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In initial reports, the vast majority of cases of AIN resulted from exposure to beta-lactam antibiotics, particularly methicillin.
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ubulointerstitial lesions'.) ●(See "Tubulointerstitial nephritis and uveitis (TINU syndrome)".) ●(See "Kidney disease in Sjögren's syndrome".) ●(See "Kidney disease in sarcoidosis".) ETIOLOGY — <span>In initial reports, the vast majority of cases of AIN resulted from exposure to beta-lactam antibiotics, particularly methicillin. However, drugs other than antibiotics, as well as infections and other underlying conditions, are also recognized as clinically significant causes. The distribution of causes of AIN has




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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

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lactam antibiotics, particularly methicillin. However, drugs other than antibiotics, as well as infections and other underlying conditions, are also recognized as clinically significant causes. <span>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 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 associated with AIN, we attribute




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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.
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and its resolution after discontinuing the drug. On the other hand, it may be difficult to identify the culprit drug in some patients with biopsy-proven AIN who are taking multiple medications. <span>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 cephalos




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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)

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medications. 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. <span>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]. Several studies h




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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].
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itors (PPIs) such as omeprazole and lansoprazole ●Indinavir ●5-aminosalicylates (eg, mesalamine) ●Anticancer drugs, such as immune checkpoint inhibitors (ICPi; such as ipilimumab and nivolumab) <span>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]. Several studies have shown an association between PPIs and AIN [26-29]. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", se




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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].
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has been attributed to treatment with 5-aminosalicylates [31,32], although AIN has also been described in treatment-naïve patients [33]. Different types of anticancer drugs can cause AIN [34]. <span>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]. In 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)




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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.
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n 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]. I<span>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. 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-i




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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.
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ent 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). <span>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 "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Kidney'.) Infections —




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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].
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atients. Additional details of kidney toxicity related to ICPis are discussed elsewhere. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Kidney'.) Infections — <span>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, Chlamydi




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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].
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coccus, Mycobacterium tuberculosis, Corynebacterium diphtheriae, Epstein-Barr virus (EBV), Yersinia, polyomavirus, Enterococcus, Escherichia coli, adenovirus, Candida, and others [10,13,40-42]. <span>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]. (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 i




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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].
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es (Leishmania, Toxoplasma) [43]. However, the most common etiology of granulomatous interstitial nephritis in westernized countries is medication-related disease [44]. (See 'Histology' below.) <span>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]. Drug-induced AIN is also relatively common among HIV-infected patients, although infections and immunologic syndromes associated with HIV infection can also induce AIN [48,49]. Associat




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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].
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s also relatively common among HIV-infected patients, although infections and immunologic syndromes associated with HIV infection can also induce AIN [48,49]. Associated with systemic disease — <span>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 "Kidney disease in Sjögren's syndrome" and "Kidney disease in sarcoidosis" and "Lupus nephritis: Diagnosis and classification", section on 'Tubulointerstitial lesions'.) Patients w




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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
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most common [13]. (See "Kidney disease in Sjögren's syndrome" and "Kidney disease in sarcoidosis" and "Lupus nephritis: Diagnosis and classification", section on 'Tubulointerstitial lesions'.) <span>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]. IgG4-related disease is a systemic d




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Relatively rare causes of AIN include immunoglobulin G4 (IgG4)-related disease [50,51] and hypocomplementemic tubulointerstitial nephritis [52-54]
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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. <span>Relatively rare causes of AIN include immunoglobulin G4 (IgG4)-related disease [50,51] and hypocomplementemic tubulointerstitial nephritis [52-54]. IgG4-related disease is a systemic disorder characterized by the infiltration of multiple organs by a lymphoplasmacytic infiltrate that is rich in IgG4-positive plasma cells, resulting




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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].
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al and salivary glands and periorbital tissue, and tubulointerstitial nephritis [50,55-61]. (See "Pathogenesis and clinical manifestations of IgG4-related disease", section on 'Renal disease'.) <span>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]. (See "Membranous nephropathy: Pathogenesis and etiology" and "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Kidney biopsy'.) Tubuloi




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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)".)
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phropathy [65]. (See "Membranous nephropathy: Pathogenesis and etiology" and "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Kidney biopsy'.) <span>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)".) 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), patie




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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].
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ssed elsewhere. (See "Tubulointerstitial nephritis and uveitis (TINU syndrome)".) Older patients — There may be differences in the distribution of underlying causes of AIN among older patients. <span>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]. There is no known biologic reason for this predilection, which is most likely related to polypharmacy in older individuals. The most common causative agents among older patients were pe




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The most common causative agents among older patients were penicillin and omeprazole.
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elated to autoimmune or systemic diseases (27 versus 7 percent) [66]. There is no known biologic reason for this predilection, which is most likely related to polypharmacy in older individuals. <span>The most common causative agents among older patients were penicillin and omeprazole. Two other forms of AIN have been described. One of them is characterized by a diffuse interstitial infiltration by immunoglobulin M (IgM)-positive plasma cells [67]. The clinical findin




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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].
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e with megalin, an antigen present in the proximal tubule. The patients were older, presented with AKI and subnephrotic proteinuria, and responded poorly to corticosteroids [68]. EPIDEMIOLOGY — <span>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]. Some studies suggest that the incidence of AIN is increasing, particularly among older subjects [13,66,70]. The reasons for this change are complex and difficult to assess but may inclu




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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.
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incidence of AIN may also be underestimated for the following reasons [26]: ●A confirmatory kidney biopsy is often not done in older and frail patients; empirical treatment is often preferred. ●<span>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. (See 'Clinical manifestations' below.) CLINICAL FEATURES Clinical manifestations — With AIN from any cause, patients may present with nonspecific signs and symptoms of acute kidney dysf




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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].
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26]. Skin rash and eosinophilia are significantly less common with these drugs than in antibiotic-induced AIN. (See 'Clinical manifestations' below.) CLINICAL FEATURES Clinical manifestations — <span>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 pres




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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]
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nt 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]. <span>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




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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
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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]. <span>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. (See 'NSAID-induced AIN and nephrotic syndrome' below and "Membranous nephropathy: Pathogenesis and etiology", section on 'Drugs'.) Patients may present with symptoms related to the ca




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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

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ated 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 [72]. <span>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 [73,74]. Rash, fever, eosinophilia, and the triad were observed in 22,




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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].
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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]. <span>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 e




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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].
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ic 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 [74,75]. <span>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]. 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, t




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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].
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l 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 [59]. <span>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]. 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 ca




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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.
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g drug. Acute kidney injury (AKI) may be severe; in two retrospective series, among 121 patients who presented with AIN, 40 percent required dialysis [73,74]. ●Eosinophilia and eosinophiluria – <span>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 eosinophil




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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
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0 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. <span>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 sixt




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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.
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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. <span>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. Some reports [74,75], though not all [78], have suggested that eosinophilia and eosinophiluria are less common in AIN induced by NSAIDs compared with other drugs. ●A characteristic urin




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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].
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probability of AIN on biopsy. Some reports [74,75], though not all [78], have suggested that eosinophilia and eosinophiluria are less common in AIN induced by NSAIDs compared with other drugs. ●<span>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]. 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 varia




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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].
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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 – <span>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]. 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




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




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




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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].
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including marked enlargement of kidneys with low-attenuation lesions, may be seen among patients with IgG4-related AIN [51]. IgG4-related disease and hypocomplementemic interstitial nephritis — <span>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]. Microbiologic features unique to different culprit organisms are presented separately. (See appropriate topic reviews.) DIAGNOSIS — AIN should be suspected in a patient who presents wit




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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.
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patients, complement C3, C4, or both were reduced in 16 [59]. Microbiologic features unique to different culprit organisms are presented separately. (See appropriate topic reviews.) DIAGNOSIS — <span>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. 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 previousl




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Thus, a relatively normal urinalysis should not exclude the diagnosis.
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orally 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]. <span>Thus, a relatively normal urinalysis should not exclude the diagnosis. A definitive diagnosis of AIN is made by kidney biopsy. It is often considered unnecessary to make a definitive diagnosis, such as among patients who have clearly documented onset of ki




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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.
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ional 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 kidney biopsy. <span>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. 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