(See also Overview of Tubulointerstitial Diseases Overview of Tubulointerstitial Diseases Tubulointerstitial diseases are clinically heterogeneous disorders that share similar features of tubular and interstitial injury. In severe and prolonged cases, the entire kidney may become... read more .)
Etiology of Tubulointerstitial Nephritis
Tubulointerstitial nephritis can be primary, but a similar process can result from glomerular damage Overview of Glomerular Disorders The hallmark of glomerular disorders is proteinuria, which is often in the nephrotic range (≥ 3 g/day). Glomerular disorders are classified based on urine changes as those that manifest predominantly... read more or renovascular disorders.
Primary tubulointerstitial nephritis may be
Acute (see table Causes of Acute Tubulointerstitial Nephritis )
Chronic (see table Causes of Chronic Tubulointerstitial Nephritis )
Acute tubulointerstitial nephritis
Acute tubulointerstitial nephritis (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.
ATIN causes acute kidney injury Acute Kidney Injury (AKI) Acute kidney injury is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia) with or without reduction in amount of urine... read more ; severe cases, delayed therapy, or continuance of an offending drug can lead to permanent injury and chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more 
.
Renal-ocular syndrome, acute tubulointerstitial nephritis plus uveitis, also occurs and is idiopathic.
Chronic tubulointerstitial nephritis
Chronic tubulointerstitial nephritis (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 chronic tubulointerstitial nephritis 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 CTIN is due to other causes, renal scarring may be unequal and involve only one kidney. Some well-characterized forms of CTIN include
Reflux nephropathy Vesicoureteral Reflux and Reflux Nephropathy Reflux nephropathy is renal scarring presumably induced by vesicoureteral reflux of infected urine into the renal parenchyma. The diagnosis is suspected in children with urinary tract infections... read more 
and myeloma Myeloma-Related Kidney Disease Patients with multiple myeloma overproduce monoclonal Ig light chains (Bence Jones proteins); these light chains are filtered by glomeruli, are nephrotoxic, and, in their various forms (free... read more 
may cause tubulointerstitial injury but the predominant pathology in these conditions is glomerular disease.
Hereditary cystic kidney diseases Overview of Cystic Kidney Disease Cystic kidney disease may be congenital or acquired. Congenital disorders may be inherited as autosomal dominant disorders or autosomal recessive disorders or have other causes (eg, sporadic... read more are discussed elsewhere.
General references
Yamaguchi Y, Kanetsuna Y, Honda K, et al: Characteristic tubulointerstitial nephritis in IgG4-related disease. Hum Pathol 43(4):536-549, 2012. doi: 10.1016/j.humpath.2011.06.002.
Correa-Rotter R, Wesseling C, Johnson RJ: CKD of unknown origin in Central America: The case for Mesoamerican nephropathy. Am J Kidney Dis63(3):506-520, 2014. doi: 10.1053/j.ajkd.2013.10.062.
Symptoms and Signs of Tubulointerstitial Nephritis
Acute tubulointerstitial nephritis
Symptoms and signs of acute tubulointerstitial nephritis (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 sodium reabsorption).
ATIN 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 months with a nonsteroidal anti-inflammatory drug (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.
Chronic tubulointerstitial nephritis
Symptoms and signs are generally absent in chronic tubulointerstitial nephritis unless renal failure develops. Edema usually is not present, and blood pressure is normal or only mildly elevated in the early stages. Polyuria and nocturia may develop.
Diagnosis of Tubulointerstitial Nephritis
Risk factors
In acute tubulointerstitial nephritis (ATIN), active urinary sediment with sterile pyuria
Sometimes renal biopsy
Usually imaging to exclude other causes
Few clinical and routine laboratory findings are specific for tubulointerstitial nephritis. Thus, suspicion should be high when the following are present:
Typical symptoms or signs
Risk factors, particularly a temporal relationship between onset and use of a potentially causative drug
Characteristic urinalysis findings, particularly sterile pyuria
Modest proteinuria, usually < 1 g/day (except with use of nonsteroidal anti-inflammatory drugs [NSAIDs], which may cause nephrotic-range proteinuria, 3.5 g/day)
Evidence of tubular dysfunction (eg, renal tubular acidosis Renal Tubular Acidosis Renal tubular acidosis (RTA) is acidosis and electrolyte disturbances due to impaired renal hydrogen ion excretion (type 1), impaired bicarbonate resorption (type 2), or abnormal aldosterone... read more , Fanconi syndrome Fanconi Syndrome Fanconi syndrome consists of multiple defects in renal proximal tubular reabsorption, causing glucosuria, phosphaturia, generalized aminoaciduria, and bicarbonate wasting. It may be hereditary... read more )
Concentrating defect out of proportion to the degree of renal failure
Eosinophiluria cannot be relied upon to make or exclude the diagnosis. Other tests (eg, imaging) are usually necessary to differentiate ATIN or chronic tubulointerstitial nephritis (CTIN) from other disorders. A presumptive clinical diagnosis of ATIN is often made based on the specific findings mentioned above, but renal biopsy Renal biopsy Biopsy of the urinary tract requires a trained specialist (nephrologist, urologist, or interventional radiologist). Indications for diagnostic biopsy include unexplained nephritic or nephrotic... read more is necessary to establish a definitive diagnosis.
Acute tubulointerstitial nephritis
Urinalysis that shows signs of active kidney inflammation (active urinary sediment), including red blood cells (RBCs), white blood cells (WBCs), and WBC casts, and absence of bacteria on culture (sterile pyuria) is typical; marked hematuria and dysmorphic RBCs are uncommon. Eosinophiluria has traditionally been thought to suggest ATIN; however, the presence or absence of urinary eosinophils is not particularly useful diagnostically. 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 potassium reabsorption) and a nonanion gap metabolic acidosis Metabolic Acidosis Metabolic acidosis is primary reduction in bicarbonate (HCO3−), typically with compensatory reduction in carbon dioxide partial pressure (Pco2); pH may be markedly low or slightly subnormal... read more (caused by a defect in proximal tubular bicarbonate reabsorption or in distal tubular acid excretion).
Ultrasonography, radionuclide scanning, or both may be needed to differentiate acute tubulointerstitial nephritis from other causes of acute kidney injury when kidney biopsy is not possible. 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 white blood cells (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 Renal biopsy Biopsy of the urinary tract requires a trained specialist (nephrologist, urologist, or interventional radiologist). Indications for diagnostic biopsy include unexplained nephritic or nephrotic... read more is usually reserved for patients with the following:
An uncertain diagnosis
Progressive renal injury
No improvement after potential causative drugs are stopped
Findings suggesting early disease
Drug-induced ATIN for which corticosteroid therapy is under consideration
In acute tubulointerstitial nephritis, glomeruli are usually normal. The earliest finding is interstitial edema, typically followed by interstitial infiltration with lymphocytes, plasma cells, eosinophils, and a few polymorphonuclear leukocytes. 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 beta-lactam antibiotics, sulfonamides, mycobacteria, or fungi may be seen. The presence of noncaseating granulomas suggests sarcoidosis. Immunofluorescence or electron microscopy seldom reveals any pathognomonic changes.
Chronic tubulointerstitial nephritis
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 chronic tubulointerstitial nephritis, 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.
Prognosis for Tubulointerstitial Nephritis
Acute tubulointerstitial nephritis
In drug-induced ATIN, renal function usually recovers within 6 to 8 weeks 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 Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more . Regardless of cause, irreversible injury is suggested by the following:
Diffuse rather than patchy interstitial infiltrate
Significant interstitial fibrosis
Delayed response to prednisone
Acute kidney injury lasting >3 weeks
Chronic tubulointerstitial nephritis
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 Overview of Cystic Kidney Disease Cystic kidney disease may be congenital or acquired. Congenital disorders may be inherited as autosomal dominant disorders or autosomal recessive disorders or have other causes (eg, sporadic... read more ), metabolic (eg, cystinosis), and toxic (eg, heavy metal) causes may not be modifiable, in which case CTIN usually evolves to end-stage renal disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more .
Treatment of Tubulointerstitial Nephritis
Treatment of cause (eg, stopping the causative drug)
Corticosteroids for immune-mediated and sometimes drug-induced acute tubulointerstitial nephritis
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 orally once/day with gradual tapering of the dose over 4 to 6 weeks) may accelerate recovery.
For drug-induced ATIN, corticosteroids are most effective when given within 2 weeks 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 chronic tubulointerstitial nephritis often requires supportive measures such as controlling blood pressure and treating anemia associated with kidney disease. In patients with CTIN and progressive renal injury, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) may slow disease progression but should not be used together because of an additive risk of hyperkalemia and accelerating disease progression.
Key Points
Causes of chronic tubulointerstitial nephritis (CTIN) are myriad and much more diverse than those for acute tubulointerstitial nephritis (ATIN), which is usually caused by an allergic reaction to a drug or by an infection.
Symptoms are often absent or nonspecific, particularly in CTIN.
Suspect the diagnosis based on risk factors and urinary sediment, exclude other causes using imaging, and sometimes confirm the diagnosis by biopsy.
Stop causative drugs, treat any other causes, and provide supportive treatment.
Treat biopsy-proven immune-mediated and sometimes drug-induced ATIN with corticosteroids (within 2 weeks of stopping any causative drugs).
