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case records of the massachusetts general hospital

Founded by Richard C. Cabot Nancy Lee Harris, m.d., Editor William F. McNeely, m.d., Associate Editor Jo-Anne O. Shepard, m.d., Associate Editor Sally H. Ebeling, Assistant Editor Stacey M. Ellender, Assistant Editor Christine C. Peters, Assistant Editor

Case 36-2003: A 68-Year-Old Woman with Impaired Renal Function

Ajay K. Singh, M.B., B.S., M.R.C.P., and Robert B. Colvin, M.D.

presentation of case
A 68-year-old woman was admitted to the hospital because of impaired renal function. One month earlier, she had had difficulty breathing and had felt as though she had a fever; she went to another hospital, where nebulizers were prescribed, and her dyspnea improved. Two weeks later, malaise and a sensation of chilliness developed, with diffuse pains in the arms and legs, which prompted her to take two or three tablets of ibuprofen every four to five hours for two weeks, although the medication was only minimally effective. Ten days before admission, pruritus developed. She consulted a physician, who found that her temperature was 37.8C and prescribed cetirizine. Four days later, she consulted her customary physician. The urine was ++ for protein; the sediment contained 50 to 100 white cells and moderate numbers of tubular cells. The urea nitrogen level was 20 mg per deciliter (7.1 mmol per liter), and the creatinine level 1.5 mg per deciliter (132.6 mol per liter), although previously, the creatinine level had been around 0.8 mg per deciliter (70.7 mol per liter). She was advised to discontinue taking ibuprofen and to return for follow-up, but on the day of admission she vomited twice, felt extremely fatigued, continued to have malaise, and produced less urine than usual. She was admitted to the hospital. The patient had a history of hypertension. Six years before admission, she had had an abdominal hysterectomy with incidental appendectomy because of endometrial carcinoma. She had smoked one pack of cigarettes daily for 20 years but had stopped smoking 30 years before admission. She consumed wine with dinner. She resided with her husband and had several children, one of whom had multiple sclerosis. Her medications were hydrochlorothiazide, conjugated equine estrogens, aspirin, and a multivitamin tablet, as well as ibuprofen. She had no recurrence of dyspnea or fever, and she reported not having had frank chills, chest pain, abdominal pain, diarrhea, dysuria, polyuria, arthralgia, or rash or having recently traveled. The temperature was 37.3C, the pulse 66 beats per minute, and the respiratory rate 20 breaths per minute. The blood pressure was 110/75 mm Hg. The oxygen saturation was 99 percent while the patient breathed ambient air. On physical examination, there was no rash or lymphadenopathy, and no petechiae were found. The jugular venous pressure was 7 cm of blood. The lungs were clear, and the heart sounds were normal. The abdomen was unremarkable. There was trace peripheral edema, and the pulses at the hands and feet were intact.
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From the Renal Division, Department of Medicine, Brigham and Womens Hospital (A.K.S.); the Department of Pathology, Massachusetts General Hospital (R.B.C.); and the Departments of Medicine (A.K.S.) and Pathology (R.B.C.), Harvard Medical School. N Engl J Med 2003;349:2055-63.
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The urine was +++ for protein, had a specific gravity above 1.030, and was trace positive for ketones; the sediment contained 0 to 2 red and white cells, moderate numbers of squamous and transitional cells, and a few bacteria per high-power field and contained 0 to 2 hyaline casts, 3 to 5 granular casts, and 0 to 2 waxy casts per low-power field. The results of hematologic and other laboratory tests performed on admission are reported in Tables 1 and 2, respectively. An electrocardiogram showed a normal rhythm at a rate of 65 beats per minute, with a corrected QT interval of 487 msec and minor ST-segment and T-wave abnormalities. An abdominopelvic computed tomographic (CT) study revealed a small amount of pericardial thickening or fluid and minimal atelectasis at the base of the left lung; no hydronephrosis was observed. The right kidney was unremarkable, and the left contained a calcification, 2 mm in diameter, which was consistent with the presence of a calculus. The urinecollecting systems and bladder were normal. There were diverticula in the sigmoid colon, but they were not inflamed. A low-attenuation lesion within the dome of the liver and another in the right hepatic lobe were unchanged relative to a study performed 18 months earlier. Several subcentimeter lymph nodes were seen in the paraaortic region, and one was seen in the right external iliac chain; several prominent inguinal nodes were noted bilaterally. The stomach, small bowel, and skeletal structures were normal. Chest radiographs showed stable thickening of the apical pleura bilaterally; the lungs, heart, mediastinum, and bony thorax were normal.

Ibuprofen and hydrochlorothiazide were discontinued, and intravenous administration of nonessential fluids was avoided. Morphine was provided for pain and lorazepam for sleeplessness, and the administration of minidose heparin was begun. The patient was afebrile at all times. On the second hospital day, her pruritus and nausea resolved, and she felt much improved. The urinary volume was 80 to 90 ml during each eight-hour shift. The results of laboratory tests performed that day are shown in Table 2. No Bence Jones protein was detected; the urine contained a large amount of albumin, a small amount of a-globulin, a moderate amount of b-globulin, and a moderate amount of probably intact immunoglobulin. The total urinary protein excretion was 3.4 g per 24 hours. On the third hospital day, the patient continued to feel well. Physical examination revealed no abnormalities except for trace peripheral edema. Intravenous administration of methylprednisolone (500 mg daily) was begun. During the next two days, the patient remained comfortable. The results of laboratory tests performed on days 3, 4, and 5 are shown in Table 2. The oliguria persisted. Culture specimens of blood and urine were sterile. A diagnostic procedure was performed on the fifth hospital day.

differential diagnosis
Dr. Ajay K. Singh: In assessing renal failure, it is important first to establish its duration and tempo. This information can provide clues about its cause as well as guide the aggressiveness of the workup. In the current case, there is little evidence, other than the history of hypertension, of an underlying chronic kidney disease. Indeed, the normal hematocrit, the absence of cortical thinning on the abdominal CT scan, the oliguria, and most important, the tempo of the decline in renal function support a diagnosis of rapidly progressive acute renal failure. In addition, this patients illness appears to have had two phases: one that developed shortly before her initial presentation, and a second that developed while she was in the hospital. The causes of acute renal failure in this patient can best be considered according to the diagnostic paradigm based on prerenal, intrinsic renal, and postrenal factors. The absence of prerenal factors (those that reduce blood flow to the kidneys) and postrenal factors (those that obstruct urine flow) suggests that intrinsic renal disease is the most like-

Table 1. Hematologic Laboratory Data on Admission. Variable Hematocrit (%) White-cell count (per mm3) Differential count (%) Neutrophils Lymphocytes Atypical lymphocytes Bands Monocytes Eosinophils Platelets (per mm3) Mean corpuscular volume (m3) Prothrombin time Partial-thromboplastin time 66 11 1 4 4 14 208,000 87 Normal Normal Value 37.2 14,700

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case records of the massachusetts general hospital

Table 2. Blood Chemical Values.* Variable Glucose Bilirubin Conjugated Total Phosphorus (mg/dl) Protein (g/dl) Albumin Globulin Cholesterol (mg/dl) High-density lipoprotein (mg/dl) Low-density lipoprotein (mg/dl) Triglycerides (mg/dl) Sodium (mmol/liter) Potassium (mmol/liter) Chloride (mmol/liter) Carbon dioxide (mmol/liter) Magnesium (mmol/liter) Urea nitrogen (mg/dl) Creatinine (mg/dl) Calcium (mg/dl) Creatine kinase Creatine kinase isoenzymes Troponin T Alkaline phosphatase Aspartate aminotransferase (U/liter) Alanine aminotransferase (U/liter) Amylase Lipase IgG (mg/dl) IgA (mg/dl) IgM (mg/dl)** C4 (mg/dl) Test for antinuclear antibodies On Admission Normal Normal Normal 6.3 7.4 2.0 5.4 181 22 98 307 124 3.3 86 20.8 43 4.0 63 6.2 2nd Hospital Day 3rd 4th 5th Hospital Day Hospital Day Hospital Day

16.1

125 3.0 95 24.5 Normal 40 3.7 7.1 Normal Normal Normal Normal 66 51 Normal Normal

120 3.6 81 14.9 80 7.2

124 4.3 83 17.6 1.0 98 7.6 5.6

Serum protein electrophoresis

1980 506 Normal 15 Positive (at 1:40 and 1:160), with a speckled pattern Abnormal (2 very low concentration bands in slow gamma region, identified as IgG kappa M components)

* To convert the values for phosphorus to millimoles per liter, multiply by 0.3229. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the value for triglycerides to millimoles per liter, multiply by 0.01129. To convert the value for magnesium to milliequivalents per liter, divide by 0.5. To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for calcium to millimoles per liter, multiply by 0.25. The normal range is 0 to 6.9 ng per milliliter. The normal range is 0 to 0.09 ng per milliliter. The normal range is 1.3 to 6.0 U per liter. The normal range is 614 to 1295 mg per deciliter. The normal range is 69 to 309 mg per deciliter. ** The normal range is 53 to 334 mg per deciliter. The normal range is 20 to 58 mg per deciliter. The normal result is negative (at 1:40 and 1:160).

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ly cause. The differential diagnosis of intrinsic renal disease includes glomerulonephritis, interstitial nephritis, tubular disease, and vascular disease. When this patient initially presented to her primary care physician, she had moderate proteinuria, pyuria, and tubular cells in the urinary sediment. These features are typical of a tubulointerstitial process rather than acute glomerulonephritis. In addition to proteinuria, the urinary sediment in patients with acute glomerulonephritis typically contains red cells (which often are dysmorphic) as well as redcell casts. This patient had neither. Nevertheless, the possibility of glomerulonephritis must be considered. The presence of antinuclear antibodies and the low complement C4 level raise the possibility of an autoimmune glomerulonephritis, such as lupus nephritis. Although it is tempting to consider this disorder as a possibility, it is very unlikely in this case because of the age of the patient, the absence of a typical systemic syndrome compatible with systemic lupus erythematosus, and the predominant tubulointerstitial features on presentation. Predominant tubulointerstitial nephritis has been reported in lupus,1 but it is rare. Another possibility is that this patient had an underlying secondary membranous glomerulonephritis associated with her endometrial cancer and that it was followed by the development of superimposed acute glomerulonephritis. The acute glomerulonephritis would then explain the acute renal failure. Such a scenario, involving a small-vessel, antineutrophil cytoplasmic antibody (ANCA)associated glomerulonephritis superimposed on membranous glomerulopathy, has been reported.2 This scenario seems unlikely in this case, however, because of the absence of clinical features compatible with a systemic vasculitis and because of urinary findings that are not consistent with the presence of acute glomerulonephritis.
interstitial nephritis

Interstitial nephritis is a category of renal diseases characterized by inflammation and scarring that are confined largely to the tubular and interstitial compartments, with sparing of the glomeruli and vasculature. Interstitial nephritis may be acute or chronic; in this case, given the tempo of the renal failure, it is clearly acute. There are three major types of acute interstitial nephritis: immune-mediated, infection-mediated, and idiopathic (Table 3). Immune-mediated acute interstitial nephritis may be either drug-related or due to an immunologic dis-

ease. The drug prototypically associated with acute interstitial nephritis is methicillin, but many other drugs have also been implicated (Table 4). In this patient, the exposure to ibuprofen, the history of pruritus (raising the possibility of skin hypersensitivity), the low-grade fever, and the findings in the urinary sediment make the likeliest diagnosis acute allergic interstitial nephritis induced by the ibuprofen. Since this patient was also receiving hydrochlorothiazide, the possibility that the thiazide diuretic is the offending agent cannot be entirely ruled out. The presence of eosinophilia favors the possibility of an acute interstitial nephritis induced by a nonsteroidal antiinflammatory drug (NSAID) over the possibility of a diuretic-induced acute interstitial nephritis, but the discriminatory value of eosinophilia in this regard is likely to be quite low. It has been long recognized that NSAIDs may be associated with several renal syndromes (Table 5).3 Several cases of ibuprofen-induced acute interstitial nephritis have been described in the literature.4-6 The association between NSAID exposure and acute renal dysfunction is well grounded in the epidemiology literature.7-9 One population-based study that evaluated the association between hospitalizations for acute renal failure and the use of NSAIDs reported a heightened risk of acute renal failure among current users of NSAIDs.7 There are similarities between acute interstitial nephritis induced by methicillin and that associated with NSAIDs.4-6 In both, extrarenal features such as a cutaneous rash and fever may be observed. In addition, eosinophilia, hematuria, pyuria, eosinophiluria, proteinuria, and renal failure also may occur. However, there are important differences between these two types of acute interstitial nephritis. Hematuria has been reported in 90 percent of cases of methicillin-induced acute interstitial nephritis (and macroscopic hematuria in 80 percent), and eosinophilia is an almost constant feature. In contrast, hematuria and eosinophilia are present in only about 40 percent of cases of NSAID-induced acute interstitial nephritis. Whereas renal dysfunction is observed in only half the cases of methicillin-induced acute interstitial nephritis, more than 90 percent of the reported cases of NSAID-induced acute interstitial nephritis involve renal dysfunction, with dialysis required in one third of those cases. Finally, the nephrotic syndrome is uncommon in cases of methicillin-induced acute interstitial nephritis, but it occurs in more than 70 percent of cases of NSAID-induced acute interstitial nephritis.

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By the time this patient was hospitalized, more severe clinical symptoms, including oliguria, had developed, and her laboratory findings had changed, suggesting the development of an additional cause of acute renal failure. Notably, her urinalysis showed increased proteinuria, and her sediment contained few red cells and white cells but 3 to 5 granular casts per low-power field. On the second hospital day, a urinary protein level of 3.4 g per 24 hours was reported. Although granular casts may be observed in patients with acute interstitial nephritis, the possibility of acute tubular necrosis, in the setting of the nephrotic syndrome must now be actively entertained in the differential diagnosis.
acute interstitial nephritis and the nephrotic syndrome

Table 3. Types of Interstitial Nephritis. Immune-mediated Drug hypersensitivity Immunologic diseases With glomerulonephritis: lupus nephritis, IgA nephropathy Without glomerulonephritis: transplant rejection, sarcoidosis, Sjgrens syndrome Infection-mediated Organism in kidney: bacterial pyelonephritis No organism in kidney (i.e., systemic infection) Bacterial infection: b-hemolytic streptococcus, legionella, brucella, mycoplasma, Treponema pallidum, rickettsia Viral infection: EpsteinBarr virus, human immunodeficiency virus, cytomegalovirus Idiopathic

It is estimated that the nephrotic syndrome occurs in more than 70 percent of cases of NSAID-induced acute interstitial nephritis.4 Patients who have the nephrotic syndrome in association with acute interstitial nephritis are typically more than 50 years of age, rarely present with fever or rash (which have an incidence of less than 10 percent), and usually have neither hematuria nor pyuria. Eosinophilia is estimated to be present in about 40 percent of the cases. Essentially all NSAIDs, including cyclooxygenase-2 inhibitors, have the propensity to induce the nephrotic syndrome.4,10 The risk factors for NSAIDinduced nephrotic syndrome remain unclear. The presence of an autoimmune syndrome, such as systemic lupus erythematosus, as a risk factor has previously been mentioned in the literature.11,12 The etiology of NSAID-associated acute interstitial nephritis with the nephrotic syndrome remains obscure.4 It has been hypothesized that NSAIDs precipitate a cascade of events that ultimately lead to the production of inflammation-inducing metabolites of eicosatetraenoic acid, which in turn leads to T-cell recruitment and activation.3

Table 4. Examples of Drug-Associated Causes of Interstitial Nephritis. Antibiotics Penicillins Cephalosporins Other (quinolones, sulfa-containing drugs) Diuretics Thiazides Furosemide Analgesics Nonsteroidal antiinflammatory drugs Anticonvulsants Phenytoin Carbamazepine Phenobarbitol Other Allopurinol Cimetidine

mone, inhibiting active chloride transport by the thick ascending limb of Henle, and regulating medullary blood flow. In the current case, water retention that was disproportionate to sodium retention probably led to the hyponatremia. Hypokalemia is not usually observed in NSAID-associated acute interstitial nephritis because of the effect that supelectrolyte abnormalities with acute interstitial nephritis pression of prostaglandin synthesis by NSAIDs has This case is also interesting because both hypo- on kaliuresis. Thus, the most likely explanation for natremia and hypokalemia were observed on ad- the hypokalemia is the vomiting, the hydrochloromission. NSAID-associated hyponatremia is well thiazide therapy, or both, rather than the NSAIDs. recognized in the literature. NSAIDs inhibit prostaglandin synthesis. A large body of evidence links acute renal failure and the nephrotic renal prostaglandins with the maintenance of wa- syndrome ter balance.3,11,13 They are important in antago- The acute renal failure in this patient might be ennizing the hydro-osmotic action of antidiuretic hor- tirely explained by acute interstitial nephritis asso-

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Table 5. Renal Syndromes Associated with the Use of Nonsteroidal Antiinflammatory Drugs. Acute renal failure Prerenal changes due to decreased intrarenal production of vasodilatory prostaglandins Acute interstitial nephritis Acute interstitial nephritis with the nephrotic syndrome Fluid and electrolyte abnormalities Edema Hypertension Hyponatremia Hyperkalemia Type IV renal tubular acidosis Chronic interstitial nephritis Renal papillary necrosis Acute Chronic

ciated with her use of NSAIDs. However, it is possible that she had two forms of acute renal failure: acute interstitial nephritis with the nephrotic syndrome initially, followed by acute tubular necrosis precipitated by hypovolemia in the setting of severe hypoalbuminemia. This hypothesis is supported by two pieces of evidence: first, the worsening of the renal failure with progression to oliguria, despite discontinuation of ibuprofen, and second, the subsequent appearance of a sediment more compatible with acute tubular necrosis than with acute interstitial nephritis. Acute renal failure in elderly patients with the nephrotic syndrome from minimal-change disease is well recognized.14-17 The earliest descriptions were published in the late 1960s. These patients often have superimposed acute tubular necrosis. Elderly patients and those in whom the serum albumin level is less than 2 g per deciliter are at especially high risk for the development of acute tubular necrosis.18 Several potential mechanisms may explain the development of acute renal failure in the setting of severe hypoalbuminemia and the nephrotic syndrome. They include a very low plasma oncotic pressure, leading to renal interstitial edema, or nephrosarca, with associated tubule compression, and severe proteinuria precipitating the formation of large proteinaceous casts that lead to intratubular obstruction. In practice, the diagnosis of drug-induced acute interstitial nephritis is often made on clinical grounds, without the need for a percutaneous renal biopsy. Detection of urinary eosinophils can be important in the evaluation of patients with acute

interstitial nephritis.19,20 Eosinophiluria is considered to be present when more than 1 percent of the white cells in the urine are eosinophils. Both the classic Wrights stain and Hansels stain are combinations of eosin and methylene blue. Studies have shown that Hansels stain has nearly four times the sensitivity of Wrights stain, in part because it is less pH-dependent.11 However, both staining methods have a relatively low sensitivity (approximately 67 percent) and only moderately good specificity (approximately 80 percent). Gallium scanning has also been suggested as a highly sensitive noninvasive test; however, its low specificity has limited its usefulness. The gold-standard test is percutaneous renal biopsy. Examination of the biopsy specimen usually reveals an edematous interstitium that is focally infiltrated by eosinophils and mononuclear cells and is accompanied by tubulitis but not glomerulitis. The histologic lesion most frequently observed on renal biopsy in the nephrotic syndrome associated with acute interstitial nephritis is an acute interstitial infiltrate with effacement of the foot processes suggesting a minimal-change lesion, although NSAIDassociated membranous glomerulopathy has also been described.21 The diagnostic procedure performed in this case was probably a renal biopsy. The indications for renal biopsy in this case include the uncertainty about the diagnosis, the advanced renal failure, and the lack of recovery after the ibuprofen had been discontinued and even though high-dose corticosteroid therapy was begun. The biopsy findings probably included an acute allergic interstitial nephritis, diffuse effacement of foot processes, and perhaps some evidence of acute tubular injury. Dr. Nancy Lee Harris (Pathology): Dr. Bazari, would you comment on your care of this patient and the diagnostic procedure? Dr. Hasan Bazari (Nephrology): The presentation with acute renal failure in a previously healthy patient with a normal base-line creatinine level in the context of drug use made us favor the diagnosis of acute interstitial nephritis due to ibuprofen, complicated by the nephrotic syndrome. We were perplexed by the eosinophilia, which has not historically been described as a prominent feature of NSAID-associated interstitial nephritis. In a patient with presumptive interstitial nephritis, we may consider either renal biopsy or empirical treatment. If the presentation is classic, with rash, eosinophiluria, and a typical urinary sediment, clinical confi-

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dence may be high enough to treat the patient simply by discontinuing the NSAID, if functional impairment is mild, or by giving corticosteroids, if the disease is severe. Unless it is contraindicated, I prefer to perform a biopsy to be certain of the diagnosis before committing a patient to high-dose corticosteroid treatment, which itself has risks. Dr. David J.R. Steele (Nephrology): This patient presented in a somewhat atypical fashion, with respiratory symptoms and eosinophilia. Was vasculitis considered, and was the ANCA titer checked at any time? Dr. Bazari: The ANCA test was performed, but the result did not come back until after the biopsy had been performed. The test result was negative.

clinical diagnosis
Acute interstitial nephritis with the nephrotic syndrome due to the use of a nonsteroidal antiinflammatory agent (ibuprofen).

dr. ajay k. singhs diagnosis

Acute interstitial nephritis with the nephrotic syndrome due to the use of a nonsteroidal antiinflammatory agent (ibuprofen), with acute tubular necrosis.

pathological discussion
Dr. Robert B. Colvin: The diagnostic procedure was a percutaneous renal biopsy. The cortex and medulla had a patchy, intense, mononuclear infiltrate associated with edema (Fig. 1A). Eosinophils were conspicuous, sometimes showing degranulation and sometimes invading tubules. Neutrophils were scant. The blood vessels were unremarkable. The tubules showed widespread injury with loss of brush borders, basophilic cytoplasm, detachment of apoptotic cells (anoikis), and occasional mitoses features that are typical of acute tubular injury. Many focal granulomas were present, with epithelioid histiocytes and scattered eosinophils around pale, amorphous, acellular material. The source of the amorphous material could be traced to ruptured tubules in several areas (Fig. 1B), but its nature was unknown. The material did not stain with periodic acidSchiff reagent and was therefore not TammHorsfall protein. Tubular reabsorption droplets were evident, indicative of heavy proteinuria. The pathological diagnosis of these light-

Figure 1. Renal-Biopsy Specimen Showing Interstitial Nephritis (Hematoxylin and Eosin). A diffuse, interstitial, mononuclear infiltrate is present in the cortex (Panel A, 125) and is associated with edema and tubular injury. A ruptured tubule (Panel B, 500) with amorphous material extruding from the tubule (straight arrow) is associated with a granulomatous response containing eosinophils (curved arrow) and invasion of the tubule by eosinophils (arrowheads).

microscopical changes is acute interstitial nephritis with a granulomatous reaction, compatible with a drug reaction. The nine glomeruli sampled were normal on periodic acidSchiff staining, with no thickening of the capillary wall, which would have suggested membranous glomerulonephritis, and no segmental scarring in the multiple levels examined (Fig. 2A). Immunofluorescence showed no immunoglobulin (IgG, IgA, and IgM), complement (C3), fibrinogen, or albumin in the four glomeruli sampled or along the tubular basement membrane, although these proteins were present in tubular reabsorption droplets. Examination of two glomeruli by electron microscopy showed widespread effacement of foot processes and villous hypertrophy of podocytes (Fig. 2B). The glomerular basement membrane and mes-

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Figure 2. Renal-Biopsy Specimen Showing MinimalChange Glomerular Disease. The glomeruli appear normal on periodic acidSchiff staining (Panel A, 500). Electron micrography reveals widespread loss of foot processes (arrows) and a normal glomerular basement membrane (Panel B, 2500). The scale bar represents 3.95 m.

angium were normal, without deposits. The diagnosis of the glomerular changes is minimal-change disease, although focal segmental sclerosis cannot be ruled out. This finding can also occur as part of a drug reaction. Rennke and colleagues were among the first to describe minimal-change disease associated with drug-induced interstitial nephritis (due to ampicillin).22 Since then, others have noted minimal-change disease during therapy with a variety of agents, including ibuprofen4-6,23,24 and other NSAIDs,24 tamoxifen, amoxicillin, lithium, and interferon alfa. I was unable to find any report in which hydrochlorothiazide was mentioned as a cause of the podocyte lesions of this disease. anatomical diagnosis Acute interstitial nephritis is a well-known, idiosyncratic reaction to any of a large variety of drugs, Acute granulomatous interstitial nephritis with tuincluding ibuprofen,12,13 other NSAIDs, hydrochlo- bular injury and minimal-change disease, due to rothiazide, and antibiotics. Granulomatous inter- a reaction to ibuprofen.

stitial nephritis may occur as an idiopathic disease, as a manifestation of sarcoidosis, or as a well-recognized form of drug allergy.21,25,26 Among the drugs that have been reported to cause the granulomatous form of hypersensitivity is hydrochlorothiazide but not yet, apparently, ibuprofen, although ibuprofen has been associated with bone marrow granulomas.27 The mechanism of drug-induced interstitial nephritis is believed to be CD4+ T-cellmediated reactivity28,29 or CD8+ cytotoxic T-cellmediated tubular damage.24 The antigen is presumed to be the drug or its metabolite, attached to autologous macromolecules. The possibility that it is an autoimmune reaction seems unlikely, since the disease abates when the drug is discontinued. The cause of the glomerular podocyte reaction is more mysterious. The glomerular podocyte reaction and tubulointerstitial nephritis have distinct mechanisms, since either may occur without the other.30 Dr. Steele: Is tubulitis a requirement for the diagnosis of acute interstitial nephritis? Dr. Colvin: Yes, in my opinion. Tubulitis is virtually always found. Dr. Harris: Dr. Bazari, could you clarify the rationale for performing a renal biopsy in this patient and then tell us how you treated her? Dr. Bazari: This patient required peritoneal dialysis after the biopsy. According to data from cases of methicillin-induced acute interstitial nephritis, the time to recovery of normal renal function without corticosteroids is six to seven weeks. In a patient who requires dialysis, the decision to provide treatment with corticosteroids is straightforward. We treated this patient with high-dose corticosteroids, starting with intravenous methylprednisolone; diuresis began a few days later. She underwent three dialysis treatments after which her renal function began to improve. She was discharged on the 12th hospital day while taking oral prednisone in tapered doses. At the time of discharge, the creatinine level was 2.9 mg per deciliter (256.4 mol per liter); three days after discharge, it was 1.2 mg per deciliter (106.1 mol per liter). The prednisone was discontinued, and she has continued to have normal renal function.

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references
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nant tubulointerstitial lupus nephritis. Am J Kidney Dis 1996;27:273-8. 2. Tse WY, Howie AJ, Adu D, et al. Association of vasculitic glomerulonephritis with membranous nephropathy: a report of 10 cases. Nephrol Dial Transplant 1997;12: 1017-27. 3. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal anti-inflammatory drugs. N Engl J Med 1984;310:563-72. 4. Regester RF. Nephrotic syndrome and renal failure associated with use of nonsteroidal anti-inflammatory drugs. J Tenn Med Assoc 1980;73:709-11. 5. Tolins JP, Seel P. Ibuprofen-induced interstitial nephritis and the nephrotic syndrome. Minn Med 1987;70:509-11. 6. Justiniani FR. Over-the-counter ibuprofen and nephrotic syndrome. Ann Intern Med 1986;105:303. 7. Ravnskov U. Glomerular, tubular and interstitial nephritis associated with non-steroidal antiinflammatory drugs: evidence of a common mechanism. Br J Clin Pharmacol 1999;47:203-10. 8. Bander SJ. Reversible renal failure and nephrotic syndrome without interstitial nephritis from zomepirac. Am J Kidney Dis 1985;6:233-6. 9. Maniglia R, Schwartz AB, Moriber-Katz S. Non-steroidal anti-inflammatory nephrotoxicity. Ann Clin Lab Sci 1988;18:240-52. 10. Tam VK, Green J, Schwieger J, Cohen AH. Nephrotic syndrome and renal insufficiency associated with lithium therapy. Am J Kidney Dis 1996;27:715-20. 11. Rettmar K, Kienast J, van de Loo J. Minimal change glomerulonephritis with reversible proteinuria during interferon alpha 2a therapy for chronic myeloid leukemia. Am J Hematol 1995;49:355-6.

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35-millimeter slides for the case records Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a medical teaching exercise or reference material is eligible to receive 35-mm slides, with identifying legends, of the pertinent x-ray films, electrocardiograms, gross specimens, and photomicrographs of each case. The slides are 2 in. by 2 in., for use with a standard 35-mm projector. These slides, which illustrate the current cases in the Journal, are mailed from the Department of Pathology to correspond to the week of publication and may be retained by the subscriber. Each year approximately 250 slides from 40 cases are sent to each subscriber. The cost of the subscription is $450 per year. Application forms for the current subscription year, which began in January, may be obtained from Lantern Slides Service, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974). Slides from individual cases may be obtained at a cost of $35 per case.

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