The diagnosis of acute interstitial nephritis caused by infection versus antibiotic-induced interstitial nephritis: a narrative review

ABSTRACT Acute interstitial nephritis (AIN) is a significant contributor to acute kidney injury and can be attributed to a variety of factors, including but not limited to allergens or drugs, infections, autoimmune or systemic diseases, and idiopathic forms of the disease. In some cases, AIN requires a therapeutic action according to a single specific etiology by handling the offending agent and applying an immunosuppressant. Although AIN can be diagnosed through renal biopsy, it is not able to pinpoint the precise cause when multiple causes are suspected to be present simultaneously. Such situations arise when a patient suffering from infection develops AIN during antibiotic therapy, the exact causative factor of which becomes a challenge for the clinicians to determine. This is attributed to the different approaches employed in different etiologies, wherein clinicians are required to maintain the current antibiotic therapy or augment the dose in cases of infection as AIN etiology, without resorting to immunosuppressant therapy as the primary objective is infection killing. In contrast, antibiotics as an etiology for AIN require an alternative drug from the antibiotics group, along with an immunosuppressant. In the interim, delaying the identification of the precise cause may result in interstitial fibrosis and chronic kidney disease. This narrative review highlights certain findings that can be typical of infection-associated ATIN compared with antibiotic-associated ATIN based on clinical history and physical examination, clinical presentation of different antibiotic drug classes, histopathological features, classical and novel biomarkers, serum and urine cytokines and chemokines, cellular biomarkers, and genetic biomarkers. Although these findings cannot provide conclusive and clear recommendations that can be useful in the clinical practice, they can entice researchers to conduct original research on these features to discover clear recommendations.


INTRODUCTION
Acute tubulointerstitial nephritis ( ATIN) , or AIN, is an immunomediated disease that affects the tubulointerstitial area of the kidneys, accompanied by histological findings of interstitial inflammation, edema and tubulitis [1 ].The tubulointerstitial area comprises 80% of the renal surface area and is composed of cellular and extracellular matrix components [2 ].AIN is an important cause of acute kidney injury ( AKI) , with various etiologies such as allergens or drugs, infections, autoimmune or systemic diseases, and idiopathic forms of the disease [3 ].It is estimated that up to 10%-27% of hospitalized AKI patients are affected by AIN, making it the third most prevalent cause of hospital-acquired AKI after acute tubular necrosis ( ATN) and prerenal AKI [4 -9 ].In developed countries, the most common cause of AIN is an immunoallergic drug reaction, accounting for 70%-90% of cases [7 , 10 ].In a 2004 report based on pooled data from three large studies, antibiotics were accounted for one-third of the cases from the drug-induced etiology in 91 of the 128 cases ( 71.1%) [11 ] ( Fig. 1 ) .Among the remaining 37 cases, 20 were induced by infection, 10 were idiopathic, 6 had tubulointerstitial nephritis with uveitis ( TINU) and 1 had sarcoidosis [11 ].A study conducted by Valluri et al .[12 ] ( Fig. 2 ) in 2015, based on 171 biopsy-confirmed cases between 2000 and 2012, revealed that antibiotics accounted for 35% of the cases, proton pump inhibitors ( 35%) , and non-steroidal anti-inflammatory drugs ( NSAIDs) ( 20%) were identified as the primary culprits.Therefore, a significant number of AIN cases can be caused by antibiotics and infections ( Figs 1 and 2 ) .
The renal biopsy procedure is widely recognized as the most reliable diagnostic method for AIN, however, it is not effective in identifying the underlying cause.Serious complications arise when a patient who is infected develops AIN during antibiotic therapy.This is due to the fact that both infection and antibiotics can be suspected as the offending agent simultaneously,  [11 ].
resulting in misguided efforts to identify the offending agent, as both etiologies may exhibit similar histopathological or clinical characteristics.Furthermore, the two etiologies require different therapeutic actions because infection as AIN etiology requires the continuation of current antibiotic therapy or even an increase in dose without the need for immunosuppressant therapy [13 -15 ].Treating the underlying infection and supportive therapy is the main initial target.On the other hand, during the case of an antibiotic-related AIN, clinicians may require the use of alternative antibiotic drugs along with the application of an immunosuppressant [3 , 6 , 16 , 17 ].The delay in finding the exact cause can lead to interstitial fibrosis and chronic kidney disease ( CKD) [1 , 3 , 11 , 13 , 18 , 19 ], and research estimates that 40% to 60% of patients develop CKD after an episode of AIN [20 -25 ].
Clinicians are required to conduct prompt diagnosis, identification and withdrawal of the offending agent, as these are crucial factors in preserving kidney function and ensuring a favorable long-term renal prognosis [26 ].A recent case series published by Fernandez-Juarez et al .[27 ] demonstrated that the culprit drug cannot be precisely identified in nearly 30% of cases.This lack of crucial information hinders the primary therapeutic option, as it entails the withdrawal of the causative agent.Furthermore, it may increase the probability of developing recurrences and partial renal recovery [1 , 11 , 18 ].Barreto et al .[13 ] demonstrated that the initial inflammatory lesions in AIN can commence to progress into irreversible interstitial fibrosis as early as 7 days after drug exposure.This may be the reason why, despite the most effective treatment options, only 40%-50% of patients with AIN experience complete recovery of kidney function [28 ].AIN may also represent an earlier clinical manifestation of an underlying systemic or infectious disease with fewer extrarenal manifestations [29 -31 ], thereby hindering the accurate diagnosis and treatment [5 ].
Drugs, particularly antibiotics, are known to cause AIN, which is a drug hypersensitivity reaction ( DHR) that manifests itself within 7-10 days of exposure to the offending drug [20 ] ( Tables 1 and 2 [32 -49 ]) .However, this time can be shorter if the patient is exposing to the same drug for the second time [25 ], thus misguiding in finding the culprit drug.AIN can also arise as a reactive, cytokine-mediated response to infection, as was first described in 1898 by Councilman for streptococcal infections [50 ] ( Table 1 [38 -48 ]) .The exact pathomechanism of infectioninduced AIN is not yet clear, though some mechanisms have been proposed.Certain microorganisms that act as planted antigens have the ability to accumulate in the interstitium, mimic a normally present antigen in the tubular basement membrane and elicit an immune response directed against this antigen ( Table 1 ) [32 -48 ].Furthermore, the direct cytopathic effects of microbial antigens or cytokine-mediated inflammation may be the explanation for the renal injury [14 , 51 ] ( Table 1 [32 -48 ]) .In order to gain a more thorough comprehension of the pathophysiology and etiology associated with early diagnosis, researchers are endeavoring to identify reliable biomarkers of the disease, with a particular emphasis on urinary cytokines and chemokines that may manifest renal local inflammation ( Table 3 ) [52 -62 ].There is a growing interest in finding cell-based tests that can identify the exact drug involved in hypersensitivity reactions to drugs, manifesting as AIN or ATIN [63 ].Some studies also found that certain single-nucleotide polymorphisms in human leukocyte antigens ( HLA) or cytokine genes confer susceptibility to some etiologies inducing ATIN [64 ].Hence, it is imperative for researchers to conduct additional research on these procedures to facilitate clinicians in the timely identification of the primary aggravating factor causing ATIN, thereby aiding in diagnosis, prognosis and follow-up.

FEATURES OF INFECTION IN CORRELATION WITH AIN
Infection-induced AIN usually results in a sterile infiltrate, indicating that immunological disturbances may be the cause of AIN [65 ].Therefore, in most instances, blood or urine culture may not be effective in identifying infection as an etiology of AIN ( Table 1 ) [32 -48 ].An early diagnosis of the cause is essential to eliminate and prevent the responsible causes from occurring in the future [65 ].Sonoda et al .[66 ] also found that local infection may induce an autoimmune response against autoantigens in the infected kidney, which could trigger organ-specific autoimmune disease.Therefore, it leads to confusion in determining whether infection is the root cause or autoimmune disease.Previously, infections were the primary causes of AIN; however, in recent times, an immuno-allergic mechanism triggered by medications such as antibiotics, NSAIDs and numerous others has emerged as the predominant cause [1 ].
Since infections and antibiotics induce AIN through autoimmune and immuno-allergic pathomechanisms, respectively, it is possible that their histopathological and clinical characteristics may overlap.According to some studies, the leading cause of AIN is bacterial pyelonephritis, which can be unilateral and typically localized to the renal pyramid [67 ].In this instance, a healthcare professional can utilize positive uroculture, or, in most instances, blood cultures as a diagnostic tool for infectionassociated AKI, particularly when AKl occurs in the absence of septic shock [67 ].The presence of a large number of neutrophils [1 ], particularly as micro-abscesses, should alert one to the possibility of pyelonephritis [68 ].The study conducted by Raghavan et al .[6 ] revealed a significant amount of neutrophilic infiltration, which tends to be negative on immunofluorescence microscopy.
Such cases can present with both oliguric and non-oliguric renal insufficiency, without the classical clinical triad of AIN ( fever, rash and arthralgia) , usually with reversible renal function if infection is treated in a timely manner [37 ] ( Tables 2 and 4 [49 ]) .In patients with infection-induced AIN, steroids may increase the risk of immunosuppression, which could worsen the infection.Therefore, steroids should be delayed until the active infection is completely controlled [13 -15 ] ( Table 1 [38 -48 ]) .

FEATURES OF ANTIBIOTICS ASSOCIATED WITH AIN
The capacity to elicit an immune response to β-lactams ( BLs) can exhibit varying degrees of variability: some patients exhibit a specific response to a specific BL and demonstrate tolerance to others, whereas other patients exhibit a universal response to all BLs [69 ] ( Table 1 [32 -38 ]) .This phenomenon may be attributable to the fact that distinct patients may possess distinct HLA alleles that exhibit distinct responses to these BLs.Therefore, further investigation is necessary to identify specific HLA alleles that are more susceptible to AIN [64 ].Perazella et al .[1 ] observed relatively short duration of exposure to the causative BL antibiotic, ranging from a few days to a few weeks, with the classical clinical triad of fever, rash or eosinophilia in > 75% of patients, and the occurrence of proteinuria, leukocyturia or hematuria in approximately 75% of affected patients.AIN can also occur in association with the administration of non-BL antibiotics, such as rifampicin, when administered intermittently to treat mycobacterial infections ( Table 1 [32 -48 ]) .The occurrence of AIN caused by sulfonamide antibiotics may be associated with typical hypersensitivity reactions, including fever, rash and eosinophilia [70 ].Patients who have been infected with HIV, transplant recipients and patients who have pre-existing renal disease are at a higher risk of developing sulfonamide-induced AIN [71 , 72 ].The fluoroquinolone antibiotics, especially ciprofloxacin, can induce AIN without hypersensitivity syndrome [1 ].
Renal pathologists suspect the drug as an offending cause when a significant eosinophilic infiltrate ( > 10 eosinophils per 20 × field) is present [1 ].Immunofluorescence microscopy is typically negative in patients with AIN, although a very few cases of methicillin-induced AIN with tubular basement membrane deposits of immunoglobulin have been reported [73 ].Immune complex deposits are relatively uncommon in drug-induced AIN-they have been reported with drugs such as methicillin and rifampin [73 -75 ], which exhibit linear or granular staining for immunoglobulin G and C3 on tubular basement membrane ( anti-tubular basement membrane antibodies) .For example, the presence of hypersensitivity may be due to drugs such as BLs or sulfonamides.Asim et al .[76 ] presented a case of hemorrhagic tubulointerstitial nephritis caused by amoxicillin-clavulanate, characterized by systemic eosinophilia, a high concentration of eosinophils and plasma cells in the interstitial infiltrate, indicating a delayed hypersensitivity immune response mediated by antigen-reactive T cells.This case demonstrates an idiosyncratic immune response, with no correlation between the dose or the duration of amoxicillin-clavulanate therapy [6 , 14 , 77 ].Although the alternative medication is typically recommended in cases of medication hypersensitivity associated AIN [3 ], it is important to note that there may be cross-reactivity between the two drugs.For instance, a case of drug reaction with eosinophilia and systemic symptoms ( DRESS) syndrome was reported, wherein cross-reactivity was observed between vancomycin and subsequent teicoplanin administration [78 ],  thereby enhancing the difficulty in determining the precise etiology.Similarly, several studies have found that patients with penicillin allergy have a higher risk of developing cephalosporin hypersensitivity associated AIN, but this finding is not universal [25 , 79 , 80 ].The structural features of BLs could be the reason for this, as all BLs contain a five-or six-member ring, with the exception of monobactams ( e.g.aztreonam) , which have no reported cross-reactivity with penicillins [20 ].

CLINICAL HISTORY AND PHYSICAL EXAMINATION IN RELATION TO INFECTION AND ANTIBIOTICS
A careful history can provide a clue about the offending agent but not a definitive confirmation, as previously described ( Tables 1 , 2 and 4 [32 -48 , 49 ]) .For instance, the onset of either a mild or intermittently spiking fever typically occurs within a span of 2 weeks following the administration of a medication [1 ].However, in the event that the patient has been previously exposed to the aforementioned drug, the duration of fever may be limited to a few hours or days [25 ].The occurrence of fever as a systemic feature of AIN is variable, and the rate of variation is contingent upon the class of drug involved [1 ] ( Table 1 [32 -38 ]) .Fever may be absent in AIN caused by many drugs, such as NSAIDs and non-BL medications, but it has been manifested in as many as 50%-100% of patients with AIN caused by penicillin derivatives, particularly methicillin [25 , 77 , 80 -82 ].The occurrence of AIN-associated rash is observed in 15%-50% of patients with drug-induced AIN, particularly with agents that can trigger a hypersensitivity reaction, such as penicillin derivatives, sulfonamides, allopurinol and phenytoin [11 , 16 , 80 ].Patients receiving rifampicin frequently experience symptoms of flank pain and tenderness, resulting from the distention of the renal capsule caused by inflammation and parenchymal swelling [83 , 84 ].

Commonly ordered tests
A series of urine and serum tests is frequently ordered to assess and distinguish the precise cause of AIN.According to a recently published study, dipstick pyuria was observed in 60-80% of AIN cases caused by antibiotics [10 ] ( Tables 2 and 4 [49 ]) .However, the absence of pyuria does not exclude the diagnosis [63 ].Numerous studies on AIN have reported the presence of mild to moderate proteinuria, which is incapable of distinguishing between infection or antibiotic as the causative agent, or among other AIN etiologies [49 ].However, nephrotic-range proteinuria is rare [4 , 5 , 10 , 28 , 85 , 86 ], and when found in the setting of AIN, it should raise suspicion for NSAID-induced nephrotoxicity or underlying glomerular diseases [5 , 10 , 87 , 88 ].Hematuria is also a nonspecific and insensitive laboratory test, despite several studies indicating a mean of 50% ( with a range of 20%-80%) in cases of AIN [10 , 85 ].It is more common with some drugs, especially methicillin and the BL class of antibiotics, which can cause hematuria in up to 90% of patients with BL antibioticinduced AIN [25 ].The presence of white blood cell ( WBC) casts has been demonstrated in the context of intrarenal infection, such as pyelonephritis, or in conjunction with inflammatory renal lesions, such as proliferative glomerulonephritis and AIN, rendering them non-specific and insensitive for AIN [49 ].Numerous studies have revealed that eosinophilia was observed in 80% of cases of drug-induced AIN caused by BL antibiotics, such as methicillin, while it was only observed in less than onethird of cases of drug-induced AIN caused by non-BL antibiotics [16 , 80 , 89 ].Eosinophiluria cannot be used in diagnosing AIN because it is detected in many renal and nonrenal diseases such as pyelonephritis, cystitis, prostatitis, atheroembolic disease, acute tubular nephritis, rapidly progressive glomerulonephritis and bladder malignancies, among others [50 , 73 , 90 , 91 ].

Novel biomarkers
In recent times, a variety of novel biomarkers have been evaluated for the identification of the distinct characteristics of interstitial infiltrates and the cytokines produced by this infiltrate, in relation to other inflammatory renal diseases ( Table 3 ) .Their detection in serum or urine has been identified as potential diagnostic and prognostic tools for ATIN.The presence of specific chemokines and cytokines can provide a clue towards a potential causative agent, as the pathophysiologic process may vary depending on the etiology.For instance, Moledina et al .[62 ] observed a higher level of the major eosinophilic attractant C-C motif ligand 3 ( CCL3) in patients with AIN compared with the control group.This finding may serve as a means to distinguish patients with AIN due to antibiotics, as they are known to have a higher number of interstitial eosinophils.On the contrary, it is possible that the level of monocyte chemoattractant protein-1 ( MCP-1) is elevated in infection-induced AIN due to its significant role in the recruitment of monocytes, neutrophils and lymphocytes in tissue inflammation processes [63 ].Furthermore, several studies have reported a higher level of neutrophils in infection-induced AIN [6 ].However, it is not feasible to assess its sensitiveness or specificity as it has been identified as a chemokine implicated in numerous autoimmune diseases [92 ].It is noteworthy that Muhammad et al .[93 ] hypothesized that drugs may be able to induce autoimmune diseases that induce AIN.Therefore, researchers are uncertain about the causative agent that triggers the MCP-1 level in such a scenario.

Cellular biomarkers
The binding of T cells to a drug is a complicated process that can be measured through cellular assays based on the demonstration of the lymphocyte proliferation response and the cytokine secretion response when exposed to the suspected drug [63 ].
Fluorescence cytometry techniques can be employed to assess the activation phenotype of lymphocytes subsequent to drug exposure.Several studies have demonstrated the detection of activation markers on the surface of lymphocytes subsequent to incubation with the offending drug, such as CD25, CD69 or HLA drug reaction ( DR) , indicating hypersensitivity [95 , 101 ].A sensitive test, the enzyme-linked immunospot ( ELISpot) assay, has been reported to be useful in evaluating drug hypersensitivity reactions.It allows the ex vivo measurement of the release of cytokines by lymphocytes in response to a certain stimulus [102 ].There is, however, limited evidence regarding the usefulness of this assays specifically in patients with AIN.Punrin et al .[103 ] reported that 50% of patients with drug-induced ATIN had a positive interferon ( IFN) -γ ELISpot assay in a cohort study.

Lymphocyte transformation test
It is possible to use the lymphocyte transformation test ( LTT) to measure the proliferation of lymphocytes in response to the pure form of a suspicious drug.Koda et al .[104 ] reported the utilization of LTT in identifying the culprit drug in ATIN among lansoprazole and nivolumab, and it demonstrated reactivity against lansoprazole, but not against nivolumab.Positive LTT has also been reported in the context of ATIN induced by BLs and NSAIDs [98 ].Nonetheless, the LTT concept can yield accurate results only if drugs are able to directly interact with the T-cell receptor and act as hapten, without any prior metabolism or binding to proteins [98 ].Beta-lactams are known to be able to act as haptens and bind to amino groups of amino acids, such as lysine [105 ].However, clinicians should understand that sometimes the reaction is not caused by the drug itself, but by a component within the drug or a metabolite which transforms this so-called pro-hapten to hapten [106 ], which may result in negative LTT. Sulfamethoxazole is a typical example of a drug that acts as prohapten, because it is transformed to sulfamethoxazole-hydroxylamine and further oxidized to sulfamethoxazole-nitroso [107 -109 ].Drugs that exhibit pseudoallergic responses in nonimmune-mediated hypersensitivity reactions by affecting the innate immune system and/or effector cells, such as basophils directly, may also be tested negative, without any evidence of involvement of the specific immune system [98 ].The possible drawback of this method could be the long time it takes for the procedure to display the result, because in the acute setting, the LTT has a low specificity because sensitization does not always associate disease [110 ].Chung et al .[111 ] confirmed through LTT that vancomycin, but not other glycopeptide antibiotics, specifically induced T-cell proliferation in the reported case.

Genetic biomarkers
Some studies have described the association of AIN, mainly in the setting of TINU, with certain HLA or single-nucleotide polymorphisms as markers of disease susceptibility.According to a study conducted in a cohort of 154 Chinese patients with different causes of AIN, HLA-DQA1*0104/DQB1*0503/DRB1*1405 are risk haplotypes for the development of AIN [64 ].These studies suggest that these variants may enhance antigen presentation and facilitate renal interstitial inflammation.Therefore, it is important to determine which specific HLA alleles are more susceptible to which etiology of AIN.We may consider combining this HLA testing for diverse etiologies of AIN with adjunctive testing, such as IFN-γ ELISpot, to obtain a more favorable outcome.

DISCUSSION
This narrative review demonstrates the relevant features of ATIN in the setting of infection, as opposed to the situation of a drug-induced immune allergic reaction, with a special focus on the antibiotic-associated ATIN.The main purpose of the study was to analyze the peculiar findings that are typical of an infection-associated ATIN compared with an antibioticassociated ATIN caused by an allergic reaction.Although these findings cannot provide conclusive and clear recommendations that can be useful in the clinical practice, they might encourage researchers to conduct original research on these features to find clear recommendations.
Hospital-acquired AKI affects up to 10%-27% of patients affected by AIN, which has various etiologies, among which antibiotics and infections account for up to 35% and 16% of cases, respectively [4 -9 ].Both etiologies necessitate distinct therapeutic measures in a timely manner, as previously described [13 -15 ].The delay in identifying the precise culprit agent can impede therapeutic measures, ultimately leading to renal fibrosis and CKD [1 , 3 , 11 , 13 , 18 , 19 ].Previous studies have demonstrated that, in up to 30% of cases, the culprit drug cannot be precisely identified, and this type of misdiagnosis can lead to partial renal recovery, recurrent disease or CKD in up to 40%-60% of cases [20 -25 ].Therefore, a timely and thorough investigation is required for complete recovery.Currently, there is no universal procedure that can be utilized to determine the precise cause, despite the fact that certain clinical and histopathological features may provide a clue towards the potential suspected cause, as previously described.Therefore, it is imperative for clinicians to exercise caution in selecting the appropriate therapeutic measures, particularly when both infections and antibiotic-related causes are suspected; however, they treat patients on the basis of clinical history, physical examinations and biopsy findings, without caring much about the exact etiology.
We have highlighted various characteristics associated with antibiotics and infections that give clues, but cannot be deemed universal findings.For example, an increase in neutrophil levels points towards infection, while an increase in eosinophils points towards hypersensitivity to drugs [6 ].In contrast, an increase in neutrophils can also be caused by urinary tract infections.Similarly, different antibiotics exhibit different hypersensitive reactions in different patients, with some individuals exhibiting tolerability to certain drugs while others exhibit hypersensitivity to other drugs.This can be challenging to discern when taking multiple antibiotics.Clinicians also follow the typical triad of fever, rash and arthralgia, but it is not always helpful.The time period from drug exposure, which typically ranges from 7-10 days, is utilized as a diagnostic indicator [20 ].However, this method is not universally accurate for all drugs, particularly when a patient is exposed to the same drug for the second time, where the hypersensitivity reaction can be more rapid, as previously described.In cases of suspected infection, some clinicians also rely on blood or urine culture, but this may not be effective because it usually results in a sterile infiltrate, as infection induces AIN primarily through immunological disturbances.Thus, both etiologies may have similar histopathological and clinical characteristics due to the same immunological pathomechanism.Clinicians may also prescribe alternative medications in case of hypersensitivity to one drug, but there may be cross-reactivity between the previous drug and the alternative, which may be misleading in finding the offending agent.
Various serum and urine tests, including dipstick pyuria, proteinuria, hematuria and WBCs, are routinely ordered and relied upon to distinguish between the two etiologies, however they are neither sensitive nor specific, as previously described.Numerous novel biomarkers including CCL3, CXCL9, MCP-1, TNF-α, IL-9, IL-5, IL-6 and IL-8 have been evaluated for the identification of the distinct characteristics of interstitial infiltrates in different etiologies.However, they are not routinely performed and are not recommended at universal guidelines.There are some reports that indicate the utility of the ELISpot assay in evaluating drug hypersensitivity reactions [64 ].However, there is limited evidence regarding its efficacy in patients with AIN.The LTT possesses several drawbacks, including the inability to display results promptly and its inability to be utilized across all classes of drugs due to the variability of drug metabolism, rendering it unsuitable for routine use.Several studies have published associations between ATIN and certain HLA or single-nucleotide polymorphisms as markers of disease susceptibility, mainly in the setting of TINU [64 ].However, there is currently no further investigation into the identification of HLA risk alleles in other causes of AIN, which is crucial for determining the prognosis of AIN.
In brief, our study does not provide conclusive and clear recommendations that can be useful in the clinical practice, and further research is required regarding the features described above.

Figure 1 :
Figure 1: Common causes of AIN.This figure is based on data from Baker and Pusey [11 ].

= 30 Healthy controls n = 15
higher levels of MCP-1, α1-MG, NGAL and NAG compared with controls; the urinary levels of MCP-1were correlated with the extent and severity of the acute lesions It is important to classify drugs based on their pathomechanism, since different drugs can induce ATIN through different pathomechanism which may aid in identifying the culprit drug Nakashima et al ., Clin Nephrol ( 2010) [54 ] IgG4 disease-related ATIN n = 4 Other cause ATIN n = 16 The expression of IL-4, IL-10 and TGF-β RNA in kidney tissue was observed to be higher in patients with IgG4 disease, as compared with other causes of ATIN Due to the small sample size and the presence of such biomarkers in other autoimmune diseases, these are not universally applicable as a diagnostic biomarkers in IgG4-disease-related ATIN Shi et al ., Am J Med Sci ( 2013) [55 ] Drug-induced ATIN n = 51 The rate of GFR decline was faster in patients with higher urinary levels of NAG, metalloproteinase 2 ( MMP2) and MMP9 It is important to classify drugs based on their pathomechanism, since different drugs can induce ATIN through different pathomechanism which may aid in identifying the culprit drug Aoyagi et al ., CEN Case Rep ( 2014) [56 ] One case of TINU During follow-up of an episode of TINU, serum TNF-α, found that these biomarkers are higher in various etiologies, making them non-sensitive and non-specific Chen et al ., Braz J Med Biol Res ( 2018) [57 ]ATIN n The serum levels of IL-6, IL-10 and TNF-α were significantly higher in ATIN patients than in controls Several studies have found that these biomarkers are higher in various etiologies, making them non-sensitive and non-specific

Table 3 : A comprehensive summary of the main publications pertaining to serum and urinary biomarkers of ATIN.
[59 ] al .[53]alsoobservedahigherlevel of MCP-1 in a cohort of 40 patients with drug-induced AIN in comparison with controls.Similarly, Yun et al .[59]foundahigherlevel of MCP-1 in serum and urine in 113 patients with AIN, resulting from different causes, through a bead-based multiplex assay.Despite the findings of Moledina et al .[60,62 , 94 ], who observed a higher