on 07-Nov-2021 (Sun)

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.

Patients with putative drug-related AIN who are not treated with glucocorticoids initially and do not have a recovery following cessation of drug therapy [2,73]. 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.

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).

In some series, granuloma formation also suggests a greater likelihood of infection-induced AIN compared with AIN without granulomas

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 in areas where infections associated with granulomatous disease are more common than in westernized countries [44]. As described above, other infections that have been associated with granulomatous AIN include fungi (histoplasmosis, coccidioidomycosis), bacteria (Brucella, Chlamydia, Francisella), spirochetes (Treponema), and parasites (Leishmania, Toxoplasma) [43]

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 prekidney 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 [88]. 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

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

Less commonly, a drug is not identified or suspected. 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

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.

● Slit lamp examination in patients with eye pain or redness to evaluate for tubulointerstitial nephritis and uveitis (TINU syndrome).

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

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 [75,89]. 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 [93].

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