Acute tubulointerstitial nephritis (general features)
Typically, acute tubulointerstitial nephritis begins abruptly, manifesting as acute renal failure. In most instances, acute tubulointerstitial nephritis occurs within days of exposure to the offending drug. In some instances (particularly with NSAIDs), acute tubulointerstitial nephritis begins after several months of exposure. With the exceptions of acute tubulointerstitial nephritis induced by rifampin and NSAIDs, patients commonly present with rash, fever, eosinophilia, eosinophiluria, and elevated immunoglobulin E (IgE) levels. In mild cases, clinical presentation may consist of subtle tubular function abnormalities, such as Fanconi syndrome (ie, aminoaciduria, glycosuria, renal tubular acidosis). Patients may present with rash and hematuria.
Proteinuria is usually absent or modest. Urinalysis may show microscopic hematuria and/or sterile pyuria (with or without eosinophils). Although the clinical presentation is often sufficient to make the diagnosis, renal biopsy is required to make a definitive diagnosis (see Image 1). Patients with acute tubulointerstitial nephritis caused by NSAIDs typically present with heavy proteinuria, often in the nephrotic range (see below). Cessation of the offending agent (see list below) usually, but not always, results in complete recovery. However, the rate of recovery is variable, and, in some patients, renal failure persists for many weeks before renal function improves. Almost all acute tubulointerstitial nephritides are caused by hypersensitivity reactions to drugs and are not mediated by direct toxicity. Although any drug can potentially cause a hypersensitivity reaction involving the kidney, the following are the most frequently implicated:
- Antibiotics (eg, penicillins, cephalosporins, sulfa drugs, quinolones)
- NSAIDs
- Diuretics (eg, thiazides, furosemide)
- Allopurinol
- Phenytoin
- Rifampin
- Interferon alfa
Acute tubulointerstitial nephritis caused by NSAIDs
This condition is more common in elderly people, perhaps because of the higher incidence of arthritic disorders in this population. Acute allergic interstitial nephritis should not be confused with the acute vasomotor renal insufficiency that can occur in patients with preexisting underperfusion of the kidney. A unique feature of allergic interstitial nephritis caused by NSAIDs is that patients may present with nephrotic syndrome. In such patients, massive proteinuria with hypoalbuminemia and edema are present in addition to the typical features of acute interstitial nephritis. Findings on kidney biopsy show features of minimal change nephrosis in addition to the characteristic findings of interstitial nephritis (see Images 1-3).
Antibiotic-induced acute tubulointerstitial nephritis
This form of nephritis is usually observed in the hospital setting during treatment of serious infections, within several days to weeks of initiation of antibiotic therapy. Rash, eosinophilia, and eosinophiluria, as well as pyuria (sterile), hematuria, and modest proteinuria (usually <1 g/d), are common. Unlike in NSAID-induced allergic interstitial nephritis, nephrotic range proteinuria is very rare. If a renal biopsy is performed, eosinophils can be a component of the interstitial nephritis (see Image 5). Occasionally, ill-defined granulomas are present (see Image 6).
Among antibiotics, rifampin is unique in that the interstitial nephritis generally occurs when the antibiotic is reintroduced after an interval. Furthermore, the interstitial nephritis associated with it does not manifest with eosinophilia. In some cases, rifampin-associated interstitial nephritis has been reported to show casts containing immunoglobulin light chains in tubular lumens without any evidence of myeloma in the patient. Flulike symptoms, flank pain, hypertension, and oliguric acute renal failure are common. In some patients, circulating antirifampin antibodies and immunoglobulin G (IgG) deposits along the tubular basement membranes have been reported.
Acute tubulointerstitial nephritis caused by miscellaneous agents
Infections with viral agents, bacteria, and fungi are occasionally associated with acute interstitial nephritis. Hantavirus, CMV, and HIV are common among the infectious agents associated with acute interstitial nephritis. In HIV disease, acute interstitial nephritis is usually observed in conjunction with glomerular disease (ie, focal segmental glomerulosclerosis). Parenchymal invasion by the virus is not always present, and other characteristic features, such as eosinophilia and fever, are usually absent. Bacterial infection with renal parenchymal invasion is sometimes responsible for acute interstitial nephritis, but this is exceedingly rare in the absence of obstruction. Other infections such as tuberculosis and histoplasmosis are also among the rare causes of acute tubulointerstitial nephritis and may be diagnostic challenges.
Chronic tubulointerstitial nephritis (general features)
The chronic form is an insidious disease and most probably represents the common final response pattern of the kidney to a variety of insults and agents (see Background). Important causes include analgesics; lead; drugs, including cyclosporine, cisplatin, and lithium; and metabolic disorders, notably hypercalcemia, potassium depletion, and hyperoxaluria. Because of its insidious nature, chronic tubulointerstitial nephritis is often diagnosed incidentally on routine laboratory screening or evaluation of hypertension. Patients are usually asymptomatic. Hypertension is common but not universal, and it is conspicuously absent in Balkan endemic nephropathy.
Clinical investigations may show modest elevation in serum creatinine, evidence of tubular dysfunction (ie, renal tubular acidosis), or Fanconi syndrome (ie, aminoaciduria, glycosuria, hypophosphatemia, hypouricemia). Proteinuria is usually mild, often less than 1 g/d. In contrast to glomerular disease, a significant fraction of the protein is low molecular weight (eg, immunoglobulin light chains, beta2 microglobulin, lysozyme, peptide hormones). These proteins are normally taken up by the proximal tubules and broken down there. Thus, in diseases predominantly involving tubular structures, decreased endocytosis of filtered proteins leads to the characteristic tubular proteinuria.
Findings on kidney biopsy in chronic tubulointerstitial nephritis usually show varying degrees of interstitial fibrosis, tubular atrophy, arteriolar sclerosis, and, occasionally, mononuclear cell infiltration (see Image 7). Often, the findings are nonspecific and the etiology is not discernible from the biopsy; some diseases, such as sarcoidosis, show noncaseating granulomas, and, in viral diseases, immunostaining can yield clues to the cause. In patients with suspected lead exposure, an ethylenediaminetetraacetic acid (EDTA) lead mobilization test or determination of tibial bone lead by x-ray fluorescence can confirm lead etiology.
Analgesic nephropathy
Analgesic nephropathy is the most common category of chronic interstitial nephritis worldwide. This disorder occurs with long-term ingestion of combinations of phenacetin, aspirin, and caffeine or phenacetin-acetaminophen or NSAIDs and acetaminophen. In its most severe form, it is associated with papillary necrosis. The amount of phenacetin-acetaminophen combination required to cause chronic interstitial nephritis has been estimated to be at least 2-3 kg over many years. Although initially thought to be exclusively associated with phenacetin-containing combinations, all analgesics, including acetaminophen, aspirin, and NSAIDs, can cause analgesic-induced chronic tubulointerstitial nephritis.
Analgesic nephropathy is most common in women in the sixth and seventh decades of life who have a history of low back pain, migraine headaches, or other chronic musculoskeletal pain. In some patients, a history can be elicited of episodes of papillary necrosis, ie, gross hematuria with flank pain occasionally accompanied by obstruction and infection. Clinically, patients with analgesic nephropathy present with renal insufficiency, modest proteinuria, sterile pyuria, and anemia. Diagnosis can be supported by history of heavy analgesic use, and computer-assisted tomograms may reveal microcalcifications at the papillary tips.
Treatment is supportive and includes discontinuation of analgesic use. Long-term follow-up studies have shown progression to end-stage renal disease requiring dialysis, and increased incidence of uroepithelial cancers is also observed in patients with analgesic nephropathy.
Lithium nephropathy
Distal tubular dysfunction (ie, polyuria, concentrating defect, down-regulation of aquaporin-2) occurs in up to 50% of patients receiving lithium. Chronic interstitial nephritis occurs in a small subset of patients receiving long-term lithium therapy who have had repeated episodes of lithium toxicity with high serum levels.
Cyclosporine- and tacrolimus-induced nephropathy
These agents, although indispensable in the management of solid organ transplantation, can cause acute and chronic nephrotoxicity. The mechanism appears to be dependent largely on the potent vasoconstrictive effects of these drugs. Chronic tubulointerstitial nephritis induced by cyclosporine or tacrolimus is common among patients receiving kidney, heart, liver, and pancreas transplants. However, it is rare in bone marrow transplant recipients because they receive the drugs for a short time and generally at lower doses. In renal transplant recipients, cyclosporine- or tacrolimus-induced chronic interstitial nephritis is similar to chronic rejection.
Because the pathophysiology of both is poorly understood, these conditions tend to be included under the generic term of chronic transplant nephropathy. Most kidney transplant patients have a stable course with mild impairment of renal function. However, up to 10% of heart transplant recipients develop progressive renal insufficiency and eventually require dialysis.
Both cyclosporine and tacrolimus frequently cause hypertension and hyperkalemia. Hypomagnesemia caused by renal magnesium wasting is also common in cyclosporine-treated patients. Concomitant use of calcium channel blockers reduces nephrotoxicity. Long-term use of cyclosporine has been associated with patchy interstitial fibrosis, usually in a striped pattern and with tubular atrophy. Thrombotic microangiopathy might further contribute to both acute and chronic nephrotoxicity.
Lead nephropathy
Since antiquity, lead has been known to cause kidney disease and gout. In the modern industrialized world, lead is a ubiquitous environmental and occupational toxin and is an important cause of chronic tubulointerstitial nephritis and hypertension, mainly in urban poor communities and particularly among black people.
Children with severe lead poisoning can present with encephalopathy and acute renal failure with Fanconi syndrome. Because lead has a biologic half-life of several decades, if untreated by chelation, both intermittent acute poisoning and low-level environmental exposure result in chronic cumulative lead poisoning. The major consequence of chronic lead poisoning is chronic tubulointerstitial disease, usually in the third to fourth decades of life.
A common source of lead poisoning is leaded paint chipping in old urban tenements. Young children attracted to the sweet taste of the leaded paint may ingest or inhale dust particles containing lead and are at particular risk. In the industrial setting, welders, smelters, battery workers, painters, and restorers of old buildings, especially in poorly ventilated work environments, can be exposed to toxic amounts of lead.
Hypertension is almost always present, and, in the absence of appropriate testing or careful exposure history, lead nephropathy is often misdiagnosed as so-called hypertensive kidney disease. Patients with lead nephropathy tend to have disproportionately worse hyperuricemia compared to patients with other kidney diseases because of the unique effects of lead on urate metabolism, and, consequently, gout is common.
In retrospect, after careful investigation including the EDTA lead mobilization test, many patients presumed to have either gouty nephropathy or hypertensive nephrosclerosis are discovered to have lead nephropathy. Identification of the lead etiology in patients presumed to have gout nephropathy has cast doubt on the existence of this entity.
Obstructive uropathy
Obstruction of urinary outflow as observed in prostate disease, stone disease, neoplasm, and retroperitoneal fibrosis, among others, can cause chronic tubulointerstitial disease. Modest proteinuria and hyperkalemic renal tubular acidosis are common. Vesicoureteral reflux disease, usually congenital, characteristically results in focal glomerulosclerosis with nephrotic syndrome and a prominent tubulointerstitial component in adult life even if the reflux has been corrected early. Superimposed infection and pyelonephritis often complicate obstruction. Recurrent urinary tract infection itself can cause ammonium magnesium phosphate stones, further aggravating tubulointerstitial disease and perpetuating infection. Similarly, papillary necrosis and infection may complicate the course and may lead to acute pyelonephritis with fever, flank pain, hematuria, and, especially in elderly patients, urosepsis.
Atherosclerotic kidney disease
As life expectancy increases, atherosclerotic disease of the kidney is emerging as a major category of chronic tubulointerstitial nephropathy. Unfortunately, no unanimity on nomenclature exists among experts, and kidney disease in this category is variably termed ischemic nephropathy, renovascular disease, and nephrosclerosis.
In all likelihood, cases of so-called hypertensive kidney disease or hypertensive nephrosclerosis belong in the category of atherosclerotic kidney disease. Lack of appropriate diagnosis can explain the discrepancy in the incidence of kidney disease in hypertensive populations in Europe and the United States. In Europe, kidney disease is found in only about 1% of hypertensive populations, while in the United States 30% of all end-stage disease requiring dialysis is attributed to hypertensive kidney disease.
Atherosclerotic kidney disease is typically observed in elderly white males who smoke, but it is by no means confined to this population. Many individuals with dyslipidemia and other atherosclerotic phenomena, such as coronary artery disease, carotid artery disease, and peripheral arterial disease, are prone to involvement of renal arteries, regardless of age.
Often, these patients have hypertension, not necessarily severe, with elevated serum creatinine and urea nitrogen and proteinuria, 1-2 g/d. The course of progression of the kidney disease is usually slower than in patients with glomerular diseases such as diabetic nephropathy. Diagnosis can usually be made clinically, and radiologic investigations, such as duplex scanning of the renal arteries, digital subtraction angiography, or magnetic resonance imaging, reveal atherosclerotic stenosis of the renal arteries. Kidney biopsy is seldom necessary and, if performed, shows nonspecific changes of chronic tubulointerstitial nephritis, ie, tubular atrophy, fibrosis, and arterial or arteriolar sclerosis with paucity of cellular infiltration. Because these patients tend to have atherosclerotic complications, they are likely to experience multiple contrast procedures and hence are at risk for acute recurrent contrast nephropathy, which can accelerate progression to end-stage renal disease.
No specific therapy is available, but good control of hypertension, cessation of smoking, and vigorous control of dyslipidemia with diet and with hepatic 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are expected to result in improved outcomes.
Cholesterol microembolic disease and nephropathy
This is a unique syndrome that has been recognized in the setting of catheter procedures involving vasculature above the renal arteries, such as coronary angiography, although it can occur in patients on anticoagulation; it can even spontaneously. The pathophysiology is destabilization of atheroma plaques, either during catheter manipulation or spontaneously, resulting in showering of cholesterol crystals downstream and eventual lodging of needle-shaped cholesterol crystals in small arterioles within the kidney vessels (see Images 8-9).
Microemboli can also occur in the central nervous system and retinal arteries (called Hollenhorst plaques). In the extremities, distal vessel emboli may result in small superficial skin infarcts (scabs). More extensive cholesterol microembolization to the extremities can result in the characteristic livedo reticularis appearance in the lower extremities. Oddly, some patients have other systemic signs and symptoms, such as low-grade fever, leukocytosis, eosinophilia, elevated sedimentation rate, and hypocomplementemia.
Cholesterol microembolism usually causes acute renal failure of varying degrees, with some spontaneous improvement in renal function but often with permanent residual renal damage. Kidney biopsy during the acute phase shows the characteristic needle-shaped clefts caused by the cholesterol crystals within the small- and medium-sized arterioles (see Images 8-9) accompanied by patchy tubulointerstitial nephritis with mild mononuclear cellular infiltration. No effective treatment for this disorder is available.
Metabolic disorders and nephropathy
Hypercalcemia, chronic potassium depletion, and cystinosis can lead to chronic tubulointerstitial nephritis. Hypercalcemia is the most common cause. Chronic hypercalcemia can occur in primary hyperparathyroidism, sarcoidosis, multiple myeloma, and other neoplasms (particularly with bone metastases) and in vitamin D intoxication. Even transient hypercalcemia can lead to chronic renal insufficiency; renal involvement is mostly confined to the distal tubular structures. Clinically, polyuria and concentrating defect are common. During acute hypercalcemia, urinary concentrating defect can lead to dehydration and may aggravate acute renal failure. Radiologic examinations may reveal nephrocalcinosis, and renal stone formation can be a complicating factor in hypercalcemia.
Balkan endemic nephropathy
This is an endemic kidney disease confined to well-defined discrete settlements located along the Danube River and its tributaries. The caseload of patients is particularly heavy in the Balkans (ie, Bosnia, Croatia, Yugoslavia, Romania, Bulgaria). The disease occurs in individuals, autochthonous or immigrant, who have resided in the endemic regions for at least 15-20 years and does not occur among residents who move to nonendemic areas. Thus, the evidence implicates environmental factor(s), but no definitive agent or factor has been identified yet. Typically, patients are nonhypertensive and have disproportionately profound anemia.
Patients are identified easily in the endemic regions by checking for tubular proteinuria. Beta2 microglobulinuria has proved particularly useful in identifying cases and has been proposed and used as a marker of the disease. Because a major criterion to identify the disease is residency in the endemic region, whether similar kidney diseases occur in other parts of the world is not known. Most patients eventually develop end-stage renal disease and require dialysis. Up to 40% of patients develop upper urinary tract uroepithelial tumors.
Chinese herb nephropathy
Chronic progressive tubulointerstitial nephritis has been observed in many countries among patients using Chinese herbal medicines for weight reduction. Most of these cases have been attributed to herbs containing aristolochic acid. The pathophysiology of nephrotoxicity is not well understood. Renal biopsies have shown severe interstitial fibrosis.
Physical: A thorough physical examination may provide clues to the diagnosis (eg, fever, rash in acute tubulointerstitial nephritis, livido reticularis and Hollenhorst plaques in the optic fundi in atheroembolic disease), but, in most patients, no characteristic findings exist. Some patients present with hypertension, although others may be normotensive or hypotensive (eg, Balkan endemic nephropathy).
- Acute allergic tubulointerstitial nephritis: Physical examination in acute tubulointerstitial nephritis may show a rash accompanying renal findings. However, rash is highly variable. Although the presence of rash can be supportive evidence of an allergic etiology of an acute renal insufficiency, its absence is not useful in ruling out acute allergic interstitial nephritis.
- Cholesterol microembolic disease: In cholesterol microembolic disease, eyeground examination may reveal the characteristic cholesterol crystals, also termed Hollenhorst plaques, in retinal vessels, which can support the diagnosis. Similarly, the presence of small skin infarcts or scabs, especially on or between the toes or fingers, is a helpful clue to cholesterol microembolism. Sometimes, particularly after displacement of a large aortic plaque, marked ischemia of the lower extremities yields a bluish-purplish discoloration (ie, livedo reticularis) of the feet or lower portions of legs.
- Atherosclerotic (ischemic) kidney disease: Evidence for other atherosclerotic disease, such as carotid or inguinal bruits, may be clues to so-called atherosclerotic kidney disease, particularly in elderly white males who smoke.
Causes:
- Acute allergic interstitial nephritis: Any drug can cause an acute allergic reaction involving the kidneys. Drugs most commonly associated with acute allergic nephritides are listed in History.
- Cholesterol microembolic disease: Underlying atherosclerotic disease, dyslipidemia, and smoking are conditions commonly associated with this disorder. Catheter manipulations above the level of the renal arteries or anticoagulation in a patient with atherosclerosis can trigger cholesterol microembolic disease.
- Balkan endemic nephropathy: Epidemiology and natural history clearly implicate environmental factors in the pathophysiology of this disease. Lead contamination of food has been considered but ruled out as a cause. 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.
- 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. Environmental exposure from leaded gasoline is decreasing because the use of leaded gasoline has ceased in the United States. 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.
- Obstructive uropathy: A variety of causes contributes to obstructive uropathy. Prostate disease in elderly males and pelvic or colonic tumors involving both ureters in both sexes can cause obstructive uropathy. Nephrolithiasis, with or without urinary tract infection, may also cause obstructive uropathy. Radiation to the pelvic area and some drugs, such as methysergide, can cause retroperitoneal fibrosis and obstruction.
- Aristolochic acid nephropathy
- Aristolochic was recognized as a potent nephrotoxin that can cause rapidly progressive interstitial fibrosis and end-stage renal disease in young women using a Chinese herb as part of a slimming regimen in Belgium in early 1990s.
- Since then many other cases have been reported from around the world referred to as Chinese herb (CH) nephropathy. This may not be an appropriate name for the disease, 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 AAN is the association with uroepithelial cancers reminiscent of Balkan nephropathy. Aristolochic acid has now been demonstrated not only trigger severe renal fibrosis, but it can also cause oncogene mutations that can explain the high incidence of renal cancer with this type of interstitial nephritis.
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