Acute Interstitial Nephritis (AIN)

Etiology and pathogenesisTop

Classification of acute interstitial nephritis (AIN) based on etiology:

1) Drug-induced AIN (the most common cause of AIN):

a) Nonsteroidal anti-inflammatory drugs (NSAIDs): Most frequently fenoprofen, phenylbutazone, ibuprofen, indomethacin, naproxen, piroxicam, cyclooxygenase-2 (COX-2) inhibitors.

b) Antibiotics: Ampicillin, methicillin, penicillin, rifampicin, sulfonamides, vancomycin, ciprofloxacin, erythromycin, tetracycline.

c) Other drugs: Proton pump inhibitors (PPIs), cimetidine, allopurinol, interferon, antiviral drugs, 5-aminosalicylic acid, immune checkpoint inhibitors (anticancer medications) such as nivolumab and pembrolizumab. There has been a higher incidence of AIN reported when immune checkpoint inhibitors are used concurrently with PPIs.

2) Infection-induced AIN:

a) Primary kidney infections: Acute bacterial pyelonephritis (see Uncomplicated Acute Pyelonephritis), renal tuberculosis, fungal nephritis.

b) Systemic infections: Bacterial (Legionella spp, Brucella spp, Salmonella spp, Streptococcus spp), viral (Epstein-Barr virus, cytomegalovirus, hantavirus, adenoviruses), fungi (histoplasmosis, coccidioidomycosis), or other etiology (mycoplasma, protozoa).

3) AIN associated with systemic diseases:

a) Immune mediated: Systemic lupus erythematosus, Sjögren syndrome, tubulointerstitial nephritis with uveitis (TINU), tubulointerstitial nephritis with hypocomplementemia.

b) Hematologic/neoplastic: Light-chain deposition disease associated with or without plasma cell dyscrasias, lymphoproliferative disorders, IgG4-related disease.

c) Sarcoidosis.

AIN accounts for 5% to 18% of kidney biopsies performed in the setting of acute kidney injury (AKI). In resource-rich countries drug-induced AIN is the leading cause of biopsy-proven AIN (>70%), whereas in resurce-restricted regions infectious AIN can account for 40% to 50% of all AIN cases. In patients with a genetic predisposition or hypersensitivity, antigens trigger immune reactions in the renal interstitium. The reactions primarily involve cellular processes associated with the presence of T cells in the interstitium and secretion of proinflammatory cytokines, and, less frequently, humoral processes, associated with activation of the complement system by antibodies.

Clinical FeaturesTop

AIN is associated with AKI, which develops over a period of days to several weeks. There is no pathognomonic sign or symptom of AIN. The following occur at varying frequencies: dull flank pain, oliguria, maculopapular rash, hematuria, fever (often in case of a relapse), joint pain, edema, and hypertension. The triad of fever, rash, and eosinophilia occurs in 10% of drug-induced AIN. On average, the symptoms appear within 3 weeks of starting the offending drug (ranging from day 1 to >2 months). In AIN associated with generalized infection the dominant symptoms are those of the underlying disease and AKI. Idiopathic AIN manifests clinically as AKI of unknown etiology.

DiagnosisTop

Most frequently the (probable) diagnosis is made on the basis of clinical manifestations (sudden onset of symptoms of kidney injury in a patient with generalized infection or treated with drugs that may cause AIN, in particular when extrarenal allergic symptoms occur simultaneously) after other causes of AKI have been excluded.

Diagnostic Tests

1. Urinalysis: Proteinuria, often mild (<1 g/d) or moderate (~2 g/d); nephrotic range proteinuria (≥3.5 g/d) suggests NSAID-induced AIN; microscopic hematuria and leukocyturia in most patients. Eosinophiluria (>1%) has historically been considered a useful diagnostic test for drug-induced AIN, but it lacks sensitivity and specificity and cannot be relied upon.Evidence 1Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the retrospective analysis of patients who had both kidney biopsy as the gold standard for diagnosis of acute interstitial nephritis and urine eosinophils tested. Muriithi AK, Nasr SH, Leung N. Utility of urine eosinophils in the diagnosis of acute interstitial nephritis. Clin J Am Soc Nephrol. 2013 Nov;8(11):1857-62. doi: 10.2215/CJN.01330213. Epub 2013 Sep 19. PMID: 24052222; PMCID: PMC3817898.

2. Blood tests: In patients with drug-induced AIN peripheral eosinophilia may occur.

3. Imaging studies: Ultrasonography reveals enlarged or normal kidneys with increased cortical echogenicity.

4. Kidney biopsy: Kidney biopsy confirms diagnosis. It is performed in case of significant uncertainty as to the cause of kidney disease, particularly when the existing AKI could have been caused by a condition that may be effectively treated (eg, rapidly progressive glomerulonephritis).

5. Urine cytokines: Elevated interleukin 9 (IL-9) and tumor necrosis factor alpha may be helpful, but these emerging tests are not widely available and clinically validated.

6. Multiplex polymerase chain reaction (PCR): For confirmation of infectious etiology, the nucleic acid material can be isolated from the renal tissue. For instance, tubercular DNA in renal biopsies can confirm the diagnosis.

TreatmentTop

1. Elimination of known or suspected causes: Aggressive treatment of systemic infections, discontinuation of drugs that might have caused AIN.

2. Management of AKI: see Acute Kidney Injury.

3. Glucocorticoids may be considered in patients with biopsy-proven drug-induced AIN after withdrawal of the offending drug.Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of studies and limited number of observed patients. Buysen JG, Houthoff HJ, Krediet RT, Arisz L. Acute interstitial nephritis: a clinical and morphological study in 27 patients. Nephrol Dial Transplant. 1990;5(2):94-9. PMID: 2113219. González E, Gutiérrez E, Galeano C, et al; Grupo Madrileno De Nefritis Intersticiales. Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis. Kidney Int. 2008 Apr;73(8):940-6. doi: 10.1038/sj.ki.5002776. Epub 2008 Jan 9. PMID: 18185501. When started early (within 2 weeks of withdrawal of the drug), glucocorticoids may limit the extent of renal fibrosis and may increase the probability of complete renal recovery. Consider a course of oral prednisone 1 mg/kg/d tapered off over 4 to 6 weeks. The role of other immunosuppression therapy (mycophenolate mofetil, cyclosporine [INN ciclosporin], cyclophosphamide) cannot be informed by the current state of evidence. Indications for immunosuppressive therapy in other forms of AIN are less evident; therapy should be preceded by kidney biopsy.

PrognosisTop

In patients in whom AIN was diagnosed early and its cause has been successfully eliminated, the rate of complete resolution is ~50%. Other patients have varying degrees of chronic kidney disease and some may require long-term renal replacement therapy.