- Author: A Brent Alper, Jr, MD, MPH; Chief Editor: Vecihi Batuman, MD, FACP, FASN more...
The term tubulointerstitial is used to broadly refer to kidney diseases that involve structures in the kidney outside the glomerulus. These diseases generally involve tubules and/or the interstitium of the kidney and spare the glomeruli, as shown in the image below.
Although primary glomerular diseases are often associated with prominent tubulointerstitial changes (see the following image), the clinical presentation is dominated by the consequences of glomerular injury; hence, they are not considered in this article.
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Acute and chronic tubulointerstitial diseases are the result of the interplay of renal cells and inflammatory cells and their products. Lethal or sublethal injury to renal cells leads to expression of new local antigens, inflammatory cell infiltration, and activation of proinflammatory and chemoattractant cytokines. These cytokines are produced by inflammatory cells (ie, macrophages, lymphocytes) and also by the renal cells (ie, proximal tubule, vascular endothelial cells, interstitial cells, fibroblasts). The outcome can be acute or chronic nephritis.
In acute interstitial nephritis, the tubular damage leads to renal tubular dysfunction, with or without renal failure. Regardless of the severity of the damage to the tubular epithelium, the renal dysfunction is generally reversible, possibly reflecting the regenerative capacity of tubules with preserved basement membrane. Conversely, chronic tubulointerstitial nephritis is characterized by interstitial scarring, fibrosis, and tubule atrophy, resulting in progressive chronic renal insufficiency.[1, 2]
The principal mechanism in acute tubulointerstitial nephritis is hypersensitivity reaction to drugs such as penicillins, nonsteroidal anti-inflammatory drugs (NSAIDs), and sulfa drugs. Another mechanism is acute cellular injury caused by infection, viral or bacterial, often associated with obstruction or reflux. The kidney is remarkably resistant to structural damage in bacterial infections, and, in the absence of obstruction, damage from bacterial infection in the kidney parenchyma is extremely unlikely to occur.
Studies have revealed transforming growth factor–beta (TGF-β) as a major participant in fibrogenesis. TGF-β favors accumulation of collagen and noncollagen basement membrane components by direct stimulation of production and by inhibiting matrix degradation enzymes such as collagenases and metalloproteinases. Activation of nuclear transcription factors, such as nuclear factor kappa B (NFκB) in injured kidney cells, with consequent transcription and release of proinflammatory cytokines into the interstitium, appears to be a major mechanism of chronic tubulointerstitial inflammation accompanying proteinuric kidney diseases.
Tubulointerstitial diseases of the kidney encompass diverse etiologies and pathophysiologic processes, and the patient can present with acute or chronic conditions. Many forms of tubulointerstitial injury involve exposure to drugs or other nephrotoxic agents such as heavy metals and, rarely, infection. By far the most common form of tubulointerstitial inflammation is hypersensitivity reaction to medications, termed allergic interstitial nephritis.
The following are causes of acute tubulointerstitial nephritis:
Hypersensitivity reactions: Any drug can cause an acute allergic reaction involving the kidneys (eg, penicillins, sulfa drugs, nonsteroidal anti-inflammatory drugs [NSAIDs] most common) (See Clinical.)
Immunologic diseases (eg, associated with lupus, Goodpasture syndrome)
Acute transplant rejection
Infections, including bacterial (must be accompanied by obstruction or reflux), viral (eg, cytomegalovirus [CMV], hantavirus, human immunodeficiency virus [HIV], hepatitis B [HBV]), fungal (eg, histoplasmosis), and parasitic (eg, Leishmania, Toxoplasma)
The following are causes of chronic tubulointerstitial nephritis:
Drugs (eg, analgesics, lithium, cyclosporine, tacrolimus) 
Heavy metals (eg, lead, cadmium, mercury)
Obstructive uropathy, nephrolithiasis, reflux disease
Immunologic diseases (eg, lupus, Sjögren syndrome, primary glomerulopathies, sarcoidosis, vasculitis, antineutrophil cytoplasmic antibody [ANCA]–associated vasculitides, Wegener granulomatosis, and chronic transplant nephropathy)
Neoplasia (eg, myeloma, leukemia, amyloidosis)
Atherosclerotic kidney disease (ischemic) - Underlying atherosclerotic disease, dyslipidemia, and smoking are conditions commonly associated with cholesterol microembolism; catheter manipulations above the level of the renal arteries or anticoagulation in a patient with atherosclerosis can trigger cholesterol microembolic disease
Metabolic diseases (eg, hypercalcemia, cystinosis, potassium depletion, hyperoxaluria)
Genetics (eg, Alport syndrome, medullary cystic disease)
Miscellaneous (eg, Balkan endemic nephropathy, Chinese herb/aristolochic acid nephropathy) [5, 6]
Environmental and occupational exposure to lead can cause chronic tubulointerstitial nephritis. Occupations in welding, smelting, the battery industry, and mining have all been responsible for lead nephropathy cases. Environmental exposure from leaded gasoline is decreasing, because the use of leaded gasoline has ceased in the United States; however, sporadic exposure is still observed, particularly among children living in deteriorating housing in urban areas. Rarely, lead poisoning can be observed among individuals who consume moonshine whiskey and those who drink beverages from imported ceramics painted with leaded glaze.
A variety of causes contribute to obstructive uropathy, including prostate disease in elderly males; pelvic or colonic tumors involving both ureters in both sexes; nephrolithiasis, with or without urinary tract infection; and radiation to the pelvic area as well as some drugs, such as methysergide, can cause retroperitoneal fibrosis and obstruction.
A study by Maripuri et al found that of 24 patients with primary Sjögren syndrome who also had renal impairment, biopsies revealed that 17 individuals had tubulointerstitial nephritis as the primary lesion behind their kidney dysfunction, and 11 of the 17 patients had the chronic form of this nephritis. The investigators suggested these results support the notion that in patients with primary Sjögren syndrome, chronic tubulointerstitial nephritis is the most frequent cause of renal impairment found through kidney biopsy.
Balkan endemic nephropathy
Epidemiology and natural history clearly implicate environmental factors in the pathophysiology of Balkan endemic nephropathy. Lead contamination of food has been considered but ruled out as a cause of this disease. Some studies have implicated a fungal toxin, called "ochratoxin," which can grow in moist grains in storage and which has been shown to cause a similar kidney disease in pigs in several central European countries. However, most experts agree that the evidence for its role in this endemic nephropathy is weak. More recent studies have linked aristolochic acid, the underlying factor in chinese herb nephropathy (see below), as a causative agent.
Chinese herb/aristolochic acid nephropathy
In the early 1990s, aristolochic acid was recognized as a potent nephrotoxin that can cause rapidly progressive interstitial fibrosis and end-stage renal disease (ESRD) in young women using a Chinese herb as part of a slimming regimen in Belgium. Since then, many other cases of so-called Chinese herb (CH) nephropathy have been reported from around the world.
Chinese herb nephropathy may not be an appropriate name for the disease, however, because aristolochic acid can be present in herbal medicines from any country. The term aristolochic acid nephropathy (AAN) more accurately characterizes this form of toxic nephropathy.
Another interesting feature of term aristolochic acid nephropathy is its association with uroepithelial cancers reminiscent of Balkan nephropathy. Aristolochic acid not only can trigger severe renal fibrosis, but it also can cause oncogene mutations that can explain the high incidence of renal cancer with this type of interstitial nephritis. Patients have also been found to have abnormal function of TP53, a known tumor suppressor gene.
A recently recognized cause of interstitial kidney disease is immunoglobulin G (IgG)-4–related disease. This multiorgan disorder, characterized by high serum levels of IgG and IgG4, is associated with a tubulointerstitial nephritis with an abundant IgG4-positive plasma cell interstitial infiltration and has a good response to steroids.
Primary tubulointerstitial diseases (ie, diseases of the renal tubules and interstitium sparing the glomeruli) constitute 10-15% of all kidney diseases both in the United States and around the world. In certain regions, such as the Balkans (ie, Yugoslavia, Bosnia, Croatia, Romania, Bulgaria), where endemic nephropathy is common, interstitial diseases may be more prevalent.[5, 6]
Neither acute nor chronic tubulointerstitial diseases of the kidney demonstrate racial predilections. However, lead nephropathy may be more common in black people because of socioeconomic factors.
Analgesic nephropathy is 5-6 times more common in women. This is generally attributed to women taking more analgesics than men. However, a greater sensitivity to the toxic effects of analgesics or differences in analgesic metabolism in women cannot be ruled out.
All toxic nephropathies are related to the cumulative effects of toxic substances, particularly lead, and consequently are likely to be observed more frequently with advancing age. However, this is highly variable. For example, people with severe lead poisoning during childhood may present with chronic tubulointerstitial nephritis in early adult life. Atherosclerotic and/or ischemic kidney disease is increasingly more common in elderly individuals. Metabolic disorders, such as cystinosis, oxalosis, and hypercalcemia, can occur in younger individuals.
Tubulointerstitial disease may progress to end-stage renal disease (ESRD) and thus require dialysis or transplantation. Electrolyte and acid-base disorders may also be observed, and an increased incidence of uroepithelial cancers is found among patients with analgesic nephropathy, aristolochic acid nephropathy, and Balkan endemic nephropathy.[5, 6]
Hypertension may also complicate any renal disease, but not all cases of interstitial renal disease are associated with hypertension (ie, Balkan endemic nephropathy, acute allergic interstitial nephritides).
Most patients with allergic interstitial nephritis recover renal function upon cessation of the offending agent.
Patients with cholesterol microembolic kidney disease often have some spontaneous improvement in renal function after the embolic event. Complete resolution of renal insufficiency is rare, however.
Although the natural history of chronic tubulointerstitial nephritides varies depending on the etiology, most chronic tubulointerstitial renal disease eventually progresses to ESRD. However, the rate of progression is generally believed to be much slower in tubulointerstitial nephritis compared to glomerular diseases.
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