Crescentic glomerulonephritis and eosinophil interstitial infiltrates 175

Crescentic glomerulonephritis and eosinophilicinterstitial infiltrates in a patient withhypereosinophilic syndrome

Paul Richardson, Gail Dickinson, Shirin Nash, Lee Hoffman, Richard Steingart, MichaelGermain

Divisions ofHematology/Oncology,Pulmonology andRenal Medicine, TuftsUniversity School ofMedicine, BaystateMedical Center,Springfield,Massachusetts, USADepartment ofMedicineP RichardsonG DickinsonL HoffmanR SteingartM GermainDepartment ofPathologyS Nash

Correspondence to PaulRichardson, MD,Department ofMedicalOncology, Dana-FarberCancer Institute, 44 BinneyStreet, Boston, MA 02115,USA

Accepted 27 October 1994

SummaryCrescentic glomerulonephritis withimmune complex deposition and acuteeosinophilic interstitial nephritis devel-oped in a patient with the hypereosino-philic syndrome. Acute renal failureensued but was rapidly reversed by high-dose oral prednisone. Confounding fac-tors and unusual findings are describedwith a review of recent literature. Thismode of presentation has not previouslybeen reported.

Keywords: immune-complex crescentic glomerulone-phritis, eosinophilic interstitial nephritis, hyper-eosinophilic syndrome, neuropathy, prednisone

Introduction

Eosinophilia can be associated with a widespectrum of organ dysfunction (box).' Patientswith an elevated eosinophil count persistentlygreater than 1.5 x 109/1 for a minimum of sixmonths who develop end-organ damage buthave no recognised underlying cause for theireosinophilia, can be considered to have theidiopathic hypereosinophilic syndrome (HES)." 3Many organs and organ systems may be

involved in HES (box).4 Acute renal failure andHES are associated only rarely and the rela-tionship is complex.5 We report crescenticglomerulonephritis, renal immune complexdeposits, interstitial nephritis, and prominentrenal eosinophilic infiltrates in a patient withHES in apparent symptomatic andhaematologic remission.

Case report

A 67-year-old woman presented in June 1990with symmetrical sensory polyneuropathy anda persistent peripheral eosinophil count over5 x 109/1. Eosinophil counts during the eightyears before presentation ranged from 0.2 to0.7 x 109/1.The patient had a seven-year history of

asthma which was asymptomatic at the timeand well controlled by theophylline prepara-tions and inhaled beta-agonists. She had alsobeen treated for sinusitis but there was nohistory of allergic rhinitis. Five yearspreviously she had developed infiltrating duc-tal carcinoma of the right breast, withoutaxillary lymph node involvement, which was

treated by modified radical mastectomy. Shehad been free of disease since. Two years priorto presentation, an 8 mm x 8 mm lung nodulewas found on routine chest radiograph. Com-puted tomography (CT) scan appearance wasconsistent with benign neural or connectivetissue tumour. The nodule remained stable andno tissue diagnosis was sought. In May 1989she presented with chest pain and a suben-docardial myocardial infarction was diagnosed.Echocardiogram showed inferior and posteriorhypokinesis with overall systolic function in thenormal range. Pulsed colour Doppler revealeda mitral valve inflow pattern consistent withmild diastolic dysfunction. A cardiac biopsywas not performed and she has had no furthercardiac symptoms.There were no known drug allergies that

might have contributed to the eosinophilia; shehad not received tryptophan at any time andthere was no clinical evidence of collagenvascular disease. Multiple screens of stool forova and parasites were negative. Serum IgE

Blood and tissue eosinophilia

Secondary to:* vasculitic syndromes* invasive parasitic infection* extrinsic allergic asthma* allergic rhinitis* pulmonary aspergillosis* certain collagen vascular diseases* skin conditions* neoplasia

Organ involvement in HES

Major:* heart* lungs* upper airways* liver* spleen* skin* nervous systemMinor:* kidneys* gastrointestinal tract* lymph nodes* eyes* muscles

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176 Richardson, Dickinson, Nash, et al

level was 619 mg/l (normal range: 12-240 mg/1). Tuberculosis screen, viral serology,antinuclear antibody, rheumatoid factor andantineutrophil cytoplasmic antibody werenegative. Her renal function and other serumchemistries were normal. Specifically, herserum creatinine was 71 limol/l with her bodyweight at 62 kg and a height of 151 cm.Bone marrow aspiration and biopsy demon-

strated marked eosinophilic hyperplasia withotherwise normal maturation and no evidenceof leukemia. Nerve conduction studies showedsensory polyneuropathy of axonal type charac-teristic of HES but no nerve biopsy was per-formed.A diagnosis of HES was made. The patient

received prednisone with resolution of herneuropathy and the eosinophil count fell tobelow 1 x 109/1. One year later, she relapsedwith recurrent neurologic symptoms andeosinophilia of 3.5 x 109/1. Therapy with hyd-roxyurea was begun but discontinued becauseof nausea and dyspepsia. Prednisone wasstarted in late June 1991 and stopped in Julywhen the neurologic symptoms disappearedand the eosinophil count decreased to0.8 x 109/1.

In early August, coliform cystitis developedwhich was first treated with ampicillin, thentrimethoprim and finally cleared byciprofloxacin. Routine screening of renal func-tion three weeks later detected renal impair-ment which progressed rapidly to acute renalfailure. At the time, the patient felt well and hadno complaints. She was normotensive andwithout rash, arthropathy, myopathy, bonytenderness, adenopathy or organomegaly.There was no evidence of peripheral vasculardisease, mass lesion in her left breast or recur-rent breast cancer in her right mastectomy scar.

Investigations revealed a peripheraleosinophil count of 0.499 x 109/1, an elevatederythrocyte sedimentation rate of 95,antinuclear antibody of 1:160, with negativeanti-ds DNA, anti-Sm, ribonucleoprotein, andrheumatoid factor. C3 and C4 were within thenormal range. Sinus X-rays were normal and arepeat antineutrophil cytoplasmic antibodywas negative. The antinuclear antibody was notconsidered significant given the low titre andthe lack ofsupporting evidence for lupus. Liverfunction tests were within normal limits.Serum immunoelectrophoresis was normal andhepatitis B surface antigen was negative. ChestX-ray showed normal heart size, no hilar ormediastinal enlargement and clear lung fieldswith no change in the appearance or size of theperipheral lung nodule noted on previousstudies. Urine analysis and microscopy demon-strated mixed cellular casts (white cells, redcells and renal tubular cells), 3 + protein,100-300 red cells, and 20-30 white cells (12%eosinophils by Hansel's stain). Serial urinecultures were negative. Spot urine protein:creatinine ratio was 2.0 (normal less than 1.5).A renal ultrasound was unremarkable.A renal biopsy was done and the specimens

were processed for light microscopy and elec-tron microscopy with immunofluorescencestudies. A total of 28 glomeruli were present on

two biopsies examined by light microscopy.Most glomeruli showed cellular or fibrocellularcrescents, segmental sclerosis and some globalsclerosis. The interstitium contained a dense,mixed inflammatory infiltrate with a markedpredominance of eosinophils. There was alsoextensive interstitial fibrosis with tubularatrophy (figure 1). Electron microscopy dem-onstrated marked thickening of the capillarybasement membranes with electron densedeposits both in mesangial and intramem-branous locations. Immunofluorescencerevealed IgG (+ +), IgA (+ to + +), IgM(+ +) and C3 (+ +) as focal and segmentalgranular deposits along the capillary basementmembranes and in the mesangium. IgE stain-ing was not done. Focal globular deposits offibrinogen were also present. The pathologywas reported as crescentic glomerulonephritiswith immune complex deposits and interstitialnephritis with abundant eosinophils.

Prednisone, 60 mg/day, was started and herrenal function improved (figure 2). The urinesediment became benign with only 2-4 redcells, 2-4 white cells and a trace of protein.Spot urine protein:creatinine ratio was 0.83.The eosinophil count fell to 0.1 x 109/1 and shehad no neurological symptoms. Prednisone wastapered off over 14 weeks and then stopped.At follow-up one year later, serum creatinine

was 10tLmol/l, spot urine protein: creatinineratio was 0.5, and urinalysis was normal. Herperipheral eosinophil count was 0.1 x 109/l andshe was clinically asymptomatic.

Discussion

Idiopathic HES is a heterogeneous group ofdisorders with prolonged eosinophilia and

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Crescentic glomerulonephritis and eosinophil interstitial infiltrates 177

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organ system dysfunction. In 55 patientsevaluated at the National Institute of Health,no cases of renal disease were seen.2 Casereports in the medical literature have describedmembranous glomerulonephritis, immune-complex glomerulonephritis, interstitial neph-ritis, and renal vasculitis.5'7 Acute renal failurefrom haemoglobinuria and Charcot-Leydencrystals has also been reported.8The immunopathogenesis of crescentic

glomerulonephritis is complex (see box).Churg- Strauss syndrome and polyarteritisnodosa are important considerations in thedifferential diagnosis of acute renal failure withcrescentic glomerulonephritis, interstitialnephritis, and a history of hypereosinophilia.This patient had no evidence of upper res-

piratory tract granulomatosis, pulmonaryinfiltrates, diffuse interstitial lung disease orcutaneous angiitis as is commonly seen in thesecauses of renal vasculitis.9"l0 There was a long-standing, very small pulmonary nodule, butthis had remained stable and was felt to bebenign and unrelated.Churg-Strauss syndrome is characterised

by three phases (see box).'1"2 This was not thepattern in our patient, although the seven-yearhistory of asthma was a confounding factor inthe diagnosis both in terms of Churg- Strausssyndrome vsHES and HES vs eosinophilia dueto asthma. The latter is a reflection of atopicactivity and mirrors the progress of the pul-monary process, usually from onset."3"14 Atpresentation, she did not have symptoms orsigns of acute asthma, lung function was stableand previous eosinophil counts were normal, sothis could not account for her syndrome.Similarly, Ghurg- Strauss syndrome could beruled out on the basis of the clinical featureswhich evolved subsequently.'2

Pathologic features seen by light microscopymay be similar in polyarteritis nodosa,Wegener's granulomatosis, or Churg-Strausssyndrome and may include granulomas with or

Immunopathogenesis of crescenticglomerulonephritis

Hypersensitivity: hypereosinophilic syndrome,allergic vasculitisDirect antibody mediated: Goodpasture'ssyndrome (via the anti-glomerular basementmembrane antibody)Immune complexformation: lupus,post-infectious, membranoproliferative,membranous, and IgA nephropathy.Cell mediated injury: idiopathic crescenticnephritis, antineutrophil cytoplasmic antibody-associated crescentic nephritis (either theanti-myeloperoxidase-type antibody inpolyarteritis nodosa and small vessel vasculitis,or the anti-pr3-type in Wegener'sgranulomatosis)

Churg-Strauss syndrome

Prodromal phase: atopic asthma, allergic rhinitisSecond phase: eosinophilic tissue infiltration,chronic pneumonia, gastroenteritis, LoefflerpictureVasculitic phase: skin rash, severe constitutionalsymptoms, mononeuritis multiplex, renaldisease (occasional)

without vasculitis.'5 While her renal biopsyshowed severe crescentic glomerulonephritis,and widespread glomerular sclerosis, the pro-minent eosinophilic interstitial infiltrates withextensive fibrosis and tubular atrophy are thedistinguishing feature. Marked eosinophilicinterstitial infiltrates would be unusual forpolyarteritis nodosa, Wegener's granulo-matosis or Churg-Strauss syndrome but aretypical oforgan involvement in HES.' Further-more, electromicroscopy and immunoflour-escence identified mesangial and intramem-branous immune complexes, which are notfound in polyarteritis nodosa, Wegener's gran-ulomatosis or Churg- Strauss syndrome.16"7The possibility that the onset and severity of

her renal disease was influenced by thepreceding antibiotic therapy was addressed.Ciprofloxacin and ampicillin rarely cause acuteinterstitial nephritis and trimethoprim in theabsence ofa sulfonamide is not recognised as anaetiologic agent.'8"'9 Drug-related acute inters-titial nephritis typically shows mixedinflammatory cell infiltrates likely to includesome neutrophils and eosinophils, togetherwith lymphocytes and plasma cells.20Eosinophils have commonly been described inbiopsies from methicillin-related cases but areless prominent in cases due to other agents.2'An allergic reaction to drug therapy is possiblebut cannot explain the severity ofthe crescenticglomerulonephritis, nor the markedly promi-nent eosinophilic interstitial infiltrate.The subendocardial infarction one year prior

to the diagnosis ofHES is of interest. In cardiacdisease associated with HES, the primary siteof damage is the endocardium.2' Echocardio-graphic findings in the heart affected by HES

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178 Richardson, Dickinson, Nash, et al

include increased left ventricular wall thicknessand impaired mitral valve leaflet motionsecondary to fibrosis of papillary muscles,chordae and valves.23 None of these featureswas described in our patient, plus theeosinophil count was normal at the time and shehas had no further cardiac symptoms or signs.Hence, the likelihood of the subendocardialinfarct being a prodrome of her HES wouldseem small but, in the absence of a tissuediagnosis, cardiac involvement cannot be ruledout with certainty.24Adenocarcinoma is associated with second-

ary eosinophilia,25 and the history of breastcancer five years prior to diagnosis might beconsidered contributory. However, she had noevidence of recurrent malignancy at the timeshe presented with HES. Furthermore, she wasover six years after mastectomy with no sugges-tion of relapse when her renal disease occurred.A causal role would be unlikely given theparaneoplastic mechanism of tumour-derivedeosinophilopoiesis.26 Further, crescenticglomerulonephritis and eosinophilic interstitialinfiltrates as paraneoplastic, renal, manifesta-tions of breast cancer have not been des-cribed27; the associated glomerulopathytypically seen being membranous glomeru-lonephritis.28

It is difficult to explain the eosinophilicinfiltration of the renal interstitium in light ofthe normal peripheral eosinophil count. Thisdiscordance confirms that other organ systeminvolvement may occur in the face of hae-

2matologic remission. Careful monitoring ofcardiac, pulmonary, neurologic, renal, and

liver function should be considered in patientswith HES who are asymptomatic and are inapparent remission.Immune complex deposition in the kidneys

is unusual in HES.8 Staining for IgE was notdone but renal deposition of IgE has beenassociated with secondary peripheral eosino-philia, immune complex glomerulonephritisand eosinophilic interstitial nephritis;'9therefore, it is possible that this immuno-globulin was involved in the process.

Cytotoxic drugs and plasma exchange havebeen recommended as first-line therapy inother causes of vasculitis and progressiveglomerulonephritis."0 The rapid, sustainedimprovement in renal function and decrease inproteinuria after a course of prednisone sug-gests that acute progressive glomerulonephritissecondary to HES may not require initial,aggressive treatment.

In conclusion, this patient represents, to thebest ofour knowledge, the first recorded case ofHES, eosinophilic interstitial nephritis, andcrescentic glomerulonephritis with immunecomplex deposits resulting in acute renalfailure rapidly resolved by steroid therapy. Ourreport illustrates the complexity surroundingthe diagnosis, management and complicationsof HES, and the importance of close follow-upof patients with this condition.

The authors are grateful toTammy Pham for her help inthe care of the patient and to Maureen Harbilas andMarla Scafuri for their help in the preparation of themanuscript.

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