Propyithiouracil-Induced Diffuse Proliferative Lupus Nephritis: Review of Immunological Complications

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1 Propyithiouracil-Induced Diffuse Proliferative Lupus Nephritis: Review of Immunological Complications G. V. RAMESH PRASAD,* SHELDON BASTACKY,t and JOHN P. JOHNSON* Departments of *Medic.i,ze and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Abstract. Propylthiouracil (PTU), used to treat Graves disease, occasionally induces a bupus-bike syndrome. A 39-year-old woman developed clinical manifestations of systemic lupus erythematosus with rash, serositis, myocarditis, and acute renal insufficiency, associated with serobogies for lupus, after 3 wk of exposure to the drug. Renal biopsy revealed diffuse probiferative bupus nephritis. This article reviews the side effects of PTU and the literature on PTU-induced nephrotoxicity. Possible mechanisms and management of drug-induced bupus nephritis are also reviewed. To facilitate early and specific intervention, clinicians should be aware of the propensity of PTU to cause lupus-like syndromes with renal involvement. (J Am Soc Nephrob 8: , 1997) Systemic lupus erythematosus (SLE) is a common systemic autoimmune disorder that affects the kidneys in approximately 50% of cases ( 1 ). It is characterized by excessive immune complex formation and B cell hyperactivity. Lupus-like syndromes may sometimes be induced by drugs, most frequently by hydralazine, procainamide, isoniazid, methyldopa, chborpromazine, and quinidine. Such syndromes are typically charactenized by the presence of an antinuclear antibody (ANA) and antihistone antibody, with anti-double-stranded DNA (anti-dsdna) antibody rarely present. Serum complement and immune complex levels are generally normal (1). Propylthiouracil (PTU), a drug commonly used in the treatment of hyperthyroid states, has several well-recognized side effects (2). Lupus-bike syndromes associated with the administration of PTU have been reported in the literature (2-4) but not in an adult with features satisfying modified American Rheumatism Association (ARA) criteria for SLE. We report a case of acute SLE with high-titer serological activity and diffuse proliferative glomerubonephritis after the administration of PTU and review the literature on PTU toxicity. Case Report An Asian woman 39 yr of age with a b-yr history of hypertension was taking no medication when she presented with dyspnea on exertion and ankle swelling of 2-wk duration. She was found to be in congestive heart failure with blood pressure 1 10/60 mmhg and was treated with diuretics. A complete blood cell count and electrolyte panel were normal. Her blood urea nitrogen (BUN) level was 19 mg/dl and serum Received October Accepted February 19, Correspondence to Dr. G. V. Ramesh Prasad, Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA / $03.0()/() Journal of the American Society of Nephrology Copyright by the American Society of Nephrology creatinine level was 0.8 mg/dl. The serum albumin level was 2. 1 g/dl. An echocardiogram revealed a left ventricular ejection fraction of45%. She was also noted to have mild, symmetrical, nontender enlargement of the thyroid gland. The serum thyroid-stimulating hormone level was below the limit of detection. The serum T4 bevel was 17.0 tg/dl (normal range, 4.5 to 10.9 tg/dl), T3 uptake was 43% (normal range, 22 to 37%), and free T4 was 7.3 p.g/dl (normal range, 1.4 to 3.0 pg/dl). A radioactive iodine thyroid scan with an uptake of 98.8% confirmed the diagnosis of Graves disease. She was discharged and prescribed the following medications: furosemide, 20 mg daily; metoprobol, 25 mg twice daily; and PTU, 150 mg every 8 h. These medications were given to control her hyperthyroid state before ablation of her thyroid gland, which was performed with radioactive iodine after 2 wk. The patient presented 3 wk later with anorexia, fatigue, pleunitic chest pain, 8 kg of weight loss, and a 2-d fever to 103#{176} F associated with a rash over her face and both lower extremities. There was no history of nausea, dyspnea, palpitations, abdominal pain, diarrhea, or tremor. Physical examination revealed a cachectic-appearing woman, with temperature 103.2#{176} F, blood pressure 83/57 mmhg seated, regular heart rate 93 beats/mm, and respiratory rate 22 breaths/mm. She was not orthostatic. The scalp hair pattern was normal. There was no ophthalmopathy. There was a confluent erythematous rash over her face. Palatal petechiae were present. The jugular venous pressure was normal. There was no enlargement or tenderness of the thyroid gland. There was no lymphadenopathy. 5, and 2 were normal, and there was a soft ejection systolic murmur at the base of the heart. The lung fields were clear. There was no hepatosplenomegaly. There was a diffuse palpable purpunic rash over both thighs extending posteriorly to the flanks. No edema was present. The neurological examination was unremarkable. A chest roentgenogram and electrocardiogram were normal. The total leukocyte count was 1,700/mm3 with 98% lymphocytes. The hematocrit was 29%, and the platelet count was

2 I 206 Journal of the American Society of Nephrology 47,0()0/mm3. Other laboratory results were as follows: serum sodium, I 35 mmobfl; potassium, 4.6 mmol/l; chloride, 111 mmol/l; CO2 18 mmob/l; BUN, 32 mg/dl; serum creatinine, 1.3 mg/dl; and serum albumin, I.4 g/dl. Urinalysis showed no white blood cells per high-power field, 20 to 50 red blood cells per high-power field, and a few coarse granular casts. An ultrasound demonstrated normal size and echogenicity of both kidneys. The 24-h urine protein excretion was 3.7 g with a creatinine clearance rate of 48 mllmin. A bone marrow aspirate was hypocellubar with no neutrophil precursors. After transfer to our medical center for management of febrile agranulocytosis, presumed to be from PTU, blood and urine cultures were obtained, and she was treated empirically with broad-spectrum antibiotics. The PTU was discontinued. Granulocyte colonystimulating factor was administered. A biopsy of the skin rash demonstrated basal vacuolization with a perivascular and penadnexal bymphocytic infiltrate, most consistent with a drug reaction; immunofluorescence was not performed. Over the next week, the BUN and serum creatinine levels rose progressively to 45 and 2.3 mg/db, respectively. The C3 was 23 mg/dl with C4 < 10 mg/dl. An ANA determination was positive at a titer of 1 : I 600. Peninuclear antineutrophil cytoplasmic autoantibody (p-anca) determination was positive, but immunoperoxidase staining was not done. Antithyroglobulin antibody and antimicrosomal antibody determination were positive. Antihistone antibody was not detectable, but the anti-dsdna titer was I : I 2,800, and a type III cryoglobulin was present. SLE was diagnosed based on modified ARA criteria. Methylprednisobone at a dose of 1 g was administered intravenousby on 3 successive d, followed by oral prednisone at 60 mg/d. The fever resolved uneventfully. The serum creatinine level stabilized and then improved, and she was discharged. The patient returned a week later with congestive heart failure, but this time with atnial fibrillation and a left ventricular ejection fraction of 25% determined by echocardiogram. Diuretics and an angiotensin-converting enzyme inhibitor were initiated. Cardiac catheterization disclosed no evidence of coronary artery disease. A percutaneous renal biopsy was performed when the platelet count rose to 135,000/mm3 (Figure 1). The serum creatinine level at that time was I. 1 mg/dl. Light microscopy showed a diffuse endocapiblany proliferative glomerubonephnitis with increased numbers of intraglomerular neutrophils and a single partial fibrocelbular crescent, patchy bymphocytic tububointerstitiab nephnitis with acute tubular injury, focal lymphocytic vascular wall permeation, and moderate arteniolar sclerosis. No chronic changes were observed in the tubules. Direct immunofluorescence demonstrated granular mesangiab and gbomerular basement membrane staining for IgG (4+), 1gM (1 +), IgA (3+), C3 (3+), and Cbq (3+); granular tubular basement staining for IgG (3+), C3 (2+), and Clq (3+); and focal granular arteniolar peritubular capillary staining for IgG (2+) and C3 (2+). Ultrastructural examination revealed immune complex deposits involving the glomerular basement membrane (predominantly subendothebiab with scattered subepithehal deposits), mesangium, and peritubular capillaries. Some deposits had a fingerprint substructure. There was focal mesangial interposition in a capillary wall, and numerous tubuloreticubar inclusions were present within the endothelial cells. This constellation of findings was compatible with diffuse proliferative bupus nephropathy (WHO class IV), high activity, and low chronicity indexes. Intravenous cyclophosphamide therapy was begun at a dose of 500 mg/rn2. One week later, the BUN level was 27 mg/dl and serum creatinine level was 1.0 mg/dl. At 3 wk, the rash had markedly improved, the ANA titer had fallen to 1 :400, and the anti-dsdna titer had fallen to 1 : 100. The C3 had risen to 43 mg/dl, and the C4 to 10 mg/dl. The patient subsequently received five monthly infusions of cycbophosphamide, and at 6 mo renal function was normal with serologies remaining negative. Serum complement levels rose further but had not yet reached normal levels. The 24-h urine protein excretion was 300 mg. She was euthyroid. Discussion This patient with Graves disease presented with diagnostic features of SLE, with diffuse proliferative gbomerubonephritis shortly after the administration of PTU. Pathogenesis PTU is a thionamide compound widely used to treat hyperthyroidism, especially in young patients (4). Side effects occasionally necessitating withdrawal of the drug may occur at any dosage with the first or repeated exposure and with any duration of therapy. Because few therapeutic alternatives are available, the drug is used commonly. Uncontrolled production of antibodies against multiple antigens is the hallmark of SLE. The number of such cells correlates well with disease activity and treatment status (5). In physiological states, there is little evidence for specific interaction between lupus-inducing drugs and histones, chromatin, or DNA (6). In drug-induced lupus, autoantibodies may form against a complex of the histone dimer H2A-H2B and DNA. DNA may contribute to part of the antigenic epitope and may be required to stabilize the complex. The thiol group in antithyroid drugs may permit binding to cellular macromolecules, and therefore may function as a hapten and induce antibody formation. Alternatively, metabolites of PTU may compete with thymidine tniphosphate as a substrate. They could inhibit DNA synthesis or be incorporated into DNA. In either instance, abnormal immune function regulation with consequent expression of adverse effects could occur (7). The mechanism of PTU-induced toxicity is possibly different from that of other drugs that induce lupus-like syndromes. Clinical Manifestations A clear temporal association with drug administration and improvement of symptoms with withdrawal are characteristic of drug-induced lupus. Drug-induced bupus is similar to lupus occurring in older individuals, with constitutional, joint, and pleuropenicardiab symptoms being more prominent. Renal and central nervous system disease, leukopenia, mucocutaneous involvement, and anemia are uncommon. The sex ratio is

3 PTU-lnduced Lupus Nephritis 1207 Figure I. Pathology of renal disease. (A) Globally hypercellular glomerulus with obliteration of capillary lumina (hematoxylin & eosin stain, X350). (B) Direct immunofluorescence with fluorescein-labeled Cbq antisera. Note granular glomerular (mesangial and peripheral basement membrane), tubular basement membrane (arrows), and peritubular capillary (arrowheads) staining (X200). (C) Electron micrograph of isolated gbomerular capillary loop and adjacent mesangium with immune complex deposits in subendothelial, subepithebiab, and mesangial locations. Note frequent tububoreticular inclusions (arrows) in endothelial cells (X9450). (D) Electron micrograph of a peritubular capillary containing intramural immune complex deposits (X750t).

4 I 208 Journal of the American Society of Nephrology approximately equal. Drug-induced lupus has been noted to occur less frequently in African-Americans (1). There are many immunologic manifestations linked to PTU (7). Agranulocytosis, the most severe complication, occurs in to 0.2% of all patients receiving PTU. Skin reactions are the most common manifestation of hypersensitivity (8). Other immunologic side effects include arthralgias, myalgias, joint effusions, a serum sickness-like syndrome, and autoimmune syndromes with features similar to rheumatoid arthritis, lupus erythematosus, or polyartentis nodosum. Vasculitis and inflammatory changes involving the skin, liver, central nervous system, pancreas, and kidney have all been described (9) and may be fatal (10). The association of antineutrophil cytoplasmic autoantibodies with vasculitis from PTU has also been reported (4, ). Pulmonary cavitation with hemoptysis has been associated with PTU (14). Hepatitis is prevalent but is not always immunologically mediated (7). Table 1 lists the reported immunologic manifestations of PTU toxicity. All of these features have not been addressed in every report. Renal involvement manifest by hematuna, pyunia, proteinunia, and/or renal insufficiency has been noted to occur with the administration of PTU (2,9,1 1-15). This is relatively uncommon, as it occurs in approximately 5% of cases compared with 50% of cases of idiopathic lupus. In addition to PTU, other implicated drugs include hydralazine, anticonvulsants, penicillamine, and procainamide (16). As listed in Table 2, a number of renal lesions may be observed with PTU. Our patient demonstrated a number of features of PTU toxicity, including agranubocytosis and an idiopathic lupus-like syndrome characterized by gbomerubonephnitis, serositis, rash, and probable myocarditis. Her clinical lupus was severe Table 1. Reported immunologic complications of PTU in 39 cases Feature No. of Cases Percentage Rash Fever Anemia Arthralgias Granubocytopenia ANA positivity Hypergammagbobulinemia Arthritis ANCA positivity 9 23 Splenomegaly 9 23 Renal involvementt 8 20 Thrombocytopenia 4 10 Agranubocytosis 2 5 Hepatitis 2 5 SLE 2 5 U References 3, 7, 9, , 15, 17 and this report. VTU, propylthiouracil: ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic autoantibody; SLE, systemic lupus erythematosus. h See Table 2. Incidence of nephnitis based on clinical manifestations may be higher. Table 2. Reported renal biopsy findings associated with PTU administration in 8 cases a Predominant Histological Feature No. of Cases Crescentic glomerulonephnitis 3 Diffuse proliferative lupus gbomerubonephritis 2 Mesangial and membranous thickening 1 Acute interstitial nephntis I Normabb a References 2, 9, 1 1, 13, 15, 17 and this report. h After I wk of steroid therapy. enough to satisfy modified ARA criteria for the diagnosis of definite SLE. The active serologic manifestations she demonstrated included p-anca, anti-dsdna antibodies, and hypocomplementemia. Although a positive p-anca may be a nonspecific finding in lupus, the patient shared clinical features of both ANCA-positive vasculitis and acute lupus with nephritis. The inability to make a clinical distinction made a renal biopsy imperative. It is noteworthy that the majority of patients with lupus-like syndromes associated with PTU administration are children and adolescents, or have received a prolonged course of the drug (2-4). In addition, only one case, that of a boy 1 1 yr of age treated for 15 mo, has been reported to fully satisfy modified ARA criteria for the diagnosis of lupus. However, the authors of his report maintained that Graves disease per se was the cause of lupus in this case ( 17). Table 3 summarizes the features of these cases. It is unclear whether the risk of drug hypersensitivity is higher in patients with hyperthyroidism from Graves disease or from other causes of hyperthyroidism (7). Compared with reported cases of PTU-induced lupus, our patient was atypical in several respects. She was significantly older and more severely affected than the majority of patients, and she had only a brief exposure to PTU. One could speculate that she had coincidentally developed spontaneous SLE, but this seems unlikely. She had no symptoms whatsoever before the PTU was begun. At minimum, if our patient does not demonstrate PTU-induced SLE, then a PTU-induced acceleration of SLE seems probable. Management The management of drug-induced lupus nephnitis is essentiably similar to that of spontaneous lupus nephritis of comparable stage. Recognition of the possibility of drug-induced SLE in a patient receiving PTU, with features including an acute deterioration of renal function accompanied by vasculitis or granulocytopenia, should lead to the drug s immediate withdrawal because its continuation may be fatal. Other thionamides should not be substituted because of significant crossreactivity (7). Other measures, such as radioactive iodine, should be used instead to control hyperthyroidism. Physicians should be suspicious of a rapidly progressive gbomerubonephnitis in patients receiving PTU. Deterioration in renal function combined with an active urine sediment is an I

5 PTU-Induced Lupus Nephritis 1209 Table 3. Characteristics of reported patients with PTU-associated bupus-like syndromesa Reference Patient Characteristics and PTU Exposure Clinical and Laboratory Features Treatment and Outcome yr-old male 150 to 300 mg/d for 2 yr 7 mo yr-old female 300 mg/d for 6 wk yr-old female 50 to 225 mg/d for 14 mo. I yr-old male Dose of PTU not given, 15 mo. a Abbreviations as in Table I. Arthralgias, fever, weight loss, weakness, pneumonitis, proteinuria to 1 g/24 h, positive ANA and LE cell preparations, hypoalbuminemia, increased IgG and 1gM. Focal glomerubar mesangial and membranous thickening in kidney. Arthritis, fever, hepatomegaly, pleunitis, pericarditis, LE cell, and latex fixation tests negative. Fever, lethargy, anorexia, rash, anemia, neutropenia, thrombocytopenia, splenomegaly, ANA positive, antineutrophib Ab-positive, hypergammagbobulinemia. Fever, chest pain, cough, hematuria, anemia, thrombocytopenia, proteinuria to 3.48 g/24 h, renal insufficiency, hypertension, ANA and anti-doublestranded DNA-positive. Class IV lupus nephnitis on biopsy. Prednisone 80 mg/d. Improved clinically. Persistent proteinunia at 8 mo. Aspirin, then prednisone 20 mg/d. Methimazobe 30 mg/d started. Improved. Intervention not mentioned. Improved. Pulse methyl prednisobone and chborambucil. Carbimazole 10 mg/d started. Persistent proteinuria and hematuria. indication for a renal biopsy. Management thereafter would be determined based on histologic features of the disease. Steroids combined with cytotoxic therapy, primarily intravenous cycbophosphamide, are used in the management of lupus nephritis (18). The prognosis with drug-induced lupus nephritis would intuitively be superior to spontaneous lupus nephritis of a comparable stage, but this has not been documented. The long-term prognosis of diffuse lupus nephnitis in general is improving with modern methods of treatment. Summary Glomerulonephritis is an uncommon manifestation of druginduced lupus, but should be suspected and therefore detected early in the course of the illness so that definitive intervention may be instituted. Awareness of uncommonly associated drugs such as PTU with lupus-bike syndromes will further facilitate identification of different forms of renal toxicity from therapeutic agents used in a variety of conditions. Acknowledgment The authors thank Dr. Arthur Greenberg for his careful review and constructive criticism of this manuscript. References 1. Schur PH: Clinical features of SLE. In: Textbook of Rheumatologv, 4th Ed.. edited by Kelley WN, Harris ED, Ruddy 5, Sledge CB, Philadelphia, W. B. Saunders, 1993, pp Amrhein JA, Kenny FM, Ross D: Granubocytopenia, lupus-like syndrome and other complications of propylthiouracil therapy. J Pediatr 76: 54-63, , Best MM, Duncan CH: A lupus-like syndrome following propybthiouracib administration. J Kentucky Med Assoc 62: 47-49, I Berkman EM, Orlin JB, Wolfsdorf J: An antineutrophil antibody associated with a propylthiouracil induced lupus-like syndrome. Trwufusion 23: , Tsokos GC: Immunologic aspects in humans. Ann Intern Med 106: 79-94, Rubin RL, Bell SA, Burlingame RW: Autoantibodies associated with bupus induced by diverse drugs target a similar epitope in the (H2A-H2B)-DNA complex. J C/in Invest 90: , , Wing 55, Fantus IG: Adverse immunologic effects of antithyroid drugs. CanMedAssocf 136: , Shabtai R, Shapiro MS. Orenstein D, Taragan R, Shenkman L: The antithyroid arthritis syndrome reviewed. Arthritis Rheum 27: , Griswold WR, Mendoza SA, Johnston W, Nichols 5: Vasculitis associated with propylthiouracil. West J Med 128: , I Reidy TJ, Upshaw JD, McCChesney T: Propylthiouracil-induced vasculitis: A fatal case. South Med J 75: , D cruz D, Chesser AMS, Lightowler C, Comer M, Hurst MJ, Baker LRI, Raine AEG: Antineutrophil cytoplasmic antibodypositive crescentic gbomerubonephritis associated with anti-thyroid drug treatment. Br J Rheumatol 34: , I Dolman KM. Gans R, Vervaat TJ, Zevenbergen G, Maingay D,

6 1210 Journal of the American Society of Nephrology Nikkels RE, Donker AJ, von dem Borne AE, Goldschmeding R: Vasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy. Lancet 342: , Vogt BA, Kim Y, Jennette JC, Falk Ri, Burke BA, Sinaiko A: Antineutrophil cytoplasmic autoantibody-positive crescentic gbmerubonephritis as a complication of treatment with propylthiouracil in children. J Pediatr 124: , Cassorla FG, Finegold DN, Parks JS, Tenore A, Thawerani H, Baker L: Vasculitis, pulmonary cavitation and anemia during antithyroid drug therapy. Am J Dis Child 137: , Reinhart SC, Moses AM, Cleary L, Scheinman Si: Acute interstitial nephritis with renal failure associated with propylthiouracil therapy. Am J Kidney Dis 24: , Lee SL, Chase PH: Drug-induced systemic lupus erythematosus: A critical review. Semin Arthritis Rheuin 5: , Fu LS, Yang LY, Chen WP, Chao T, Ooi 5K, Lin CY: Class IV lupus nephritis associated with Graves disease. Child Nephrol Urol 12: 51-54, Steinberg AD, Steinberg SC: Long term preservation of renal function in patients with lupus nephritis receiving treatment that includes cycbophosphamide versus those treated with prednisone only. Arthritis Rheum 34: , 1991 Nephrology Fellowships at the University of Pittsburgh Nephrobogy fellowships at the University of Pittsburgh are for 2 yr. with an option for additional years for individuals who wish to obtain further experience in clinical or basic research. Fellows spend the first year rotating on four clinical services: University of Pittsburgh Medical Center (UPMC) consultations, renal transplantation, Veterans Administration Medical Center (VAMC), and outpatient dialysis. The UPMC is a 550-bed medical surgical hospital. The consultation service covers approximately admissions or consultations annually. Together with the renal transplantation service, the university supervises 5000 acute dialysis treatments each year. Two hundred renal transplants are performed annually. Experience in the management of end-stage renal disease patients is obtained at a free-standing, university-directed dialysis unit with a census of 150 in-center and home hemodialysis patients and home-trained penitoneal dialysis patients. Additional outpatient dialysis experience is provided at the VAMC. UPMC serves as the major academic referral institution for western Pennsylvania and parts of eastern Ohio, West Virginia, and the southern tier of New York, in addition to providing primary care for a large section of Pittsburgh. Thus, the patient mix is very broad. Fellows obtain a longitudinal patient care experience at the university and VAMC renal and hypertension clinics throughout their 2 yr of training. The second year program is tailored to the individual trainee s interest. Fellows may work with a faculty preceptor on a clinical or basic research project. Alternatively, additional clinical training or structured electives in renal pathology or pediatric nephrobogy are available. Fellows may pursue the M.P.H. degree at the university s School of Public Health. The division has 13 full-time M.D.s and 3 Ph.D.s. Basic laboratory research is located in the Laboratory for Epithebial Cell Biology, with emphasis on mechanisms of water transport, regulation of sodium transport by aldosterone, and mechanisms regulating intracellular trafficking of proteins. Areas of clinical research interest include penitoneal dialysis, continuous renal replacement therapy, therapy of electrolyte disorders, and acute renal failure.