Interstitial nephritis was first described histologically in 1898 in the kidneys of patients who died from diphtheria and scarlet fever.¹ Interstitial nephritis is characterized by histologic changes due to infiltration of the renal interstitium and tubular cells by inflammatory cells accompanied by interstitial edema or fibrosis and varying degrees of tubular atrophy. These inflammatory changes usually spare the glomeruli and renal vasculature. Interstitial nephritis is now termed tubulointerstitial nephritis (TIN). Acute TIN refers to acute renal dysfunction and is usually reversible. Common types of acute TIN include drug induced, infectious, immune mediated, and idiopathic.

Chronic TIN describes a more insidious decline in renal function. Chronic TIN in children is far less common than acute TIN and is most often seen in the setting of obstructive uropathy, progressive renal disorders, and metabolic and hereditary disorders.² In chronic TIN the tubular epithelial cell damage is similar to that seen in acute TIN, but with eventual progression to interstitial fibrosis and tubular atrophy. Tubulointerstitial nephritis with uveitis (TINU) syndrome is a rare form of TIN in which the renal findings are associated with uveal inflammation. Uveitis may recur and persist even when renal symptoms resolve.^3-5

The true prevalence of TIN in the pediatric population is difficult to determine. The diagnosis of acute TIN is often made when there is clinical improvement or, as is the case of drug-induced acute TIN, after empiric removal of the likely trigger. According to the 2008 annual report from the North American Pediatric Renal Transplant Cooperative Study, TIN and pyelonephritis account for approximately 1.8% of all identified causes of chronic kidney disease and 1.7% of all causes of end-stage renal disease in the United States.⁶ Published data between 1983 and 2009 show that acute TIN has been diagnosed by percutaneous kidney biopsy in 3% to 7% of children and adolescents with acute kidney injury.^7,8 The incidence of TINU has been reported anywhere from 10% up to 25% in some case series. This incidence is higher than previously reported in the literature.⁵

PATHOPHYSIOLOGY

The exact pathophysiologic mechanism for TIN in humans is not completely understood. The most widely accepted hypothesis is that of cell-mediated immunity via T-lymphocyte infiltration in response to endogenous antigens (Tamm-Horsfall proteins, megalin, cumulin), or to exogenous antigens internalized and processed by tubular membrane cells.^2,9-12 After internalization and processing, MHC class I molecules then present potential antigens to CD8+ cytotoxic T-cells leading to tubular cell damage. Delayed or type IV hypersensitivity reactions are also thought to play a role in the pathogenesis of drug-induced TIN with a mixture of CD8+ and CD4+ T-cells, B-cells, macrophages, and natural killer cells.^2,9-12 Immunohistochemical staining of kidney tissue in TIN occasionally demonstrates the presence of antibodies, antibody-antigen complexes, and complement proteins, suggesting a role for antibody-mediated immunity and the complement cascade. Antigens of drug origin or microbial origin can mimic tubular basement membrane (TBM) antigens or renal interstitial antigens and induce an immune response against the TBM or renal interstitium.^2,9,10,12 Alternatively, drugs or drug components can bind to the renal interstitial cells and act as haptens, stimulating the production of anti-TBM antibodies. One additional mechanism described is direct binding of antigens to the tubular basement membrane or deposition of antigen-antibody complexes into the renal interstitium. This can lead to MHC class II processing of antigens by renal tubular epithelial cells and presentation to CD4+ T-cells. Activation of cytokines leads to amplification of renal injury.^2,9,10,12

The clinical presentation of TIN is quite variable. Fever, abdominal pain, nausea, vomiting, arthralgia, myalgia, and rash are some of the common presenting symptoms in children. Complaints of malaise, weight loss, and asthenia have also been reported in some case series. Often there are no specific signs or symptoms that point to a renal etiology unless some degree of renal failure is already present. If hematuria is present, it is usually microscopic, while oliguria is not a common finding on presentation. Nocturia, polyuria, and polydipsia may be present in some patients as a sign of tubular dysfunction and defective sodium reabsorption.^2,8,11,12 Patients with chronic TIN may exhibit symptoms of anorexia, weight loss, poor growth, and hypertension.

Due to the nonspecific nature of many presenting signs and symptoms, clinicians must have a high index of suspicion in cases of acute TIN. History of exposure to medications and the temporal relationship to such exposure as well as knowledge of any concurrent conditions known to cause TIN have significant diagnostic importance. The onset of symptoms can occur as late as 7 to 10 days after drug exposure in acute TIN. It is also important to note that drug-induced acute TIN is not a dose-dependent phenomenon, but symptoms can reoccur if a patient is exposed to the offending drug again.^2,4,8,11-14 A classic hypersensitivity triad of fever, rash, and eosinophilia was frequently reported in early literature. More recent evidence suggests that only about 15% of patients present with this constellation of symptoms.^11,13,14 In children, the most common medications known to cause acute TIN are antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs). A common clinical scenario in the inpatient setting is one of an already hospitalized patient with an otherwise unexplained acute rise in serum creatinine or blood urea nitrogen levels. A listing of some specific etiologic agents and disorders is provided in Table 114-1.