Tubulointerstitial Nephritis

Tubulointerstitial nephritis involves the immune-mediated infiltration of the kidney interstitium by inflammatory cells. ^[2] Lethal or sublethal injury to kidney 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 kidney 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 acute kidney injury. Regardless of the severity of the damage to the tubular epithelium, the kidney 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 kidney insufficiency. ^{[3, 4]}

The principal mechanism in acute tubulointerstitial nephritis is a 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.

Serum components — in particular, matrix metalloproteinases MMP1 and MMP7 — can directly injure the downstream tubular portions of the kidney. This can lead to secretion of inflammatory cytokines and extracellular remodeling, which may promote kidney fibrosis. ^[5]

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, ^[6] 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 ^[7] :

• Hypersensitivity reactions: Any pharmacologic agent can cause an acute allergic reaction involving the kidneys (eg, penicillins, sulfa drugs, antineoplastic agents, ^{[8, 9]} nonsteroidal anti-inflammatory drugs [NSAIDs], vaccines ^{[10, 11]} ) (See Presentation.)

• 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]), COVID-19, ^[11] fungal (eg, histoplasmosis), and parasitic (eg, Leishmania, Toxoplasma)

The following are causes of chronic tubulointerstitial nephritis:

• Drugs (eg, analgesics, lithium, cyclosporine, tacrolimus) ^[12]

• 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, ^[13] granulomatosis with polyangiitis, chronic transplant nephropathy)

• Neoplasia (eg, myeloma, leukemia)

• 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, medullary amyloidosis ^[14] )

• Miscellaneous (eg, Balkan endemic nephropathy, Chinese herb/aristolochic acid nephropathy) ^{[15, 16]}

Lead nephropathy

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. The removal of lead from gasoline in the United States has reduced environmental exposure, but sporadic cases from exposure to lead-based paint is still observed, particularly among children living in deteriorating older housing in urban areas. Rarely, lead poisoning can be observed in individuals who consume moonshine whiskey and those who drink beverages from imported ceramics painted with leaded glaze.

Obstructive uropathy

A variety of causes contribute to obstructive uropathy, including the following:

• Prostate disease in elderly men
• Pelvic or colonic tumors involving both ureters, in both sexes
• Nephrolithiasis, with or without urinary tract infection
• Radiation to the pelvic area
• Drugs, such as methysergide, that can cause retroperitoneal fibrosis

Sjögren syndrome

In a study by Maripuri et al, kidney biopsies in 24 patients with primary Sjögren syndrome who also had kidney dysfunction revealed that 17 individuals had tubulointerstitial nephritis as the primary lesion, ^[17] and 11 of those 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. 

Similarly, a prospective study by Jain et al of renal involvement in 70 patients with primary Sjögren syndrome reported that tubulointerstitial nephritis was the most common disorder found on kidney biopsy. Tubulointerstitial nephritis was identified in nine of 17 biopsies in this study. ^[18]

Balkan endemic nephropathy

Balkan endemic nephropathy is a form of chronic tubulointerstitial nephritis characterized by insidious onset, gradual progression to end-stage renal disease, and frequent association with urothelial carcinoma of the upper urinary tract (UTUC). The disease was reported in the Balkan peninsula of southeastern Europe, in rural areas around tributaries of the Danube River. It was eventually traced to consumption of home-baked bread made with flour contaminated with aristolochic acid from Aristolochia clematitis, a common weed in wheat fields in the region. ^[16]

Chinese herb/aristolochic acid nephropathy

In the early 1990s, aristolochic acid was recognized as a potent nephrotoxin that was causing 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, and is the environmental phytotoxin that causes Balkan endemic nephropathy (see above). The term aristolochic acid nephropathy (AAN) more accurately characterizes this form of toxic nephropathy. ^[15]

As with Balkan endemic nephropathy, AAN from other causes is also associated with UTUC. This appears to occur because aristolochic acid can trigger oncogene mutations, including alterations in the tumor-suppressor gene TP53. ^[19]

IgG-4–related nephropathy

Immunoglobulin G (IgG)-4–related disease can affect almost any anatomic site, and often affects multiple sites, but approximately 20% of cases involve the kidney only. ^{[20, 21, 22, 23]} IgG4-related disease is characterized by high serum levels of IgG and IgG4, and in the kidney, tubulointerstitial nephritis with an abundant IgG4-positive plasma cell interstitial infiltration. ^[24]  

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. ^[16]

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 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. ^{[15, 16]}

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 than in glomerular diseases.