Diagnosis and Management of Acute Interstitial Nephritis.pdf

Diagnosis and Management of Acute Interstitial Nephritis CHARLES M. KODNER, M.D., and ARCHANA KUDRIMOTI, M.D. University of Louisville School of Medicine, Louisville, Kentucky Acute interstitial nephritis is an important cause of acute renal failure resulting from immune-mediated tubulointerstitial...

Diagnosis and Management of Acute Interstitial Nephritis CHARLES M. KODNER, M.D., and ARCHANA KUDRIMOTI, M.D. University of Louisville School of Medicine, Louisville, Kentucky Acute interstitial nephritis is an important cause of acute renal failure resulting from immune-mediated tubulointerstitial injury, initiated by medications, infection, and other O A patient informa- causes. Acute interstitial nephritis may be implicated in up to 15 percent of patients hos- tion handout on kid- ney failure, written by pitalized for acute renal failure. Clinical features are essentially those of acute renal fail- the authors of this ure from any cause, and apart from a history of new illness or medication exposure, there article, is provided on are no specific history, physical examination, or laboratory findings that distinguish acute page 2539. interstitial nephritis from other causes of acute renal failure. Classic findings of fever, rash, and arthralgias may be absent in up to two thirds of patients. Diagnostic studies such as urine eosinophils and renal gallium 67 scanning provide suggestive evidence, but they are unable to reliably confirm or exclude the diagnosis of acute interstitial nephri- tis. Renal biopsy remains the gold standard for diagnosis, but it may not be required in mild cases or when clinical improvement is rapid after removal of an offending agent or medication. The time until removal of such agents, and renal biopsy findings, provide the best prognostic information for return to baseline renal function. Corticosteroids appear to provide some benefit in terms of clinical improvement and return of renal function, but no controlled clinical trials have been conducted to confirm this. (Am Fam Physician 2003;67:2527-34,2539. Copyright© 2003 American Academy of Family Physicians.) A cute interstitial nephritis (AIN) stitium. The term was first used by Council- defines a pattern of renal injury man1 in 1898 when he noted the histopatho- usually associated with an abrupt logic changes in autopsy specimens of patients deterioration in renal function with diphtheria and scarlet fever. Although the characterized histopathologically term acute interstitial nephritis is more com- by inflammation and edema of the renal inter- monly used, acute tubulointerstitial nephritis more accurately describes this disease entity, because the renal tubules, as well as the intersti- TABLE 1 tium, are involved. AIN has become an impor- Disease Processes Associated with AIN tant cause of acute renal failure caused by drug hypersensitivity reactions as a result of the Disease category Specific examples increasing use of antibiotics and other medica- Bacterial infections Corynebacterium diphtheriae, legionella3, staphylococci, tions that may induce an allergic response in the streptococci, yersinia interstitium. AIN has been reported to occur in Viral infections Cytomegalovirus, Epstein-Barr virus, hantaviruses, approximately 1 percent of renal biopsies dur- hepatitis C, herpes simplex virus, human ing the evaluation of hematuria or proteinuria. immunodeficiency virus, mumps4, polyoma virus In some studies of patients with acute renal fail- Other infections Leptospira, mycobacterium, mycoplasma, rickettsia, ure, approximately 5 to 15 percent had AIN.2 syphilis, toxoplasmosis Immune and Acute rejection of a renal transplant, glomerulonephritis, Etiology neoplastic lymphoproliferative disorders, necrotizing vasculitis, The most frequent causes of AIN can be disorders plasma cell dyscrasias, systemic lupus erythematosus found in one of three general categories: drug- induced, infection-associated, and cases asso- AIN = acute interstitial nephritis. ciated with immune or neoplastic disorders Information from references 2 through 4. (Table 1 2-4). Other causes of tubulointerstitial nephropathy also are addressed. JUNE 15, 2003 / VOLUME 67, NUMBER 12 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2527  associated with indirect injury caused by medications used DRUG-INDUCED AIN in the treatment of infections. For example, human The list of drugs implicated in causing AIN continues to immunodeficiency virus (HIV) can be responsible for AIN expand (Table 2 2,5-16). Drugs are more frequently recog- caused by opportunistic infections or using drugs such as nized as etiologic factors in AIN because of the increased indinavir (Crixivan), sulfonamide antibiotics, and others. frequency with which drugs are used, the increased use of Sometimes depressed cell-mediated immunity may have renal biopsy, and the characteristic clinical presentation. the impact of protecting the patient from developing AIN. Some classes of medication often are associated with cer- tain clinical features of AIN, as summarized in Table 3. IMMUNE DISORDERS Development of drug-induced AIN is not dose-related. AIN may be caused by local or systemic autoimmune AIN may become clinically evident an average of two weeks processes. Several types of glomerulonephritis result in or longer after starting a medication.17 interstitial inflammation, possibly associated with anti- tubular basement membrane (anti-TBM) autoantibodies. INFECTIONS Sjögren’s syndrome, systemic lupus erythematosus, and AIN is associated with primary renal infections such as Wegener’s granulomatosis also may cause immune com- acute bacterial pyelonephritis, renal tuberculosis, and fun- plex-mediated disease. gal nephritis. Systemic infections can cause direct injury because of pathologic processes in the kidney or can be Clinical Features Patients with AIN typically present with nonspecific symptoms of acute renal failure, including oliguria, TABLE 2 malaise, anorexia, or nausea and vomiting, with acute or Medications Associated with AIN subacute onset.5 The clinical presentation can range from asymptomatic elevation in creatinine or blood urea nitro- Medication class Specific examples gen (BUN) or abnormal urinary sediment, to generalized hypersensitivity syndrome with fever, rash, eosinophilia, Antibiotics Cephalosporins*, ciprofloxacin6 (Cipro), and oliguric renal failure. A relatively rapid decrease in ethambutol (Myambutol), isoniazid (INH), macrolides, penicillins*, rifampin* (Rifadin), renal function, as measured by elevated creatinine and sulfonamides*, tetracycline, vancomycin7 BUN, is typical. Other nonspecific laboratory findings, (Vancocin) with expected ranges for AIN, are listed in Table 4. NSAIDs* Almost all agents2 The classic triad of low-grade fever, skin rash, and Diuretics* Furosemide (Lasix), thiazides, triamterene arthralgias was primarily described with methicillin (Dyrenium) (Staphcillin)-induced AIN, but it was present only about Miscellaneous Acyclovir (Zovirax), allopurinol* (Zyloprim), one third of the time. This triad is present in only 5 percent amlodipine8 (Norvasc), azathioprine (Imuran), of cases of AIN overall. Each component of the triad is pre- captopril (Capoten), carbamazepine (Tegretol), sent in 70 to 100 percent, 30 to 50 percent, and 15 to clofibrate (Atromid-S), cocaine, creatine9, 20 percent of AIN cases, respectively.17 Other associated diltiazem10 (Cardizem), famotidine (Pepcid), symptoms may include flank pain, gross hematuria, or indinavir11 (Crixivan), mesalazine12 (Asacol), omeprazole13 (Prilosec), phenteramine14 other clinical findings associated with an underlying dis- (Zantryl), phenytoin (Dilantin), pranlukast ease process. (Ultair)15, propylthioruacil16 (Propacil), quinine (Quinamm), ranitidine (Zantac) Pathology The hallmark of AIN is the infiltration of inflammatory AIN = acute interstitial nephritis; NSAIDs = nonsteroidal anti- cells within the renal interstitium, with associated edema, inflammatory drugs. sparing the glomeruli and blood vessels.2,18 Interstitial *—Frequent or clinically important. fibrosis is initially sparse, but develops later in the course of Information from references 2 and 5 through 16. the illness. Fibrotic lesions may be diffuse or patchy, begin- ning deep in the renal cortex, most prominently at the 2528 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 67, NUMBER 12 / JUNE 15, 2003  Interstitial Nephritis medullocortical junction. The inflammatory infiltrate is typically composed of mononuclear cells and T lympho- Patients with acute interstitial nephritis typically cytes, with a variable number of plasma cells and present with nonspecific symptoms of acute eosinophils. Eosinophils may be totally absent from the renal failure. infiltrate or may concentrate in small foci, forming eosinophilic microabscesses. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly associated with glomerular involvement pro- beneath the TBM may occur with mild to extensive tubular ducing a nil lesion (minimal change disease). Peritubular damage, which may be difficult to distinguish from acute infiltration and occasional invasion of lymphocytes tubular necrosis (ATN). In chronic interstitial nephritis, the cellular infiltrate is largely replaced by interstitial fibrosis. A third pathologic category is granuloma formation TABLE 3 with epithelioid giant cells usually found in AIN secondary Clinical Features of AIN Associated to tuberculosis, sarcoidosis, or Wegener’s granulomatosis. with Specific Medication Classes Pathogenesis Medication classes Special features There is strong evidence that AIN is immunologically Beta lactams and Allergic and hypersensitivity reactions mediated. The precise disease mechanism is unclear, but cephalosporins seen histologically antigen-driven immunopathology is the key mechanism. (prototype: methicillin Classic triad of symptoms (fever, rash, The presence of helper-inducer and suppressor-cytotoxic [Staphcillin]) arthralgias) more common T lymphocytes in the inflammatory infiltrate suggests No correlation between drug dosage and duration with development of AIN that T-cell mediated hypersensitivity reactions and cyto- AIN can occur in people sensitized to toxic T-cell injury are involved in pathogenesis of AIN.19 In penicillin while on cephalosporins some cases, humoral mechanisms are involved with com- and vice versa plement proteins, immunoglobulins, and anti-TBM anti- Sulfonamides and Vasculitis seen histologically bodies found in the interstitium. diuretics Cross reaction between the sulfonamide antimicrobials and the diuretics—use Diagnosis nonsulfonamide diuretics such as ethacrynic acid if requested The diagnostic approach to renal failure in general has Nonsteroidal Most frequent and clinically important been described elsewhere.20 Renal biopsy is the only defin- anti-inflammatory AIN can occur with over-the-counter itive method of establishing the diagnosis of AIN; this step drugs agents such as ibuprofen usually is undertaken when the diagnosis is unclear and Development of AIN is more common there are no contraindications for the procedure, or when in older populations the patient does not improve clinically following discon- Nephrotic range proteinuria is more common tinuation of the medication suspected as the cause of AIN Hematuria is rare and renal failure. Other laboratory features (Table 4) are Histologically pure lesion with/without used to provide suggestive evidence of AIN, to guide con- papillary necrosis with absence of servative management, or to permit empiric treatment glomerular disease with steroids. Unfortunately, none of these tests have suffi- Mixed variety with minimal change glomerulonephritis also is seen cient predictive value to be diagnostically reliable. A num- histologically ber of other diagnostic studies have been proposed to help Antituberculous drugs Associated with intermittent or confirm or exclude AIN. (prototype: rifampin discontinuous dosing [Rifadin]) URINE EOSINOPHILS Urine eosinophils are frequently tested to provide confir- AIN = acute interstitial nephritis. matory evidence of AIN, though the typical constellation of fever, rash, arthralgias, eosinophiluria, and renal insuffi- JUNE 15, 2003 / VOLUME 67, NUMBER 12 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2529 TABLE 4 Laboratory Features Associated with AIN Laboratory study Typical findings Expected range, diagnostic use, or value Urinalysis Proteinuria Present to variable degrees, usually < 1 g per 24 hours except in AIN associated with NSAIDs Pyuria Leukocytes or leukocyte casts Hematuria Red cell casts are rare in AIN Renal tubular epithelial cells or casts Nonspecific finding Elevated urine major basic protein Lacks adequate predictive value to confirm or exclude diagnosis Eosinophiluria Positive predictive value 38 percent (95 percent CI, 15 to 65 percent) Serum chemistry Elevated BUN and creatinine Variable degree of renal injury profile Hyperkalemia or hypokalemia Variable based on severity of renal failure and associated electrolyte or fluid changes Hyperchloremic metabolic acidosis Suggests tubulointerstitial injury Fractional excretion of sodium Usually greater than 1 percent Complete Eosinophilia More often associated with beta-lactam antibiotic-induced AIN blood count Anemia Variable Liver function tests Elevated serum transaminase levels In patients with associated drug-induced liver injury Miscellaneous Elevated serum IgE levels AIN = acute interstitial nephritis; NSAIDs = nonsteroidal anti-inflammatory drugs; CI = confidence interval; BUN = blood urea nitrogen; IgE = immune globulin E. ciency rarely presents completely. Early studies21,22 found disorders such as minimal-change glomerulonephritis, cor- that Hansel’s stain for eosinophils was more sensitive than tical necrosis, and ATN have resulted in positive gallium Wright’s stain but did not conclusively demonstrate that 67 scans. Nonrenal disorders such as iron overload or severe urine eosinophils were diagnostically useful in confirming liver disease also can result in positive gallium 67 scans. or excluding AIN. A more recent study23 found a positive Likewise, patients with biopsy-proven acute tubulointer- predictive value of 38 percent (95 percent confidence inter- stitial disease have had negative gallium 67 scans, therefore val [CI], 15 to 65 percent) and a negative predictive value of the predictive value of this test is limited. In general, 74 percent (95 percent CI, 57 to 88 percent) among patients with ATN have negative scans, and in patients who 51 patients for whom urine eosinophils were ordered to are poor candidates for renal biopsy, gallium 67 scanning help diagnose an acute renal condition; 15 of these were may be useful in distinguishing ATN from AIN. suspected to have AIN, though biopsy was not performed in all patients. Other conditions such as cystitis, prostatitis, RENAL BIOPSY and pyelonephritis also can be associated with eosinophil- Renal biopsy is the gold standard for diagnosis of AIN, uria. Other studies have found similar results; thus, the with the typical histopathologic findings of plasma cell and diagnostic value of urine eosinophils remains unclear. lymphocytic infiltrates in the peritubular areas of the inter- stitium, usually with interstitial edema. IMAGING STUDIES Renal biopsy is not needed in all patients. In patients for Renal ultrasonography may demonstrate kidneys that whom the diagnosis seems likely, for whom a probable are normal to enlarged in size, with increased cortical precipitating drug can be easily withdrawn, or who echogenicity, but there are no ultrasonographic findings improve readily after withdrawal of a potentially offending that will reliably confirm or exclude AIN versus other drug, supportive management can proceed safely without causes of acute renal failure. renal biopsy. Patients who do not improve following with- Gallium 67 scanning has been proposed24,25 as a useful drawal of likely precipitating medications, who have no test to diagnose AIN. In one small series,26 nine patients contraindications to renal biopsy and do not refuse the with AIN had positive gallium 67 scans, while six patients procedure, and who are being considered for steroid ther- with ATN had negative scans. In other studies,27 other renal apy, are good candidates for renal biopsy (Figure 15). Indi- 2530 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 67, NUMBER 12 / JUNE 15, 2003  Diagnosis and Management of AIN Patient with renal insufficiency, AIN suspected Withdraw potentially offending medications. Clinical improvement No clinical improvement (increased urine output, falling creatinine level, resolution of clinical Contraindication to renal biopsy, symptoms) or patient refuses biopsy? Observation, supportive No Yes management Perform renal biopsy. Consider alternative Biopsy diagnostic of AIN? diagnostic study (gallium 67 scan, renal ultrasound). No Yes Treat appropriately or Fibrosis on biopsy Results Results not continue evaluation consistent consistent for other causes of with AIN with AIN renal failure. Severe None or minimal Continue evaluation for other causes of renal failure. Contraindication to steroid therapy? Yes No Trial of steroid therapy (prednisone 1 mg per kg per day) Improvement in renal function? No Yes Continue supportive management; consider trial Continue steroid of alternative immunosuppressive therapy if therapy (see text). not contraindicated. FIGURE 1. Algorithm for the diagnosis and management of interstitial nephritis. (AIN = acute interstitial nephritis) Adapted with permission from Cruz DN, Perazella MA. Drug-inducted acute tubulointerstitial nephritis: the clinical spectrum. Hosp Pract 1998;33:163. JUNE 15, 2003 / VOLUME 67, NUMBER 12 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2531  If offending medications are withdrawn early, TABLE 5 most patients with acute interstitial nephritis will Indications and Contraindications for Renal Biopsy in Suspected AIN recover normal or near-normal renal function in a few weeks. Indications Contraindications Acute renal failure from AIN Bleeding diathesis* suspected clinically Solitary kidney Exposure to potential offending Patient unable to cooperate cations and contraindications for renal biopsy are listed in medications with percutaneous procedure Table 5.28 Typical symptoms of rash, fever, End-stage renal disease with arthralgias small kidneys Prognosis Suggestive evidence on Severe uncontrolled Most patients with AIN in whom offending medications laboratory data hypertension are withdrawn early can be expected to recover normal or No improvement after Patient refusal withdrawal of medication Sepsis or renal parenchymal near-normal renal function within a few weeks. Patients Patient agrees to procedure infection who discontinue offending medications within two weeks of the onset of AIN (measured by increased creatinine) are AIN = acute interstitial nephritis. more likely to recover nearly baseline renal function than those who remain on the precipitating medication for *—May be controlled or may indicate open biopsy if required diagnostically. three or more weeks. A number of investigators have tried to identify other Information from Tisher CC, Croker BP. Indications for and interpreta- tion of the renal biopsy: evaluation by light, electron, and immuno- clinical and renal biopsy features that will provide prog- fluorescence microscopy. In: Scrier RW, Gottschalk CW, eds. Diseases nostic information in terms of recovery of renal function. of the kidney. 6th ed. Boston: Little, Brown, 1997:435-41. One study29 noted two phases to recovery in AIN: an ini- tial rapid phase of improvement lasting six to eight weeks, followed by a phase of slower improvement to the previ- ous or new baseline renal function lasting approximately fuse (versus patchy) inflammation on biopsy; excess num- one year. ber of neutrophils (1 to 6 percent); and extent or severity Adverse prognostic factors in AIN recovery include dif- of interstitial fibrosis, which was noted to correlate most closely with the final glomerular filtration rate.29 Management The Authors Figure 15 shows an algorithm for diagnosis and manage- CHARLES M. KODNER, M.D., is assistant professor in the Department ment of patients with suspected AIN. of Family and Community Medicine at the University of Louisville School of Medicine in Louisville, Ky. He earned his medical degree at SUPPORTIVE CARE Washington University School of Medicine in St. Louis, and completed a residency in family practice at the Mercy Family Practice Residency Withdrawal of medications that are likely to cause AIN program at St. John’s Mercy Medical Center in St. Louis, Mo. is the most significant step in early management of sus- ARCHANA KUDRIMOTI, M.D., is research fellow in the University of pected or biopsy-proven AIN.30 If multiple potentially pre- Louisville Family Medicine Residency program of the Department of cipitating medications are being used by the patient, it is Family and Community Medicine at the University of Louisville School of Medicine, Louisville, Ky., where she completed her residency. She reasonable to substitute other medications for as many of earned her medical degree at Osmania Medical College in Hyderabad, these as possible and to withdraw the most likely etiologic India, and completed residency training in obstetrics and gynecology at agent among medications that cannot be substituted. The Gandhi Medical College and Hospital in Hyderabad, India. majority of patients with AIN improve spontaneously fol- Address correspondence to Charles M. Kodner, M.D., Med Center One lowing the withdrawal of medications that resulted in renal Bldg., Department of Family and Community Medicine, University of Louisville School of Medicine, Louisville, KY 40202. Reprints are not failure, and such patients should be listed as having had an available from the authors. adverse reaction to these medications. 2532 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 67, NUMBER 12 / JUNE 15, 2003  Interstitial Nephritis TABLE 6 TABLE 7 Supportive Care Measures Other Clinical Syndromes Manifesting as Interstitial Nephritis Fluid and electrolyte management Maintain adequate hydration Syndrome Typical features Avoid volume depletion or overload Analgesic-induced AIN History of chronic pain or aspirin use; Identify and correct electrolyte abnormalities associated with epigastric symptoms, Symptomatic relief for fever and systemic symptoms anemia, sterile pyuria Symptomatic relief for rash Avoid use of nephrotoxic drugs Toxin-induced AIN (lead) Progressive renal failure associated with lead exposure, hypertension, Avoid use of drugs that impair renal blood flow gout, and proteinuria Adjust drug dosages for existing level of renal function Sarcoidosis and AIN Granulomatous interstitial nephritis associated with hypercalcemia and pulmonary involvement Other supportive care interventions are listed in Table 6. Chronic interstitial Heavy metal exposure or other causes; Indications for renal dialysis in the management of acute nephritis mild proteinuria, glucosuria with normal serum glucose renal failure have been described elsewhere,31 and these include uncontrolled hyperkalemia, azotemia with mental Tubulointerstitial Diffuse eosinophilic nephritis with nephritis-uveitis bone marrow and lymphoid status changes, and other symptomatic fluid or electrolyte syndrome granulomas seen in pubertal females derangements. with constitutional symptoms and uveitis CORTICOSTEROID THERAPY HIV-associated renal AIDS nephropathy, drug-induced AIN, There are no randomized trials to support the use of disease proteinuria, other renal disorders corticosteroids in treatment of AIN. Small case reports and studies32 have demonstrated rapid diuresis, clinical AIN = acute interstitial nephritis; HIV = human immunodeficiency improvement, and return of normal renal function within virus; AIDS = acquired immunodeficiency syndrome. 72 hours after starting steroid treatment, although some case reports indicate lack of efficacy, especially in cases of NSAID-induced AIN. The decision to use steroids should be guided by the clinical course following withdrawal of The authors indicate that they do not have any conflicts of inter- offending medications. est. Sources of funding: none reported. If steroid therapy is started, a reasonable dosage is pred- REFERENCES nisone, 1 mg per kg per day orally (or equivalent intra- venous dose) for two to three weeks,30,33 followed by a 1. Councilman WT. Acute interstitial nephritis. J Exp Med gradually tapering dose over three to four weeks. In 1898;3:393-420. 2. Michel DM, Kelly CJ. Acute interstitial nephritis. 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