Acute interstitial nephritis (AIN), also known as acute tubulointerstitial nephritis (ATIN), refers to a clinical-pathological syndrome characterized by sudden renal function decline caused by various etiologies. Its primary pathological features include interstitial edema and infiltration of inflammatory cells, with minimal or no involvement of the glomeruli and renal vasculature.
Etiology and Pathogenesis
AIN has diverse causes, with medications and infections being the most common.
Medications
Drugs or their metabolites can act as haptens within the renal interstitium, mimicking endogenous interstitial structures and triggering immune-inflammatory responses. The mechanisms may vary depending on the specific drug.
- Antibiotics: Penicillins; anti-tuberculosis drugs such as rifampin and ethambutol; sulfonamides; vancomycin; ciprofloxacin; cephalosporins; macrolides such as erythromycin.
- Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Non-selective cyclooxygenase inhibitors such as ibuprofen, naproxen, acetaminophen, indomethacin, and diclofenac; selective cyclooxygenase-2 inhibitors such as celecoxib.
- Medications for Peptic Ulcer Disease: H2 receptor antagonists such as ranitidine; proton pump inhibitors (PPIs) such as omeprazole.
- Neurological or Psychiatric Medications: Phenobarbital, phenytoin, valproic acid, carbamazepine.
- Antineoplastic Drugs: All-trans retinoic acid, immune checkpoint inhibitors, among others.
- Others: Allopurinol, azathioprine, penicillamine, propylthiouracil, cyclosporine, gold compounds, ephedrine, warfarin, interferons, and others.
Systemic Infections
Various pathogens causing systemic infections can induce interstitial inflammatory responses in the kidney. Some may also directly infect the kidney, triggering adaptive immune responses within the renal interstitium. Examples include brucellosis, diphtheria, Legionnaires' disease, streptococcal infections, Mycoplasma pneumonia, infectious mononucleosis, cytomegalovirus infection, leptospirosis, syphilis, and toxoplasmosis.
Primary Renal Infections
These include pyelonephritis, renal tuberculosis, and fungal infections of the kidney.
Autoimmune Diseases
Examples include tubulointerstitial nephritis and uveitis syndrome (TINU syndrome), as well as those secondary to connective tissue diseases such as systemic lupus erythematosus, primary Sjögren's syndrome, necrotizing vasculitis, and IgG4-related diseases. Acute T-cell-mediated rejection in transplanted kidneys is another example.
Idiopathic Cases
Some cases present as acute kidney injury with typical pathological findings of AIN, but the underlying cause remains unclear. In certain cases, dynamic monitoring of disease progression may eventually reveal the etiology.
Pathology
Pathological findings include focal or diffuse infiltration of mononuclear cells (T lymphocytes and monocytes), with T cells being a mixed population but predominantly CD4+ T lymphocytes. Neutrophils, plasma cells, and eosinophils (especially in drug-induced cases) may also be present. Interstitial edema is often observed, leading to separation of renal tubules and kidney enlargement. Severe cases may show tubular basement membrane damage. Non-necrotizing epithelial granulomas may occasionally appear within the renal interstitium. Inflammatory cells can invade the tubular walls, causing tubulitis, and in severe cases, focal tubular necrosis may occur. The extent of necrosis often correlates with the degree of renal impairment. Fibrosis is absent during the acute phase. The glomeruli and vasculature are typically normal, except for rare cases with mesangial proliferation. Immunofluorescence findings are usually negative.
In cases caused by NSAIDs, glomeruli appear normal in light microscopy, while electron microscopy may reveal foot process effacement in podocytes, resembling minimal change disease.
Clinical Manifestations
Most patients present with asymptomatic elevations in serum creatinine or abnormalities on urinalysis. Symptomatic cases vary in severity and lack specificity. In infection- or drug-associated AIN, patients may experience fever and flank or back pain. Fewer than 1/3 of patients exhibit allergic reactions, characterized by maculopapular rash, fever, and eosinophilia.
Oliguria or anuria occurs in 20%–50% of cases, accompanied by varying degrees of azotemia. The rate of renal function decline depends on the severity of the immune response, ranging from a few days to several weeks. Re-exposure to the causative drug may result in rapid deterioration of renal function. Urinalysis findings in some patients include hematuria, with gross hematuria being rare, and sterile pyuria, with eosinophiluria observed in a minority of cases. Urine sediment may reveal red blood cell casts or white blood cell casts. Proteinuria is typically mild to moderate, with most cases showing less than 2 g/day, and usually less than 1 g/day. Nephrotic-range proteinuria is uncommon unless minimal change disease coexists, which may occur in cases caused by NSAIDs or interferons.
Tubular dysfunction is prominent, with findings such as renal glycosuria, low-molecular-weight proteinuria, and increased urinary excretion of markers like β2-microglobulin and N-acetyl-β-D-glucosaminidase (NAG). Urine specific gravity and osmolality are often reduced. Type I renal tubular acidosis is common, and Fanconi syndrome or electrolyte disturbances are occasionally observed.
In cases where systemic diseases primarily manifest as interstitial nephritis, clinical and laboratory evidence of the underlying condition may also be present. For example, systemic lupus erythematosus-associated cases may show positive ANA and anti-dsDNA antibodies, primary Sjögren's syndrome cases may exhibit positive anti-SSA and anti-SSB antibodies, and IgG4-related kidney disease may be associated with elevated serum IgG4 levels.
Ultrasound or CT imaging often reveals kidneys of normal or slightly increased size. Ultrasound findings may include enhanced cortical echogenicity, which could be related to diffuse interstitial inflammatory cell infiltration.
Diagnosis and Differential Diagnosis
Typical cases can be diagnosed based on a history of drug use, infection, or systemic disease, combined with laboratory findings. Definitive diagnosis relies on renal biopsy.
Differential diagnosis involves distinguishing AIN from other causes of acute kidney injury (AKI), including acute tubular necrosis (ATN) and rapidly progressive glomerulonephritis (RPGN). Additionally, for cases presenting with clinical features consistent with AIN, it is necessary to determine whether AIN is primary to the renal interstitium or secondary to glomerular diseases such as focal segmental glomerulosclerosis (FSGS), IgA nephropathy, lupus nephritis, or diabetic kidney disease.
Treatment
Removal of the Underlying Cause
Discontinuation of suspected drugs is essential. For infection-associated cases, appropriate antibiotics should be administered to treat systemic or localized infections.
Supportive Therapy
Symptomatic management is necessary. In cases of AKI with indications for renal replacement therapy, such as hyperkalemia or pulmonary edema, blood purification therapy may be required.
Immunosuppressive Therapy
For non-infectious AIN (preferably confirmed by renal biopsy), oral prednisone at a dose of 0.75–1 mg/(kg·d) may be considered. Renal function often improves within 1–2 weeks of treatment. A treatment course of 4–6 weeks is recommended, followed by a gradual taper. If renal function does not improve, additional immunosuppressants such as mycophenolate mofetil or cyclophosphamide may be considered. Lack of response after 6 weeks of treatment suggests chronic changes, and further immunosuppressive therapy is unlikely to provide additional benefit. In such cases, immunosuppressants should be tapered and discontinued.
Prognosis
Timely recognition and intervention are critical for a favorable prognosis in AIN. However, some patients may progress to chronic kidney disease despite treatment.