AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

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, AIN 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 AIN 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 AIN, but, in an ironic twist, antibiotics dramatically increased the rates of drug-associated AIN.

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

Pathophysiology

Both humoral and cell-mediated immune reactions are implicated in the pathophysiology of AIN. Drug-specific antibodies have been found in patients with rifampin-related AIN. Patients with methicillin-related AIN 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 AIN due to nonsteroidal anti-inflammatory drugs (NSAIDs) typically present with features of minimal change disease, including fusion of foot processes.

Frequency

International

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.

CLINICAL

Section 3 of 11  

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• Clinical
• Differentials
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• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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History

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 AIN any time following exposure.
• 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 AIN have a history of NSAID use, and symptoms of nephrotic syndrome may be present (eg, lower extremity edema, lethargy).

Physical

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 AIN, it is sometimes exfoliative.
• Fever is present in 60-100% of cases.

Causes

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

• Drug hypersensitivity reactions
• • Many drugs can cause AIN.
  • The first medications noted to cause AIN were sulfonamide antibiotics (1950s).
  • By the end of the 1960s, reports surfaced of AIN due to methicillin. According to one study, up to 15% of patients receiving a 2-week course developed AIN.
  • The lengthy list of other medications that have been linked to AIN include rifampin, penicillins, cephalosporins, and NSAIDs.
  • When NSAIDs lead to AIN, patients often present with nephrotic-range proteinuria. Extrarenal signs, such as eosinophilia and rash, are less common with NSAIDs than with other medications.
  • AIN can occur at any point following administration of these medications, from a few weeks to several months later.

• Infections
• • Many infections have been associated with AIN. Determining whether the infection or its treatment is responsible for AIN 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 and the proliferation of organisms within the kidney, sometimes leading to abscess formation.
  • Viral etiologies include cytomegalovirus, polyomavirus, and rubeola.
  • Other implicated organisms include Toxoplasma gondii, Rickettsia rickettsii, and Leishmania donovani.

• Immune-mediated disease
• • AIN 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 AIN 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 AIN may prove to be little more than the initial symptoms of one of these systemic diseases.

• Glomerular
• • 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 AIN.

• Tubulointerstitial nephritis-uveitis
• • TINU is an uncommon subtype of AIN.

  • 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.

  • Fortunately, this syndrome is rare.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• 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 AIN to less than 1 g/d in others.

Imaging Studies

• 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 AIN and acute tubular necrosis, which has a uniformly negative scan result.

Procedures

• The criterion standard diagnostic test for AIN is renal biopsy. Unfortunately, little else is available to help make a definitive diagnosis. Biopsy frequently reveals either a diffuse or segmental mixed infiltrate.

TREATMENT

Section 6 of 11  

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• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Medical Care

• Offending agents
• • The most important aspect of treatment is removal of the offending agents.

  • Occasionally, more than one agent may be causing 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.

• Corticosteroids
• • If removing the inciting agents or treating the underlying infection does not improve renal function, consider corticosteroid therapy.

  • No prospective randomized controlled trials have been performed to evaluate this treatment. Despite this, prednisone treatment is commonly recommended to treat biopsy-proven AIN.

• Cyclophosphamide
• • 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 AIN.

Consultations

Consider consultation with a nephrologist in all patients thought to have AIN. 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 AIN, consider consultation early in the course of illness.

MEDICATION

Section 7 of 11  

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• Miscellaneous
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• References

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

Drug Category: Corticosteroids

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

Drug Category: Antineoplastics

Inhibit cell growth and proliferation

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Most AIN is diagnosed in the hospital setting. Carefully monitor renal function until resolved. Make patients aware of any drug that may have caused the episode, and advise them not to take it again.

Prognosis

• If AIN 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.
• 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

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

MISCELLANEOUS

Section 9 of 11  

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• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Medical/Legal Pitfalls

• Make a diligent effort to exclude any potentially offending medications; stop any new medication until it can be completely excluded.

MULTIMEDIA

Section 10 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Nephropathy, hypersensitivity. Acute interstitial nephritis with mononuclear cell infiltrate.
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Media file 2:  Nephropathy, hypersensitivity. Mononuclear cell infiltrate between tubules.
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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
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• Follow-up
• Miscellaneous
• Multimedia
• References

• Alpers CE. The evolving contribution of renal pathology to understanding interstitial nephritis. Ren Fail. Nov 1998;20(6):763-71. [Medline].
• Councilman WT. Acute interstitial nephritis. Journal of Experimental Medicine. 1898;3:393-420.
• Fried T. Acute interstitial nephritis. Why do the kidneys suddenly fail?. Postgrad Med. Apr 1993;93(5):105-6, 111-2, 117-20. [Medline].
• Kleinknecht D. Interstitial nephritis, the nephrotic syndrome, and chronic renal failure secondary to nonsteroidal anti-inflammatory drugs. Semin Nephrol. May 1995;15(3):228-35. [Medline].
• Michel DM, Kelly CJ. Acute interstitial nephritis. J Am Soc Nephrol. Mar 1998;9(3):506-15. [Medline].
• Reddy S, Salant DJ. Treatment of acute interstitial nephritis. Ren Fail. Nov 1998;20(6):829-38. [Medline].
• Ruffing KA, Hoppes P, Blend D, Cugino A, Jarjoura D, Whittier FC. Eosinophils in urine revisited. Clin Nephrol. Mar 1994;41(3):163-6. [Medline].

Article Last Updated: Oct 10, 2006