-icant renal impairment, despite immunosuppression.

Serologically, all patients were anti-MPO positive, andone half were anti-PR3 ANCA positive. Consistent withearlier observations in drug-associated AAV (5), patientswith cocaine-associated AAV had higher anti-MPO levels(15 times) than patients with idiopathic AAV over the sameperiod (range 51075–7988 versus median 5112; P,0.01),and many patients had additional abnormal serologies(ANA positive, 14 of 17; low C3 and/or C4, seven of 11;anti-dsDNA antibody positive, three of nine; positive lupusanticoagulant, six of nine). During the same time period, 15of 21 new patients with AAV that were dual-ANCA posi-tive (anti-PR3 and anti-MPO) were attributed to cocaine.The mechanism of levamisole-associated AAV is unclear.HLA B27 positivity has been shown to increase the risk oflevamisole-associated agranulocytosis (22,23), but its asso-ciation with AAV has not been explored.Treatment has focused on cessation of cocaine use and

the use of immunosuppression in severe cases. However,cocaine’s widespread use and addictive nature present aunique challenge. Health care providers should have ahigh level of suspicion for cocaine/levamisole AAV in pa-tients with high-titer anti-MPO ANCA, coexistent MPOand PR3 ANCA, other autoimmune serologies, leukopenia,severe cutaneous lesions, and recurrent AAV episodes.AntithyroidDrugs. Reports emerged in the 1990s of AAV,

somewith crescentic/pauci-immune GN, in patients treatedwith PTU, carbimazole, and/or methimazole for hyperthy-roidism (4,24–28). Gunton et al. (29) then explored the linkbetween antithyroid drugs and ANCAs, finding that onlyone of 10 newly diagnosed patients developed ANCAs(atypical cytoplasmic ANCA and high anti-MPO titer) 8months after starting carbimazole in contrast to eight of30 (27%) long-term patients. Patients who were ANCA pos-itive were mostly p-ANCA/anti-MPO antibody positive,on PTU (seven of eight), and had a longer mean drug ex-posure (8.9 versus 2.8 years). Four of these patients hadpossible vasculitis symptoms that resolved after stoppingthe medications, although renal disease was not specificallymentioned. Five of eight patients became ANCA negativewithin 6 months of stopping antithyroid therapy. Guntonet al. (29) concluded that ANCA positivity associated withlong-term use of antithyroid medications.A cross-sectional analysis of 207 patients with hyperthy-

roidism in The Netherlands found that exposure to anti-thyroid medication (PTU, methimazole, and carbimazole)was associated with an 11.8 times higher odds (95% con-fidence interval, 1.5 to 93.3) of developing a positive ANCAserology (p-ANCA, cytoplasmic ANCA, or atypical p-ANCAon immunofluorescence or ELISA positive for anti-MPO,PR3, or human lactoferrin antibody) versus nonexposure(30); four of 13 patients with positive ANCA serologies hadclinical signs or symptoms of vasculitis, three of whom hadkidney biopsies showing necrotizing and crescentic GN.However, the association between antithyroid medicationsand development of a positive ANCA serology was nolonger observed when patients with only anti–human lacto-ferrin antibody (a nonpathogenic ANCA) were excluded,and ANCA positivity was not related to any individual an-tithyroid drug or treatment duration. A second study byAfeltra et al. (31) detected a positive ANCA in 29% (six of21) of patients with Graves Disease not being treated withPTU versus 9% (one of 11) of patients with Hashimotos

Figure 2. | Digital cutaneous vasculitis of a patient with levamisole-associated, ANCA-associated vasculitis. Reprinted from Joan VonFeldt and Robert Michelleti, with permission.

Figure 1. | A glomerulus from a patient who used cocaine thatcontained levamisole and presented with rapidly progressive GNand high-titer anti-myeloperoxidase ANCA. The glomerulus exhibitsfibrinoid necrosis, multifocal rupture of the glomerular basementmembrane, and an overlying, circumferential cellular crescent. Jonesmethenamine silver, 3400.

1302 Clinical Journal of the American Society of Nephrology

thryoiditis and zero of 20 controls. These two studies sup-port the hypothesis that the risk for a positive ANCA serol-ogy may be linked to underlying autoimmunity rather thandrug exposure.The pathogenesis of drug AAV with these medications is

poorly understood. One study showed a higher reactivityof sera in patients with PTU AAV against specific MPOfragments versus both patients with idiopathic AAV andpatients with PTU-associated anti-MPO antibodies withoutclinical vasculitis (32). Other hypotheses include (1) PTUand/or its metabolites accumulate in neutrophils and bindto MPO, altering its configuration and promoting auto-antibody formation (29,33–35), (2) PTU oxidization in thepresence of activated neutrophils creates reactive drugmetabolites that stimulate ANCA production (30,36), and(3) PTU decreases the degradation of neutrophil extracel-lular traps, resulting in autoimmunity (37).Hydralazine. Evidence for hydralazine-associated vascu-

litis dates to the pre-ANCA era, including rapidly progres-sive GN. A 2009 review of the literature found 68 hydralazinevasculitis reports (mean duration of drug exposure 54.7years; mean dose 5142 mg/d) (38). Similar to the findingsby Choi et al. (5), kidney disease was common on presen-tation (81%), and patients had additional serologic evi-dence of an autoimmune process (96% ANA positive,26% anti-dsDNA antibody positive, and 44% hypocomple-mentemia). Combined pulmonary-renal syndrome withhydralazine-associated AAV is rare, with only 15 suspectedcases in the literature (39–42). Given the overlap in the clin-ical presentation of hydralazine-associated SLE and AAV,both diagnoses should be considered.Hypotheses for the mechanism of hydralazine-associated

AAV include (1) neutrophil apoptosis in response to hydral-azine MPO binding, resulting in the production of multipleautoantibodies (38), (2) increased expression of neutrophilautoantigens through hydralazine-induced reversal of epi-genic silencing of MPO and PR3, and (3) a break in toler-ance in slow versus fast acetylators of hydralazine (43).Other Drugs. Initial reports linked minocycline to AAV

(44), but subsequent data on this association are conflicting.A cross-sectional study in patients of dermatology foundANCA positivity in 12 of 174 (7%) of patients with past/current minocycline use compared with zero of 71 patientswithout exposure (45). However, Choi et al. (46) found thatno patient developed a positive ANCA after 48 weeks ofminocycline in a smaller RA cohort. Polyarteritis nodosawith p-ANCA positivity, sometimes with renal involvement,has also been reported in patients exposed to minocycline(47,48). Fifteen patients with nonpolyarteritis nodosa mino-cycline AAV have been reported to date, but none had renalinvolvement (47).Exposures to penicillamine (n52), sulfasalazine (n51),

and allopurinol (n52) were noted in patients with highanti-MPO titers in the series by Choi et al. (5). However,in a second study, Choi et al. (46) found no ANCA sero-conversions in patients given high- or low-dose penicilla-mine for scleroderma or sulfasalazine for rheumatologicdiseases. Allopurinol-associated vasculitis has been notedin case reports (49), but reports of serology-positive AAVare rare (50).The association between the use of TNF-a inhibitors and

AAV is not clear. A French survey–based registry of TNF-

a inhibitor AAV found it in 39 of 1200 patients, five ofwhom were ANCA positive (51). Another prospective se-ries of patients with ankylosing spondylitis did not show asignificant increase in ANCA seroconversion in treatedpatients (52). Six patients with TNF-a inhibitor AAVhave been reported to date (53,54).Case reports exist (some with renal involvement) for IFN

AAV during treatment for hepatitis C (55,56). This is achallenging diagnosis, because autoantibodies (includingANCAs) may be seen with hepatitis C infection (commonlyanti-PR3) (57); also, the presentation of AAV may overlapclinically with cryoglobulinemic vasculitis. Cutaneous vas-culitis has been described after treatment with granulocytefactors and GM-CSFs (58,59), but ANCA titers were notchecked in most patients, and renal disease has not beendescribed. Both isoniazid and rifampin have been implicatedas causes of vasculitis in case reports (60,61), but the associ-ation between these drugs and AAV is confounded by stud-ies that have shown a high prevalence of positive ANCAserologies in patients with tuberculosis (62). Evidence for theassociation of other medications and AAV is limited to iso-lated case reports (63–65).

DILEpidemiology, Clinical Presentation, and PathogenesisSince the first description of lupus in 1945 with sulfadi-

azine therapy (66), many drugs have been associated withthe production of autoantibodies, but true DIL is uncom-mon. DIL may be limited to the skin or resemble SLE.Although no prospective studies exist in DIL, it is estimatedthat there are 15,000–30,000 patients with DIL annually (67).Previously, the drugs most commonly associated with DILwere hydralazine and procainamide, with incidences as highas 5%–8% and 20%, respectively, during the first year oftherapy (68). There has been a reduction in DIL in parallelwith decreased use of these agents (69). However, the newerbiologics (e.g., anti–TNF-a therapy) have been found tocarry a risk for DIL, which was reported to be 0.1% in aregistry study (70). Table 2 lists the most common drugsreported to be associated with lupus-like disease. Althoughherbal compounds, such as L-canavanine in alfalfa supple-ments and Echinacea, have been implicated in causing lu-pus, the data in humans are sparse (71,72).DIL has only a minor increase in preponderance in

women and tends to occur in older individuals comparedwith idiopathic SLE. Systemic symptoms, including fever,anorexia, weight loss, and arthralgia, are common. Skinmanifestations (including macular, maculopapular, urti-carial, or vasculitic rashes) are less common than in classicSLE. Although arthritis, serositis, and hepatosplenomegalymay occur, major organ involvement is rare (67,73). GN isuncommon but has been reported with hydralazine (74),sulfasalazine (75), PTU (76), penicillamine (77), and anti–TNF-a therapy (78).Serologic abnormalities in procainamide and hydralazine

DIL are similar but share notable differences from idio-pathic SLE. Antihistone antibodies are common in DIL,with (H2A-H2B)-DNA subnucleosome being the predom-inant antigen in procainamide DIL (79) and H1 and theH3-H4 complex being the predominant antigens in hydral-azine DIL (80). Anti-dsDNA antibodies have been observed


in patients with TNF-a inhibitor DIL (81) but are rare inprocainamide and hydralazine DIL (68). The serologic pro-file of minocycline DIL is also different from other DIL withthe occurrence of positive ANA, anti-dsDNA antibodies,and p-ANCA (82). Complement levels are variably reducedin DIL, and hypocomplementemia is seen more commonlywith quinidine and TNF-a inhibitors (67,69). The clinical andserologic manifestations of DIL differ somewhat betweendrugs as discussed below and noted in Table 3.One clue to the presence of drug-induced autoimmunity

is the presence of multiple additional abnormal serologies(e.g., the presence of p-ANCA antibodies with multiple spe-cificities along with antiphospholipid antibodies and antihis-tone antibodies) (83).DIL is a type B (hypersensitivity) reaction. Research on

DIL pathogenesis has focused on drug-specific generationof autoimmunity and predisposing factors in affected pa-tients, mechanisms that are poorly understood and likelydrug specific. Jiang et al. (36) showed that activated neutro-phils convert multiple DIL agents (including procainamide

and hydralazine) into cytotoxic products in vitro through anMPO-dependent pathway. Several mechanisms have beenproposed to explain the production of autoantibodies inDIL, including disruption of central T cell tolerance by cul-prit drug metabolites, leading to the production of reactive Tcells that lead to a peripheral autoantibody response (73). AT cell response may also be provoked by drugs or theiroxidative metabolites (84). Unlike in SLE, the clearance ofcirculating immune complexes by the reticuloendothelialsystem seems to be intact in DIL. The antibodies in DILare true autoantibodies and not antibodies to drug products(73). Patients with slow acetylation phenotypes may be pre-disposed to certain drug-induced etiologies of DIL. The ev-idence for drug-specific DIL is presented below.

DiagnosisAlthough no firm criteria exist, some works (67,85) have

proposed diagnostic guidelines for DIL: (1) sufficient (atleast 1 month) and continuing exposure to a specific drug,(2) at least one symptom compatible with SLE (such as

Table 2. Drugs and risk for developing drug-induced lupus

Drug CategoryRisk for Drug-Induced Lupus

High Moderate Low Very Low

Antiarrhythmics Procainamide Quinidine Disopyramide, propafenone,amiodarone

Antihypertensives Hydralazine Methyldopa, captopril,acebutolol

Enalapril, lisinopril,clonidine, atenolol, labetalol,pindolol, minoxidil, prazosin

Antipsychotics Chlorpromazine Phenelzine, chlorprothixene, lithiumAntibiotics Isoniazid, minocycline Nalidixic acid, sulfamethoxazole,

quinineAnticonvulsants Carbamazepine Clobazam, phenytoin, trimethadione,

primidone, ethosuximide, valproicacid

Antithyroid PropylthiouracilDiuretics Chlorthalidone, hydrochlorothiazideBiologics TNF-a inhibitors IFN-aMiscellaneous Statins, levodopa, aminoglutethimide,

timolol drops, ticlodipine

Modified from ref. 73.

Table 3. Comparison of clinical and laboratory features of three drugs associated with drug-induced lupus

Drug Clinical Features Laboratory Features Positive Antibody Tests

Hydralazine Rash, fever, myalgias,pleuritis, polyarthritisnephritis ,10%

Anemia, leukopenia ANA, anti-dsDNA, ANCA,antihistone

Procainamide Polyarthritis, polyarthralgiasserositis nephritis ,10%

Anemia Anti-dsDNA, antihistone,anticardiolipin

TNF-ainhibitors

Systemic symptomspredominant (nephritisin 7%); skin manifestationsdominate

Thrombocytopenia,hypocomplementemia

ANA, anti-dsDNA,antinucleosome, anticardiolipin

ANA, antinuclear antibody; dsDNA, double-stranded DNA antibody.


arthralgia, myalgia, malaise, fever, serositis, and/or rash),(3) no history suggestive of SLE before starting the drug,and (4) resolution of symptoms within weeks (sometimesmonths) after discontinuation of the putative offendingagent (67). The latter observation is critical to separateDIL from drug exacerbation or unmasking of SLE, wherethe clinical symptoms persist, despite stopping the drug. Itis important to note that there is no characteristic syn-drome associated with a particular drug. Thus, placingheavy reliance on the presence/absence of organs involvedand specific antibody patterns is not recommended.

Treatment and PrognosisThere are few data and no randomized trials or guide-

lines for the treatment of DIL. The first step is to withdrawthe offending agent. Symptoms typically resolve in days toweeks, although serologic abnormalities may take monthsto resolve. If disease persists, both antimalarials and cor-ticosteroids have been used for symptoms, such as sero-sitis, and nonsteroidal anti-inflammatory drugs (NSAIDs)have been used for arthritis. The involvement of majororgans (especially kidneys, brain, lungs, and heart) re-quires escalation of immunosuppressive therapy, such asin SLE, with high-dose corticosteroids, antimetabolites,or alkylating agents (86). The prognosis for recovery isgood, except when severe major organ involvement oc-curs. Significant organ damage and death have been re-ported under these circumstances, especially with TNF-ainhibitors (87).

Drugs Associated with DILProcainamide. DIL is most closely associated with pro-

cainamide; 80%–90% of patients develop a positive ANAover 2 years of therapy, and approximately 20%–30% de-velop DIL. Middle-aged men are most commonly affected,likely because of increased prescription in this population.Presentation with pulmonary symptoms and serositis iscommon, whereas arthritis and major organ involvement(including the kidney) are rare (69,88).Although the exact mechanism of procainamide DIL is

unclear, in a small study of 20 patients receiving chronicprocainamide therapy, patients who were slow acetylatorsdeveloped antinuclear antibodies sooner (2.9 months) thanfast acetylators (7.3 months) (89). Procainamide was alsofound to be a potent T cell activator through a hypome-thylation pathway in mice, leading to autoreactivity andautoimmunity (90).Hydralazine. Renal involvement is uncommon in hydral-

azine DIL. In one case series, hydralazine DIL occurred in14 of 281 (5%) patients. Six patients had evidence of renalinvolvement. These six patients were all women, were taking50–300 mg/d hydralazine for 0.5–7 years, and commonlyhad positive ANA (100%), anti-dsDNA antibody (66%),and hypocomplementemia (50%). All patients were slowacetylators, and four had HLA-DR4 genotype. The patientsimproved after stopping hydralazine and treatment withimmunosuppressive therapy (74).Likewith procainamide, slow acetylators have an increased

risk of hydralazine DIL versus fast acetylators (91), and stud-ies have found an increased frequency of HLA-DR4 antigensin patients with hydralazine DIL (92). Another study showed

a higher prevalence of complement C4 null alleles in patientswith hydralazine DIL compared with the general population,implying higher lupus risk through activation of the classiccomplement pathway (93).Biologic Agents, Including TNF-a Inhibitors. Piga et al.

(87) found 26 patients with biologic-associated (includingTNF-a inhibitors) autoimmune renal disease through a cohortstudy analysis and literature review. On the basis of clinicalmanifestations and renal histology, patients were classifiedinto GN associated with systemic vasculitis (GNSV), GN inlupus-like syndrome, and isolated autoimmune renal dis-orders (IARDs). TNF-a inhibitors included etanercept (15patients; 51.7%), adalimumab (nine patients; 31.0%), andinfliximab (three patients; 10.3%). Other drugs associatedwith DIL included tocilizumab and abatacept (one patienteach; 3.4% each); 13 of 29 (44.8%) patients were classifiedwith IARD, 12 (41.3%) patients were classified with GNSV,and four (13.9%) patients were classified with GN in lupus-like syndrome. A worse outcome was associated withGNSV and continued use of biologics; end stage renal failurewas reported in three patients with GNSV and one patientwith IARD, and one death was reported in GNSV (87).In a review of 25 published case reports of TNF-a inhibitor

DIL (86), skin involvement occurred in 67% of patients, re-nal manifestations were noted in 7% of patients, anti-dsDNAantibodies were common (72%), and low complements oc-curred in 17%. Similarly, in a French Registry, cutaneousmanifestations alone were seen in 10 patients, and systemicsymptoms (without renal involvement) were found in 12 of866 patients (70). Symptoms began approximately 6 monthsafter drug initiation and took 1–4 months to resolve afterdiscontinuation (87).The proposed pathogenesis of anti–TNF-a DIL differs

from that of other agents. Low TNF-a levels lead to severelupus-like autoimmunity (94), and recombinant TNF-a de-lays the development of lupus (95) in the NZB mouse model.Several theories have been proposed to explain TNF-a in-hibitor DIL. In the cytokine shift paradigm, TNF-a block-ade suppresses production of Th1 cytokines, driving theimmune response toward Th2 cytokine production, IL-10,and IFN-a. The resulting cytokine imbalance results inautoantibody production and lupus manifestations(96,97). Furthermore, anti–TNF-a drugs may induce apo-ptosis in inflammatory cells, releasing autoantigens thatstimulate autoantibody formation (98,99). It is important tonote that anti–TNF-a agents are given to patients for thetreatment of autoimmune diseases, such as RA and inflam-matory bowel diseases, which themselves are associatedwith other autoimmune diseases, such as lupus. Improve-ment in lupus symptoms after stopping anti–TNF-a drugs isthe only way to determine whether the latter agent wasimplicated in causing DIL.

Drugs That Exacerbate SLEMany drugs have been associated with SLE exacerba-

tions, including antibiotics (penicillin), anticonvulsants(mesantoin), hormones, NSAIDs, sulfonamides, para-aminosalacylic acid, hydrochlorothiazide, and cimetidine. Itis of interest that patients with SLE are significantly moreprone to develop drug allergies, especially to antibiotics,such as sulfonamides, penicillin/cephalosporin, and eryth-romycin (100).


Drug-Induced MNEpidemiology, Pathogenesis, Histology, and TreatmentMN is the most common etiology of primary NS in white

adults (101). The majority of patients with MN have pri-mary disease, and most patients with primary MN haveautoantibodies directed against the phospholipase A2 re-ceptor (PLA2R) (102). In contrast, 25%–30% of patientshave secondary forms of disease (103,104). In a review ofnine published series on MN, 6.6% of patients representeddrug-induced disease (103). A more recent cohort identifieda drug-induced etiology in 14% of patients (104). Testing foranti-PLA2R antibodies should be performed on renal bio-psies or serum in patients with MN. On the basis of ourunderstanding, the finding of anti-PLA2R antibodies inglomeruli or serum strongly supports the diagnosis of pri-mary MN and excludes a secondary drug–induced form ofdisease.The pathogenesis of drug-induced MN (DIMN) likely

involves an immune response to a therapeutic agent or itsbyproduct. The most plausible mechanism is that cationicdrug–derived antigens traverse the glomerular basementmembrane (GBM), are planted at the subepithelial aspectof the GBM, and become bound in situ to circulating anti-bodies directed against these antigens. This mechanismunderlies the early-childhood MN that occurs in responseto cationic BSA present in cow’s milk (105).Pathologically, MN is defined by subepithelial immune

complex deposits and associated GBM alterations that in-clude intervening spike formation, overly neomembraneformation, and remodeling (Figure 3). Pathologic findingsdo not distinguish between primary MN and DIMN, high-lighting the importance of obtaining a detailed clinical his-tory regarding drug use.Treatment of DIMN begins with withdrawal of the cul-

prit drug. In the case of some therapeutic agents, such asgold salts, penicillamine, and bucillamine, proteinuriaand MN are so frequent that urine monitoring is required.With severe symptoms of NS and/or lack of improvementafter withdrawal, immunosuppressive therapy may bewarranted.

Drugs Associated with MNGold Therapy. Gold salts, including oral and parenteral

preparations, have been used in the treatment of RA formore than three quarters of a century, but recently, they havebeen largely replaced by safer, more efficacious agents. Themost common side effect of gold is proteinuria, which de-velops in 3%–7% of patients (106,107). Renal biopsy mostcommonly reveals stage 1 or 2 MN, indicating early detec-tion because of screening. After withdrawal, proteinuria re-solves in most patients (106,108). Experimental studies haveshown that gold inclusions mainly localize to proximaltubules, and the same is true in a rodent model of gold-induced MN, suggesting that gold targets tubular epithe-lia and leads to release of tubular antigens that cross-reactwith podocyte antigens, akin to the mechanism of Heymannnephritis (109,110).Penicillamine and Bucillamine. Similar to gold, peni-

cillamine and bucillamine are used to treat RA, proteinuriais the most frequent indication for discontinuing therapy,and the most common biopsy finding is MN stage 1 (111–113). Penicillamine has been used to treat RA for nearly

50 years, and the incidence of proteinuria may exceed 10%(111). Outcomes after penicillamine withdrawal are excel-lent, with complete resolution of proteinuria in the absenceof immunosuppression in 32 of 33 patients in one series(112).Bucillamine is a more recently developed antirheumatic

drug that is mainly used in Asia and differs from penicil-lamine by an additional sulfhydryl group. Similar to peni-cillamine, proteinuria resolves in nearly all patients afterwithdrawal (113). The mechanism by which penicillamineand bucillamine produce MN is unknown but may involvemodification of the immune response and/or hapten forma-tion.Mercury. Mercury exposure is associated with severe tox-

icity involving multiple organ systems, most notably thecentral nervous system. Sources of mercury include con-taminated foods (in particular, fish), dental amalgams, cos-metics, occupational exposures, and skin-lightening creams.Chronic mercury exposure is infrequently associated with NSand in most cases, MN (114). After discontinuation, remissionof proteinuria occurs in most patients (114). A recent reportdescribed two patients who developed DIMN after the useof skin creams that contained mercury (115). The absence ofanti-PLA2R antibodies in these two patients as well as thepreviously established rat model of mercury-induced MN(116) provide support for the association between mercuryand MN.Captopril. Captopril is an angiotensin-converting enzyme

inhibitor (ACE-I) that is commonly used to treat hyperten-sion and reduce proteinuria. Ironically, captopril seems tobe the only ACE-I associated with the development of NSand in most cases, biopsy findings of MN (117). This com-plication of therapy, which is seen in up to 1% of patients(118), has been attributed to a sulfhydryl group, which isunique to captopril among the ACE-Is but a feature that itshares in common with penicillamine and bucillamine(119). After discontinuation, significant reduction in pro-teinuria commonly occurs.

Figure 3. | A glomerulus from a patient who developed nephroticsyndromewhile receiving a nonsteroidal anti-inflammatory drug forarthritis. The glomerulus exhibits global thickening of the glomerularbasement with spike formation, which is characteristic of stage 2membranous changes. Jones methenamine silver, 3400.


NSAIDs. NSAIDs are widely used for their analgesic,antipyretic, and anti-inflammatory properties. NSAIDs in-hibit cyclooxygenase-1 (COX-1) andCOX-2, thereby blockingprostaglandin, prostacyclin, and thromboxane production.MN has been reported after the use of multiple classes ofNSAIDs with varying chemical structures, including pro-prionic acid derivatives (ketoprofen, fenoprofen, and ibu-profen), acetic acid derivatives (diclofenac, sulindac, andtolmetin), enolic acid derivatives (piroxicam), and selectiveCOX-2 inhibitors (etodolac and celecoxib) (120,121). The de-velopment of MN with these diverse agents suggests amechanism of DIMN that likely involves the common phar-macologic effects of NSAIDs on mediators of inflammation.Given the widespread use of NSAIDs, the incidence of

NSAID-associated MN is difficult to determine. A stringentcriterion for this diagnosis is the requirement for rapidremission after withdrawal. Radford et al. (120) examinedNSAID-associated MN over a 20-year period at the MayoClinic. Considering only patients with stage 1 or earlystage 2 MN, 29 of 125 patients were taking NSAIDs, and13 had a rapid remission after drug withdrawal, suggest-ing that NSAID-associated MN represented 10% of pa-tients with early MN.Additional Drug-Induced Etiologies of MN. There are

many published case reports describing an associationbetween MN and individual therapeutic agents as well assmall series describing DIMN after treatment with tio-pronin for cystinuria (122) or trimethadione, an anticonvul-sant (123).

DisclosuresNone.

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