Clinical manifestations and diagnosis of acute interstitial nephritis

INTRODUCTION — 

Acute interstitial nephritis (AIN) is a kidney lesion that typically causes a decline in kidney 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 disease, sarcoidosis), a variety of infections remote to the kidney (eg, Legionella, leptospirosis, and streptococcal organisms), immunoglobulin G4 (IgG4) disease, 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 disease is also discussed elsewhere.

●(See "Lupus nephritis: Diagnosis and classification", section on 'Tubulointerstitial lesions'.)

●(See "Tubulointerstitial nephritis and uveitis (TINU syndrome)".)

●(See "Kidney disease in primary Sjögren's disease".)

●(See "Kidney disease in sarcoidosis".)

ETIOLOGY — 

In initial reports, the vast majority of cases of acute interstitial nephritis (AIN) resulted from exposure to beta-lactam antibiotics, particularly methicillin [5,11,12], which is no longer manufactured. However, drugs other than antibiotics, as well as infections and other underlying conditions, are also recognized as clinically significant causes.

Distribution of causes — The distribution of underlying causes of AIN has been reported as follows [6,9,13-15]:

●Drugs – 70 to 75 percent (with antibiotics responsible for approximately 30 to 50 percent of these cases)

●Non-infectious systemic disease including sarcoidosis, Sjögren's disease, tubulointerstitial nephritis and uveitis (TINU) syndrome, immunoglobulin G4 (IgG4)-related disease, and others – 10 to 20 percent

●Infections – 4 to 10 percent

●Other causes – less than 5 percent

The distribution of causes of AIN may be different in older and younger patients. In one review, patients 65 years and older were more likely to have drug-induced AIN compared with patients aged 18 to 64 years (87 versus 64 percent), and less likely to have AIN related to autoimmune or systemic diseases (7 versus 27 percent) [16]. There is no known biologic reason for this predilection, which is most likely related to polypharmacy in older individuals. (See 'Drugs' below.)

Drugs — Drugs are the most common cause of AIN.

●Specific drugs and dose – Virtually any drug can cause AIN, although only several have been reported with significant frequency. The development of drug-induced AIN is not dose-dependent, and a recurrence or exacerbation of AIN can occur with a second exposure to the same or a related drug [17].

Drugs commonly implicated as a cause of AIN include [2-4,12,15,18-31]:

•Nonsteroidal antiinflammatory agents (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors

•Penicillins and cephalosporins

•Rifampin

•Antimicrobial sulfonamides, including trimethoprim-sulfamethoxazole

•Ciprofloxacin and, perhaps to a lesser degree, other quinolones

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

•Cimetidine (only rare cases have been described with other H-2 blockers such as ranitidine)

•Allopurinol

•Proton pump inhibitors (PPIs) such as omeprazole and lansoprazole

•5-aminosalicylates (eg, mesalamine)

•Anticancer drugs, such as immune checkpoint inhibitors (ICPi; such as ipilimumab and nivolumab)

While there are single case reports of many drugs associated with AIN, we attribute cause to a previously unreported drug only when the study reports that AIN was confirmed by kidney biopsy and the patient was not concomitantly taking other drugs that can cause AIN. In many cases, a causal link with the drug is established by observing the onset of kidney function impairment after initiating the drug and its resolution after discontinuing the drug.

●Conditions prompting suspicion for drug-induced AIN – The following conditions are often treated with drugs that may cause AIN:

•Gastroesophageal reflux – Several studies have shown an association between PPIs and AIN [28-31]. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Kidney disease'.)

•Cancer – Different types of anticancer drugs can cause AIN [32]. AKI has been reported in approximately 1 to 5 percent of patients receiving an ICPi (ie, ipilimumab, nivolumab, pembrolizumab, atezolizumab); AIN is the most common type of kidney pathology in such patients [33-38]. In the largest observational study of ICPi-associated AKI, 93 percent of the patients biopsied had AIN [37]. Median time of onset of AKI was 14 weeks (interquartile range 6 to 37 weeks). A lower baseline estimated glomerular filtration rate, concomitant use of PPIs, and combination therapy with different ICPis were independently associated with an increased risk of developing AKI. The vast majority of patients stopped the ICPi (97 percent) and were treated with glucocorticoids (86 percent). Complete or partial recovery was observed in 85 percent of patients. Re-introduction of the ICPi led to a recurrence of AKI in only 23 percent of patients. Additional details of kidney toxicity related to ICPis are discussed elsewhere. (See "Overview of toxicities associated with immune checkpoint inhibitors", section on 'Kidney'.)

•Inflammatory bowel disease – AIN can be a common complication among patients with inflammatory bowel diseases (IBD). In most patients with IBD, AIN has been attributed to treatment with 5-aminosalicylates [39,40], although AIN has also been described in treatment-naïve patients [41].

•HIV – Drug-induced AIN is also relatively common among patients with human immunodeficiency virus (HIV), although infections and immunologic syndromes associated with HIV infection also can induce AIN [42,43]. Drugs associated with AIN in this population include antiretroviral agents (eg, abacavir) and agents used to treat or prevent opportunistic infections (eg, trimethoprim-sulfamethoxazole, foscarnet) [42-44].

Non-infectious systemic disease — Numerous non-infectious systemic disorders have been associated with AIN. These primarily include the following autoimmune diseases:

●Sarcoidosis (See "Kidney disease in sarcoidosis".)

●Sjögren's disease (See "Kidney disease in primary Sjögren's disease".)

●Tubulointerstitial nephritis and uveitis (TINU) syndrome (See "Tubulointerstitial nephritis and uveitis (TINU syndrome)".)

●IgG4-related disease [45,46] (See "Clinical manifestations and diagnosis of IgG4-related disease".)

●Systemic lupus erythematosus (SLE) (See "Lupus nephritis: Diagnosis and classification", section on 'Tubulointerstitial lesions'.)

Patients with SLE, as well as those with an antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (eg, granulomatosis with polyangiitis), often have interstitial nephritis accompanying the characteristic glomerular disease but rarely can present with AIN in the absence of glomerular disease. Myelodysplastic syndrome also has been associated with AIN [47].

In a series of 133 patients with biopsy-proven AIN, of autoimmune etiologies, sarcoidosis was the most common [15].

Infections — Multiple infectious pathogens have been associated with AIN, including the following [10,15,48-50]:

●Legionella

●Leptospira

●Cytomegalovirus (CMV)

●Streptococcus

●Mycobacterium tuberculosis

●Corynebacterium diphtheriae

●Epstein-Barr virus (EBV)

●Yersinia

●BK polyomavirus

●Enterococcus, Escherichia coli, adenovirus, Candida, and others

AIN also has been reported in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infection. With infection, the AIN may have been related to medications rather than the viral infection itself [51,52]. AIN has also been reported after vaccination for SARS CoV-2 although proof of the vaccination as the etiologic stimulus is unproven [53].

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 [49,50]. However, more recent reports describe the identification of organism-specific antigens or DNA in kidney proximal tubule cells of patients with AIN [48,54-56].

Although medications are the most common etiology of granulomatous interstitial nephritis in resource-abundant countries [57], infection with the following organisms also may cause AIN characterized by granuloma formation [58]:

●Mycobacterium

●Fungi (histoplasmosis, coccidioidomycosis)

●Bacteria (Brucella, Chlamydia, Francisella)

●Spirochetes (Treponema)

●Parasites (Leishmania, Toxoplasma)

Other causes — Rare causes of AIN include the following:

●Idiopathic hypocomplementemic tubulointerstitial nephritis [59-61]

●Antitubular basement membrane (TBM) antibodies [62-64]

●Interstitial infiltration by immunoglobulin M (IgM)-positive plasma cells [65]

●Antibrush border antibody (ABBA) disease [66]

In anti-TBM mediated AIN, anti-TBM antibodies lead to linear staining with immunoglobulin along the TBMs on immunofluorescence microscopy [62-64,67]. This can occur in the presence or absence of concurrent antiglomerular basement membrane antibodies [62,63] and has been described in patients with membranous nephropathy [67]. (See "Membranous nephropathy: Pathogenesis and etiology" and "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Kidney biopsy'.)

IgM plasma cell-mediated AIN is characterized by diffuse interstitial infiltration by IgM-positive plasma cells [65]. The clinical findings include a mild-to-moderate kidney function impairment and a high prevalence of distal renal tubular acidosis, Fanconi syndrome, and antimitochondrial antibodies. Serum IgM levels are markedly elevated. Corticosteroid treatment may lead to kidney function improvement in some patients.

ABBA disease is caused by circulating antibodies reactive to proximal tubule proteins such as megalin/LRP2 or cubilin and amnionless [68-70]. Most patients are elderly men who present with AKI and subnephrotic proteinuria. Concurrent pathologies are frequently identified (eg, diverse glomerular and systemic diseases, malignancies, monoclonal paraproteinemia). Renal biopsy shows IgG staining along tubular basement membranes as a distinctive feature. The prognosis is poor, although some cases respond to immunosuppression.

EPIDEMIOLOGY — 

Acute interstitial nephritis (AIN) is demonstrated in 1 to 3 percent of all kidney biopsies [71,72]. When analysis is restricted to biopsies performed in the setting of acute kidney injury (AKI), the percentage rises to approximately 13 to 19 percent [72,73].

The true incidence of AIN may also be underestimated for the following reasons [28]:

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

●The prevalence of AIN caused by proton pump inhibitors (PPIs), 5-aminosalicylates, and nonsteroidal antiinflammatory drugs (NSAIDs) and often without obvious associated symptoms is increasing [28]. Skin rash and eosinophilia are significantly less common with these drugs than in antibiotic-induced AIN. (See 'Clinical manifestations' below.)

Some studies suggest that the incidence of AIN is increasing, particularly among older subjects [15,16,72]. The reasons for this change are complex and difficult to assess but may include an aging population base, increasing polypharmacy (including NSAIDs and PPIs) in older people, and an increasingly less restrictive policy of kidney biopsies in older patients with AKI.

PATHOLOGY — 

The major histologic changes on kidney biopsy are interstitial edema and a marked interstitial infiltrate consisting primarily of T lymphocytes and monocytes (picture 1A-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 acute interstitial nephritis (AIN). As an example, granuloma formation is particularly characteristic of sarcoidosis, although it may be seen in any form of AIN [74]. In some series, 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 kidney 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 [75]. However, in a number of other series, medication-induced interstitial nephritis was the leading cause of granulomatous interstitial nephritis, equaling or exceeding sarcoidosis in all.

Infection is a more likely etiology of granulomatous AIN in resource-poor areas, where infection with culprit organisms such as Mycobacterium is more common [57]. Other infections that have been associated with granulomatous AIN include fungi (histoplasmosis, coccidioidomycosis), bacteria (Brucella, Chlamydia, Francisella), spirochetes (Treponema), and parasites (Leishmania, Toxoplasma) [58]. (See 'Infections' above.)

Characteristic features that suggest immunoglobulin G4 (IgG4)-related disease include a plasma cell-rich interstitial infiltrate, storiform interstitial fibrosis, an increase in IgG4-positive plasma cells, and the presence of TBM immune complex deposits [46,76]. A small proportion of patients with IgG4-related interstitial nephritis also have membranous nephropathy (MN): in a study of 118 patients with IgG4-related interstitial nephritis, 13 patients (11 percent) were found to have concomitant MN [76].

Patients with interstitial nephritis related to lupus usually have concurrent glomerular lesions. (See "Lupus nephritis: Diagnosis and classification", section on 'Clinical features' and "Lupus nephritis: Diagnosis and classification", section on 'Histopathologic classification of LN' and "Lupus nephritis: Diagnosis and classification", section on 'Other forms of lupus kidney disease'.)

CLINICAL FEATURES

Time of onset — The mean interval between the start of an offending drug and the onset of drug-induced acute interstitial nephritis (AIN) is ten days [5]; however, the duration of this latent period is highly variable. As examples, the latent period from initial drug exposure may be as short as one day with rifampin [3] or as long as 18 months with an NSAID [77].

The onset of drug-induced AIN after a subsequent exposure to an offending drug is typically more rapid than after the initial exposure (eg, three to five days) [2,3].

Clinical manifestations — Patients with AIN may have signs and symptoms related to kidney dysfunction or to the cause of AIN.

Related to kidney dysfunction — With AIN from any cause, patients may present with nonspecific signs and symptoms of acute kidney 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 [13].

Patients usually do not have significant proteinuria, and nephrotic syndrome occurs in <1 percent of patients with AIN [13]. An exception occurs among patients who have NSAID-induced AIN, which may occur concurrently with NSAID-induced minimal change disease or membranous nephropathy [77-80]. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Secondary causes' and "Membranous nephropathy: Pathogenesis and etiology", section on 'Drugs'.)

Related to drug allergy — Classically, patients with drug-induced AIN were reported to have symptoms and/or signs of an allergic-type reaction, including rash, fever, and eosinophilia [81]. 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 [82,83]. Rash, fever, eosinophilia, and the triad were observed in 22, 36, 35, and 11 percent, respectively [13]. Arthralgias were observed in 45 percent of the patients [13].

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 [77,83].

Related to systemic disease — Patients who have AIN that is not related to a drug may have symptoms related to an associated infection or systemic condition such as sarcoidosis, Sjögren's disease, or systemic lupus erythematosus (SLE). (See "Kidney disease in sarcoidosis" and "Kidney disease in primary Sjögren's disease" and "Lupus nephritis: Diagnosis and classification", section on 'Tubulointerstitial lesions'.)

Patients with the tubulointerstitial nephritis with uveitis (TINU) syndrome 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)".)

Patients with immunoglobulin G4 (IgG4)-related interstitial nephritis often have extrarenal signs and symptoms (see "Clinical manifestations and diagnosis of IgG4-related disease"). 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 [45,84-90]. The following studies of patients with IgG4-related interstitial nephritis illustrate the spectrum of extrarenal disease:

●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 [88]. 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) [88].

●In another study that included 118 patients with IgG4-related interstitial nephritis, extrarenal involvement by IgG4-related disease was present in 79 percent [76]. The most common extrarenal organs/tissues involved were the pancreas (40 percent), liver/biliary tract (18 percent), salivary glands (17 percent), lung (16 percent), and retroperitoneum (retroperitoneal fibrosis; 9 percent).

Laboratory and radiographic findings — In general, patients with AIN present with some combination of the following findings, with some variation based upon the underlying cause [2-4,9,82]:

●Blood tests

•Increased plasma creatinine – Virtually all patients have a rise in the plasma creatinine concentration on presentation [82,83]. 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 [82,83].

•Eosinophilia – Although eosinophilia (defined by an absolute blood eosinophil count of ≥500 eosinophils/microL) is only found in 25 to 35 percent of AIN cases [9,13,82,83], its finding in a patient with AKI with no other apparent cause should raise the suspicion of drug-induced AIN.

Some reports [77,83], though not all [91], have suggested that eosinophilia is less common in AIN induced by NSAIDs compared with other drugs.

•Other findings

-Patients with IgG4-related disease or idiopathic hypocomplementemic interstitial nephritis usually have elevated serum total IgG and/or IgG4 levels or hypergammaglobulinemia and may have low serum complement concentrations [88,92]. In one series of IgG4-related tubulointerstitial nephritis, among 23 patients, complement C3, C4, or both were reduced in 16 [88]. In another study that included 118 patients with IgG4-related interstitial nephritis, elevated IgG4 levels were present in approximately 80 percent and low C3 or C4 was present in approximately 60 percent of patients who had available laboratories [76].

-Evidence of tubulointerstitial damage such as the Fanconi syndrome (manifesting as non-anion gap metabolic acidosis, hypokalemia, or hypophosphatemia) may be present but rarely dominates the clinical picture [27].

●Urine tests

•Characteristic urine sediment – The urine sediment usually reveals white cells or white cell casts (picture 2 and picture 3). Red blood cells and, rarely, red blood cell casts also can be observed [93-95]. 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.

•Variable degree of proteinuria – Although patients usually do not have significant proteinuria, urinary protein excretion is variable, ranging 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 [82,83]. Older individuals may be more likely to have significant proteinuria [73].

Occasional patients will have nephrotic-range proteinuria [2,3,13]. Concurrent nephrotic syndrome due to minimal change disease or membranous nephropathy can rarely be seen with NSAIDs (see 'Clinical manifestations' above) and, in selected cases, induced by ampicillin, rifampin, interferon, or ranitidine [13,26,77,96,97]. 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 [83]. In addition, although these and other drugs may induce heavy proteinuria [11], 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.

•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", section on 'Approach to using fena in acute kidney injury'). However, lower values may be seen, particularly in patients who are nonoliguric and have less severe kidney failure [98,99].

•Eosinophiluria – Eosinophiluria, defined by eosinophils that account for more than 1 percent of urinary white cells by Hansel stain [5,100], has been associated with AIN [101]. 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 [91]. 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.

●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 [46].

DIAGNOSIS

When to suspect acute interstitial nephritis — Acute interstitial nephritis (AIN) should be suspected in a patient who presents with an elevated serum creatinine and a urinalysis that shows white cells or white cell casts. 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.

A relatively normal urinalysis does not exclude the diagnosis since some patients have a bland sediment with few cells or casts [20].

Initial evaluation — Patients with suspected AIN should be thoroughly evaluated for other causes of AKI, as detailed elsewhere. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting" and "Evaluation of acute kidney injury among hospitalized adult patients".)

For patients with pyuria, we obtain a urine culture. A positive urine culture does not rule out a diagnosis of AIN but provides an alternate explanation for the presence of white cells in the urine. Conversely, sterile pyuria suggests AIN. We do not test the urine for eosinophils. (See 'Laboratory and radiographic findings' above.)

Making the diagnosis — A definitive diagnosis of AIN is made by kidney biopsy. However, it is often unnecessary to make a definitive diagnosis, such as among patients who have clearly documented onset of kidney failure after initiation of a common culprit drug and who improve immediately upon stopping the offending agent. The management of patients with suspected drug-induced AIN, including the role of kidney biopsy and empiric treatment, is detailed elsewhere. (See "Treatment of acute interstitial nephritis", section on 'Treatment of drug-induced allergic interstitial nephritis'.)

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 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 without first obtaining a kidney biopsy. However, among patients who do not improve after the first five to seven days of empiric glucocorticoid therapy, those without contraindications should have a biopsy in order to exclude other diagnoses or severe interstitial fibrosis. (See "The kidney biopsy", section on 'Contraindications' and "Treatment of acute interstitial nephritis".)

●Patients with putative drug-related AIN who are not treated with glucocorticoids initially and do not have a recovery following cessation of drug therapy [2,82]. We typically perform a kidney biopsy approximately two weeks after cessation of the offending drug if there has been no improvement in the kidney function over that time. However, clinicians wait a variable amount of time to allow for recovery before performing a biopsy. Some wait for three to four days, whereas others wait until the patient is approaching the need for kidney replacement therapy.

●Patients who present with advanced kidney failure, providing the onset of kidney 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.

Prediction models have been created to diagnose AIN from the electronic medical record [102,103]. However, the role of such models in clinical care is currently unclear.

Differential diagnosis — In general, the urinary findings will help distinguish AIN from other causes of AKI (see 'Laboratory and radiographic findings' above). The urinalysis, for example, typically shows the following:

●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

●Few, if any, abnormalities in hemodynamic AKI or obstruction

Among patients with a predominance of white blood cells and white blood cell casts, renal atheroemboli should be considered, particularly among older patients [104]. Similarly to AIN, renal atheroemboli may present with eosinophiluria, eosinophilia, and skin lesions. However, atheroemboli are more commonly associated with a reticular pattern (livedo reticularis) and digital infarcts, whereas AIN is associated with a characteristic rash that is diffuse and maculopapular. The history may also distinguish between AIN and renal atheroemboli. Many atheroemboli occur in the setting of atherosclerotic cardiovascular disease and 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'.)

Novel noninvasive biomarkers such as tumor necrosis factor-alpha, interleukin-9, the urine ratio of retinol-binding protein-to-creatinine, and the urinary protein CXCL9 may help distinguish AIN from other diagnoses [105-107]. However, the role of such biomarkers in clinical care is currently unclear. Additional studies are also needed to delineate the potential role of F¹⁸-FDG PET-CT imaging in diagnosing AIN [108,109].

DETERMINING THE CAUSE — 

We determine the cause of acute interstitial nephritis (AIN) to guide treatment (see "Treatment of acute interstitial nephritis"). Our approach is outlined below:

●Review medications – The vast majority of cases of AIN are caused by a drug (see 'Drugs' above). 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. However, it may be difficult to identify the culprit drug in some patients with biopsy-proven AIN who are taking multiple medications; our approach in this setting is detailed elsewhere. (See "Treatment of acute interstitial nephritis", section on 'Initial approach'.)

●Search for underlying disease – Less commonly, a drug is not identified or suspected as a cause of AIN. Among such patients, a biopsy confirmed diagnosi of AIN should provoke a search for underlying infection and systemic disorders including systemic lupus erythematosus (SLE), sarcoidosis, Sjögren's disease, tubulointerstitial nephritis and uveitis (TINU) syndrome, IgG4 disease, and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

Histologic features of the kidney biopsy and the results of additional diagnostic testing are generally used to identify the etiology of non-drug-related AIN, as detailed below:

•Histologic features – In some cases, histologic features may suggest the underlying disease that is associated with AIN (see 'Pathology' above). 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 IgG4-positive plasma cells in the interstitium [46].

Such histologic features, although often suggestive, do not establish definitively the cause of AIN.

•Additional diagnostic tests – If present, extrarenal manifestations of an underlying infectious or autoimmune disease should guide additional diagnostic testing (see 'Infections' above and 'Related to systemic disease' above). For example, we obtain slit lamp examination in patients with eye pain or redness to evaluate for TINU syndrome.

For patients without apparent extrarenal symptoms or signs, 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.

-Measurement of serum calcium and angiotensin-converting enzyme (ACE) levels to evaluate for sarcoidosis. Hypercalcemia and/or hypercalciuria with evidence of excessive 1-alpha-hydroxylase activity (ie, elevated serum levels of 1,25 dihydroxyvitamin D with low or low-normal levels of parathyroid hormone) suggests sarcoidosis. Serum ACE has limited utility as a diagnostic test, but an elevated ACE level also may suggest sarcoidosis, especially in conjunction with other data. (See "Kidney disease in sarcoidosis" and "Clinical manifestations and diagnosis of sarcoidosis".)

-Serum QuantiFERON gold test or a purified protein derivative (PPD) to exclude tuberculosis in patients with granulomatous AIN.

-ANCA to exclude ANCA-associated vasculitides.

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

-C3 and C4 to evaluate for SLE, IgG4-related disease, and idiopathic hypocomplementemic AIN. These tests, however, neither diagnose nor exclude these disorders. In patients with kidney histology suggestive of IgG4-related disease, we also check serum IgG subclasses and serum protein electrophoresis. (See 'Related to systemic disease' above and "Clinical manifestations and diagnosis of IgG4-related disease".)

-Anti-Ro/SSA, anti-La/SSb antibodies, C-reactive protein, and rheumatoid factor to exclude Sjögren's disease. (See "Kidney disease in primary Sjögren's disease".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute kidney injury in adults".)

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 5^th to 6^th 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 10^th to 12^th 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

●Overview – Acute interstitial nephritis (AIN) is a kidney lesion that causes a decline in kidney function and is characterized by an inflammatory infiltrate in the kidney interstitium. Drugs are the most common cause of AIN. Other causes include autoimmune disorders and infections. (See 'Introduction' above and 'Distribution of causes' above.)

●Etiology

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

•Autoimmune disorders – Autoimmune disorders that have been associated with AIN include sarcoidosis, Sjögren's disease, the TINU syndrome, immunoglobulin G4 (IgG4)-related disease, and systemic lupus erythematosus (SLE). Patients with SLE, as well as those with an antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (eg, granulomatosis with polyangiitis), often have interstitial nephritis accompanying the characteristic glomerular disease but rarely can present with AIN in the absence of glomerular disease. (See 'Non-infectious systemic disease' above.)

•Infections – 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 BK polyomavirus. Mycobacterium infection is associated with a granulomatous variant of AIN. (See 'Infections' above.)

●Clinical features

•Clinical manifestations – Patients with AIN may 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 manifestations' above.)

•Laboratory findings – 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 or white cell casts, though red blood cells also can be observed. 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.)

●Diagnosis – AIN should be suspected in a patient who presents with an elevated serum creatinine and a urinalysis that shows white cells or white cell casts. 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 kidney biopsy. However, it is often unnecessary to make a definitive diagnosis. (See 'Diagnosis' above.)

●Determining the cause – Patients who have a biopsy confirmed diagnosis of AIN and are not on a drug known to cause AIN should be evaluated for another underlying etiology. (See 'Determining the cause' above.)