Hypersensitivity Nephropathy 

Updated: Dec 01, 2015
Author: Micah L Thorp, DO, MPH; Chief Editor: Vecihi Batuman, MD, FASN 



Acute interstitial nephritis (AIN) was brought to prominence as a pathological entity by an official who described 42 patients with interstitial nephritis in an 1898 treatise. 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 etiologies 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-associated acute interstitial nephritis.

Recently, proton pump inhibitors have been identified as an etiology of acute interstitial nephritis. One retrospective study from Australia indicates this class of drugs may be the etiology of most acute interstitial nephritis cases currently.[1]


Both humoral and cell-mediated immune reactions are implicated in the pathophysiology of acute interstitial nephritis. Drug-specific antibodies have been found in patients with rifampin-related acute interstitial nephritis. Patients with methicillin-related acute interstitial nephritis often have both a linear fluorescence along the tubular basement membrane as well as an antibody directed against a hapten bound to the tubular basement membrane.

Renal biopsy samples taken from patients reveal a diffuse or patchy inflammatory cell infiltrate under light microscopy. The infiltrate is typically composed of mixed T lymphocytes, plasma cells, eosinophils, and monocytes. The CD4-to-CD8 ratio is similar to that in blood. Glomerular lesions are generally not present. Immunofluorescence is usually unremarkable, although immunoglobulin G (IgG) or immunoglobulin M (IgM) staining of the tubular basement membrane is occasionally present. Patients who have acute interstitial nephritis due to nonsteroidal anti-inflammatory drugs (NSAIDs) typically present with features of minimal change disease, including fusion of foot processes.




Obtaining estimates of prevalence is difficult, especially because the criterion standard diagnostic test is a renal biopsy. One large study of Finnish conscripts with hematuria or proteinuria found a prevalence of only 1%. In studies of patients with acute renal failure, rates up to 10-15% have been established. Until a noninvasive means of making a reliable diagnosis is available, accurate data will probably not be available.




Patients invariably present with an abrupt onset of renal dysfunction. Patients with other symptoms are much less uniform in their presentation. Possible presentations include the following:

  • Recent etiological exposure (eg, drugs, infection) can cause acute interstitial nephritis at any time following exposure.[2, 3, 4]

  • Fever is present in 60-100% of patients.

  • Patients with tubulointerstitial nephritis-uveitis (TINU) usually present with a 2- to 3-week history of uveitis. Uveitis may precede nephritis, occur subsequent to nephritis, or occur simultaneous with nephritis.

  • 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).


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.


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. In early reports of methicillin-associated acute interstitial nephritis, onset usually occurred after 10-20 days of administration, although it must be noted that this is not always the case. Acute interstitial nephritis is quite heterogeneous in its presentation, and the time course is often subject to variation. Acute interstitial nephritis can also be grouped into acute and chronic subgroups.

Drug hypersensitivity reactions

Many drugs can cause acute interstitial nephritis. The first medications noted to cause acute interstitial nephritis were sulfonamide antibiotics (1950s). By the end of the 1960s, reports surfaced of acute interstitial nephritis due to methicillin. According to one study, up to 15% of patients receiving a 2-week course developed acute interstitial nephritis.

Other medications that have been linked to acute interstitial nephritis include rifampin, penicillins, cephalosporins, and NSAIDs.

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.

Acute interstitial nephritis can occur at any point following administration of the above medications, from a few weeks to several months later.


Many infections have been associated with acute interstitial nephritis. Determining whether the infection or its treatment is responsible for acute interstitial nephritis is often difficult.

Common bacterial infections associated with interstitial nephritis include Staphylococcus aureus and Escherichia coli. These infectious agents 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.[5] Patients who are HIV positive may develop acute interstitial nephritis, although it is usually secondary to medications rather than the virus itself.[6]

See the images below.

Acute interstitial nephritis with mononuclear cell Acute interstitial nephritis with mononuclear cell infiltrate.
Mononuclear cell infiltrate between tubules. Mononuclear cell infiltrate between tubules.

Other implicated organisms include Toxoplasma gondii, Rickettsia rickettsii, and Leishmania donovani.

Immune-mediated disease

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-uveitis

TINU is an uncommon subtype of acute interstitial nephritis. Patients with this syndrome present with diffuse eosinophilic interstitial nephritis associated with granulomas in the bone marrow and lymph nodes. Uveitis and systemic malaise usually precede other symptoms, but, in some cases, uveitis occurs after nephritis.

TINU most often manifests in pubertal females, but fortunately, this syndrome is rare.





Laboratory Studies

See the list below:

  • Urine is often examined for eosinophils, but this method lacks adequate sensitivity and specificity. One study found a positive predictive value of 38%. 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.

Imaging Studies

See the list below:

  • 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.


See the list below:

  • 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.



Medical Care

Offending agents

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).

After removing the inciting agents, administer prednisone.


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.[7] The study further found that delays in treatment led to decreased function.[7]


Cyclophosphamide therapy is controversial. This treatment causes significant short-term adverse effects in many patients, which makes many clinicians reluctant to use it in primary therapy.

Cyclophosphamide has been studied in experimental animal models of acute interstitial nephritis.


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.



Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.


Class Summary

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Orasone, Sterapred)

DOC with AIN not responsive to removal of offending agents.


Class Summary

Inhibit cell growth and proliferation



Further Outpatient Care

See the list below:

  • Most cases of acute interstitial nephritis (AIN) are diagnosed in the hospital setting. Carefully monitor renal function until resolved.

  • Make patients aware of any drug that may have caused the episode of acute interstitial nephritis, and advise them not to take it again.


See the list below:

  • If acute interstitial nephritis is detected early and the offending agent is removed, the patient will most likely return to 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.

Patient Education

See the list below:

  • Educate patients about agents that lead to acute interstitial nephritis, and instruct them to avoid using the offending agents.