Interstitial nephritis (IN) is an immune-mediated form of tubulointerstitial nephritis that may occur secondary to drugs, autoimmune disease, infections, and hematologic disorders or as a reactive process. Drug-induced acute interstitial nephritis (DI-AIN) is found in 0.5%-3% of all kidney biopsies and in 5%-27% of biopsies performed for acute kidney injury. Drugs are implicated in 70%-90% of biopsy-proved IN with a prevalence of 50% in less developed to 78% in more developed countries.[1]
Drug-induced AIN continues to be the most common type of hypersensitivity nephropathy, but it requires a careful differential diagnosis with other entities (tubulointerstitial nephritis with uveitis syndrome, IgG4-related disease, drug reaction with eosinophilia and systemic symptom syndrome, sarcoidosis and other systemic diseases) that can also induce AIN. Infection is still an important cause of AIN in less developed countries.[2]
The symptoms of DI-AIN are variable and often not specific; thus, kidney biopsy is required to make a firm diagnosis. The classic presentation, mostly induced by antibiotics and accompanied by evident hypersensitivity manifestations (skin rash, eosinophilia, fever) has been largely replaced by oligosymptomatic presentations that require a higher index of suspicion.[2] The incidence of DI-AIN appears to be increasing—particularly in the elderly, in whom kidney biopsy is underused and identification of the offending agent may be complicated by polypharmacy. Because rapid drug discontinuation may improve prognosis, the possibility of DI-AIN should always be considered in a patient with acute kidney injury.[1]
Acute interstitial nephritis (AIN) was brought to prominence as a pathological entity by an 1898 treatise that described 42 patients with the disorder.[16] During the preceding century, acute interstitial nephritis had primarily been reported in association with scarlet fever, but the 1898 report confirmed the disease as a separate and significant clinical entity.
Infections were the predominant etiology of acute interstitial nephritis until the middle of the 20th century, when the widespread availability of antibiotics altered the usual course of most common infections. This change markedly decreased the prevalence of infection-related acute interstitial nephritis, but, in an ironic twist, antibiotics dramatically increased the rates of drug-induced acute interstitial nephritis.
Both humoral and cell-mediated immune reactions are implicated in the pathophysiology of acute interstitial nephritis (AIN). Haptens are epitopes represented by drugs, part of drug molecules, or biologic substances transformed into immunogenic epitopes by drugs or other processes. The immunologic reaction to haptens causes disease by the inflammatory effect of antibody-hapten interaction. This occurs mainly in the renal interstitium, where haptens bind to tubular basement membranes (BMs) or interstitial matrix, leading to AIN. Drug-induced AIN can progress to a chronic form attended by fibroblast activation, ending in interstitial fibrosis, tubular atrophy and, finally, end-stage renal disease.[3]
Often the reaction is IgE or IgG4 mediated, with eosinophils infiltrating the interstitium, attended by eosinophiluria. This is so-called “allergic” AIN, even though the antigen is not an allergen and could be a hapten or a non-allergic, immunogenic epitope. Type B idiosyncratic non–immunoglobulin-E mediated immune reaction is marked by cell-mediated immune injury to the renal tubule-interstitium, carried out by CD4+ T-lymphocytes. The drug becomes immunogenic through antigen mimicry, haptenization, or neo-antigen formation. Dendritic cells of renal interstitium, and tubular epithelial cells can transform the injury into a chronic process.
The recruitment of T-lymphocyte immunity represents the hallmark of evolution into chronically progressive interstitial disease. It is almost always caused by T-cell activation, CD4 and CD8+, which, in turn, can recruit either an IgE- or IgG4-mediated pathway.[3]
Acute interstitial nephritis can be categorized into 5 groups based on the inciting etiology: (1) drug hypersensitivity reactions, (2) infections, (3) immune-mediated disease, (4) glomerular, and (5) idiopathic. All of these entities manifest as an abrupt onset of renal dysfunction, which may occur at any time following exposure to the inciting agent.
More than 250 different drugs from various classes have been incriminated as causative agents of drug-induced acute interstitial nephritis (DI-AIN), the third most common cause of acute kidney injury in hospitalized patients.[4] Antibiotics are the most implicated class of medication in DI-AIN, followed by proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory agents, and 5-aminosalicylates. Diuretics, allopurinol, phenytoin and other anti-seizure medications, and H2 receptor antagonists are known offenders while chemotherapeutic agents are an under-recognized cause.[1]
One retrospective study from Australia found that currently, PPIs may be the cause of most AIN cases.[2] While the association between PPIs and AIN is well described, the population incidence of PPI-induced AIN and its contribution to the burden of chronic kidney disease (CKD) was less clear.
However, a population-based study that analyzed a community-based cohort of over 10,000 adults found use of PPIs was independently associated with a 20–50% higher risk of CKD, after adjusting for several potential confounding variables, including demographics, socioeconomic status, clinical measurements, prevalent comorbidities, and concomitant use of other medications.[5] These results were further expanded in a study of a primary cohort of new users of PPI (n=173,321) followed over 5 years to ascertain renal outcomes. In addition to reporting an association between PPI and the risk of CKD, PPI use was associated with an increased risk of CKD progression (doubling of serum creatinine, estimated glomerular filtration rate [eGFR] decline > 30%) and end-stage renal disease (ESRD).[6]
Many infections have been associated with acute interstitial nephritis. Determining whether the infection or its treatment is responsible is often difficult.
Common bacterial pathogens associated with interstitial nephritis include Staphylococcus aureus and Escherichia coli. These bacteria are often associated with mononuclear infiltration (shown below) and the proliferation of organisms within the kidney, sometimes leading to abscess formation. Viral etiologies include cytomegalovirus, polyomavirus, and rubeola. Hantavirus causes an acute hemorrhagic interstitial nephritis.[7] Patients who are HIV positive may develop acute interstitial nephritis, although it is usually secondary to medications rather than the virus itself.[8] Other implicated organisms include Toxoplasma gondii, Rickettsia rickettsii, and Leishmania donovani.
Acute interstitial nephritis may manifest in conjunction with a variety of immune-mediated diseases. These include sarcoidosis, systemic lupus erythematosus, Sjögren syndrome, and essential cryoglobulinemia.
The presentation of acute interstitial nephritis in the course of these diseases may be in conjunction with an exacerbation of the systemic symptoms or as an isolated entity.
Often, what is described as idiopathic acute interstitial nephritis may prove to be little more than the initial symptoms of one of these systemic diseases.
Renal biopsies from patients with glomerulopathies often reveal tubulointerstitial nephritis. Some authors feel that the important contribution of tubulointerstitial disease to the development of end-stage renal disease warrants adding glomerulonephritis to the list of potential etiologies of acute interstitial nephritis.
Tubulointerstitial nephritis and uveitis (TINU) syndrome is an uncommon subtype of acute interstitial nephritisis defined as the combination of tubulointerstitial nephritis and uveitis occurring in the absence of other systemic diseases that can cause either interstitial nephritis or uveitis. Although important genetic contributions have been proposed, no ‘pro-TINU’ haplotype has been identified. Drugs and infections have been proposed as the leading acquired risk factors for the development of TINU.[9] Loss of T-cell tolerance is suggested by several reports identifying a strong link between TINU and human leukocyte antigen (HLA) type. In 2018, Kanno and colleagues reported five cases of TINU in which HLA-DR4 or the allele of DRB1∗04 was present in all patients.[10]
Obtaining estimates of prevalence is difficult, especially because the criterion standard diagnostic test is a renal biopsy. Until a noninvasive means of making a reliable diagnosis is available, accurate data will probably not be available.
If acute interstitial nephritis is detected early and the offending agent is removed, the patient will most likely recover baseline renal function. If the diagnosis is overlooked or if the patient is rechallenged with the same offending agent, the initial inflammatory response may become chronic, leading to fibrosis and tubular atrophy.
The prognosis is further delineated by the pathology found at biopsy. Patients with a diffuse infiltrate have a poorer prognosis than those without. In addition, the presence of 1-6% neutrophils in the infiltrate suggests a poorer prognosis.
Educate patients about agents that lead to acute interstitial nephritis, and instruct them to avoid using the offending agents.
For patient information, see Kidney Disease
Patients with hypersensitivity nephropathy present with an abrupt onset of renal dysfunction due to acute interstitial nephritis, which may occur from a few weeks to several months following exposure to the cause (eg, drugs, infection)later.[11, 12, 13] Fever is present in 60-100% of patients. Other symptoms are much less uniform in their presentation.
Patients with tubulointerstitial nephritis-uveitis (TINU) usually present with a 2- to 3-week history of uveitis. Uveitis may precede, accompany, or follow nephritis. Most patients with TINU experience a bilateral sudden-onset anterior uveitis with typical symptoms of redness, pain and photophobia. Patients may present with nonspecific constitutional symptoms including fever, rash, joint pain, malaise, or flank tenderness or be asymptomatic and detected through abnormal renal function (estimated GFR) tests. A proportion of patients develop peripheral blood eosinophilia but this is in an inconsistent feature.[9]
Patients with NSAID-associated acute interstitial nephritis have a history of NSAID use, and symptoms of nephrotic syndrome may be present (eg, lower extremity edema, lethargy). When NSAIDs lead to acute interstitial nephritis, patients often present with nephrotic-range proteinuria. Extrarenal signs, such as eosinophilia and rash, are less common with NSAIDs than with other medications.
Frequently, nothing unusual is discovered on physical examination. The two most common findings are rash and fever. The rash is frequently described as maculopapular, although, in allopurinol-related acute interstitial nephritis, it is sometimes exfoliative. Fever is present in 60-100% of cases.
Urine is often examined for eosinophils, but this method lacks adequate sensitivity and specificity. One study found a positive predictive value of 38%.[21] Regular urine microscopy must be supplanted with specific stains for eosinophils (Hansel stain).
Eosinophilia may be present, but this is also an unreliable diagnostic finding.
Urinalysis often reveals sterile pyuria with microscopic hematuria. Proteinuria is often present, but the quantity varies greatly, ranging from nephrotic levels in patients with NSAID-associated acute interstitial nephritis (AIN) to less than 1 g/d in others.
Renal ultrasound is of minimal value. Normal-sized kidneys with a slight increase in echogenicity are typically noted.
Gallium scans often show diffuse bilateral uptake. This can be helpful in differentiating acute interstitial nephritis and acute tubular necrosis, which has a uniformly negative scan result.
The criterion standard diagnostic test for acute interstitial nephritis is renal biopsy. Unfortunately, little else is available to help make a definitive diagnosis. Biopsy frequently reveals either a diffuse or segmental mixed infiltrate.
 View Image | Acute interstitial nephritis with mononuclear cell infiltrate. |
View Image | Mononuclear cell infiltrate between tubules. |
Most cases of acute interstitial nephritis (AIN) are diagnosed in the hospital setting. Carefully monitor renal function until resolved.
The most important aspect of treatment is removal of the offending agents. Occasionally, more than one agent may be causing acute interstitial nephritis (AIN). Consider the likelihood of each potential agent and substitute for each of the most likely agents (if possible).
Although corticosteroids are widely used in drug-induced AIN to speed kidney function recovery and avoid chronic kidney disease, their efficacy has not been tested by randomized controlled trials. If removing the inciting agents or treating the underlying infection does not improve renal function, consider corticosteroid therapy.
A retrospective study of 61 patients with biopsy-proven acute interstitial nephritis found 52 treated with corticosteroids, one half of whom showed a significant clinical improvement. The study further found that delays in treatment led to decreased function.[14]
Occasionally, AIN patients who had shown a positive response to corticosteroids, present a relapse coinciding with treatment discontinuation.Cortico-dependant, relapsing AIN poses an important therapeutic challenge[2]
Consider consultation with a nephrologist in all patients thought to have acute interstitial nephritis. This is particularly important among patients whose renal function does not improve following the removal of suspected medications. Because prognosis is tied to the length of time a patient has acute interstitial nephritis, consider consultation early in the course of illness.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Clinical Context: DOC with AIN not responsive to removal of offending agents.
Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
Acute interstitial nephritis with mononuclear cell infiltrate.
Mononuclear cell infiltrate between tubules.
Acute interstitial nephritis with mononuclear cell infiltrate.
Mononuclear cell infiltrate between tubules.
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