What makes UpToDate so powerful?

  • over 10000 topics
  • 22 specialties
  • 5,700 physician authors
  • evidence-based recommendations
See more sample topics
Find Patient Print
0 Find synonyms

Find synonyms Find exact match

Clinical manifestations and diagnosis of acute interstitial nephritis
UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
Clinical manifestations and diagnosis of acute interstitial nephritis
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Oct 12, 2016.

INTRODUCTION — Acute interstitial nephritis (AIN) is a renal lesion that causes a decline in renal function and is characterized by an inflammatory infiltrate in the kidney interstitium [1]. It is most often induced by drug therapy. AIN is also caused by autoimmune disorders or other systemic disease (eg, systemic lupus erythematosus [SLE], Sjögren's syndrome, sarcoidosis), a variety of infections remote to the kidney (eg, Legionella, leptospirosis, and streptococcal organisms), and tubulointerstitial nephritis with uveitis (TINU) syndrome [2-10].

An overview of the clinical manifestations and diagnosis of AIN is presented in this topic review. The treatment of AIN is discussed separately. (See "Treatment of acute interstitial nephritis".)

Interstitial nephritis associated with SLE, sarcoidosis, the TINU syndrome, and Sjögren's syndrome is also discussed elsewhere. (See "Diagnosis and classification of renal disease in systemic lupus erythematosus", section on 'Tubulointerstitial nephritis' and "Tubulointerstitial nephritis and uveitis (TINU syndrome)" and "Renal disease in Sjögren's syndrome" and "Renal disease in sarcoidosis".)

ETIOLOGY — In initial reports, the vast majority of cases of AIN resulted from exposure to beta-lactam antibiotics, particularly methicillin. More recently, drugs other than antibiotics as well as infections and other underlying conditions have been recognized as clinically significant causes.

The distribution of causes of AIN has been reported as follows [6,9,11-13]:

Drugs (with antibiotics responsible for 30 to 49 percent of these cases) – 70 to 75 percent

Infections – 4 to 10 percent

Tubulointerstitial nephritis and uveitis (TINU) syndrome – 5 to 10 percent

Systemic disease including sarcoidosis, Sjögren's syndrome, systemic lupus erythematosus (SLE), and others – 10 to 20 percent

Drugs — Virtually any drug can cause AIN, although only a few have been reported with any frequency. While there are single case reports of many drugs apparently causing AIN, we generally only consider a case report of a previously unreported drug as likely to reflect a real effect if there is biopsy-proven AIN and the patient was not taking any other drugs that might cause AIN.

On the other hand, it may be difficult to identify the culprit drug in some patients with biopsy-proven AIN, especially among patients who are taking multiple medications and may not recall which agents are newly started.

AIN was particularly common with methicillin, occurring in up to 17 percent of patients who had been treated for more than 10 days [5,14,15]. Methicillin is no longer available in the United States.

The most common drug causes of AIN now include [2-4,13,15-23]:

Nonsteroidal anti-inflammatory agents (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors

Penicillins and cephalosporins

Rifampin

Antimicrobial sulfonamides, including trimethoprim-sulfamethoxazole

Diuretics, including loop diuretics such as furosemide and bumetanide, and thiazide-type diuretics

Ciprofloxacin and, perhaps to a lesser degree, other quinolones

Cimetidine (only rare cases have been described with other H-2 blockers such as ranitidine) [24,25]

Allopurinol

Proton pump inhibitors (PPIs) such as omeprazole and lansoprazole

Indinavir

5-aminosalicylates (eg, mesalamine)

The development of drug-induced AIN is not dose dependent, and recurrence or exacerbation can occur with a second exposure to the same or a related drug [26].

Several studies have shown an association between PPIs and AIN [27-30]. The interval between the onset of these drugs and detection of AIN is very variable (from one week to nine months), although 10 to 11 weeks is the most common interval. In many cases, it is difficult to establish a temporal relationship between PPI consumption and AIN given the frequent discontinuity in their intake and the sparse symptoms associated with PPI-induced AIN. One study found that renal function decline in PPI-induced AIN was less severe than in antibiotic-induced AIN, but the possibility of recovery at six months was lower [31]. PPIs are one of the most frequently prescribed drug classes worldwide. Studies have suggested that repeated episodes of PPI-induced AIN, many of them undetected, can contribute to the development of chronic kidney disease (CKD), and, indeed, an association between consumption of PPI and the presence of CKD has been found in epidemiological studies [32,33]. (See "Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders", section on 'Kidney disease'.)

Studies suggest that AIN can be a common complication among patients with inflammatory bowel diseases. In most of them, AIN has been attributed to treatment with 5-aminosalicylates [34,35], although AIN has been also found in treatment-naïve patients [36]. Different types of anticancer drugs can induce AIN [37], and drug-induced AIN is also relatively common among human immunodeficiency virus (HIV)-infected patients, although infections and immunologic syndromes associated with HIV infection can also induce AIN [38,39].

Infections — Multiple organisms have been associated with AIN including Legionella, Leptospira, cytomegalovirus (CMV) Streptococcus, Mycobacterium tuberculosis, Corynebacterium diphtheriae, Epstein-Barr virus (EBV), Yersinia, polyomavirus, Enterococcus, Escherichia coli, adenovirus, Candida, and others [10,13,40-42]. A histologic variant of AIN that is characterized by granuloma formation has been associated with Mycobacterium, fungi (histoplasmosis, coccidioidomycosis), bacteria (Brucella, Chlamydia), spirochetes (Francisella, Treponema), and parasites (Leishmania, Toxoplasma) [43]. (See 'Histology' below.)

Initial reports suggested that organisms such as Legionella, Leptospira, CMV, and Streptococcus primarily invaded organs remote from the kidney and exerted an inflammatory response in the kidney without invading the kidney [41,42]. However, more recent reports describe the identification of organism-specific antigens or DNA in kidney proximal tubule cells of patients with AIN [40,44-46].

Associated with systemic disease — Numerous systemic disorders have been associated with AIN. These primarily include SLE, sarcoidosis, and Sjögren's syndrome. In a series of 133 patients with biopsy-proven AIN, of autoimmune etiologies, sarcoidosis was the most common [13]. (See "Diagnosis and classification of renal disease in systemic lupus erythematosus", section on 'Tubulointerstitial nephritis' and "Renal disease in Sjögren's syndrome" and "Renal disease in sarcoidosis".)

Patients with SLE and granulomatosis with polyangiitis (formerly called Wegener’s granulomatosis) often have an interstitial nephritis accompanying the characteristic glomerular disease and may rarely present with AIN, even in the absence of glomerular disease.

Relatively rare causes of AIN include immunoglobulin G4 (IgG4)-related disease [47,48] and hypocomplementemic tubulointerstitial nephritis [49-51]. IgG4-related disease is a systemic disorder that was initially described in 2003 and reported to cause tubulointerstitial nephritis in 2004 [52-55]. IgG4-related disease is characterized by the infiltration of multiple organs by a lymphoplasmacytic infiltrate that is rich in IgG4-positive plasma cells, resulting in diverse clinical manifestations, including autoimmune pancreatitis, enlarged lacrimal and salivary glands and periorbital tissue, and tubulointerstitial nephritis [47]. (See "Overview of IgG4-related disease".)

Kidneys are reportedly involved in approximately 30 percent of cases of IgG4-related disease [47,56]. Tubulointerstitial nephritis is the most commonly associated renal lesion, although glomerular lesions (mostly membranous nephropathy) have been reported [56-58]. In a case series from Japan, among 153 patients with IgG4-related disease, 23 patients (15 percent) had tubulointerstitial nephritis, and two patients had a concurrent membranous nephropathy lesion [56]. The clinical and laboratory features that characterize IgG4-related tubulointerstitial nephritis are described below. (See 'Clinical features' below.)

Hypocomplementemic tubulointerstitial nephritis, described in a small case series [50] and a number of case reports, is characterized by massive tubulointerstitial deposits and lymphoid or plasma cell infiltration observed on kidney biopsy and systemic hypocomplementemia [49-51]. It is possible that many of the early reports of hypocomplementemic tubulointerstitial nephritis were due to IgG4-related disease, which is also characterized by lymphoplasmacytic infiltrates and systemic hypocomplementemia, since IgG4 immunostaining was not available at the time of the initial reports [50]. However, both IgG4-positive and IgG4-negative cases of hypocomplementemic interstitial nephritis have since been diagnosed at the same institution that reported the defining case series, suggesting that these diseases should be considered distinct entities.

A rare cause of AIN is due to anti-tubular basement membrane (TBM) antibodies, leading to linear staining with immunoglobulin along the TBMs on immunofluorescence microscopy [59-62]. This can occur in the presence or absence of concurrent anti-glomerular basement membrane antibodies [59,60] and has been described in patients with membranous nephropathy [62]. (See "Pathogenesis and diagnosis of anti-GBM antibody (Goodpasture's) disease", section on 'Renal biopsy' and "Causes and diagnosis of membranous nephropathy".)

Older patients — There may be differences in the distribution of underlying causes of AIN among older patients. In one review, compared with patients ages 18 to 64 years (n = 88), patients older than 65 years (n = 45) were more likely to have drug-induced AIN (64 versus 87 percent) and less likely to have AIN related to autoimmune or systemic diseases (27 versus 7 percent) [31]. There is no known biologic reason for this predilection, which is most likely related to polypharmacy in older individuals. In addition, some systemic diseases that cause tubulointerstitial nephritis are more frequent among older individuals. The most common causative agents among older patients were penicillin and omeprazole.

EPIDEMIOLOGY — AIN is demonstrated in 1 to 3 percent of all renal biopsies [63,64]. When analysis is restricted to biopsies performed in the setting of acute kidney injury (AKI), the percentage rises to 13 to 27 percent [64,65].

Some studies suggest that the incidence of AIN is increasing, particularly among older subjects [13,31,64]. The reasons for this change are complex and difficult to assess but may include an aging population base, increasing polypharmacy (including nonsteroidal anti-inflammatory drugs [NSAIDs] and proton pump inhibitors [PPIs]) in older people, and an increasingly less restrictive policy of renal biopsies in older patients with AKI. The true incidence of AIN may also be underestimated for the following reasons [27]:

A confirmatory renal biopsy is often not done in older and frail patients; empirical treatment is often preferred.

The prevalence of AIN caused by PPIs, 5-aminosalicylates, and NSAIDs and often without obvious associated symptoms is increasing [27]. Skin rash and eosinophilia are significantly less common with these drugs than in antibiotic-induced AIN. (See 'Clinical manifestations' below.)

CLINICAL FEATURES

Clinical manifestations — With AIN from any cause, patients may present with nonspecific signs and symptoms of acute renal dysfunction. These may include the acute or subacute onset of nausea, vomiting, and malaise. However, many patients are asymptomatic [10]. Patients may be oliguric or nonoliguric; in a retrospective study that included 60 cases of AIN (92 percent of which were drug induced, with the remainder idiopathic), oliguria was present among 51 percent [11]. Gross hematuria occurs in approximately 5 percent of individuals [11].

Patients usually do not have significant proteinuria, and nephrotic syndrome occurs in <1 percent of patients with AIN [11]. An exception occurs among patients who have nonsteroidal anti-inflammatory drug (NSAID)-induced AIN, which may occur concurrently with NSAID-induced membranous nephropathy or minimal change disease. (See 'NSAID-induced AIN and nephrotic syndrome' below and "Causes and diagnosis of membranous nephropathy", section on 'Nonsteroidal anti-inflammatory drugs' and "Etiology, clinical features, and diagnosis of minimal change disease in adults", section on 'Drugs'.)

Patients may present with symptoms related to the cause of the AIN. Classically, patients with drug-induced AIN were reported to have symptoms and/or signs of an allergic-type reaction, including rash, fever, and eosinophilia [66]. However, in a more recent review of three series that totaled 128 patients with AIN (of whom 70 percent had drug-induced disease), these findings of a typical allergic response were relatively less common at presentation [9]:

Rash – 15 percent

Fever – 27 percent

Eosinophilia – 23 percent

Triad of rash, fever, and eosinophilia – 10 percent

A similar incidence of findings was reported in two retrospective series, which collected a total of 121 patients [67,68]. Rash, fever, eosinophilia, and the triad were observed in 22, 36, 35, and 11 percent, respectively [11]. Arthralgias were observed in 45 percent of the patients [11].

Thus, the originally described classic triad is less commonly observed than initially reported. This is probably due to the absence of cases of methicillin-induced AIN and (perhaps) the increased inclusion of cases not directly resulting from an allergic response [10]. In addition, some agents, such as NSAIDs and proton pump inhibitors (PPIs), are less commonly associated with fever, rash, and eosinophilia compared with other agents [68,69].

There is no typical range of onset for medication-induced AIN. The onset of drug-induced AIN following drug exposure may range from three to five days (as occurs with a second exposure to an offending drug), to as long as several weeks, to many months (as occurs following a first exposure to an offending drug) [2,3]. However, the latent period may be as short as one day with rifampin [3] or as long as 18 months with an NSAID [69].

Patients who have AIN that is not related to a drug may have symptoms related to an associated infection or systemic condition such as systemic lupus erythematosus (SLE), sarcoidosis, the tubulointerstitial nephritis with uveitis (TINU) syndrome, and Sjögren's syndrome. (See "Diagnosis and classification of renal disease in systemic lupus erythematosus", section on 'Tubulointerstitial nephritis' and "Tubulointerstitial nephritis and uveitis (TINU syndrome)" and "Renal disease in Sjögren's syndrome" and "Renal disease in sarcoidosis".)

Patients with immunoglobulin G4 (IgG4)-related interstitial nephritis may have extrarenal signs and symptoms. In a series of 23 patients, nonspecific symptoms such as fever, arthralgias, skin lesions, and edema were present in three, five, one, and two patients, respectively [56].

Overall, 96 percent of patients with IgG4-related AIN had extrarenal lesions, including sialadenitis in 19 (82 percent), lymphadenopathy in 10 (44 percent), autoimmune pancreatitis in 9 (39 percent), dacryoadenitis in 7 (30 percent), and lung lesions (interstitial pneumonia and nodular lesions) in 6 (26 percent) [56].

Tubulointerstitial nephritis and uveitis (TINU) syndrome — Some patients with interstitial nephritis have the TINU syndrome. Patients present with interstitial nephritis and uveitis and occasionally with systemic findings including fever, weight loss, fatigue, malaise, anorexia, asthenia, abdominal and flank pain, arthralgias, myalgias, headache, polyuria, and/or nocturia. The TINU syndrome is discussed elsewhere. (See "Tubulointerstitial nephritis and uveitis (TINU syndrome)".)

Laboratory and radiographic findings — In general, patients with AIN present with some combination of the following laboratory findings, with some variation based upon the underlying cause [2-4,9,67]:

Increased plasma creatinine – Virtually all patients have a rise in the plasma creatinine concentration on presentation [67,68]. If AIN is drug induced, the increase in creatinine is temporally related to administration of the offending drug. Acute kidney injury (AKI) may be severe; in two retrospective series, among 121 patients who presented with AIN, 40 percent required dialysis [67,68].

Eosinophilia and eosinophiluria – Although eosinophilia (defined by an absolute blood eosinophil count of ≥500 eosinophils/microL) is only found in 25 to 35 percent of AIN cases [9,11,67,68], its finding in a patient with AKI with no other apparent cause should raise the suspicion of drug-induced AIN. Eosinophiluria, defined by eosinophils that account for more than 1 percent of urinary white cells by Hansel stain [5,70], has been associated with AIN [71]. However, urinary eosinophils are not useful in distinguishing AIN from other causes of AKI, and the absence of eosinophiluria does not exclude the possibility of AIN. The lack of clinical utility of eosinophils in diagnosing AIN was best shown in a retrospective study that correlated urinary eosinophils with biopsy-proven AIN [72]. Five-hundred sixty-six patients had both a kidney biopsy and a test for urinary eosinophils performed for AKI. Among 179 patients who had a positive test for urinary eosinophils (defined as ≥1 percent of urinary white cells), only 28 had AIN on biopsy. Conversely, among 387 patients who had a negative test for eosinophils, 63 had biopsy-proven AIN. In this study, urinary eosinophils were found in multiple other kidney diseases, including acute tubular necrosis and crescentic and proliferative glomerulonephritis, and their presence did not alter the pretest probability of AIN on biopsy.

This study may have been limited by selection bias since many patients who had AIN but were excluded from the study because they did not undergo biopsy may have had urinary eosinophils.

Some reports [68,69], though not all [72], have suggested that eosinophilia and eosinophiluria are less common in AIN induced by NSAIDs compared with other drugs.

A characteristic urine sediment – The urine sediment usually reveals white cells, red cells, and white cell casts (picture 1A-B). Red blood cell casts, which are typically seen in glomerulonephritis, have also been described in AIN, although this is rare [73]. Some patients will, however, have no urinary sediment findings or isolated microhematuria and leukocyturia. The absence of urinary findings does not exclude a diagnosis of AIN.

A variable degree of proteinuria – Proteinuria can range from none or minimal to >1 g/day. In two retrospective series that included a total of 121 patients, the mean and median protein excretions were 0.9±1.1 g/day (range 0 to 6 g/day) and 0.70 g/day (interquartile range 0.39 to 1.0 g/day), respectively [67,68]. Older individuals may be more likely to have significant proteinuria [65].

Occasional patients will have nephrotic-range proteinuria [2,3,11]. Concurrent nephrotic syndrome due to minimal change disease or membranous nephropathy can rarely be seen with NSAIDs and, in selected cases, induced by ampicillin, rifampin, interferon, or ranitidine [11,24,69,74,75]. In one study cited above, however, although proteinuria was significantly higher among NSAID-induced AIN as compared with other types of drug-induced AIN, nephrotic-range proteinuria was rare [68]. In addition, although these and other drugs may induce heavy proteinuria [14], an underlying disease (such as diabetic nephropathy or glomerulonephritis due to bacterial endocarditis) may be responsible for at least part of the proteinuria in some patients.

Evidence of tubulointerstitial damage – Signs of tubulointerstitial damage, such as the Fanconi syndrome and renal tubular acidosis, may be present but rarely dominate the clinical picture [25].

High fractional sodium excretion – The fractional excretion of sodium (FENa) may be >1 percent, which is in part indicative of tubular damage [2]. Calculators for the FENa are available using either standard units (calculator 1) or SI units (calculator 2) (see "Fractional excretion of sodium, urea, and other molecules in acute kidney injury (acute renal failure)", section on 'Fractional excretion of sodium in acute kidney injury'). However, lower values may be seen, particularly in patients who are nonoliguric and have less severe renal failure [76,77].

Radiographic findings – There are no radiographic findings that are diagnostic for AIN. Radiographic findings, including marked enlargement of kidneys with low-attenuation lesions, may be seen among patients with IgG4-related AIN [48].

IgG4-related disease and hypocomplementemic interstitial nephritis — In addition to the above findings, patients with immunoglobulin G4 (IgG4)-related disease or hypocomplementemic interstitial nephritis usually have elevated serum total IgG and/or IgG4 levels or hypergammaglobulinemia and may have low serum complement concentrations. In one series of IgG4-related tubulointerstitial nephritis, among 23 patients, complement C3, C4, or both were reduced in 16 [56].

Microbiologic features unique to different culprit organisms are presented separately. (See appropriate topic reviews.)

DIAGNOSIS — AIN should be suspected in a patient who presents with an elevated serum creatinine and a urinalysis that shows white cells, white cell casts, and, in some cases, eosinophiluria. Red blood cells and even red blood cell casts can be also observed [78,79], although gross hematuria is distinctly unusual. Drug-induced AIN should be suspected when the onset of characteristic laboratory findings is temporally related to the initiation of a new drug, particularly one that has been previously reported to cause AIN. However, occasional patients have a bland sediment with few cells or casts [18]. Thus, a relatively normal urinalysis should not exclude the diagnosis.

A definitive diagnosis of AIN is made by renal biopsy. It is often considered unnecessary to make a definitive diagnosis, such as among patients who have clearly documented onset of renal failure after initiation of a common culprit drug and who improve immediately upon stopping the offending agent.

We suggest a kidney biopsy for the following patients who are suspected of having AIN:

Patients who have a characteristic urinalysis for AIN but are not being treated with a drug known to cause AIN.

Patients who are being treated with a drug known to cause AIN but do not have a characteristic urinalysis. Some of the drugs that cause AIN can also produce other forms of acute kidney injury (AKI). As an example, nonsteroidal anti-inflammatory drugs (NSAIDs) can exacerbate prerenal disease by inhibiting the production of vasodilator prostaglandins [69]. (See "NSAIDs: Acute kidney injury (acute renal failure)".)

Patients who are being considered for treatment with glucocorticoids for AIN (usually drug induced). Among selected patients (such as those at high risk of complications of a biopsy or who do not wish to undergo a biopsy), glucocorticoids may be initiated in the absence of a biopsy. However, among such patients who do not improve after the first five to seven days of steroid treatment, most should have a biopsy in order to exclude other diagnoses or the presence of severe interstitial fibrosis.

Patients with putative drug-related AIN who are not treated with glucocorticoids initially and do not have a recovery following cessation of drug therapy [2,67]. Clinicians wait a variable amount of time to allow recovery before performing a biopsy. Some will perform a biopsy if there is no evidence of recovery within three to four days, whereas others wait until the patient is approaching the need for renal replacement therapy.

Patients who present with advanced renal failure, providing the onset of renal failure is known to be relatively recent (ie, within three months).

Patients with any features (such as high-grade proteinuria) that cause the diagnosis of AIN to be uncertain.

Patients who have a characteristic urinalysis for AIN but do not have an elevated creatinine may also be considered for biopsy, but such patients rarely come to medical attention since the urinalysis is usually only performed after the detection of an increased serum creatinine. Moreover, it is usually simpler and safer just to remove potential offending medications in such cases.

The approach to the treatment of patients diagnosed with AIN, tubulointerstitial nephritis with uveitis (TINU), and renal sarcoidosis is presented separately. (See "Treatment of acute interstitial nephritis" and "Renal disease in sarcoidosis" and "Tubulointerstitial nephritis and uveitis (TINU syndrome)".)

Histology — The major histologic changes are interstitial edema and a marked interstitial infiltrate consisting primarily of T lymphocytes and monocytes (picture 2A-E) [2,9]. Eosinophils, plasma cells, and neutrophils also may be found. The classic lesion of "tubulitis" is found when inflammatory cells invade the tubular basement membrane (TBM).

Some histologic features may suggest particular variants of AIN. As an example, granuloma formation is particularly characteristic of sarcoidosis, although it may be seen in any form of AIN [80]. Granuloma formation also suggests a greater likelihood of infection-induced AIN compared with AIN without granulomas. In a review of 40 biopsies of patients with granulomatous renal disease (including 37 patients with interstitial nephritis, two with associated pauci-immune crescentic glomerulonephritis, and one with vasculitis), sarcoidosis was present in 20 patients (50 percent) and drug-induced and Mycobacterium infection present in seven (18 percent) and five (13 percent), respectively [81]. As described above, other infections that have been associated with granulomatous AIN include fungi (histoplasmosis, coccidioidomycosis), bacteria (Brucella, Chlamydia), spirochetes (Francisella, Treponema), and parasites (Leishmania, Toxoplasma) [43]. (See 'Infections' above.)

Characteristic histologic features that suggest immunoglobulin G4 (IgG4)-related disease include the presence of TBM immune complex deposits and an increase in IgG4-positive plasma cells in the interstitium [48].

Patients with interstitial nephritis related to lupus usually have concurrent glomerular lesions. (See "Diagnosis and classification of renal disease in systemic lupus erythematosus", section on 'Tubulointerstitial nephritis'.)

Differential diagnosis — The differential diagnosis of AIN includes all other causes of AKI. The diagnostic approach to the patient with AKI from any cause is presented elsewhere. (See "Diagnostic approach to the patient with subacute kidney injury in an outpatient setting".)

In general, the urinary findings will distinguish AIN from other causes of AKI. The urinalysis, for example, typically shows granular and epithelial cell casts and free epithelial cells in acute tubular necrosis; red cell casts, as well as red and white cells in acute glomerulonephritis; and few, if any, abnormalities in prerenal disease and obstruction.

Among patients with a predominance of white blood cells and white blood cell casts, renal atheroemboli should be considered, particularly among older patients [82]. Similarly to AIN, renal atheroemboli may present with eosinophiluria, eosinophilia, and skin lesions. However, the skin lesions associated with atheroemboli are more commonly reticular (livedo reticularis) with digital infarcts, whereas the characteristic rash associated with AIN is a diffuse, maculopapular one. The history may also distinguish between AIN and renal atheroemboli since the majority of cases of atheroemboli are preceded by an endovascular procedure. (See "Clinical presentation, evaluation, and treatment of renal atheroemboli" and "Clinical presentation, evaluation, and treatment of renal atheroemboli", section on 'Risk factors'.)

Among patients who have a completely negative sediment, as in all patients with AKI of obscure origin, obstruction should be considered as part of the differential diagnosis. Imaging studies (usually an ultrasound) generally exclude the presence of obstruction, except in rare cases when the diagnosis of AKI is made within the first two to three days (see "Clinical manifestations and diagnosis of urinary tract obstruction and hydronephrosis", section on 'Diagnosis'). In all patients, imaging should be done prior to renal biopsy.

ESTABLISHING THE CAUSE — Once a diagnosis of AIN is made by biopsy, the underlying cause should be determined. As discussed above, the vast majority of cases of AIN are caused by a drug. A careful review of medications, including the timing of initiation in relation to the onset of acute kidney injury (AKI), may reveal the likely culprit agent.

Less commonly, a drug is not identified. Among such patients, a histologic diagnosis of AIN should provoke a search for underlying infection and systemic disorders including systemic lupus erythematosus (SLE), sarcoidosis, Sjögren's syndrome, tubulointerstitial nephritis and uveitis (TINU) syndrome, and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

In some cases, histologic features may suggest the underlying disease that is associated with AIN. As an example, granulomas are more likely to be seen in patients with sarcoidosis than in other forms of AIN. Additionally, AIN related to SLE may be accompanied by characteristic glomerular lesions. Immunoglobulin G4 (IgG4)-related disease may be suggested by the presence of tubular basement membrane (TBM) immune complex deposits and an increase in immunoglobulin G4 (IgG4)-positive plasma cells in the interstitium [48]. However, testing for IgG-4 specific plasma cells is not routinely performed at most centers.

Such histologic features are not diagnostic, and, in general, the etiology of non-drug-related AIN must be established by means other than the renal biopsy. Among patients who have AIN that is not believed to be related to a drug, we perform the following tests:

Chest radiograph to evaluate for sarcoidosis, tuberculosis, and other infections. Among patients in whom the chest radiograph is nondiagnostic, a high-resolution chest computed tomography (CT) should be obtained to evaluate for sarcoidosis.

Serum levels of angiotensin-converting enzyme (ACE) and measurement of serum calcium and urinary calcium excretion to evaluate for sarcoidosis.

A purified protein derivative (PPD) to exclude tuberculosis, particularly in granulomatous AIN.

Serologic tests, in select cases, to exclude histoplasmosis, coccidioidomycosis, toxoplasmosis, and Epstein-Barr virus (EBV). Urinary antigen test to exclude Legionella infection and urine culture to exclude leptospirosis.

ANCA to exclude ANCA-associated vasculitides.

Antinuclear antibody (ANA) and double-stranded DNA (dsDNA) to exclude SLE.

C3 and C4 to evaluate for SLE and IgG4-related disease and hypocomplementemic AIN. These tests, however, neither diagnose nor exclude these disorders.

Anti-Ro/SSA, anti-La/SSb antibodies, C-reactive protein, and rheumatoid factor to exclude Sjögren's syndrome.

Serum protein electrophoresis.

The diagnostic evaluation of a particular infection-related AIN should be guided by extrarenal clinical manifestations.

NSAID-INDUCED AIN AND NEPHROTIC SYNDROME — Nonsteroidal anti-inflammatory drugs (NSAIDs) may cause AIN with an interstitial infiltrate composed primarily of T lymphocytes, with the nephrotic syndrome due to minimal change disease or membranous nephropathy [69,83,84].

This disorder is most likely to occur with fenoprofen but probably can be induced by any nonselective NSAID. There have also been case reports of selective cyclooxygenase (COX)-2 inhibitors also being associated with this pattern of injury [85].

How NSAIDs produce AIN and nephrotic syndrome are not known; it is possible that COX inhibition by the NSAID results in the preferential conversion of arachidonic acid to leukotrienes, which can then activate helper T cells.

Affected patients typically present with hematuria, pyuria, white cell casts, proteinuria, and an acute rise in the plasma creatinine concentration. The full picture of an allergic reaction (fever, rash, eosinophilia, and eosinophiluria) is typically absent, but one or more of these findings may be present. Spontaneous recovery generally occurs within weeks to a few months after therapy is discontinued [69,83]. All NSAIDs should be terminated in patients suspected of having NSAID-induced AIN. Since topically administered NSAIDs can be systemically absorbed, such therapy should also be terminated [86].

There is no definitive evidence that corticosteroid therapy is beneficial in this setting. However, a course of prednisone may be considered in patients whose renal failure persists more than one to two weeks after the NSAID has been discontinued [2]. (See "Treatment of acute interstitial nephritis".)

Such patients should avoid the subsequent administration of NSAIDs. Relapse may occur with rechallenge [87].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Acute interstitial nephritis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Acute interstitial nephritis (AIN) is a renal lesion that causes a decline in renal function and is characterized by an inflammatory infiltrate in the kidney interstitium. Drugs, particularly antibiotics, are the most common cause of AIN. Other causes include autoimmune disorders, infections, sarcoidosis, and tubulointerstitial nephritis with uveitis (TINU) syndrome. (See 'Introduction' above.)

Drugs that most commonly cause AIN are nonsteroidal anti-inflammatory drugs (NSAIDs, including selective cyclooxygenase [COX]-2 inhibitors), penicillins and cephalosporins, rifampin, antimicrobial sulfonamides, ciprofloxacin and other quinolones, diuretics, cimetidine, allopurinol, proton pump inhibitors (PPIs), indinavir, and 5-aminosalicylates (eg, mesalamine). Many other drugs can occasionally cause AIN. (See 'Drugs' above.)

Infections that have been associated with AIN include Legionella, Leptospira, cytomegalovirus (CMV), and Streptococcus. Other, less commonly associated organisms include Corynebacterium diphtheriae, Epstein-Barr virus (EBV), Yersinia, and polyomavirus. Mycobacterium infection is associated with a granulomatous variant of AIN. (See 'Infections' above.)

Autoimmune disorders that have been associated with AIN include sarcoidosis, Sjögren’s syndrome, systemic lupus erythematosus (SLE), and granulomatosis with polyangiitis (Wegener’s). Rare causes of AIN are immunoglobulin G4 (IgG4)-related disease, anti-tubular basement membrane (TBM) antibodies, hypocomplementemic tubulointerstitial nephritis, and the TINU syndrome. (See 'Associated with systemic disease' above.)

Patients with AIN present with nonspecific signs and symptoms associated with acute kidney injury (AKI). Signs and symptoms of an allergic-type reaction may be present, including rash, fever, and eosinophilia, although only 10 percent of patients have the full triad of rash, fever, and eosinophilia. (See 'Clinical features' above.)

Patients generally present with a rise in the plasma creatinine concentration, which (if drug induced) is temporally related to administration of the offending drug. Urine sediment usually reveals white cells, red cells, and white cell casts. Urinary eosinophils may be present but lack the specificity and sensitivity to either exclude or diagnose AIN. Protein excretion is usually only mildly or moderately increased. (See 'Laboratory and radiographic findings' above and "The significance of urinary eosinophils".)

AIN should be suspected in a patient who presents with an elevated serum creatinine and a urinalysis that shows white cells, white cell casts, and, in some cases, eosinophiluria. Drug-induced AIN should be suspected when the onset of characteristic laboratory findings are temporally related to the initiation of a new drug, particularly one that has been previously reported to cause AIN. A definitive diagnosis of AIN is made by renal biopsy. Selected patients with suspected AIN will benefit from renal biopsy. (see 'Diagnosis' above)

Patients who have a histologic diagnosis of AIN and are not on a drug known to cause AIN should be evaluated for an underlying etiology. (See 'Establishing the cause' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

  1. Rossert JA, Fischer EA. Acute interstitial nephritis. In: Comprehensive Clinical Nephrology, 2, Johnson RJ, Feehally J. (Eds), Elsevier Limited, Philadelphia 2003. Vol 1, p.769.
  2. Neilson EG. Pathogenesis and therapy of interstitial nephritis. Kidney Int 1989; 35:1257.
  3. Ten RM, Torres VE, Milliner DS, et al. Acute interstitial nephritis: immunologic and clinical aspects. Mayo Clin Proc 1988; 63:921.
  4. Michel DM, Kelly CJ. Acute interstitial nephritis. J Am Soc Nephrol 1998; 9:506.
  5. Rossert J. Drug-induced acute interstitial nephritis. Kidney Int 2001; 60:804.
  6. Schwarz A, Krause PH, Kunzendorf U, et al. The outcome of acute interstitial nephritis: risk factors for the transition from acute to chronic interstitial nephritis. Clin Nephrol 2000; 54:179.
  7. Yang CW, Wu MS, Pan MJ, et al. The Leptospira outer membrane protein LipL32 induces tubulointerstitial nephritis-mediated gene expression in mouse proximal tubule cells. J Am Soc Nephrol 2002; 13:2037.
  8. Tsai JD, Lee HC, Lin CC, et al. Epstein-Barr virus-associated acute renal failure: diagnosis, treatment, and follow-up. Pediatr Nephrol 2003; 18:667.
  9. Baker RJ, Pusey CD. The changing profile of acute tubulointerstitial nephritis. Nephrol Dial Transplant 2004; 19:8.
  10. Kodner CM, Kudrimoti A. Diagnosis and management of acute interstitial nephritis. Am Fam Physician 2003; 67:2527.
  11. Praga M, González E. Acute interstitial nephritis. Kidney Int 2010; 77:956.
  12. Buysen JG, Houthoff HJ, Krediet RT, Arisz L. Acute interstitial nephritis: a clinical and morphological study in 27 patients. Nephrol Dial Transplant 1990; 5:94.
  13. Muriithi AK, Leung N, Valeri AM, et al. Biopsy-proven acute interstitial nephritis, 1993-2011: a case series. Am J Kidney Dis 2014; 64:558.
  14. Nolan CM, Abernathy RS. Nephropathy associated with methicillin therapy. Prevalence and determinants in patients with staphylococcal bacteremia. Arch Intern Med 1977; 137:997.
  15. Galpin JE, Shinaberger JH, Stanley TM, et al. Acute interstitial nephritis due to methicillin. Am J Med 1978; 65:756.
  16. Nessi R, Bonoldi GL, Redaelli B, di Filippo G. Acute renal failure after rifampicin: a case report and survey of the literature. Nephron 1976; 16:148.
  17. Allon M, Lopez EJ, Min KW. Acute renal failure due to ciprofloxacin. Arch Intern Med 1990; 150:2187.
  18. Lo WK, Rolston KV, Rubenstein EB, Bodey GP. Ciprofloxacin-induced nephrotoxicity in patients with cancer. Arch Intern Med 1993; 153:1258.
  19. World MJ, Stevens PE, Ashton MA, Rainford DJ. Mesalazine-associated interstitial nephritis. Nephrol Dial Transplant 1996; 11:614.
  20. Torpey N, Barker T, Ross C. Drug-induced tubulo-interstitial nephritis secondary to proton pump inhibitors: experience from a single UK renal unit. Nephrol Dial Transplant 2004; 19:1441.
  21. Esteve JB, Launay-Vacher V, Brocheriou I, et al. COX-2 inhibitors and acute interstitial nephritis: case report and review of the literature. Clin Nephrol 2005; 63:385.
  22. Hoppes T, Prikis M, Segal A. Four cases of nafcillin-associated acute interstitial nephritis in one institution. Nat Clin Pract Nephrol 2007; 3:456.
  23. Wang YC, Lin YF, Chao TK, et al. Acute interstitial nephritis with prominent eosinophil infiltration. Clin Nephrol 2009; 71:187.
  24. Gaughan WJ, Sheth VR, Francos GC, et al. Ranitidine-induced acute interstitial nephritis with epithelial cell foot process fusion. Am J Kidney Dis 1993; 22:337.
  25. Neelakantappa K, Gallo GR, Lowenstein J. Ranitidine-associated interstitial nephritis and Fanconi syndrome. Am J Kidney Dis 1993; 22:333.
  26. Schubert C, Bates WD, Moosa MR. Acute tubulointerstitial nephritis related to antituberculous drug therapy. Clin Nephrol 2010; 73:413.
  27. Praga M, Sevillano A, Auñón P, González E. Changes in the aetiology, clinical presentation and management of acute interstitial nephritis, an increasingly common cause of acute kidney injury. Nephrol Dial Transplant 2015; 30:1472.
  28. Brewster UC, Perazella MA. Proton pump inhibitors and the kidney: critical review. Clin Nephrol 2007; 68:65.
  29. Leonard CE, Freeman CP, Newcomb CW, et al. Proton pump inhibitors and traditional nonsteroidal anti-inflammatory drugs and the risk of acute interstitial nephritis and acute kidney injury. Pharmacoepidemiol Drug Saf 2012; 21:1155.
  30. Blank ML, Parkin L, Paul C, Herbison P. A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use. Kidney Int 2014; 86:837.
  31. Muriithi AK, Leung N, Valeri AM, et al. Clinical characteristics, causes and outcomes of acute interstitial nephritis in the elderly. Kidney Int 2015; 87:458.
  32. Wyatt CM. Proton pump inhibitors and chronic kidney disease: is it time to sound the alarm? Kidney Int 2016; 89:732.
  33. Lazarus B, Chen Y, Wilson FP, et al. Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. JAMA Intern Med 2016; 176:238.
  34. Ambruzs JM, Walker PD, Larsen CP. The histopathologic spectrum of kidney biopsies in patients with inflammatory bowel disease. Clin J Am Soc Nephrol 2014; 9:265.
  35. Gisbert JP, González-Lama Y, Maté J. 5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review. Inflamm Bowel Dis 2007; 13:629.
  36. Waters AM, Zachos M, Herzenberg AM, et al. Tubulointerstitial nephritis as an extraintestinal manifestation of Crohn's disease. Nat Clin Pract Nephrol 2008; 4:693.
  37. Airy M, Raghavan R, Truong LD, Eknoyan G. Tubulointerstitial nephritis and cancer chemotherapy: update on a neglected clinical entity. Nephrol Dial Transplant 2013; 28:2502.
  38. Parkhie SM, Fine DM, Lucas GM, Atta MG. Characteristics of patients with HIV and biopsy-proven acute interstitial nephritis. Clin J Am Soc Nephrol 2010; 5:798.
  39. Zaidan M, Lescure FX, Brochériou I, et al. Tubulointerstitial nephropathies in HIV-infected patients over the past 15 years: a clinico-pathological study. Clin J Am Soc Nephrol 2013; 8:930.
  40. Chang JF, Peng YS, Tsai CC, et al. A possible rare cause of renal failure in streptococcal infection. Nephrol Dial Transplant 2011; 26:368.
  41. Ellis D, Fried WA, Yunis EJ, Blau EB. Acute interstitial nephritis in children: a report of 13 cases and review of the literature. Pediatrics 1981; 67:862.
  42. Dharmarajan TS, Yoo J, Russell RO, Boateng YA. Acute post streptococcal interstitial nephritis in an adult and review of the literature. Int Urol Nephrol 1999; 31:145.
  43. Agrawal V, Crisi GM, D'Agati VD, Freda BJ. Renal sarcoidosis presenting as acute kidney injury with granulomatous interstitial nephritis and vasculitis. Am J Kidney Dis 2012; 59:303.
  44. Hung CC, Chang CT, Chen KH, et al. Upregulation of chemokine CXCL1/KC by leptospiral membrane lipoprotein preparation in renal tubule epithelial cells. Kidney Int 2006; 69:1814.
  45. Farr RW. Leptospirosis. Clin Infect Dis 1995; 21:1.
  46. Baksh FK, Finkelstein SD, Swalsky PA, et al. Molecular genotyping of BK and JC viruses in human polyomavirus-associated interstitial nephritis after renal transplantation. Am J Kidney Dis 2001; 38:354.
  47. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012; 366:539.
  48. Raissian Y, Nasr SH, Larsen CP, et al. Diagnosis of IgG4-related tubulointerstitial nephritis. J Am Soc Nephrol 2011; 22:1343.
  49. Vaseemuddin M, Schwartz MM, Dunea G, Kraus MA. Idiopathic hypocomplementemic immune-complex-mediated tubulointerstitial nephritis. Nat Clin Pract Nephrol 2007; 3:50.
  50. Kambham N, Markowitz GS, Tanji N, et al. Idiopathic hypocomplementemic interstitial nephritis with extensive tubulointerstitial deposits. Am J Kidney Dis 2001; 37:388.
  51. Gupta A, Jothy S, Somerville P, Zaltzman JS. Hypocomplementaemic immune complex tubulointerstitial nephritis. NDT Plus 2010; 3:78.
  52. Uchiyama-Tanaka Y, Mori Y, Kimura T, et al. Acute tubulointerstitial nephritis associated with autoimmune-related pancreatitis. Am J Kidney Dis 2004; 43:e18.
  53. Takeda S, Haratake J, Kasai T, et al. IgG4-associated idiopathic tubulointerstitial nephritis complicating autoimmune pancreatitis. Nephrol Dial Transplant 2004; 19:474.
  54. Saeki T, Saito A, Yamazaki H, et al. Tubulointerstitial nephritis associated with IgG4-related systemic disease. Clin Exp Nephrol 2007; 11:168.
  55. Saeki T, Nishi S, Ito T, et al. Renal lesions in IgG4-related systemic disease. Intern Med 2007; 46:1365.
  56. Saeki T, Nishi S, Imai N, et al. Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis. Kidney Int 2010; 78:1016.
  57. Fervenza FC, Downer G, Beck LH Jr, Sethi S. IgG4-related tubulointerstitial nephritis with membranous nephropathy. Am J Kidney Dis 2011; 58:320.
  58. Cornell LD. IgG4-related kidney disease. Curr Opin Nephrol Hypertens 2012; 21:279.
  59. Andres G, Brentjens J, Kohli R, et al. Histology of human tubulo-interstitial nephritis associated with antibodies to renal basement membranes. Kidney Int 1978; 13:480.
  60. Paueksakon P, Revelo M, Lee SM, et al. Acute renal failure in a 64-year-old white man. Am J Kidney Dis 2000; 36:669.
  61. Clayman MD, Michaud L, Brentjens J, et al. Isolation of the target antigen of human anti-tubular basement membrane antibody-associated interstitial nephritis. J Clin Invest 1986; 77:1143.
  62. Katz A, Fish AJ, Santamaria P, et al. Role of antibodies to tubulointerstitial nephritis antigen in human anti-tubular basement membrane nephritis associated with membranous nephropathy. Am J Med 1992; 93:691.
  63. Cameron JS. Allergic interstitial nephritis: clinical features and pathogenesis. Q J Med 1988; 66:97.
  64. Goicoechea M, Rivera F, López-Gómez JM, Spanish Registry of Glomerulonephritis. Increased prevalence of acute tubulointerstitial nephritis. Nephrol Dial Transplant 2013; 28:112.
  65. Haas M, Spargo BH, Wit EJ, Meehan SM. Etiologies and outcome of acute renal insufficiency in older adults: a renal biopsy study of 259 cases. Am J Kidney Dis 2000; 35:433.
  66. Baldwin DS, Levine BB, McCluskey RT, Gallo GR. Renal failure and interstitial nephritis due to penicillin and methicillin. N Engl J Med 1968; 279:1245.
  67. 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.
  68. González E, Gutiérrez 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.
  69. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1984; 310:563.
  70. 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.
  71. Corwin HL, Korbet SM, Schwartz MM. Clinical correlates of eosinophiluria. Arch Intern Med 1985; 145:1097.
  72. Muriithi AK, Nasr SH, Leung N. Utility of urine eosinophils in the diagnosis of acute interstitial nephritis. Clin J Am Soc Nephrol 2013; 8:1857.
  73. Sigala JF, Biava CG, Hulter HN. Red blood cell casts in acute interstitial nephritis. Arch Intern Med 1978; 138:1419.
  74. Neugarten J, Gallo GR, Baldwin DS. Rifampin-induced nephrotic syndrome and acute interstitial nephritis. Am J Nephrol 1983; 3:38.
  75. Averbuch SD, Austin HA 3rd, Sherwin SA, et al. Acute interstitial nephritis with the nephrotic syndrome following recombinant leukocyte a interferon therapy for mycosis fungoides. N Engl J Med 1984; 310:32.
  76. Saha H, Mustonen J, Helin H, Pasternack A. Limited value of the fractional excretion of sodium test in the diagnosis of acute renal failure. Nephrol Dial Transplant 1987; 2:79.
  77. Lins RL, Verpooten GA, De Clerck DS, De Broe ME. Urinary indices in acute interstitial nephritis. Clin Nephrol 1986; 26:131.
  78. Fogazzi GB, Ferrari B, Garigali G, et al. Urinary sediment findings in acute interstitial nephritis. Am J Kidney Dis 2012; 60:330.
  79. Perazella MA. Diagnosing drug-induced AIN in the hospitalized patient: a challenge for the clinician. Clin Nephrol 2014; 81:381.
  80. Joss N, Morris S, Young B, Geddes C. Granulomatous interstitial nephritis. Clin J Am Soc Nephrol 2007; 2:222.
  81. Javaud N, Belenfant X, Stirnemann J, et al. Renal granulomatoses: a retrospective study of 40 cases and review of the literature. Medicine (Baltimore) 2007; 86:170.
  82. Espejo B, Herrero JC, Torres A, et al. [Immunoallergic interstitial nephritis vs. cholesterol atheroembolism. Differentiating characteristics]. Nefrologia 2003; 23:125.
  83. Abraham PA, Keane WF. Glomerular and interstitial disease induced by nonsteroidal anti-inflammatory drugs. Am J Nephrol 1984; 4:1.
  84. Warren GV, Korbet SM, Schwartz MM, Lewis EJ. Minimal change glomerulopathy associated with nonsteroidal antiinflammatory drugs. Am J Kidney Dis 1989; 13:127.
  85. Alper AB Jr, Meleg-Smith S, Krane NK. Nephrotic syndrome and interstitial nephritis associated with celecoxib. Am J Kidney Dis 2002; 40:1086.
  86. Andrews PA, Sampson SA. Topical non-steroidal drugs are systemically absorbed and may cause renal disease. Nephrol Dial Transplant 1999; 14:187.
  87. Mohammed EP, Stevens JM. Recurrence of Arthrotec-associated nephrotic syndrome with re-challenge. Clin Nephrol 2000; 53:483.
Topic 7234 Version 17.0

Topic Outline

GRAPHICS

CALCULATORS

RELATED TOPICS

All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.