on 05-Nov-2021 (Fri)

In initial reports, the vast majority of cases of AIN resulted from exposure to beta-lactam antibiotics, particularly methicillin.

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

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

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

● Infections – 4 to 10 percent

● Tubulointerstitial nephritis and uveitis (TINU) syndrome – less than 5 percent

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 manufactured.

Other common drugs that cause AIN include [2-4,13,15-29]:

● 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

● Indinavir

● 5-aminosalicylates (eg, mesalamine)

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

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 [30].

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 [35-39].

n the largest observational study of ICPi-associated AKI, 93 percent of the patients biopsied had AIN [ 38]. 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.

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.

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, Francisella), spirochetes (Treponema), and parasites (Leishmania, Toxoplasma) [43]. However, the most common etiology of granulomatous interstitial nephritis in westernized countries is medication-related disease [44].

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 [40,45-47].

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].

Patients with SLE and those with granulomatosis with polyangiitis often have 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 [50,51] and hypocomplementemic tubulointerstitial nephritis [52-54]

A rare cause of AIN results from anti-tubular basement membrane (TBM) antibodies, leading to linear staining with immunoglobulin along the TBMs on immunofluorescence microscopy [62-65]. This can occur in the presence or absence of concurrent anti-glomerular basement membrane antibodies [62,63] and has been described in patients with membranous nephropathy [65].

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)".)

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) [66].

The most common causative agents among older patients were penicillin and omeprazole.

AIN is demonstrated in 1 to 3 percent of all kidney biopsies [69,70]. When analysis is restricted to biopsies performed in the setting of acute kidney injury (AKI), the percentage rises to 13 to 27 percent [70,71].

The prevalence of AIN caused by PPIs, 5-aminosalicylates, and NSAIDs and often without obvious associated symptoms is increasing [26]. Skin rash and eosinophilia are significantly less common with these drugs than in antibiotic-induced AIN.

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 [ 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 antiinflammatory drug (NSAID)-induced AIN, which may occur concurrently with NSAID-induced membranous nephropathy or minimal change disease

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

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 [74,75].

There is no typical range of time 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 from initial drug exposure may be as short as one day with rifampin [3] or as long as 18 months with an NSAID [75].

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) [59].

Although eosinophilia (defined by an absolute blood eosinophil count of ≥500 eosinophils/microL) is only found in 25 to 35 percent of AIN cases [9,11,73,74], 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 [ 5,76], has been associated with AIN [77]. 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 [ 78]. 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.

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 [79].

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 [73,74]. Older individuals may be more likely to have significant proteinuria [71].

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

The fractional excretion of sodium (FENa) may be >1 percent, which is in part indicative of tubular damage [2].

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 [59].

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, rarely, red blood cell casts can be also observed [84,85], although gross hematuria is distinctly unusual.

Thus, a relatively normal urinalysis should not exclude the diagnosis.

It is often considered 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.