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; severe cases, delayed therapy, or continuance of an offending medication can lead to permanent injury and chronic kidney disease.

Renal-ocular syndrome, acute tubulointerstitial nephritis plus uveitis, also occurs and is idiopathic.

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, medications, 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

• Analgesic nephropathy

• Metabolic nephropathies

• Heavy metal nephropathy

• Reflux nephropathy

• Myeloma kidney

Reflux nephropathy and myeloma may cause tubulointerstitial injury but the predominant pathology in these conditions is glomerular disease.

Hereditary cystic kidney diseases are discussed elsewhere.

1. 1. 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

2. 2. Correa-Rotter R, Wesseling C, Johnson RJ: CKD of unknown origin in Central America: The case for Mesoamerican nephropathy. Am J Kidney Dis 63(3):506-520, 2014. doi: 10.1053/j.ajkd.2013.10.062

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 second 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 medication-induced ATIN, but the classically described triad of fever, rash, and eosinophilia is present in < 10% of patients with medication-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 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.

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 (caused by a defect in proximal tubular bicarbonate reabsorption or in distal tubular acid excretion). Elevated serum total immunoglobulin G (IgG) and/or IgG4 levels and low serum complement concentrations (ie, low C3 and C4) may be present in patients with IgG4-related disease or hypocomplementemic interstitial nephritis.

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 is usually reserved for patients with the following:

• An uncertain diagnosis

• Progressive renal injury

• No improvement after potential causative medications are stopped

• Findings suggesting early disease

• Medication-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. A lymphoplasmacytic infiltration of the kidney interstitium with storiform fibrosis suggests IgG4-related tubulointerstitial nephritis. Immunofluorescence or electron microscopy seldom reveals any pathognomonic changes.

Acute Tubulointerstitial Nephritis

Image

Image provided by Agnes Fogo, MD, and the American Journal of Kidney Diseases' Atlas of Renal Pathology (see www.ajkd.org).

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. However, if there is concern for alternative diagnoses, it could be pursued. 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 medication-induced ATIN, renal function usually recovers within 6 to 8 weeks when the causative medication 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 medications. 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:

• Diffuse rather than patchy interstitial infiltrate

• Significant interstitial fibrosis

• Delayed response to prednisone

• Acute kidney injury lasting >3 weeks

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, previous exposure to heavy metals) causes may not be modifiable, in which case CTIN usually evolves to end-stage kidney disease.