- Email: [email protected]
Acute Interstitial Nephritis
C H A P T E R
60
Acute Interstitial Nephritis Jerome A. Rossert, Evelyne A. Fischer
DEFINITION Acute interstitial nephritis (AIN) is an acute, often reversible disease characterized by inflammatory infiltrates within the interstitium. AIN is a rare cause of acute kidney injury (AKI), but it should not be overlooked because it usually requires specific therapeutic interventions.
PATHOGENESIS Most studies suggest that AIN is an immunologically induced hypersensitivity reaction to an antigen that is classically a drug or an infectious agent. Evidence for a hypersensitivity reaction in drug-induced AIN includes the following: it occurs only in a small percentage of individuals; it is not dose dependent; it is often associated with extrarenal manifestations of hypersensitivity; it recurs after accidental reexposure to the same drug or to a closely related one; and it is sometimes associated with evidence of delayed-type hypersensitivity reaction (renal granulomas). Similarly, AIN secondary to infections can be differentiated from pyelonephritis by the relative absence of neutrophils in the interstitial infiltrates and the failure to isolate the infective agent from the renal parenchyma, again suggesting an immunologic basis to the disease. Studies of experimental models of AIN have shown that three major categories of antigens can induce AIN.1 Antigens may be tubular basement membrane (TBM) components (such as the glycoproteins 3M-1 and TIN-Ag/TIN1), secreted tubular proteins (such as Tamm-Horsfall protein), or nonrenal proteins (such as from immune complexes). Although some types of human AIN may be secondary to an immune reaction directed against a renal antigen, the majority of cases of AIN are probably induced by extrarenal antigens, being produced in particular by drugs or infectious agents. These antigens may be able to induce AIN by a variety of mechanisms. These mechanisms include binding to kidney structures (“planted antigen”); acting as haptens that modify the immunogenicity of native renal proteins; mimicking renal antigens, resulting in a cross-reactive immune reaction; and precipitating within the interstitium as circulating immune complexes. Studies of experimental models of AIN show that their pathogenesis involves either cell-mediated immunity or antibodymediated immunity (Fig. 60.1). In humans, most forms of AIN are not associated with antibody deposition, which suggests that cell-mediated immunity plays a major role. This hypothesis is reinforced by the fact that interstitial infiltrates usually contain numerous T cells and that these infiltrates sometimes form granulomas. Nevertheless, deposition of anti-TBM antibodies or of immune complexes can be observed occasionally in renal biopsy
specimens, and antibody-mediated immunity may play a role in the pathogenesis of the disease in these cases. Formation of immune complexes within the interstitium, or interstitial infiltration with T cells, will result in an inflammatory reaction. This reaction is triggered by many events, including activation of the complement cascade by antibodies and release of inflammatory cytokines by T lymphocytes and phagocytes (see Fig. 60.1). Although the interstitial inflammatory reaction may resolve without sequelae, it sometimes induces interstitial fibroblast proliferation and extracellular matrix synthesis, leading to interstitial fibrosis and chronic renal failure. Cytokines such as transforming growth factor ß appear to play a key role in this latter process.
EPIDEMIOLOGY AIN is an uncommon cause of AKI and is identified in only about 2% to 3% of all renal biopsy specimens.2 However, it may account for up to 10% to 25% of patients undergoing renal biopsy for unexplained or drug-induced AKI, respectively.2 Although AIN can occur at any age, it appears to be rare in children. Before antibiotics were available, AIN was most commonly associated with infections, such as scarlet fever and diphtheria. Currently, AIN is most often induced by drugs, particularly antimicrobial agents, proton pump inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs). Drug-induced AIN appears to account for about 75% to 90% of all cases.
DRUG-INDUCED ACUTE INTERSTITIAL NEPHRITIS Clinical Manifestations In the 1960s and 1970s, most cases of drug-induced AIN were caused by methicillin, and the clinical manifestations of methicillin-induced AIN were considered the prototypical presentation of AIN. Since then, many other drugs have been implicated in the induction of AIN (Fig. 60.2), of which antimicrobial agents (in particular, b-lactam antibiotics, sulfonamides, fluoroquinolones, and rifampin) and NSAIDs (especially fenoprofen) as well as cyclooxygenase 2 (COX-2) inhibitors have been most commonly involved. Antiulcer agents, diuretics, phenindione, phenytoin, and allopurinol have also been reported to cause AIN. There are increasing numbers of reports of AIN induced by proton pump inhibitors, with more than 70 reported biopsyproven cases.3 Recently, cases of drug-induced AIN have also been reported in human immunodeficiency virus (HIV)–infected patients treated with highly active antiretroviral therapy (HAART)4 and in cancer patients treated with tyrosine kinase 729
730
SECTION
XI Tubulointerstitial and Vascular Diseases
Immune Mechanisms in Acute Interstitial Nephritis Cell-mediated mechanisms
Antibody-mediated mechanisms Blood vessel
Blood vessel Neutrophil
(+)
Neutrophils
Monocyte
MHC class II
(+)
(+)
Macrophage
(+)
Th1 lymphocyte (+)
Cytotoxic T lymphocyte MHC class I
Natural killer cell
Tubule
(+)
Processed antigen
Neutrophil (+)
(+)
Macrophage
Th lymphocyte
(+)
Monocyte
Th2 lymphocyte (+)
MHC class II B lymphocyte
Eosinophil Natural killer cell
Complement
(+) Complement
Tubule
Figure 60.1 Immune mechanisms that can be involved in acute interstitial nephritis. Both cell-mediated and antibody-mediated mechanisms occur. The cell-mediated mechanism is primarily associated with macrophages and T cells. The antibody-mediated mechanism is frequently associated with neutrophil or eosinophil infiltration as well as with local complement activation. MHC, major histocompatibility complex.
inhibitors.5 Most other drugs have only rarely been linked with AIN (see Fig. 60.2). The clinical characteristics of drug-induced AIN are now recognized as much more varied and nonspecific than the spectrum seen in classic methicillin-induced AIN (Fig. 60.3).6,7 Renal Manifestations Symptoms of AIN usually develop a few days to a few weeks after the inciting drug is started, although cases have occurred months after initial exposure to the drug. The typical presentation is sudden impairment in renal function, associated with mild proteinuria (<1 g/day) and abnormal urinalysis, in a patient with flank pain, normal blood pressure, and no edema. In patients with AIN not caused by methicillin, the clinical presentation is often incomplete (see Fig. 60.3), and AIN should be considered in any patient with unexplained AKI.6,7 The renal dysfunction may be mild or severe; dialysis is required in about one third of patients. Hematuria and pyuria are present in a little more than half of the patients, and although leukocyte casts are common, hematuria is almost never associated with red blood cell casts. Flank pain, reflecting distention of the renal capsule, is observed in about one third of the patients and can be the main complaint on hospital admission. On occasion, patients have a low fractional excretion of sodium. Standard imaging procedures show kidneys normal in size or slightly enlarged. Ultrasound usually discloses an increased cortical echogenicity (comparable to or higher than that of the liver). Extrarenal Manifestations Extrarenal symptoms consistent with a hypersensitivity reaction are occasionally observed, including low-grade fever, maculo-
papular rash (Fig. 60.4), mild arthralgias, and eosinophilia. If patients with methicillin-induced AIN are not considered, each of these symptoms is present in less than half of the patients (see Fig. 60.3), and all these symptoms are present together in less than 10% of patients.2,6,7 With some drugs, other manifestations of hypersensitivity, such as hemolysis or hepatitis, can be present. Serum IgE levels may also be elevated. The association of AKI either with clinical signs suggestive of hypersensitivity or with eosinophilia should lead to consideration of a diagnosis of AIN. However, signs of hypersensitivity can also be observed in patients with AKI not related to AIN, including patients with drug-induced acute tubular necrosis. Other Specific Drug Associations The clinical and biologic manifestations of AIN may have some specificity, depending on the drug involved. As outlined earlier, methicillin-induced AIN is characterized by a high frequency of abnormal urinalysis and extrarenal symptoms and by good preservation of renal function. Renal failure has been reported in only about 50% of patients (see Fig. 60.3). More than 200 cases of rifampin-induced AKI have been reported. Most have been observed either after readministration of rifampin or several months after intermittent administration of the drug. Renal failure is usually associated with the sudden onset of fever, gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain), and myalgias. It may also be associated with hemolysis, thrombocytopenia, and less frequently hepatitis. Renal biopsy typically discloses tubular injury in addition to interstitial inflammatory infiltrates. Although circulating anti-rifampin antibodies are usually found in these patients, immunofluorescence staining of renal biopsy specimens has been
CHAPTER
60 Acute Interstitial Nephritis
731
Drugs Responsible for Acute Interstitial Nephritis ANTIMICROBIAL AGENTS PENICILINS Amoxicillin Ampicillin* Aztreonam Carbenicillin Cloxacillin Methicillin* Mezlocillin Nafcillin Oxacillin* Penicillin G* (benzylpenicillin*) Piperacillin CEPHALOSPORINS Cefaclor Cefamandole Cefazolin Cefixim Cefoperazone Cefotaxime Cefotetan Cefoxitin Ceftriaxone Cephalexin Cephaloridine Cephalothin Cephapirin Cephradine Latamoxef QUINOLONES Ciprofloxacin* Levofloxacin* Moxifloxacin Norfloxacin OTHERS Abicavir Acyclovir Atazanavir Azithromycin Clarithromycin Colistin Cotrimoxazole* Erythromycin* Ethambutol Flurithromycin Foscarnet Gentamicin Indinavir Interferon Isoniazid Lincomycin Minocycline Nitrofurantoin* Piromidic acid Polymixin B*
Quinine Rifampin* (rifampicin*) Spiramycine* Sulfonamides* Teicoplamin Telithromycin Tetracycline Vancomycin* NSAIDs INCLUDING SALICYLATES SALICYLATES AND DERIVATIVES Aspirin (acetyl salicylic acid) Diflunisal*
ANALGESICS Aminopyrine Antipyrine Antrafenin Clometacin* (clometazin*) Dipyrone (noramidopyrine, metamizol) Floctafenin* Glafenin* ANTICONVULSANTS
PROPIONIC ACID DERIVATIVES Benoxaprofen Fenbufen Fenoprofen* Flurbiprofen Ibuprofen* Ketoprofen Naproxen Pirprofen Suprofen
Carbamazepine* Diazepam Phenobarbital (phenobarbitone) Phenytoin* Valproic acid (valproate sodium)
ACETIC ACID DERIVATIVES Indomethacin* (indometacin) Alclofenac Diclofenac Fenclofenac Sulindac Zomepirac
Chlortalidone Ethacrynic acid Furosemide* (frusemide*) Hydrochlorothiazide* Indapamide Tienilic acid* Triamterene*
ENOLIC ACID DERIVATIVES Meloxicam Piroxicam* FENAMIC ACID DERIVATIVES Mefenamic acid Niflumic acid COXIBS Celecoxib Rofecoxib OTHERS Azapropazone Mesalamine (mesalazine, 5ASA) Phenazone Phenylbutazone Sulfasalazine Tolmetin
DIURETICS
ANTIULCER AGENTS H2-RECEPTOR ANTAGONISTS Cimetidine* Famotidine Ranitidine
OTHERS Allopurinol* Alpha Methyl Dopa Amlodipine Azathioprine Betanidine* Bismuth salts Captopril* Carbimazole Chlorpropamide* Clofibrate Clozapine Cyamemazine* Cyclosporine Cytosine Arabinoside Desferasirox Diltiazem D-penicillamine Etanercept Fenofibrate* Fluindione Gold salts Griseofluvin Interleukin 2 Lamotrigine* Linezolid Nicergolin Phenindione* Phenothiazine Phentermine/ Phendimetrazine Phenylpropanolamine Probenecid Propanolol Propylthiouracil Sorafenib Streptokinase Sulphinpyrazone Sunitinib Warfarin Zopiclone
PROTON PUMP INHIBITORS Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole
Figure 60.2 Drugs responsible for acute interstitial nephritis. Drugs most commonly involved are in bold. NSAIDs, nonsteroidal anti-inflammatory drugs. *Drugs that can cause granulomatous AIN.
negative in most cases, suggesting that cell-mediated immunity plays a key role in the induction of the nephritis. In a few cases, AIN developed after continuous treatment with rifampin for 1 to 10 weeks. It was almost never associated with extrarenal symptoms or with anti-rifampin antibodies, and renal biopsy specimens showed severe interstitial infiltrates but few tubular lesions.
Phenindione-induced AIN is generally associated with the development of hepatitis, which can be fatal. Allopurinol-induced AIN appears to occur more often in patients with chronic kidney disease (CKD) and is usually seen in association with rash and liver dysfunction. It has been suggested that the decreased excretion of oxypurinol, a metabolite of allopurinol, might favor the occurrence of AIN. There is also
732
SECTION
XI Tubulointerstitial and Vascular Diseases
Clinical Manifestation of Drug-Induced Acute Interstitial Nephritis Methicillin Eosinophilia Extrarenal symptoms Mild proteinuria Pyuria Hematuria Macroscopic hematuria Oliguria Renal failure 0%
20%
40% 60% 80% Percentage of patients
100%
Other drugs Eosinophilia Extrarenal symptoms Mild proteinuria Pyuria
Figure 60.4 Maculopapular rash in a patient with drug-induced acute interstitial nephritis. Such cutaneous lesions occur in about 40% of patients with drug-induced AIN, but they can also be seen in patients with drug-induced acute tubular necrosis.
Hematuria Macroscopic hematuria Oliguria Renal failure 0%
20%
40% 60% 80% Percentage of patients
100%
Figure 60.3 Clinical manifestations of drug-induced acute interstitial nephritis. Data were pooled from different case reports, including 95 patients with methicillin-induced AIN and more than 200 patients with other drug-induced AIN. Patients with AIN associated with a nephrotic syndrome are not included.
Clinical Presentation of AIN and Nephrotic Syndrome Associated with NSAID Use
Eosinophilia Extrarenal symptoms Pyuria
some experimental evidence that in the setting of renal impairment, allopurinol may precipitate as microcrystals or crystals and cause direct nephrotoxicity. Whether this can occur in humans is unknown, but it may provide an additional reason to reduce allopurinol doses in subjects with CKD. AIN occurring secondary to NSAIDs is associated with nephrotic syndrome in about three fourths of cases. This usually occurs in patients older than 50 years, and although it has been observed with all NSAIDs, including COX-2–selective inhibitors, half of the incidents have been reported with fenoprofen. Most occurrences develop after the patient has taken NSAIDs for some months (mean, 6 months), but AIN can occur within days or after more than a year. With the exception of the heavy proteinuria and associated edema, the presentation of these patients is similar to that of patients with other drug-induced AIN (Fig. 60.5). The main difference is that extrarenal symptoms are present in only about 10% of patients. Renal disease caused by NSAIDs must be differentiated from other NSAID-induced nephropathies, including hemodynamically mediated AKI, papil-
Macroscopic hematuria Hematuria Hypertension Edema 0%
20%
40%
60%
80%
100%
Percentage of patients
Figure 60.5 Clinical presentation of AIN and nephrotic syndrome associated with NSAID use. Data were pooled from different case reports from more than 60 patients.
lary necrosis, and NSAID-induced membranous nephropathy. Drugs other than NSAIDs can rarely induce AIN associated with a nephrotic syndrome; a few cases have been reported after administration of ampicillin, rifampin, lithium, interferon, phenytoin, pamidronate, and d-penicillamine.
Pathology The hallmark of AIN is the presence of inflammatory infiltrates within the interstitium (Fig. 60.6). These infiltrative lesions are often patchy, predominating in the deep cortex and in the outer medulla, but they can be diffuse in severe cases. They are composed mostly of T cells and monocytes-macrophages, but plasma cells, eosinophils, and a few neutrophilic granulocytes may also be present. The relative number of CD4+ T cells and CD8+ T cells is variable from one patient to another. In some cases, T lymphocytes infiltrate across the TBM and between tubular cells, mainly in distal tubules, and the resulting lesion is referred to as tubulitis. In some cases of drug-induced AIN, renal biopsy shows interstitial granulomas (Fig. 60.7). These granulomas are usually sparse and non-necrotic, with few giant cells, and are associated with nongranulomatous interstitial infiltrates. Granulomas are also found in AIN related to infection (see Fig 60.10), sarcoidosis, Sjögren’s syndrome, and Wegener’s granulomatosis. Interstitial infiltrates are always associated with an interstitial edema, which is responsible for separating the tubules (see Fig. 60.6). They can also be associated with focal tubular lesions, which range from mild cellular alterations to extensive necrosis of epithelial cells and are sometimes associated with a disruption of the TBM. These tubular lesions usually predominate where the inflammatory infiltrates are most extensive.
Figure 60.6 Drug-induced acute interstitial nephritis. On light microscopy, the characteristic feature is interstitial infiltration with mononuclear cells, with normal glomeruli. It is usually associated with interstitial edema and tubular lesions. (Courtesy of Dr. B. Mougenot, Paris VI University, Paris France.)
Figure 60.7 Drug-induced granulomatous acute interstitial nephritis. Some drugs can induce the formation of interstitial granulomas, which reflect a delayed-type hypersensitivity reaction. (Courtesy of Dr. B. Mougenot, Paris VI University, Paris France)
CHAPTER
60 Acute Interstitial Nephritis
733
Tubulointerstitial lesions are not associated with vascular or glomerular lesions. Even in AIN associated with a nephrotic syndrome, glomeruli appear normal on light microscopy; glomerular lesions are similar to those seen in minimal change disease (see Chapter 17). In most patients with AIN, renal biopsy specimens do not show immune deposits, and both immunofluorescence and electron microscopy are negative. Nevertheless, staining of the tubular or capsular basement membrane for IgG or complement may occasionally be seen by immunofluorescence; the staining pattern is either granular or linear (Fig. 60.8). Linear fixation of IgG along the TBM indicates the presence of antibodies directed against membrane antigens or against drug metabolites bound to the TBM, and circulating anti-TBM antibodies have been detected in some cases. These linear deposits are seen mostly in patients taking methicillin, NSAIDs, phenytoin, or allopurinol.
Diagnosis The most accurate way to diagnose AIN is by renal biopsy. However, both eosinophiluria and gallium scanning have been suggested as helpful in making the diagnosis. Eosinophils can be detected in urine with use of either the Wright stain or the Hansel stain, which both are eosin–methylene blue combinations, but the Hansel stain appears to be much more sensitive.8,9 The result of this test is usually considered positive if more that 1% of urinary white blood cells are eosinophils. However, although eosinophiluria is frequently used to corroborate the diagnosis of drug-induced AIN, review of four large series shows that this test has rather poor sensitivity (67%) and a low positive predictive value, even when only patients with AKI are considered (50%) (Fig. 60.9).8-11 In these series, the specificity of the test was 87%, and eosinophiluria was also observed in patients with acute tubular necrosis, postinfectious or crescentic glomerulonephritis, atheroembolic renal disease, urinary tract infection, urinary schistosomiasis, and even pre renal AKI. In particular, 28% of patients with urinary tract infection had eosinophiluria. Because of these limitations, eosinophiluria should no longer be used as a screening test. An increased renal uptake of gallium 67 has been reported in AIN.12 Analysis of available series shows that in 45 patients with AIN, 88% had an abnormal renal scan (maximum after 48 hours),
Figure 60.8 Linear deposits of IgG in methicillin-induced acute interstitial nephritis. Deposits along the TBM are shown on immunofluorescence microscopy. These antibodies recognize either a component of the TBM or a methicillin metabolite (dimethoxyphenylpenicilloyl) bound to the TBM. (Courtesy of Dr. B. Mougenot, Paris VI University, Paris France.)
734
SECTION
XI Tubulointerstitial and Vascular Diseases
Eosinophiluria and the Diagnosis of Acute Interstitial Nephritis
Figure 60.9 Eosinophiluria in the diagnosis of acute interstitial nephritis. The four large available series were analyzed to assess the value of eosinophiluria (defined by the presence of >1% of eosinophils in urine) for the diagnosis of drug-induced AIN. Only 67% of AIN was associated with eosinophiluria, whereas 13% of non-AIN was associated with eosinophiluria.
Corwin et al. [8]
Nolan et al. [9]
Corwin et al. [10]
Ruffin et al. [11]
All series n (%)
Patients with AIN (n) Eosinophiluria No eosinophiluria
9 8 1
11 10 1
8 5 3
15 6 9
43 29 (67%) 14 (33%)
Patients without AIN (n) Eosinophiluria No eosinophiluria
56 27 29
81 12 69
175 15 160
184 10 174
496 64 (13%) 432 (87%)
Corwin et al. [8]
Nolan et al. [9]
Corwin et al. [10]
Ruffin et al. [11]
All series
Patients with AIN (n) Eosinophiluria No eosinophiluria
9 8 1
11 10 1
8 5 3
15 6 9
43 29 (67%) 14 (33%)
Patients without AIN (n) Eosinophiluria No eosinophiluria
14 6 8
46 5 41
84 2 82
23 6 17
167 19 (11%) 148 (89%)
Patients with acute kidney injury
whereas it was normal in 17 of 18 patients with acute tubular necrosis. However, these studies were small and retrospective, and gallium 67 renal scanning is not specific for AIN and may be abnormal in patients with pyelonephritis, cancer, or glomerular diseases. Therefore, we also do not recommend use of gallium scanning as a diagnostic tool. Because the clinical presentation of AIN may be polymorphic and because noninvasive diagnostic procedures have important limitations, renal biopsy is often essential for the diagnosis of AIN. Several studies have shown that prebiopsy diagnosis may be incorrect in a substantial number of patients. Identification of the Causative Drug Identification of the causative drug is relatively easy when AIN occurs in a patient taking only one drug. However, patients are often taking more than one drug capable of inducing AIN. Two biologic tests have been used, primarily in research laboratories, to help identify the causative drug: the lymphocyte stimulation test and the identification of circulating antidrug antibodies. Identification of circulating antidrug antibodies has been used mostly for patients thought to have AIN induced by rifampin. Anti-rifampin antibodies are present in most patients with rifampin-induced AIN; but unfortunately, they have also been detected in patients taking rifampin and having no adverse reaction to the drug, so this test has a limited diagnostic value. The lymphocyte stimulation test has been used since the 1960s to identify a sensitizing drug. It is based on the measurement of lymphocyte proliferation in the presence of different drugs; a high proliferative index reflects a sensitization of T lymphocytes against the drug. However, this test lacks specificity and we do not recommend using it.
Natural History Drug-induced AIN was long considered benign, with complete recovery of renal function if the inciting agent was removed. For
example, with methicillin-induced AIN, a complete normalization of serum creatinine has been observed in about 90% of uremic patients. Nevertheless, although hematuria, leukocyturia, and extrarenal symptoms usually disappeared within 2 weeks, complete recovery of renal function was often delayed, with an average recovery time of about 1.5 months. More recent studies show that with drugs other than methicillin, the course of AIN is not always benign and that serum creatinine remains elevated in about 40% to 50% of patients.6,13 Moreover, as for methicillin, recovery of renal function can be delayed, and an increase in serum creatinine can persist for several weeks. Unfortunately, few prognostic factors are available. The severity of renal failure does not appear to be linked with the prognosis.6 It has been suggested that the presence on renal biopsy of diffuse neutrophil- or macrophage-rich infiltrates, interstitial granulomas, or tubular atrophy is associated with a poor prognosis, but this has not been consistently found in all series. The best prognostic factors may actually be the duration of AKI and the severity of interstitial fibrosis.
Treatment In addition to removal of the inciting agent, corticosteroids have been used to treat AIN. Most commonly, patients received an initial daily dose of 1 mg/kg prednis(ol)one, which is then tapered during about 1 month; this oral therapy is sometimes associated with pulses of methylprednisolone. Analysis of series comparing patients who did or did not receive corticosteroids does not allow firm conclusion about the effect of corticosteroid therapy on long-term renal function, all the series being small, uncontrolled, and retrospective. However, some authors advocate an early and systematic use of a short course of corticosteroids.7,13 In addition, it seems that a brief course of corticosteroids can hasten the recovery of renal function. In different series, corticosteroids rapidly induced a reduction in serum creatinine in patients whose renal function did not improve within about 1 week after discontinuation of the inciting agent. Interestingly, in patients with
NSAID-induced AIN, corticosteroids do not seem to modify the course of the nephrotic syndrome. On the basis of anecdotal case reports, some authors have also advocated use of mycophenolate mofetil in patients resistant to corticosteroids.14 We recommend administration of a short course of prednis(ol) one in patients who are dialysis dependent or whose renal function fails to improve rapidly within 1 week after discontinuation of the inciting drug and return to baseline values, provided the diagnosis of AIN has been confirmed by renal biopsy. We initiate the treatment with 1 mg/kg per day of prednis(ol)one, and after 1 to 2 weeks, we progressively taper the dose so that the total duration of treatment is 4 to 6 weeks.
ACUTE INTERSTITIAL NEPHRITIS SECONDARY TO INFECTIOUS DISEASES Infections were once the most common cause of AIN, but the frequency of AIN induced by an infection has dramatically decreased with the widespread use of antibiotics. Nevertheless, the diagnosis of infectious AIN should not be overlooked, and AIN occurring in patients treated with antibiotics should not always be attributed to the drug. Infectious agents can cause renal parenchymal inflammation by direct infection, resulting in acute pyelonephritis (see Chapter 51). However, many infectious agents may also induce an immunologically mediated AIN in the absence of direct invasion (Fig. 60.10). In this case, the clinical presentation depends mostly on the underlying infection. On histologic examination, lesions are identical to those described for drug-induced AIN, and they can also occasionally result in granulomas (see Fig. 60.10). Infectionassociated AIN usually resolves with the treatment of the underlying infection, and corticosteroid therapy is not recommended. An important cause of infection-associated AIN is hantavirus.15 Hantavirus infections occur worldwide and are responsible for a disease that has been known as hemorrhagic fever with renal syndrome, epidemic hemorrhagic fever, or nephropathia epidemica. Rodents are the main reservoir of the virus, and humans are most probably infected by the airborne route. Extrarenal symptoms usually include fever, headache, lightheadedness, abdominal pain, nausea and vomiting, and thrombocytopenia; the last can be responsible for hemorrhagic complications. AKI is almost always associated with proteinuria, sometimes in the nephrotic range, and with hematuria. When a kidney biopsy is performed, it discloses not only interstitial inflammatory infiltrates, which predominate in the medulla, but also vascular congestion and interstitial bleeding (Fig. 60.11). In about 50% of the patients, immunofluorescence studies show granular immune deposits along the TBM and within glomeruli. Serum creatinine concentration usually starts to decrease after a few days, and a complete recovery of renal function is the rule. Nevertheless, in the more severe cases, recovery can be complicated by the occurrence of hemorrhagic complications or severe shock. The diagnosis is based on serologic test results, which become positive early (within weeks) in the course of the disease. Tubulointerstitial lesions are common in HIV-positive patients who undergo a renal biopsy for AKI. Interstitial infiltrates are often associated with glomerular lesions, but they can also be isolated. These forms of AIN have been observed in both white and black patients, and they might be related not only to drugs and opportunistic infections but also to the HIV infection itself.16
CHAPTER
60 Acute Interstitial Nephritis
735
Infections that can be Associated with Acute Interstitial Nephritis Bacteria
Viruses
Brucella species Adenovirus Campylobacter jejuni
Parasites
Others
Toxoplasma Chlamydia species* species
Cytomegalovirus Leishmania donovani
Mycoplasma species
Corynebacterium Epstein-Barr diphtheriae virus* Escherichia coli
Hantaan virus
Legionella species
Hepatitis A virus
Leptospira species
Hepatitis B virus
Mycobacterium tuberculosis*
Herpes simplex virus
Salmonella species*
Human immunodeficiency virus
Staphylococcus species
Measles virus
Streptococcus species
Polyomavirus
Yersinia pseudotuberculosis
Rickettsia
Figure 60.10 Infections that can be associated with acute interstitial nephritis. *Infections that can induce granulomatous AIN.
Figure 60.11 Acute interstitial nephritis secondary to hantavirus infection. Vascular congestion and foci of medullary hemorrhage are suggestive of the diagnosis. (Courtesy Dr. B. Mougenot, Paris VI University, Paris France.)
ACUTE INTERSTITIAL NEPHRITIS ASSOCIATED WITH SYSTEMIC DISEASES Sarcoidosis In sarcoidosis, renal impairment usually occurs as a complication of hypercalciuria and hypercalcemia, but granulomatous AIN associated with sarcoidosis has also been reported (Fig. 60.12).17,18 The presentation is usually that of AKI, which can be isolated or associated with mild proteinuria and sterile leukocyturia. It is
736
SECTION
XI Tubulointerstitial and Vascular Diseases
merular lesions and rarely lesions of the arterioles, and treatment is the same as for cryoglobulinemia-induced glomerulonephritis (see Chapter 21). Most renal lesions associated with small-vessel vasculitis (such as Wegener’s granulomatosis) consist of both an extracapillary glomerulonephritis and a tubulointerstitial nephritis. Nevertheless, a few patients with AIN and minimal glomerular lesions have been described.
ACUTE INTERSTITIAL NEPHRITIS ASSOCIATED WITH MALIGNANT NEOPLASMS Figure 60.12 Granulomatous acute interstitial nephritis in a patient with sarcoidosis. (Courtesy Dr. B. Mougenot, Paris VI University, Paris France.)
associated with extrarenal symptoms of sarcoidosis in about 90% of patients, most frequently with lymphadenopathy and lung, eye, or liver involvement. Nevertheless, only slightly more than half of the patients have hilar lymphadenopathy or pulmonary interstitial fibrosis at the time of diagnosis.19 Treatment with high-dose corticosteroids quickly improves renal function, but most patients do not recover completely. The starting dose should be 1 mg/kg prednis(ol)one daily, and corticosteroid therapy should be tapered slowly and not withdrawn before at least 1 year to prevent relapses. Whereas some authors advocate long-term maintenance therapy with low-dose corticosteroids, we usually stop corticosteroids after 2 to 3 years. Because of the risk of late relapse, these patients should be observed for a prolonged time.
Sjögren’s Syndrome Clinically significant interstitial nephritis is rare in Sjögren’s syndrome and usually results in chronic tubular dysfunction.20 Some patients may present with severe symptomatic hypokalemia with distal renal tubular acidosis. Rarely, Sjögren’s syndrome presents with AKI due to AIN. In these patients, treatment with high-dose corticosteroids may dramatically improve renal function.
Systemic Lupus Erythematosus About two thirds of renal biopsies performed in patients with systemic lupus show some tubulointerstitial involvement, but significant tubulointerstitial injury in the setting of minimal glomerular abnormalities is rare, with only about 10 cases reported in the literature.21 In these cases, renal biopsy shows typical features of AIN on light microscopy, and immunofluorescence staining always discloses immune deposits along the TBM, usually with a granular pattern. Renal function improves after high-dose corticosteroids and does not usually require additional immunosuppressive drugs. However, azathioprine has been used as a corticosteroid-sparing agent.
Other Systemic Diseases Among patients with cryoglobulinemia and AKI, a few exhibit significant interstitial inflammatory infiltrates associated with granular immune deposits in the interstitium and along the TBM. This AIN is usually associated with characteristic glo-
Infiltration of renal parenchyma by malignant cells is common in patients with leukemia or lymphoma. Most of the time, this infiltration is totally asymptomatic or only causes enlarged kidneys, but a few patients with AKI have been described.22 Chemotherapy or radiotherapy may rapidly improve renal function in these patients, but before these treatments are started, it is important to exclude more common causes of AKI associated with neoplastic diseases (see Chapter 66).
IDIOPATHIC ACUTE INTERSTITIAL NEPHRITIS More than 50 cases of idiopathic AIN with anterior uveitis have been reported (TINU syndrome).23 This syndrome is found most commonly in girls of pubertal age but can also occur in pubertal boys and in adults. Initial symptoms may be ocular, with ocular pain and visual impairment, or pseudoviral, with fever, myalgia, and asthenia. AIN is responsible for AKI, ranging from mild to severe, that may or may not be associated with abnormal urinalysis. Renal biopsy shows diffuse interstitial inflammatory infiltrates, almost always without granulomas and without immune deposits. In children, renal prognosis is excellent, and serum creatinine usually returns to baseline values within a few weeks, with or without corticosteroid therapy. In adults, the renal prognosis seems to be less favorable, and corticosteroid therapy might be useful in preventing evolution to chronic renal failure. Uveitis, which can occur at any time in respect to AIN, is usually responsive to topical corticosteroids, but it may relapse without any recurrence of AIN. A few cases of idiopathic AIN have been reported. Immunofluorescence studies of renal biopsy specimens can show linear deposits of IgG along the TBM, granular deposits of IgG along the TBM, or no immune deposits, suggesting that this entity is heterogeneous. The treatment of patients with idiopathic AIN is still controversial. Patients who receive corticosteroids usually show a dramatic improvement of renal function, but others have recovered normal renal function without any treatment.
ACUTE INTERSTITIAL NEPHRITIS IN RENAL TRANSPLANTS Acute rejection is by far the most common cause of AIN in renal allograft recipients (see Chapter 100). Nevertheless, AIN can also be induced by drugs or infections. Cases of drug-induced AIN have been reported even in the first weeks after transplantation, when immunosuppression is maximal.24 Among infectious AIN, the frequency of polyomavirus-induced AIN appears to be increasing, and it should be suspected in patients with acute deterioration of renal function and so-called decoy cells in urine (see Chapter 101).25
REFERENCES 1. Neilson EG. Pathogenesis and therapy of interstitial nephritis. Kidney Int. 1989;35:1257-1270. 2. Clarkson MR, Giblin L, O’Connell FP, et al. Acute interstitial nephritis: Clinical features and response to corticosteroid therapy. Nephrol Dial Transplant. 2004;19:2778-2783. 3. Brewster UC, Perazella MA. Acute kidney injury following proton pump inhibitor therapy. Kidney Int. 2007;71:589-593. 4. Schmid S, Opravil M, Moddel M, et al. Acute interstitial nephritis of HIV-positive patients under atazanavir and tenofovir therapy in a retrospective analysis of kidney biopsies. Virchows Arch. 2007;450:665-670. 5. Winn SK, Ellis S, Savage P, et al. Biopsy-proven acute interstitial nephritis associated with the tyrosine kinase inhibitor sunitinib: A class effect? Nephrol Dial Transplant. 2009;24:673-675. 6. Rossert J. Drug-induced acute interstitial nephritis. Kidney Int. 2001;60: 804-817. 7. Baker RJ, Pusey CD. The changing profile of acute tubulointerstitial nephritis. Nephrol Dial Transplant. 2004;19:8-11. 8. Corwin HL, Bray RA, Haber MH. The detection and interpretation of urinary eosinophils. Arch Pathol Lab Med. 1989;113:1256-1258. 9. Nolan CR 3rd, Anger MS, Kelleher SP. Eosinophiluria—a new method of detection and definition of the clinical spectrum. N Engl J Med. 1986;315:1516-1519. 10. Corwin HL, Korbet SM, Schwartz MM. Clinical correlates of eosinophiluria. Arch Intern Med. 1985;145:1097-1099. 11. Ruffing KA, Hoppes P, Blend D, et al. Eosinophils in urine revisited. Clin Nephrol. 1994;41:163-166. 12. Linton AL, Richmond JM, Clark WF, et al. Gallium 67 scintigraphy in the diagnosis of acute renal disease. Clin Nephrol. 1985;24:84-87. 13. Gonzalez E, Gutierrez E, Galeano C, et al. Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis. Kidney Int. 2008;73:940-946.
CHAPTER
60 Acute Interstitial Nephritis
737
14. Preddie DC, Markowitz GS, Radhakrishnan J, et al. Mycophenolate mofetil for the treatment of interstitial nephritis. Clin J Am Soc Nephrol. 2006;1:718-722. 15. Ferluga D, Vizjak A. Hantavirus nephropathy. J Am Soc Nephrol. 2008;19:1653-1658. 16. Cohen SD, Chawla LS, Kimmel PL. Acute kidney injury in patients with human immunodeficiency virus infection. Curr Opin Crit Care. 2008;14:647-653. 17. Rajakariar R, Sharples EJ, Raftery MJ, et al. Sarcoid tubulo-interstitial nephritis: Long-term outcome and response to corticosteroid therapy. Kidney Int. 2006;70:165-169. 18. Mahevas M, Lescure FX, Boffa JJ, et al. Renal sarcoidosis: Clinical, laboratory, and histologic presentation and outcome in 47 patients. Medicine (Baltimore). 2009;88:98-106. 19. Hannedouche T, Grateau G, Noel LH, et al. Renal granulomatous sarcoidosis: Report of six cases. Nephrol Dial Transplant. 1990;5:1824. 20. Goules A, Masouridi S, Tzioufas AG, et al. Clinically significant and biopsy-documented renal involvement in primary Sjögren syndrome. Medicine (Baltimore). 2000;79:241-249. 21. Mori Y, Kishimoto N, Yamahara H, et al. Predominant tubulointerstitial nephritis in a patient with systemic lupus nephritis. Clin Exp Nephrol. 2005;9:79-84. 22. Tornroth T, Heiro M, Marcussen N, et al. Lymphomas diagnosed by percutaneous kidney biopsy. Am J Kidney Dis. 2003;42:960-971. 23. Liakopoulos V, Ioannidis I, Zengos N, et al. Tubulointerstitial nephritis and uveitis (TINU) syndrome in a 52-year-old female: A case report and review of the literature. Ren Fail. 2006;28:355-359. 24. Josephson MA, Chiu MY, Woodle ES, et al. Drug-induced acute interstitial nephritis in renal allografts: Histopathologic features and clinical course in six patients. Am J Kidney Dis. 1999;34:540-548. 25. Hariharan S. BK virus nephritis after renal transplantation. Kidney Int. 2006;69:655-662.
60
Acute Interstitial Nephritis Jerome A. Rossert, Evelyne A. Fischer
DEFINITION Acute interstitial nephritis (AIN) is an acute, often reversible disease characterized by inflammatory infiltrates within the interstitium. AIN is a rare cause of acute kidney injury (AKI), but it should not be overlooked because it usually requires specific therapeutic interventions.
PATHOGENESIS Most studies suggest that AIN is an immunologically induced hypersensitivity reaction to an antigen that is classically a drug or an infectious agent. Evidence for a hypersensitivity reaction in drug-induced AIN includes the following: it occurs only in a small percentage of individuals; it is not dose dependent; it is often associated with extrarenal manifestations of hypersensitivity; it recurs after accidental reexposure to the same drug or to a closely related one; and it is sometimes associated with evidence of delayed-type hypersensitivity reaction (renal granulomas). Similarly, AIN secondary to infections can be differentiated from pyelonephritis by the relative absence of neutrophils in the interstitial infiltrates and the failure to isolate the infective agent from the renal parenchyma, again suggesting an immunologic basis to the disease. Studies of experimental models of AIN have shown that three major categories of antigens can induce AIN.1 Antigens may be tubular basement membrane (TBM) components (such as the glycoproteins 3M-1 and TIN-Ag/TIN1), secreted tubular proteins (such as Tamm-Horsfall protein), or nonrenal proteins (such as from immune complexes). Although some types of human AIN may be secondary to an immune reaction directed against a renal antigen, the majority of cases of AIN are probably induced by extrarenal antigens, being produced in particular by drugs or infectious agents. These antigens may be able to induce AIN by a variety of mechanisms. These mechanisms include binding to kidney structures (“planted antigen”); acting as haptens that modify the immunogenicity of native renal proteins; mimicking renal antigens, resulting in a cross-reactive immune reaction; and precipitating within the interstitium as circulating immune complexes. Studies of experimental models of AIN show that their pathogenesis involves either cell-mediated immunity or antibodymediated immunity (Fig. 60.1). In humans, most forms of AIN are not associated with antibody deposition, which suggests that cell-mediated immunity plays a major role. This hypothesis is reinforced by the fact that interstitial infiltrates usually contain numerous T cells and that these infiltrates sometimes form granulomas. Nevertheless, deposition of anti-TBM antibodies or of immune complexes can be observed occasionally in renal biopsy
specimens, and antibody-mediated immunity may play a role in the pathogenesis of the disease in these cases. Formation of immune complexes within the interstitium, or interstitial infiltration with T cells, will result in an inflammatory reaction. This reaction is triggered by many events, including activation of the complement cascade by antibodies and release of inflammatory cytokines by T lymphocytes and phagocytes (see Fig. 60.1). Although the interstitial inflammatory reaction may resolve without sequelae, it sometimes induces interstitial fibroblast proliferation and extracellular matrix synthesis, leading to interstitial fibrosis and chronic renal failure. Cytokines such as transforming growth factor ß appear to play a key role in this latter process.
EPIDEMIOLOGY AIN is an uncommon cause of AKI and is identified in only about 2% to 3% of all renal biopsy specimens.2 However, it may account for up to 10% to 25% of patients undergoing renal biopsy for unexplained or drug-induced AKI, respectively.2 Although AIN can occur at any age, it appears to be rare in children. Before antibiotics were available, AIN was most commonly associated with infections, such as scarlet fever and diphtheria. Currently, AIN is most often induced by drugs, particularly antimicrobial agents, proton pump inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs). Drug-induced AIN appears to account for about 75% to 90% of all cases.
DRUG-INDUCED ACUTE INTERSTITIAL NEPHRITIS Clinical Manifestations In the 1960s and 1970s, most cases of drug-induced AIN were caused by methicillin, and the clinical manifestations of methicillin-induced AIN were considered the prototypical presentation of AIN. Since then, many other drugs have been implicated in the induction of AIN (Fig. 60.2), of which antimicrobial agents (in particular, b-lactam antibiotics, sulfonamides, fluoroquinolones, and rifampin) and NSAIDs (especially fenoprofen) as well as cyclooxygenase 2 (COX-2) inhibitors have been most commonly involved. Antiulcer agents, diuretics, phenindione, phenytoin, and allopurinol have also been reported to cause AIN. There are increasing numbers of reports of AIN induced by proton pump inhibitors, with more than 70 reported biopsyproven cases.3 Recently, cases of drug-induced AIN have also been reported in human immunodeficiency virus (HIV)–infected patients treated with highly active antiretroviral therapy (HAART)4 and in cancer patients treated with tyrosine kinase 729
730
SECTION
XI Tubulointerstitial and Vascular Diseases
Immune Mechanisms in Acute Interstitial Nephritis Cell-mediated mechanisms
Antibody-mediated mechanisms Blood vessel
Blood vessel Neutrophil
(+)
Neutrophils
Monocyte
MHC class II
(+)
(+)
Macrophage
(+)
Th1 lymphocyte (+)
Cytotoxic T lymphocyte MHC class I
Natural killer cell
Tubule
(+)
Processed antigen
Neutrophil (+)
(+)
Macrophage
Th lymphocyte
(+)
Monocyte
Th2 lymphocyte (+)
MHC class II B lymphocyte
Eosinophil Natural killer cell
Complement
(+) Complement
Tubule
Figure 60.1 Immune mechanisms that can be involved in acute interstitial nephritis. Both cell-mediated and antibody-mediated mechanisms occur. The cell-mediated mechanism is primarily associated with macrophages and T cells. The antibody-mediated mechanism is frequently associated with neutrophil or eosinophil infiltration as well as with local complement activation. MHC, major histocompatibility complex.
inhibitors.5 Most other drugs have only rarely been linked with AIN (see Fig. 60.2). The clinical characteristics of drug-induced AIN are now recognized as much more varied and nonspecific than the spectrum seen in classic methicillin-induced AIN (Fig. 60.3).6,7 Renal Manifestations Symptoms of AIN usually develop a few days to a few weeks after the inciting drug is started, although cases have occurred months after initial exposure to the drug. The typical presentation is sudden impairment in renal function, associated with mild proteinuria (<1 g/day) and abnormal urinalysis, in a patient with flank pain, normal blood pressure, and no edema. In patients with AIN not caused by methicillin, the clinical presentation is often incomplete (see Fig. 60.3), and AIN should be considered in any patient with unexplained AKI.6,7 The renal dysfunction may be mild or severe; dialysis is required in about one third of patients. Hematuria and pyuria are present in a little more than half of the patients, and although leukocyte casts are common, hematuria is almost never associated with red blood cell casts. Flank pain, reflecting distention of the renal capsule, is observed in about one third of the patients and can be the main complaint on hospital admission. On occasion, patients have a low fractional excretion of sodium. Standard imaging procedures show kidneys normal in size or slightly enlarged. Ultrasound usually discloses an increased cortical echogenicity (comparable to or higher than that of the liver). Extrarenal Manifestations Extrarenal symptoms consistent with a hypersensitivity reaction are occasionally observed, including low-grade fever, maculo-
papular rash (Fig. 60.4), mild arthralgias, and eosinophilia. If patients with methicillin-induced AIN are not considered, each of these symptoms is present in less than half of the patients (see Fig. 60.3), and all these symptoms are present together in less than 10% of patients.2,6,7 With some drugs, other manifestations of hypersensitivity, such as hemolysis or hepatitis, can be present. Serum IgE levels may also be elevated. The association of AKI either with clinical signs suggestive of hypersensitivity or with eosinophilia should lead to consideration of a diagnosis of AIN. However, signs of hypersensitivity can also be observed in patients with AKI not related to AIN, including patients with drug-induced acute tubular necrosis. Other Specific Drug Associations The clinical and biologic manifestations of AIN may have some specificity, depending on the drug involved. As outlined earlier, methicillin-induced AIN is characterized by a high frequency of abnormal urinalysis and extrarenal symptoms and by good preservation of renal function. Renal failure has been reported in only about 50% of patients (see Fig. 60.3). More than 200 cases of rifampin-induced AKI have been reported. Most have been observed either after readministration of rifampin or several months after intermittent administration of the drug. Renal failure is usually associated with the sudden onset of fever, gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain), and myalgias. It may also be associated with hemolysis, thrombocytopenia, and less frequently hepatitis. Renal biopsy typically discloses tubular injury in addition to interstitial inflammatory infiltrates. Although circulating anti-rifampin antibodies are usually found in these patients, immunofluorescence staining of renal biopsy specimens has been
CHAPTER
60 Acute Interstitial Nephritis
731
Drugs Responsible for Acute Interstitial Nephritis ANTIMICROBIAL AGENTS PENICILINS Amoxicillin Ampicillin* Aztreonam Carbenicillin Cloxacillin Methicillin* Mezlocillin Nafcillin Oxacillin* Penicillin G* (benzylpenicillin*) Piperacillin CEPHALOSPORINS Cefaclor Cefamandole Cefazolin Cefixim Cefoperazone Cefotaxime Cefotetan Cefoxitin Ceftriaxone Cephalexin Cephaloridine Cephalothin Cephapirin Cephradine Latamoxef QUINOLONES Ciprofloxacin* Levofloxacin* Moxifloxacin Norfloxacin OTHERS Abicavir Acyclovir Atazanavir Azithromycin Clarithromycin Colistin Cotrimoxazole* Erythromycin* Ethambutol Flurithromycin Foscarnet Gentamicin Indinavir Interferon Isoniazid Lincomycin Minocycline Nitrofurantoin* Piromidic acid Polymixin B*
Quinine Rifampin* (rifampicin*) Spiramycine* Sulfonamides* Teicoplamin Telithromycin Tetracycline Vancomycin* NSAIDs INCLUDING SALICYLATES SALICYLATES AND DERIVATIVES Aspirin (acetyl salicylic acid) Diflunisal*
ANALGESICS Aminopyrine Antipyrine Antrafenin Clometacin* (clometazin*) Dipyrone (noramidopyrine, metamizol) Floctafenin* Glafenin* ANTICONVULSANTS
PROPIONIC ACID DERIVATIVES Benoxaprofen Fenbufen Fenoprofen* Flurbiprofen Ibuprofen* Ketoprofen Naproxen Pirprofen Suprofen
Carbamazepine* Diazepam Phenobarbital (phenobarbitone) Phenytoin* Valproic acid (valproate sodium)
ACETIC ACID DERIVATIVES Indomethacin* (indometacin) Alclofenac Diclofenac Fenclofenac Sulindac Zomepirac
Chlortalidone Ethacrynic acid Furosemide* (frusemide*) Hydrochlorothiazide* Indapamide Tienilic acid* Triamterene*
ENOLIC ACID DERIVATIVES Meloxicam Piroxicam* FENAMIC ACID DERIVATIVES Mefenamic acid Niflumic acid COXIBS Celecoxib Rofecoxib OTHERS Azapropazone Mesalamine (mesalazine, 5ASA) Phenazone Phenylbutazone Sulfasalazine Tolmetin
DIURETICS
ANTIULCER AGENTS H2-RECEPTOR ANTAGONISTS Cimetidine* Famotidine Ranitidine
OTHERS Allopurinol* Alpha Methyl Dopa Amlodipine Azathioprine Betanidine* Bismuth salts Captopril* Carbimazole Chlorpropamide* Clofibrate Clozapine Cyamemazine* Cyclosporine Cytosine Arabinoside Desferasirox Diltiazem D-penicillamine Etanercept Fenofibrate* Fluindione Gold salts Griseofluvin Interleukin 2 Lamotrigine* Linezolid Nicergolin Phenindione* Phenothiazine Phentermine/ Phendimetrazine Phenylpropanolamine Probenecid Propanolol Propylthiouracil Sorafenib Streptokinase Sulphinpyrazone Sunitinib Warfarin Zopiclone
PROTON PUMP INHIBITORS Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole
Figure 60.2 Drugs responsible for acute interstitial nephritis. Drugs most commonly involved are in bold. NSAIDs, nonsteroidal anti-inflammatory drugs. *Drugs that can cause granulomatous AIN.
negative in most cases, suggesting that cell-mediated immunity plays a key role in the induction of the nephritis. In a few cases, AIN developed after continuous treatment with rifampin for 1 to 10 weeks. It was almost never associated with extrarenal symptoms or with anti-rifampin antibodies, and renal biopsy specimens showed severe interstitial infiltrates but few tubular lesions.
Phenindione-induced AIN is generally associated with the development of hepatitis, which can be fatal. Allopurinol-induced AIN appears to occur more often in patients with chronic kidney disease (CKD) and is usually seen in association with rash and liver dysfunction. It has been suggested that the decreased excretion of oxypurinol, a metabolite of allopurinol, might favor the occurrence of AIN. There is also
732
SECTION
XI Tubulointerstitial and Vascular Diseases
Clinical Manifestation of Drug-Induced Acute Interstitial Nephritis Methicillin Eosinophilia Extrarenal symptoms Mild proteinuria Pyuria Hematuria Macroscopic hematuria Oliguria Renal failure 0%
20%
40% 60% 80% Percentage of patients
100%
Other drugs Eosinophilia Extrarenal symptoms Mild proteinuria Pyuria
Figure 60.4 Maculopapular rash in a patient with drug-induced acute interstitial nephritis. Such cutaneous lesions occur in about 40% of patients with drug-induced AIN, but they can also be seen in patients with drug-induced acute tubular necrosis.
Hematuria Macroscopic hematuria Oliguria Renal failure 0%
20%
40% 60% 80% Percentage of patients
100%
Figure 60.3 Clinical manifestations of drug-induced acute interstitial nephritis. Data were pooled from different case reports, including 95 patients with methicillin-induced AIN and more than 200 patients with other drug-induced AIN. Patients with AIN associated with a nephrotic syndrome are not included.
Clinical Presentation of AIN and Nephrotic Syndrome Associated with NSAID Use
Eosinophilia Extrarenal symptoms Pyuria
some experimental evidence that in the setting of renal impairment, allopurinol may precipitate as microcrystals or crystals and cause direct nephrotoxicity. Whether this can occur in humans is unknown, but it may provide an additional reason to reduce allopurinol doses in subjects with CKD. AIN occurring secondary to NSAIDs is associated with nephrotic syndrome in about three fourths of cases. This usually occurs in patients older than 50 years, and although it has been observed with all NSAIDs, including COX-2–selective inhibitors, half of the incidents have been reported with fenoprofen. Most occurrences develop after the patient has taken NSAIDs for some months (mean, 6 months), but AIN can occur within days or after more than a year. With the exception of the heavy proteinuria and associated edema, the presentation of these patients is similar to that of patients with other drug-induced AIN (Fig. 60.5). The main difference is that extrarenal symptoms are present in only about 10% of patients. Renal disease caused by NSAIDs must be differentiated from other NSAID-induced nephropathies, including hemodynamically mediated AKI, papil-
Macroscopic hematuria Hematuria Hypertension Edema 0%
20%
40%
60%
80%
100%
Percentage of patients
Figure 60.5 Clinical presentation of AIN and nephrotic syndrome associated with NSAID use. Data were pooled from different case reports from more than 60 patients.
lary necrosis, and NSAID-induced membranous nephropathy. Drugs other than NSAIDs can rarely induce AIN associated with a nephrotic syndrome; a few cases have been reported after administration of ampicillin, rifampin, lithium, interferon, phenytoin, pamidronate, and d-penicillamine.
Pathology The hallmark of AIN is the presence of inflammatory infiltrates within the interstitium (Fig. 60.6). These infiltrative lesions are often patchy, predominating in the deep cortex and in the outer medulla, but they can be diffuse in severe cases. They are composed mostly of T cells and monocytes-macrophages, but plasma cells, eosinophils, and a few neutrophilic granulocytes may also be present. The relative number of CD4+ T cells and CD8+ T cells is variable from one patient to another. In some cases, T lymphocytes infiltrate across the TBM and between tubular cells, mainly in distal tubules, and the resulting lesion is referred to as tubulitis. In some cases of drug-induced AIN, renal biopsy shows interstitial granulomas (Fig. 60.7). These granulomas are usually sparse and non-necrotic, with few giant cells, and are associated with nongranulomatous interstitial infiltrates. Granulomas are also found in AIN related to infection (see Fig 60.10), sarcoidosis, Sjögren’s syndrome, and Wegener’s granulomatosis. Interstitial infiltrates are always associated with an interstitial edema, which is responsible for separating the tubules (see Fig. 60.6). They can also be associated with focal tubular lesions, which range from mild cellular alterations to extensive necrosis of epithelial cells and are sometimes associated with a disruption of the TBM. These tubular lesions usually predominate where the inflammatory infiltrates are most extensive.
Figure 60.6 Drug-induced acute interstitial nephritis. On light microscopy, the characteristic feature is interstitial infiltration with mononuclear cells, with normal glomeruli. It is usually associated with interstitial edema and tubular lesions. (Courtesy of Dr. B. Mougenot, Paris VI University, Paris France.)
Figure 60.7 Drug-induced granulomatous acute interstitial nephritis. Some drugs can induce the formation of interstitial granulomas, which reflect a delayed-type hypersensitivity reaction. (Courtesy of Dr. B. Mougenot, Paris VI University, Paris France)
CHAPTER
60 Acute Interstitial Nephritis
733
Tubulointerstitial lesions are not associated with vascular or glomerular lesions. Even in AIN associated with a nephrotic syndrome, glomeruli appear normal on light microscopy; glomerular lesions are similar to those seen in minimal change disease (see Chapter 17). In most patients with AIN, renal biopsy specimens do not show immune deposits, and both immunofluorescence and electron microscopy are negative. Nevertheless, staining of the tubular or capsular basement membrane for IgG or complement may occasionally be seen by immunofluorescence; the staining pattern is either granular or linear (Fig. 60.8). Linear fixation of IgG along the TBM indicates the presence of antibodies directed against membrane antigens or against drug metabolites bound to the TBM, and circulating anti-TBM antibodies have been detected in some cases. These linear deposits are seen mostly in patients taking methicillin, NSAIDs, phenytoin, or allopurinol.
Diagnosis The most accurate way to diagnose AIN is by renal biopsy. However, both eosinophiluria and gallium scanning have been suggested as helpful in making the diagnosis. Eosinophils can be detected in urine with use of either the Wright stain or the Hansel stain, which both are eosin–methylene blue combinations, but the Hansel stain appears to be much more sensitive.8,9 The result of this test is usually considered positive if more that 1% of urinary white blood cells are eosinophils. However, although eosinophiluria is frequently used to corroborate the diagnosis of drug-induced AIN, review of four large series shows that this test has rather poor sensitivity (67%) and a low positive predictive value, even when only patients with AKI are considered (50%) (Fig. 60.9).8-11 In these series, the specificity of the test was 87%, and eosinophiluria was also observed in patients with acute tubular necrosis, postinfectious or crescentic glomerulonephritis, atheroembolic renal disease, urinary tract infection, urinary schistosomiasis, and even pre renal AKI. In particular, 28% of patients with urinary tract infection had eosinophiluria. Because of these limitations, eosinophiluria should no longer be used as a screening test. An increased renal uptake of gallium 67 has been reported in AIN.12 Analysis of available series shows that in 45 patients with AIN, 88% had an abnormal renal scan (maximum after 48 hours),
Figure 60.8 Linear deposits of IgG in methicillin-induced acute interstitial nephritis. Deposits along the TBM are shown on immunofluorescence microscopy. These antibodies recognize either a component of the TBM or a methicillin metabolite (dimethoxyphenylpenicilloyl) bound to the TBM. (Courtesy of Dr. B. Mougenot, Paris VI University, Paris France.)
734
SECTION
XI Tubulointerstitial and Vascular Diseases
Eosinophiluria and the Diagnosis of Acute Interstitial Nephritis
Figure 60.9 Eosinophiluria in the diagnosis of acute interstitial nephritis. The four large available series were analyzed to assess the value of eosinophiluria (defined by the presence of >1% of eosinophils in urine) for the diagnosis of drug-induced AIN. Only 67% of AIN was associated with eosinophiluria, whereas 13% of non-AIN was associated with eosinophiluria.
Corwin et al. [8]
Nolan et al. [9]
Corwin et al. [10]
Ruffin et al. [11]
All series n (%)
Patients with AIN (n) Eosinophiluria No eosinophiluria
9 8 1
11 10 1
8 5 3
15 6 9
43 29 (67%) 14 (33%)
Patients without AIN (n) Eosinophiluria No eosinophiluria
56 27 29
81 12 69
175 15 160
184 10 174
496 64 (13%) 432 (87%)
Corwin et al. [8]
Nolan et al. [9]
Corwin et al. [10]
Ruffin et al. [11]
All series
Patients with AIN (n) Eosinophiluria No eosinophiluria
9 8 1
11 10 1
8 5 3
15 6 9
43 29 (67%) 14 (33%)
Patients without AIN (n) Eosinophiluria No eosinophiluria
14 6 8
46 5 41
84 2 82
23 6 17
167 19 (11%) 148 (89%)
Patients with acute kidney injury
whereas it was normal in 17 of 18 patients with acute tubular necrosis. However, these studies were small and retrospective, and gallium 67 renal scanning is not specific for AIN and may be abnormal in patients with pyelonephritis, cancer, or glomerular diseases. Therefore, we also do not recommend use of gallium scanning as a diagnostic tool. Because the clinical presentation of AIN may be polymorphic and because noninvasive diagnostic procedures have important limitations, renal biopsy is often essential for the diagnosis of AIN. Several studies have shown that prebiopsy diagnosis may be incorrect in a substantial number of patients. Identification of the Causative Drug Identification of the causative drug is relatively easy when AIN occurs in a patient taking only one drug. However, patients are often taking more than one drug capable of inducing AIN. Two biologic tests have been used, primarily in research laboratories, to help identify the causative drug: the lymphocyte stimulation test and the identification of circulating antidrug antibodies. Identification of circulating antidrug antibodies has been used mostly for patients thought to have AIN induced by rifampin. Anti-rifampin antibodies are present in most patients with rifampin-induced AIN; but unfortunately, they have also been detected in patients taking rifampin and having no adverse reaction to the drug, so this test has a limited diagnostic value. The lymphocyte stimulation test has been used since the 1960s to identify a sensitizing drug. It is based on the measurement of lymphocyte proliferation in the presence of different drugs; a high proliferative index reflects a sensitization of T lymphocytes against the drug. However, this test lacks specificity and we do not recommend using it.
Natural History Drug-induced AIN was long considered benign, with complete recovery of renal function if the inciting agent was removed. For
example, with methicillin-induced AIN, a complete normalization of serum creatinine has been observed in about 90% of uremic patients. Nevertheless, although hematuria, leukocyturia, and extrarenal symptoms usually disappeared within 2 weeks, complete recovery of renal function was often delayed, with an average recovery time of about 1.5 months. More recent studies show that with drugs other than methicillin, the course of AIN is not always benign and that serum creatinine remains elevated in about 40% to 50% of patients.6,13 Moreover, as for methicillin, recovery of renal function can be delayed, and an increase in serum creatinine can persist for several weeks. Unfortunately, few prognostic factors are available. The severity of renal failure does not appear to be linked with the prognosis.6 It has been suggested that the presence on renal biopsy of diffuse neutrophil- or macrophage-rich infiltrates, interstitial granulomas, or tubular atrophy is associated with a poor prognosis, but this has not been consistently found in all series. The best prognostic factors may actually be the duration of AKI and the severity of interstitial fibrosis.
Treatment In addition to removal of the inciting agent, corticosteroids have been used to treat AIN. Most commonly, patients received an initial daily dose of 1 mg/kg prednis(ol)one, which is then tapered during about 1 month; this oral therapy is sometimes associated with pulses of methylprednisolone. Analysis of series comparing patients who did or did not receive corticosteroids does not allow firm conclusion about the effect of corticosteroid therapy on long-term renal function, all the series being small, uncontrolled, and retrospective. However, some authors advocate an early and systematic use of a short course of corticosteroids.7,13 In addition, it seems that a brief course of corticosteroids can hasten the recovery of renal function. In different series, corticosteroids rapidly induced a reduction in serum creatinine in patients whose renal function did not improve within about 1 week after discontinuation of the inciting agent. Interestingly, in patients with
NSAID-induced AIN, corticosteroids do not seem to modify the course of the nephrotic syndrome. On the basis of anecdotal case reports, some authors have also advocated use of mycophenolate mofetil in patients resistant to corticosteroids.14 We recommend administration of a short course of prednis(ol) one in patients who are dialysis dependent or whose renal function fails to improve rapidly within 1 week after discontinuation of the inciting drug and return to baseline values, provided the diagnosis of AIN has been confirmed by renal biopsy. We initiate the treatment with 1 mg/kg per day of prednis(ol)one, and after 1 to 2 weeks, we progressively taper the dose so that the total duration of treatment is 4 to 6 weeks.
ACUTE INTERSTITIAL NEPHRITIS SECONDARY TO INFECTIOUS DISEASES Infections were once the most common cause of AIN, but the frequency of AIN induced by an infection has dramatically decreased with the widespread use of antibiotics. Nevertheless, the diagnosis of infectious AIN should not be overlooked, and AIN occurring in patients treated with antibiotics should not always be attributed to the drug. Infectious agents can cause renal parenchymal inflammation by direct infection, resulting in acute pyelonephritis (see Chapter 51). However, many infectious agents may also induce an immunologically mediated AIN in the absence of direct invasion (Fig. 60.10). In this case, the clinical presentation depends mostly on the underlying infection. On histologic examination, lesions are identical to those described for drug-induced AIN, and they can also occasionally result in granulomas (see Fig. 60.10). Infectionassociated AIN usually resolves with the treatment of the underlying infection, and corticosteroid therapy is not recommended. An important cause of infection-associated AIN is hantavirus.15 Hantavirus infections occur worldwide and are responsible for a disease that has been known as hemorrhagic fever with renal syndrome, epidemic hemorrhagic fever, or nephropathia epidemica. Rodents are the main reservoir of the virus, and humans are most probably infected by the airborne route. Extrarenal symptoms usually include fever, headache, lightheadedness, abdominal pain, nausea and vomiting, and thrombocytopenia; the last can be responsible for hemorrhagic complications. AKI is almost always associated with proteinuria, sometimes in the nephrotic range, and with hematuria. When a kidney biopsy is performed, it discloses not only interstitial inflammatory infiltrates, which predominate in the medulla, but also vascular congestion and interstitial bleeding (Fig. 60.11). In about 50% of the patients, immunofluorescence studies show granular immune deposits along the TBM and within glomeruli. Serum creatinine concentration usually starts to decrease after a few days, and a complete recovery of renal function is the rule. Nevertheless, in the more severe cases, recovery can be complicated by the occurrence of hemorrhagic complications or severe shock. The diagnosis is based on serologic test results, which become positive early (within weeks) in the course of the disease. Tubulointerstitial lesions are common in HIV-positive patients who undergo a renal biopsy for AKI. Interstitial infiltrates are often associated with glomerular lesions, but they can also be isolated. These forms of AIN have been observed in both white and black patients, and they might be related not only to drugs and opportunistic infections but also to the HIV infection itself.16
CHAPTER
60 Acute Interstitial Nephritis
735
Infections that can be Associated with Acute Interstitial Nephritis Bacteria
Viruses
Brucella species Adenovirus Campylobacter jejuni
Parasites
Others
Toxoplasma Chlamydia species* species
Cytomegalovirus Leishmania donovani
Mycoplasma species
Corynebacterium Epstein-Barr diphtheriae virus* Escherichia coli
Hantaan virus
Legionella species
Hepatitis A virus
Leptospira species
Hepatitis B virus
Mycobacterium tuberculosis*
Herpes simplex virus
Salmonella species*
Human immunodeficiency virus
Staphylococcus species
Measles virus
Streptococcus species
Polyomavirus
Yersinia pseudotuberculosis
Rickettsia
Figure 60.10 Infections that can be associated with acute interstitial nephritis. *Infections that can induce granulomatous AIN.
Figure 60.11 Acute interstitial nephritis secondary to hantavirus infection. Vascular congestion and foci of medullary hemorrhage are suggestive of the diagnosis. (Courtesy Dr. B. Mougenot, Paris VI University, Paris France.)
ACUTE INTERSTITIAL NEPHRITIS ASSOCIATED WITH SYSTEMIC DISEASES Sarcoidosis In sarcoidosis, renal impairment usually occurs as a complication of hypercalciuria and hypercalcemia, but granulomatous AIN associated with sarcoidosis has also been reported (Fig. 60.12).17,18 The presentation is usually that of AKI, which can be isolated or associated with mild proteinuria and sterile leukocyturia. It is
736
SECTION
XI Tubulointerstitial and Vascular Diseases
merular lesions and rarely lesions of the arterioles, and treatment is the same as for cryoglobulinemia-induced glomerulonephritis (see Chapter 21). Most renal lesions associated with small-vessel vasculitis (such as Wegener’s granulomatosis) consist of both an extracapillary glomerulonephritis and a tubulointerstitial nephritis. Nevertheless, a few patients with AIN and minimal glomerular lesions have been described.
ACUTE INTERSTITIAL NEPHRITIS ASSOCIATED WITH MALIGNANT NEOPLASMS Figure 60.12 Granulomatous acute interstitial nephritis in a patient with sarcoidosis. (Courtesy Dr. B. Mougenot, Paris VI University, Paris France.)
associated with extrarenal symptoms of sarcoidosis in about 90% of patients, most frequently with lymphadenopathy and lung, eye, or liver involvement. Nevertheless, only slightly more than half of the patients have hilar lymphadenopathy or pulmonary interstitial fibrosis at the time of diagnosis.19 Treatment with high-dose corticosteroids quickly improves renal function, but most patients do not recover completely. The starting dose should be 1 mg/kg prednis(ol)one daily, and corticosteroid therapy should be tapered slowly and not withdrawn before at least 1 year to prevent relapses. Whereas some authors advocate long-term maintenance therapy with low-dose corticosteroids, we usually stop corticosteroids after 2 to 3 years. Because of the risk of late relapse, these patients should be observed for a prolonged time.
Sjögren’s Syndrome Clinically significant interstitial nephritis is rare in Sjögren’s syndrome and usually results in chronic tubular dysfunction.20 Some patients may present with severe symptomatic hypokalemia with distal renal tubular acidosis. Rarely, Sjögren’s syndrome presents with AKI due to AIN. In these patients, treatment with high-dose corticosteroids may dramatically improve renal function.
Systemic Lupus Erythematosus About two thirds of renal biopsies performed in patients with systemic lupus show some tubulointerstitial involvement, but significant tubulointerstitial injury in the setting of minimal glomerular abnormalities is rare, with only about 10 cases reported in the literature.21 In these cases, renal biopsy shows typical features of AIN on light microscopy, and immunofluorescence staining always discloses immune deposits along the TBM, usually with a granular pattern. Renal function improves after high-dose corticosteroids and does not usually require additional immunosuppressive drugs. However, azathioprine has been used as a corticosteroid-sparing agent.
Other Systemic Diseases Among patients with cryoglobulinemia and AKI, a few exhibit significant interstitial inflammatory infiltrates associated with granular immune deposits in the interstitium and along the TBM. This AIN is usually associated with characteristic glo-
Infiltration of renal parenchyma by malignant cells is common in patients with leukemia or lymphoma. Most of the time, this infiltration is totally asymptomatic or only causes enlarged kidneys, but a few patients with AKI have been described.22 Chemotherapy or radiotherapy may rapidly improve renal function in these patients, but before these treatments are started, it is important to exclude more common causes of AKI associated with neoplastic diseases (see Chapter 66).
IDIOPATHIC ACUTE INTERSTITIAL NEPHRITIS More than 50 cases of idiopathic AIN with anterior uveitis have been reported (TINU syndrome).23 This syndrome is found most commonly in girls of pubertal age but can also occur in pubertal boys and in adults. Initial symptoms may be ocular, with ocular pain and visual impairment, or pseudoviral, with fever, myalgia, and asthenia. AIN is responsible for AKI, ranging from mild to severe, that may or may not be associated with abnormal urinalysis. Renal biopsy shows diffuse interstitial inflammatory infiltrates, almost always without granulomas and without immune deposits. In children, renal prognosis is excellent, and serum creatinine usually returns to baseline values within a few weeks, with or without corticosteroid therapy. In adults, the renal prognosis seems to be less favorable, and corticosteroid therapy might be useful in preventing evolution to chronic renal failure. Uveitis, which can occur at any time in respect to AIN, is usually responsive to topical corticosteroids, but it may relapse without any recurrence of AIN. A few cases of idiopathic AIN have been reported. Immunofluorescence studies of renal biopsy specimens can show linear deposits of IgG along the TBM, granular deposits of IgG along the TBM, or no immune deposits, suggesting that this entity is heterogeneous. The treatment of patients with idiopathic AIN is still controversial. Patients who receive corticosteroids usually show a dramatic improvement of renal function, but others have recovered normal renal function without any treatment.
ACUTE INTERSTITIAL NEPHRITIS IN RENAL TRANSPLANTS Acute rejection is by far the most common cause of AIN in renal allograft recipients (see Chapter 100). Nevertheless, AIN can also be induced by drugs or infections. Cases of drug-induced AIN have been reported even in the first weeks after transplantation, when immunosuppression is maximal.24 Among infectious AIN, the frequency of polyomavirus-induced AIN appears to be increasing, and it should be suspected in patients with acute deterioration of renal function and so-called decoy cells in urine (see Chapter 101).25
REFERENCES 1. Neilson EG. Pathogenesis and therapy of interstitial nephritis. Kidney Int. 1989;35:1257-1270. 2. Clarkson MR, Giblin L, O’Connell FP, et al. Acute interstitial nephritis: Clinical features and response to corticosteroid therapy. Nephrol Dial Transplant. 2004;19:2778-2783. 3. Brewster UC, Perazella MA. Acute kidney injury following proton pump inhibitor therapy. Kidney Int. 2007;71:589-593. 4. Schmid S, Opravil M, Moddel M, et al. Acute interstitial nephritis of HIV-positive patients under atazanavir and tenofovir therapy in a retrospective analysis of kidney biopsies. Virchows Arch. 2007;450:665-670. 5. Winn SK, Ellis S, Savage P, et al. Biopsy-proven acute interstitial nephritis associated with the tyrosine kinase inhibitor sunitinib: A class effect? Nephrol Dial Transplant. 2009;24:673-675. 6. Rossert J. Drug-induced acute interstitial nephritis. Kidney Int. 2001;60: 804-817. 7. Baker RJ, Pusey CD. The changing profile of acute tubulointerstitial nephritis. Nephrol Dial Transplant. 2004;19:8-11. 8. Corwin HL, Bray RA, Haber MH. The detection and interpretation of urinary eosinophils. Arch Pathol Lab Med. 1989;113:1256-1258. 9. Nolan CR 3rd, Anger MS, Kelleher SP. Eosinophiluria—a new method of detection and definition of the clinical spectrum. N Engl J Med. 1986;315:1516-1519. 10. Corwin HL, Korbet SM, Schwartz MM. Clinical correlates of eosinophiluria. Arch Intern Med. 1985;145:1097-1099. 11. Ruffing KA, Hoppes P, Blend D, et al. Eosinophils in urine revisited. Clin Nephrol. 1994;41:163-166. 12. Linton AL, Richmond JM, Clark WF, et al. Gallium 67 scintigraphy in the diagnosis of acute renal disease. Clin Nephrol. 1985;24:84-87. 13. Gonzalez E, Gutierrez E, Galeano C, et al. Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis. Kidney Int. 2008;73:940-946.
CHAPTER
60 Acute Interstitial Nephritis
737
14. Preddie DC, Markowitz GS, Radhakrishnan J, et al. Mycophenolate mofetil for the treatment of interstitial nephritis. Clin J Am Soc Nephrol. 2006;1:718-722. 15. Ferluga D, Vizjak A. Hantavirus nephropathy. J Am Soc Nephrol. 2008;19:1653-1658. 16. Cohen SD, Chawla LS, Kimmel PL. Acute kidney injury in patients with human immunodeficiency virus infection. Curr Opin Crit Care. 2008;14:647-653. 17. Rajakariar R, Sharples EJ, Raftery MJ, et al. Sarcoid tubulo-interstitial nephritis: Long-term outcome and response to corticosteroid therapy. Kidney Int. 2006;70:165-169. 18. Mahevas M, Lescure FX, Boffa JJ, et al. Renal sarcoidosis: Clinical, laboratory, and histologic presentation and outcome in 47 patients. Medicine (Baltimore). 2009;88:98-106. 19. Hannedouche T, Grateau G, Noel LH, et al. Renal granulomatous sarcoidosis: Report of six cases. Nephrol Dial Transplant. 1990;5:1824. 20. Goules A, Masouridi S, Tzioufas AG, et al. Clinically significant and biopsy-documented renal involvement in primary Sjögren syndrome. Medicine (Baltimore). 2000;79:241-249. 21. Mori Y, Kishimoto N, Yamahara H, et al. Predominant tubulointerstitial nephritis in a patient with systemic lupus nephritis. Clin Exp Nephrol. 2005;9:79-84. 22. Tornroth T, Heiro M, Marcussen N, et al. Lymphomas diagnosed by percutaneous kidney biopsy. Am J Kidney Dis. 2003;42:960-971. 23. Liakopoulos V, Ioannidis I, Zengos N, et al. Tubulointerstitial nephritis and uveitis (TINU) syndrome in a 52-year-old female: A case report and review of the literature. Ren Fail. 2006;28:355-359. 24. Josephson MA, Chiu MY, Woodle ES, et al. Drug-induced acute interstitial nephritis in renal allografts: Histopathologic features and clinical course in six patients. Am J Kidney Dis. 1999;34:540-548. 25. Hariharan S. BK virus nephritis after renal transplantation. Kidney Int. 2006;69:655-662.