Tubulointerstitial nephritis is primary injury to renal tubules and interstitium resulting in decreased renal function. The acute form is most often due to allergic drug reactions or to infections. The chronic form occurs with a diverse array of causes, including genetic or metabolic disorders, obstructive uropathy, and chronic exposure to environmental toxins or to certain drugs and herbs. Diagnosis is suggested by history and urinalysis and often confirmed by biopsy. Treatment and prognosis vary by the etiology and potential reversibility of the disorder at the time of diagnosis.
Tubulointerstitial nephritis can be primary, but a similar process can result from glomerular damage (see Glomerular Disorders: Overview of Glomerular Disorders) or renovascular disorders (see Renovascular Disorders).
Primary tubulointerstitial nephritis may be
Acute tubulointerstitial nephritis (ATIN):
ATIN involves an inflammatory infiltrate and edema affecting the renal interstitium that often develops over days to months. Over 95% of cases result from infection or an allergic drug reaction. A syndrome of ATIN plus uveitis (renal-ocular syndrome) also occurs and is idiopathic. ATIN causes acute kidney injury; severe cases, delayed therapy, or continuance of an offending drug can lead to permanent injury and chronic kidney disease.
Chronic tubulointerstitial nephritis (CTIN):
CTIN arises when chronic tubular insults cause gradual interstitial infiltration and fibrosis, tubular atrophy and dysfunction, and a gradual deterioration of renal function, usually over years. Concurrent glomerular involvement (glomerulosclerosis) is much more common in CTIN than in ATIN. Causes of CTIN are myriad; they include immunologically mediated disorders, infections, reflux or obstructive nephropathy, drugs, and other disorders. CTIN due to toxins, metabolic derangements, hypertension, and inherited disorders results in symmetric and bilateral disease; when CITN is due to other causes, renal scarring may be unequal and involve only one kidney. Some well-characterized forms of CTIN include analgesic (see Tubulointerstitial Diseases: Analgesic Nephropathy), metabolic (see Tubulointerstitial Diseases: Metabolic Nephropathies), heavy metal (see Tubulointerstitial Diseases: Heavy Metal Nephropathy), and reflux nephropathy (see Tubulointerstitial Diseases: Reflux Nephropathy) and myeloma kidney (see Tubulointerstitial Diseases: Myeloma-Related Kidney Disease). Hereditary cystic kidney diseases are discussed elsewhere (see Cystic Kidney Disease: Overview of Cystic Kidney Disease).
Symptoms and Signs
Symptoms and signs of ATIN may be nonspecific and are often absent unless symptoms and signs of renal failure develop. Many patients develop polyuria and nocturia (due to a defect in urinary concentration and Na reabsorption). Symptom onset may be as long as several weeks after initial toxic exposure or as soon as 3 to 5 days after a 2nd exposure; extremes in latency range from 1 day with rifampin to 18 mo with an NSAID. Fever and urticarial rash are characteristic early manifestations of drug-induced ATIN, but the classically described triad of fever, rash, and eosinophilia is present in < 10% of patients with drug-induced ATIN. Abdominal pain, weight loss, and bilateral renal enlargement (caused by interstitial edema) may also occur in ATIN and with fever may mistakenly suggest renal cancer or polycystic kidney disease. Peripheral edema and hypertension are uncommon unless renal failure occurs.
Symptoms and signs are generally absent in CTIN unless renal failure develops. Edema usually is not present, and BP is normal or only mildly elevated in the early stages. Polyuria and nocturia may develop.
Few clinical and routine laboratory findings are specific. Thus, suspicion should be high when the following are present:
Other tests (eg, imaging) are usually necessary to differentiate ATIN or CTIN from other disorders. A presumptive clinical diagnosis of ATIN is often made based on the specific findings mentioned above, but renal biopsy is necessary to establish a definitive diagnosis.
Signs of active kidney inflammation (active urinary sediment), including RBCs, WBCs, and WBC casts, and absence of bacteria on culture (sterile pyuria) are typical; marked hematuria and dysmorphic RBCs are uncommon. Eosinophiluria has a positive predictive value of 50% (specificity of about 85 to 93%) and a negative predictive value of up to 90% for ATIN (sensitivity of about 63 to 91%). Thus, the presence of urinary eosinophils is not diagnostic, but their absence significantly decreases the likelihood of the diagnosis. Proteinuria is usually minimal but may reach nephrotic range with combined ATIN-glomerular disease induced by NSAIDs, ampicillin, rifampin, interferon alfa, or ranitidine. Blood test findings of tubular dysfunction include hypokalemia (caused by a defect in K reabsorption) and a nonanion gap metabolic acidosis (caused by a defect in HCO3 reabsorption or acid excretion).
Ultrasonography, radionuclide scanning, or both may be needed to differentiate ATIN from other causes of acute kidney injury, such as acute tubular necrosis. In ATIN, ultrasonography may show kidneys that are greatly enlarged and echogenic because of interstitial inflammatory cells and edema. Radionuclide scans may show kidneys avidly taking up radioactive gallium-67 or radionuclide-labeled WBCs. Positive scans strongly suggest ATIN (and indicate that acute tubular necrosis is less likely), but a negative scan does not exclude ATIN.
Renal biopsy is usually reserved for patients with the following:
In ATIN, glomeruli are usually normal. The earliest finding is interstitial edema, typically followed by interstitial infiltration with lymphocytes, plasma cells, eosinophils, and a few PMNs. In severe cases, inflammatory cells can be seen invading the space between the cells lining the tubular basement membrane (tubulitis); in other specimens, granulomatous reactions resulting from exposure to methicillin, sulfonamides, mycobacteria, or fungi may be seen. The presence of noncaseating granulomas suggests sarcoidosis. Immunofluorescence or electron microscopy seldom reveals any pathognomonic changes.
Findings of CTIN are generally similar to those of ATIN, although urinary RBCs and WBCs are uncommon. Because CTIN is insidious in onset and interstitial fibrosis is common, imaging tests may show small kidneys with evidence of scarring and asymmetry.
In CTIN, renal biopsy is not often done for diagnostic purposes but has helped characterize the nature and progression of tubulointerstitial disease. Glomeruli vary from normal to completely destroyed. Tubules may be absent or atrophied. Tubular lumina vary in diameter but may show marked dilation, with homogeneous casts. The interstitium contains varying degrees of inflammatory cells and fibrosis. Nonscarred areas appear almost normal. Grossly, the kidneys are small and atrophic.
In drug-induced ATIN, renal function usually recovers within 6 to 8 wk when the causative drug is stopped, although some residual scarring is common. Recovery may be incomplete, with persistent azotemia above baseline. Prognosis is usually worse if ATIN is caused by NSAIDs than by other drugs. When other factors cause ATIN, histologic changes usually are reversible if the cause is recognized and removed; however, some severe cases progress to fibrosis and chronic kidney disease. Regardless of cause, irreversible injury is suggested by the following:
In CTIN, prognosis depends on the cause and on the ability to recognize and stop the process before irreversible fibrosis occurs. Many genetic (eg, cystic kidney disease), metabolic (eg, cystinosis), and toxic (eg, heavy metal) causes may not be modifiable, in which case CTIN usually evolves to end-stage renal disease.
Treatment of both ATIN and CTIN is management of the cause. For immunologically induced ATIN and sometimes drug-induced ATIN, corticosteroids (eg, prednisone 1 mg/kg po once/day with gradual tapering of the dose over 4 to 6 wk) may accelerate recovery. For drug-induced ATIN, corticosteroids are most effective when given within 2 wk of stopping the causative drugs. NSAID-induced ATIN is less responsive to corticosteroids than other drug-induced ATIN. ATIN should be proven by biopsy before corticosteroids are started. Treatment of CTIN often requires supportive measures such as controlling BP and treating anemia associated with kidney disease. In patients with CTIN and progressive renal injury, ACE inhibitors or angiotensin II receptor blockers may slow disease progression.
Last full review/revision March 2013 by Navin Jaipaul, MD, MHS
Content last modified March 2013