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Glomerular Tip Lesion Associated With NonsteroidalAnti-Inflammatory Drug–Induced Nephrotic Syndrome

Inderpreet Sekhon, MD, Sandeep Munjal, MD, Byron Croker, MD, PhD, Richard J. Johnson, MD,and A. Ahsan Ejaz, MD

Glomerular tip lesion and its relation to different glomerular diseases is a subject of controversy. The therapeuticnd prognostic clinical implications of glomerular tip lesions are ambiguous. We present a case of glomerular tipesion associated with nonsteroidal anti-inflammatory drug–induced nephrotic syndrome that further complicateshis issue. To our knowledge, this is the first case report of glomerular tip lesion associated with nonsteroidalnti-inflammatory drug–induced nephrotic syndrome. Am J Kidney Dis 46:E55-E58.2005 by the National Kidney Foundation, Inc.

NDEX WORDS: Glomerular tip lesion; nonsteroidal anti-inflammatory drug (NSAID); minimal change disease; acute

nterstitial nephritis.

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ONSTEROIDAL anti-inflammatory drugs(NSAIDs) are used commonly because of

heir beneficial effects on various disease pro-esses. Despite their good patient safety record,ases of reversible and irreversible renal injury,ncluding minimal change disease, have been re-orted (Table 1).1-6 NSAID-induced minimalhange disease can be independent of dosage andan resolve spontaneously without medical interven-ion.7 Classic renal biopsy findings of patients withSAID-induced minimal change disease are theresence of normal-appearing glomeruli and evi-ence of tubulointerstitial inflammatory changesnder light microscopy.8 Glomerular tip lesion is aollection of intracapillary foam cells and markedacuolization of epithelial cells of the glomerularegment adjacent to the origin of the proximalubule.9,10 We present a hitherto unreported case oflomerular tip lesion associated with NSAID-nduced glomerular damage.

CASE REPORT

A 34-year-old African-American woman presented to herhysician with symptoms of sudden onset of lower-extrem-ty edema, facial puffiness, shortness of breath, abdominalightness, and a 15-lb weight gain during a 3-day period. Theatient had been taking numerous analgesic medications ondaily basis for chronic pain syndrome secondary to a motorehicle accident that she experienced 3 years ago. Her painedications included tramadol hydrochloride, 25 mg, 4

imes daily for the past 18 months; a combination of butalbi-al, 50 mg, acetaminophen, 325 mg, and caffeine, 40 mg,wice daily for the past 18 months; sumatriptan succinate, 25g, average of 10 tablets/mo for the past 36 months;

cetaminophen, 325 mg, 4 times daily for the past 12onths; oxycodone, 5 mg, twice daily for the past 12onths; and ibuprofen on an as-needed basis for the last 36

onths. Additionally, she started taking ibuprofen, 600 mg,

merican Journal of Kidney Diseases, Vol 46, No 4 (October), 200

wice daily regularly for the previous 2 to 3 weeks to controler pain symptoms.Physical examination showed the following significant

ndings: blood pressure, 160/90 mm Hg; heart rate, 72eats/min; respiratory rate, 18 breaths/min; weight, 76.8 kg;acial swelling; regular heart beats; lungs clear to ausculta-ion and percussion; and 4� lower-extremity edema. Labora-ory findings are listed in Table 2.

These laboratory test results had been in the normal rangemonths earlier. All medications were discontinued at initial

valuation by the primary care physician, and treatment withn angiotensin-converting enzyme inhibitor (lisinopril, 20g/d) and a diuretic (furosemide, 40 mg/d) were initiated.he patient presented to the renal clinic 2 weeks later withymptoms of persistent facial puffiness, lower-extremitydema, and dyspnea on exertion. Physical examination nowhowed blood pressure of 150/80 mm Hg, heart rate of 70eats/min, respiratory rate of 14 breaths/min, weight of 70g, facial swelling, clear lungs, and 2� lower-extremityitting edema. Laboratory findings are listed in Table 1.erological test results for hepatitis B and C, human immu-odeficiency virus, antineutrophil cytoplasmic antibody, andntinuclear antibody were negative. Renal ultrasound showedormal-sized kidneys without evidence of hydronephrosis.renal biopsy was recommended and performed.Multiple levels of hematoxylin and eosin, periodic acid–

chiff, and periodic acid–methenamine silver staining of

From the Division of Nephrology, Hypertension, andransplantation and Department of Pathology, University oflorida, Gainesville, FL.Received February 23, 2005; accepted in revised formay 31, 2005.Originally published online as doi:10.1053/j.ajkd.2005.05.034

n September 6, 2005.Address reprint requests to A. Ahsan Ejaz, MD, Division

f Nephrology, Hypertension, and Transplantation, Univer-ity of Florida, PO Box 100224, Gainesville, FL 32610-224. E-mail: ejazaa@medicine.ufl.edu© 2005 by the National Kidney Foundation, Inc.0272-6386/05/4604-0033$30.00/0

doi:10.1053/j.ajkd.2005.05.034

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enal biopsy tissue were evaluated (Fig 1A to D). Sectionsontained 17 glomeruli. There was no evidence of focal orlobal glomerular sclerosis, segmental sclerosis, mesangialxpansion, or crescents. Capillary walls were thin and gener-lly patent. A collection of intracapillary foam cells andarked vacuolization of epithelial cells of the glomerular

egment adjacent to the origin of the proximal tubule wereresent (Fig 1D, arrow) in 3 of 17 glomeruli, consistent withlomerular tip lesion. Tubular atrophy, interstitial fibrosis,nd evidence for chronic inflammation with few eosinophilsFig 1A, arrows point to eosinophils) were shown. Immuno-uorescence staining with immunoglobulin G (IgG), IgM,nd IgA; complement component 3 and 1q (C3 and C1q);nd albumin were unremarkable. Electron microscopyhowed endothelial swelling and foot-process retractionFig 2).

The patient presented for follow-up in the renal clinicfter the kidney biopsy, approximately 3 weeks after thenset of initial symptoms. Her blood pressure on presenta-ion was 120/60 mm Hg, weight had decreased to 69 kg, anderipheral edema and facial puffiness had resolved. Herreatinine level on follow-up was 0.8 mg/dL (71 �mol/L),nd 24-hour urine had protein of 26 mg/d. Urinalysis wasegative for protein. She had not received any immunosup-

Table 1. Manifestations of NSAID-InducedRenal Injury

GlomerularMinimal change disease1

Membranous nephropathy2,3

TubulointerstitialAcute tubulointerstitial nephritis4

Chronic tubulointerstitial nephritis4

Papillary necrosis5

Acute tubular necrosis6

Table 2. Pertinen

erum Sodium (mEq/L)Potassium (mEq/L)Chloride (mEq/L)Bicarbonate (mEq/L)Blood urea nitrogen (mg/dL)Creatinine (mg/dL)Glucose (mg/dL)Albumin (g/dL)Total cholesterol (mg/dL)Triglycerides (mg/dL)

rine Specific gravitypHProtein (mg)Urine protein-creatinine

NOTE. To convert serum sodium, potassium, bicarbonitrogen in mg/dL to mmol/L, multiply by 0.357; creatinine iultiply by 0.05551; albumin in g/dL to g/L, multiply by 10;

n mg/dL to mmol/L, multiply by 0.01129.

ressive treatment. The only treatment was discontinuationf all her pain medications (including ibuprofen), except forxycodone/acetaminophen (Percocet, Endo Pharmaceuti-als Inc, Chadds Ford, PA), and initiation of lisinopril, anngiotensin-converting enzyme inhibitor.

DISCUSSION

NSAIDs are important in the management inultiple disease processes, especially treatment

f rheumatologic disorders and various pain syn-romes. Side effects of NSAIDs consist of mostlyastrointestinal and renal impairment. NSAIDsxert their influence on renal hemodynamic, glo-erular, and tubulointerstitium by their effects

n prostaglandin synthesis11 and T-lymphocyteells.12-14 T Cells may be activated as a conse-uence of NSAID-induced preferential conver-ion of arachidonic acid to leukotrienes.15 Acti-ated T cells secrete cytokines that may causeodocyte injury and increased glomerular perme-bility. Our patient had a prolonged history ofSAID use, with a recent increase in ibuprofenosage and subsequent clinical symptoms andiochemical changes of nephrotic syndrome. Theramatic improvement in renal function afteriscontinuation of NSAID therapy is suggestivef its role in the pathogenesis of nephrotic syn-rome in this patient.The mild tubulointerstitial inflammation shown

n the renal biopsy specimen from our patient isot an uncommon accompaniment in NSAID-

ratory Findings

esentation After 2 Weeks After 3 Weeks

1 139 1394.6 3.8 3.90 102 1019 30 269 9 111.3 0.9 0.80 90 883.2 3.3 3.6001.023 1.015 1.0166.0 6.0 5.50 30 07.7 0.39 0.1

d chloride in mEq/L to mmol/L, multiply by 1; blood ureaL to �mol/L, multiply by 88.4; glucose in mg/dL to mmol/L,erol in mg/dL to mmol/L, multiply by 0.02586; triglycerides

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GLOMERULAR TIP LESION WITH NSAID e57

nduced glomerular damage.4 Typical systemicigns and symptoms associated with allergic in-erstitial nephritis are absent, possibly because ofnti-inflammatory effects of the drug. Rapid reso-ution of nephrotic syndrome has been reported.7

An interesting finding in the renal biopsypecimen is the presence of glomerular tipesion. Glomerular tip lesion is a collection ofntracapillary foam cells and marked vacuoliza-ion of epithelial cells of the glomerular seg-ent adjacent to the origin of the proximal

ubule, first described by Howie and Brewer9

n 1984. It is controversial whether glomerularip lesion represents a distinct entity or simplycommon response to heavy proteinuria.9,10,14

Figure 1. (A) View of the renal medulla shows chroriginal magnification �300.) (B) Low-power view of rerchitecture. (Hematoxylin and eosin; original magnifihe tubular pole is evident at 9 o’clock, and a portioartially obliterated capillary loops. (Periodic acid–me

esion from a second glomerulus with the tubular pole aoam cells. An adhesion between the tuft and Bowman

n patients with glomerular tip lesion at the p

nitial biopsy, classic focal segmental glomeru-osclerosis subsequently has been diagnosedn repeated renal biopsy16; it has been associ-ted with membranous and IgA nephropathy.17

n a recent retrospective review, glomerular tipesion was identified as a distinctive and prog-ostically favorable clinicopathologic entityor which presenting features and outcomeore closely approximate those of minimal

hange disease.18

The occurrence of glomerular tip lesion withther drugs or conditions associated with mini-al change disease has not been reported despite

xtensive literature on nonsteroidal-induced ne-hritic states. The possibility that analgesic poly-

ammation with eosinophils. (Hematoxylin and eosin;rtex shows 2 glomeruli and generally well-preserved�100.) (C) Higher power view of glomerulus from B.e glomerular tuft appears adherent at the point withine silver; original magnification �500.) (D) A similar

lock. The glomerular tip is ectatic and contains severalle is not evident in this view.

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ar tip lesion in the present case cannot bentirely excluded. Despite this, the uniqueness ofhe observation of glomerular tip lesion associ-ted with NSAID-induced nephrotic syndrome isresented here.

REFERENCES

1. Alper AB Jr, Meleg-Smith S, Krane NK: Nephroticyndrome and interstitial nephritis associated with cele-oxib. Am J Kidney Dis 40:1086-1090, 2002

2. Markowitz GS, Falkowitz DC, Isom R, et al: Membra-ous glomerulopathy and acute interstitial nephritis follow-ng treatment with celecoxib. Clin Nephrol 59:137-142,0033. Radford MG Jr, Holley KE, Grande JP, et al: Revers-

ble membranous nephropathy associated with the use ofonsteroidal anti-inflammatory drugs. JAMA 276:466-469,9964. Levin ML: Patterns of tubulo-interstitial damage asso-

iated with nonsteroidal antiinflammatory drugs. Semin

Figure 2. Electron microscope shows foot-processffacement.

ephrol 8:55-61, 1988 s

5. Kovacevic L, Bernstein J, Valentini RP, Imam A,upta N, Mattoo TK: Renal papillary necrosis induced byaproxen. Pediatr Nephrol 8:826-829, 20036. Murray MD, Brater DC: Effects of NSAIDs on the

idney. Prog Drug Res 49:155-171, 19977. Warren GV, Korbet SM, Schwartz MM, Lewis EJ:inimal change glomerulopathy associated with nonsteroi-

al anti-inflammatory drugs. Am J Kidney Dis 13:127-130,9898. Porile JL, Bakris GL, Garella S: Acute interstitial

ephritis with glomerulopathy due to nonsteroidal anti-nflammatory agents: A review of its clinical spectrum andffects of steroid therapy. J Clin Pharmacol 30:468-475,9909. Howie AJ, Brewer DB: The glomerular tip lesion: A

reviously undescribed type of segmental glomerular abnor-ality. J Pathol 142:205-220, 198410. Haas M, Yousefzadeh N: Glomerular tip lesion ininimal change nephropathy: A study of autopsies before

950. Am J Kidney Dis 39:1168-1175, 200211. Carmichael J, Shankel SW: Effects of nonsteroidal

nti-inflammatory drugs on prostaglandins and renal func-ion. Am J Med 78:992-1000, 1985

12. Finkelstein A, Fraley DS, Stachura I, Feldman HA,andy DR, Bourke E: Fenoprofen nephropathy: Lipoidephrosis and interstitial nephritis. A possible T-lymphocyteisorder. Am J Med 72:81-87, 198213. Stachura I, Jayakumar S, Bourke E: T and B lympho-

yte subsets in fenoprofen nephropathy. Am J Med 75:9-16,98314. D’Agati VD, Theise ND, Pirani CL, Knowles DM,

ppel GB: Interstitial nephritis related to nonsteroidal anti-nflammatory agents and beta-lactam antibiotics: A compara-ive study of the interstitial infiltrates using monoclonalntibodies. Mod Pathol 2:390-396, 1989

15. Torres VE: Present and future of the nonsteroidalnti-inflammatory drugs in nephrology. Mayo Clin Proc7:389-393, 198216. Howie AJ, Pankhurst T, Sarioglu S, Turhan N, Adu D:

volution of nephrotic-associated focal segmental glomeru-osclerosis and relation to the glomerular tip lesion. Kidneynt 67:987-1001, 2005

17. Howie AJ: Changes at the glomerular tip: A feature ofembranous nephropathy and other disorders associatedith proteinuria. J Pathol 150:13-20, 198618. Stokes MB, Markowitz GS, Lin J, Valeri AM, D’Agati

D: Glomerular tip lesion: A distinct entity within theinimal change disease/focal segmental glomerulosclerosis

pectrum. Kidney Int 65:1690-1702, 2004