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Acute Interstitial Nephritis
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Acute Interstitial Nephritis Ursula C. Brewster | Asghar Rastegar
In 1898, W.T. Councilman defined acute interstitial nephritis (AIN) as “an acute inflammation of the kidney characterized by cellular and fluid exudation in the interstitial tissue, accompanied by, but not dependent on, degeneration of the epithelium; the exudation is not purulent in character, and the lesions may be both diffuse and focal.” This was seen on postmortem examination of patients with scarlet fever and, less commonly, other systemic infectious diseases that had no evidence for direct bacterial invasion of the kidney parenchyma. More than a century later, definitive diagnosis of AIN requires the pathologic findings of interstitial edema and infiltration with acute inflammatory cells including polymorphonucleocytes (PMNs), eosinophils, and lymphocytes. In the years since Councilman’s description, the causes of AIN have changed dramatically with pharmacologic agents the most common etiology (more than 75%). In this chapter we will focus primarily on acute tubulointerstitial inflammation, while briefly covering direct parenchymal invasion by infectious agents. The incidence of AIN varies greatly depending on the clinical scenario. An incidence of 0.7% is seen in asymptomatic patients with proteinuria or hematuria, whereas hospitalized patients with acute kidney injury (AKI) of unknown etiology experience an incidence of 10% to 15%. Although AIN can occur in all age groups, it is more common in the elderly. In one report, biopsy-proven AIN was seen in 3.0% of the elderly compared to 1.9% of younger subjects. This may reflect greater exposure of elderly patients to drugs and other inciting factors.
CLINICAL PRESENTATION The presenting symptoms of AIN include an acute or subacute decline in kidney function, often in patients exposed to multiple drugs. Although the “classical” presentation of skin rash, arthralgia, and eosinophilia is occasionally seen, this triad occurs in only 5% to 10% of unselected patients. This presentation is more commonly seen in association with certain drugs, such as penicillin derivatives, in comparison to nonsteroidal antiinflammatory drugs (NSAIDs). Fever, the most common clinical sign, is present in up to 50% of patients with drug-induced AIN but only in 30% of unselected patients. Skin rash is reported in one third of patients and is usually maculopapular. No clinical symptom or sign is sensitive or specific enough to establish a definitive diagnosis. Nonoliguric AKI usually accompanies AIN, but oliguric AKI with rapid rise in creatinine also occurs. Increasingly, AIN develops in patients with underlying chronic kidney disease (CKD) and multiple comorbidities,
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which makes a diagnosis challenging. AIN should therefore be considered in any patient with acute or subacute decline in kidney function with no clear inciting factor.
LABORATORY FINDINGS Common laboratory findings in AIN are summarized in Table 35.1. The most common abnormality is a slow and steady rise in blood urea nitrogen and serum creatinine concentration. Rapid and fulminant presentation of AIN occurs less often. Other major laboratory findings include eosinophilia, eosinophiluria, and abnormal urinary sediment. Eosinophilia is common in β-lactam antibiotic associated AIN, reported in up to 80% of cases, where only a third of other drug-induced AIN cases develop eosinophilia. Hyperkalemia, with or without hyperchloremic metabolic acidosis, is occasionally seen. Urinalysis and examination of the urine sediment are often the most useful laboratory tests. Low-grade proteinuria (1-2+) and positive leukocyte esterase are noted on urine dipstick in most patients. Quantitative proteinuria measurements are usually less than 1 g/day. Macroscopic hematuria is rare, whereas microscopic hematuria is present less than 50% of the time. Leukocytes are present on urine microscopy in virtually all cases of methicillin-induced AIN, but they may be absent in as many as 50% of patients with AIN due to other drugs. The absence of leukocyturia, therefore, should not eliminate this diagnosis from the differential. Classically, urine microscopy will show hematuria, leukocyturia, leukocyte casts, and renal tubular epithelial (RTE) cells (Fig. 35.1). Cellular casts are seen in most cases of methicillin-associated AIN and in up to 50% of patients with AIN resulting from other etiologies. Eosinophiluria, once thought to be hallmark of this disease, is both insensitive and nonspecific and should not be used to make a diagnosis. This test has a sensitivity of 67% and a specificity of 83% in patients with AKI. The techniques used to stain urine for eosinophils (Wright stain and Hansel stain) have proven unreliable and cumbersome. In addition, other disease states such as cystitis, pyelonephritis, atheroembolic kidney disease, and rapidly progressive glomerulonephritis may present with eosinophiluria, making the test nonspecific in diagnosing AIN.
IMAGING Kidney ultrasound in the setting of AIN typically shows normal to enlarged kidneys with normal echogenicity. However,
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Table 35.1 Laboratory Findings in Acute Interstitial Nephritis Eosinophilia Eosinophiluria Urinary sediment Protein excretion Fractional excretion of sodium (FeNa) Proximal tubular defect Distal tubular defect Medullary defect
Inconsistent finding seen more commonly in drug-induced AIN Sensitivity 63% to 91%, specificity 52% to 94% Hematuria, leukocyteuria, leukocyte casts, RTE cells, and RTE casts Less than 1 g/24 h Greater than 1% Glycosuria, phosphaturia, bicarbonaturia, aminoaciduria Hyperkalemia, distal RTA, sodium wasting Nephrogenic diabetes insipidus
AIN, Acute interstitial nephritis; RTA, renal tubular acidosis; RTE, renal tubular epithelial.
Figure 35.1 Urine microscopy showing a white blood cell cast (arrow) and surrounding white blood cells and red blood cells (×60).
these findings are also nonspecific and may be seen with other forms of kidney disease. Although Gallium-67 scan was initially reported as highly sensitive in AIN, this has not been supported over time, and its only role may be to differentiate AIN from acute tubular necrosis (ATN) in those patients who cannot undergo a kidney biopsy. Positron emission tomography has shown diagnostic promise in several AIN cases, but needs further evaluation before widespread use.
PATHOLOGY Although suspicion of AIN is based on clinical clues, definitive diagnosis often requires a kidney biopsy. Major pathologic findings include interstitial edema, inflammation, and tubulitis without glomerular or vascular involvement (Fig. 35.2). Interstitial infiltration may be diffuse but is often patchy in nature and consists of lymphocytes, mononuclear cells, eosinophils, neutrophils, and plasma
Figure 35.2 Kidney biopsy showing acute interstitial nephritis. A diffuse interstitial infiltrate is present (arrows) along with severe tubular injury and tubulitis (arrowhead) where lymphocytes have crossed the tubular basement membrane. Also present are eosinophils (curved arrows). (Hematoxylin and eosin ×200.)
cells. T lymphocytes are primarily composed of CD4 and CD8 cells. The number of eosinophils is highly variable and is more prominent in drug-induced AIN. Granulomas are uncommon but occasionally seen, especially with sarcoidosis and drug-induced AIN. Tubulitis, characterized by the invasion of inflammatory cells though the tubular basement membrane, results in tubular injury and is often seen in association with severe inflammation. Severity of interstitial inflammation, however, does not always correlate with clinical outcome. Poor prognosis is more directly related to the degree of interstitial fibrosis and tubular atrophy. Immunofluorescence and electron microscopic studies are usually unrevealing. NSAID-associated AIN is sometimes associated with glomerular changes of minimal change disease or membranous nephropathy. In contrast to isolated AIN, full-blown nephrotic syndrome accompanies AKI in these cases.
PATHOGENESIS The clinical and histopathologic findings summarized earlier strongly point to an immune-mediated mechanism initiating and sustaining tubulointerstitial damage. The immunologic basis of injury is supported by the low frequency of AIN in persons exposed to a drug, lack of dose dependency, presence of systemic symptoms in some patients, and recurrence of AIN upon reexposure. The antigens initiating the immune-mediated injury could be of endogenous origin (Tamm-Horsfall protein, megalin, and tubular base membrane components) or exogenous, such as drugs and chemicals. Exogenous antigens may be trapped directly or may circulate as immune complexes that are deposited in the kidney interstitium. They may bind to a tubular antigen acting as a hapten, or mimic a normal tubular or interstitial antigen, thereby triggering an immune reaction. In animal models, both cell-mediated and humoral immunity is involved. The injury is initiated by the presentation of endogenous or exogenous antigens to antigen-presenting
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lymphocytes resulting in the activation of T cells. These cells induce differentiation and proliferation of other T cells responsible for delayed hypersensitivity and cytotoxicity. The resultant inflammatory infiltrates within the interstitium produce a variety of fibrinogenic cytokines and chemokines, such as transforming growth factor-β (TGF-β), platelet-derived growth factor-BB (PDGF-BB), epidermal growth factor (EGF), and fibroblast growth factor-2 (FGF2). The fibroblasts invading the interstitium are the product of epithelial-to-mesenchymal transition. Ultimately, this inflammatory process results in the accumulation of extracellular matrix, interstitial fibrosis, and tubular loss.
CAUSES OF ACUTE INTERSTITIAL NEPHRITIS There are multiple causes of AIN, but pharmacologic agents are the most common (Table 35.2). Diagnosis of AIN should trigger a review of the medication list to identify culpable agents and limit further drug exposure. In addition to various drugs, certain infectious agents may induce AIN. Although less common in the antibiotic era, infectious agents must be considered when the clinical scenario is consistent. Finally, systemic diseases, primarily rheumatologic, are associated with the pathologic finding of AIN. These diseases are usually evident from the clinical presentation (Table 35.3).
Table 35.2 Common Drugs Associated With Acute Interstitial Nephritis Drug Class
Examples
Antibiotics
β-lactams, sulfonamides, fluoroquinolones, rifampin, vancomycin, erythromycin, ethambutol, chloramphenicol Acyclovir, atazanavir, abacavir, indinavir NSAIDs, selective COX-2 inhibitors PPIs, H2-receptor blockers, 5-aminosalicylates Phenytoin, carbamazepine, phenobarbital Hydrochlorothiazide, furosemide, triamterene, chlorthalidone Allopurinol, Chinese herbs
Antivirals Analgesics GI medications Anticonvulsants Diuretics Others
COX-2, Cyclooxygenase-2; GI, gastrointestinal; NSAIDs, nonsteroidal antiinflammatory drugs; PPIs, proton pump inhibitors.
Table 35.3 Common Diseases Associated With Acute Interstitial Nephritis Bacterial infection Viral infection Autoimmune
DRUG-ASSOCIATED INTERSTITIAL NEPHRITIS
Neoplastic diseases
Legionella, Staphylococcus, Streptococcus, Yersinia Hantavirus, CMV, EBV, HIV, herpes simplex, Hep C Systemic lupus erythematosis, Sjögren syndrome, sarcoidosis Lymphoproliferative disorders, plasma cell dyscrasias
ANTIBIOTICS β-LACTAM ANTIBIOTICS Methicillin and other β-lactam antibiotics are the most common agents associated with AIN. Methicillin is immunogenic and leads to a hypersensitivity syndrome more often than other drugs, including those in the β-lactam class. The time course is variable, but AIN usually develops approximately 10 to 14 days following drug exposure, unless the patient was previously sensitized. Patients with β-lactam–induced AIN frequently manifest systemic symptoms of fever, rash, arthralgias, and eosinophilia along with AKI. These symptoms may be fleeting or nonexistent, making them unreliable clinical tools for diagnosing AIN. Urinalysis and urine microscopy demonstrate low-grade proteinuria, hematuria, and leukocyturia in approximately 75% of cases (see Fig. 35.1). Because of its association with AIN, methicillin is rarely used thanks to the availability of other β-lactam agents. Cephalosporins may cause a similar clinical presentation of AIN; however, this is less common than with traditional penicillins. On withdrawal of the drug, kidney function usually recovers, although CKD may persist in some. NON β-LACTAM ANTIBIOTICS Rifampin-induced AIN can be severe and appears to occur more frequently with intermittent dosing as compared to continuous dosing regimens. AIN develops in a dosedependent fashion in most but not all patients, and, at
CMV, Cytomegalovirus; EBV, Epstein-Barr virus; Hep C, hepatitis C virus; HIV, human immunodeficiency virus.
times, circulating antibodies to rifampin may be detected. Systemic manifestations include fever, chills, abdominal pain, and myalgia. Laboratory abnormalities include liver function test disturbances, hemolytic anemia, and thrombocytopenia. Renal histopathology demonstrates interstitial inflammation with invasion of mononuclear cells and occasional eosinophils. Tubular epithelial cell injury and tubular necrosis related to vasomotor injury may also occur. Patients with a history of a severe reaction should not be reexposed to the agent because of the potential risk of hemodynamic collapse. Sulfonamides are widely used antibiotics associated with kidney injury. When these drugs were introduced in the first half of the twentieth century, the most common kidney injury was tubular obstruction from crystalline deposition of insoluble drug and/or metabolite. Currently AIN is the most common cause of kidney injury reported with these agents. Patients exposed to these drugs often present with an acute hypersensitivity syndrome characterized by fever, rash, and eosinophilia. Patients with human immunodeficiency virus (HIV) infection, kidney transplant recipients, or those with underlying CKD appear to be more susceptible to an allergic reaction, but the increased use of agents such as trimethoprim-sulfamethoxazole in these
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populations may account for this observation. Patients who are slow acetylators of sulfonamides may be at higher risk because of drug accumulation, even with routine dosing schedules. Fluoroquinolones, particularly ciprofloxacin, may cause kidney injury by several mechanisms; however, AIN is the most common kidney complication. It often pre sents with a slowly progressive decline in kidney function despite the absence of a hypersensitivity syndrome. Other agents in this class have been associated with AIN, but ciprofloxacin, based on its widespread use, is most commonly described. Azithromycin, erythromycin, ethambutol, gentamicin, nitrofurantoin, tetracycline, vancomycin, and multiple antiviral agents have all been associated with AIN. No drug is beyond suspicion, and every agent must be considered in the evaluation.
NONSTEROIDAL ANTIINFLAMMATORY AGENTS Nonsteroidal antiinflammatory agents are widely used by patients including those with chronic illness and chronic pain. Both NSAIDs and the selective cyclooxygenase-2 (COX-2) inhibitors are associated with AIN. Given the high frequency of NSAID use, AIN remains a relatively rare event, supporting an idiosyncratic drug reaction. NSAIDs cause several renal syndromes (see Chapter 37), marked by hemodynamic AKI, electrolyte/acid-base disturbances, and nephrotic syndrome. AIN associated with NSAIDs presents more insidiously than that seen with antibiotics. It often occurs months after starting therapy, with an average onset time of 6 to 18 months. Classically, patients do not develop a hypersensitivity syndrome, and fever, eosinophilia, and rash are rare. An interstitial infiltrate, which is less intense and has fewer eosinophils than seen with other culprit agents, and tubulitis are noted on renal histopathology. Despite multiple classes of NSAIDs with a variety of chemical structures, the pattern of kidney injury is remarkably similar across all agents, arguing against a single epitope-induced immune response. By their mechanism of action, which is inhibition of the conversion of arachidonic acid into its derivatives, NSAIDs may blunt the formation of inflammatory intermediates and the degree of kidney injury. Interestingly, this effect may modulate immune function and alter the clinical presentation, making the diagnosis of AIN more difficult.
GASTROINTESTINAL AGENTS Proton pump inhibitors (PPIs) have emerged as perhaps the most frequent cause of AIN worldwide. In many countries, these agents are available over the counter, further increasing their use. Since omeprazole became available in the early 1990s, the number of prescriptions for PPIs continues to increase. The mean time to AIN diagnosis from drug initiation is approximately 11 weeks, although it can occur after months of therapy. Only 10% of patients with PPI-induced AIN will present with the classic hypersensitivity syndrome of fever, rash, and eosinophilia, and therefore symptoms are either absent or very mild and nonspecific. Early recognition and treatment of AIN is associated with a relatively good prognosis and rare need
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for renal replacement therapy, although CKD does occur in some patients. 5-Aminosalicylates are the mainstay of therapy for patients with inflammatory bowel disease. Most patients require long-term treatment and many years of drug exposure. Kidney impairment is rare with these drugs, occurring in 1 in 200 to 500 patients on therapy. A hypersensitivity reaction can occur and cause AIN. In the absence of early recognition, CKD from chronic interstitial fibrosis may develop. This reaction usually occurs within the first year of therapy, but it can develop at any time in a nondose-dependent fashion.
DIURETICS Diuretic-induced AKI is almost always related to kidney hypoperfusion from decreased intravascular volume. There are, however, multiple case reports of diuretic-induced AIN from furosemide, hydrochlorothiazide, chlorthalidone, and triamterene. AIN is relatively rare despite widespread use of these drugs. In published reports, most patients experience systemic symptoms including fever, rash, and eosinophilia, suggesting a hypersensitivity syndrome. Drug discontinuation generally leads to renal recovery.
INFECTIONS INVASIVE INFECTIONS In the preantibiotic era, streptococcal and diphtheria infections caused inflammatory reactions in the kidney in the absence of direct tissue invasion. However, infection-related AIN diminished in frequency after antibiotics became readily available. Now, when AKI develops in the setting of an infection treated with antibiotics, the drug is assumed to be the culprit. If AKI persists despite antibiotic withdrawal, an acute postinfectious glomerulonephritis or AIN should be considered. Tubulointerstitial injury can occur either from direct invasion by an organism as in pyelonephritis or indirectly by an immune-mediated mechanism. Unlike AIN, pyelonephritis is usually confined to one pyramid in the kidney. In the setting of urinary obstruction, it becomes more diffuse, resulting in AKI. Although clinical history and symptoms usually differentiate the two conditions readily, CT imaging showing a wedge-shaped area of inflammation supports a diagnosis of pyelonephritis rather than AIN. A number of infectious agents have been linked with invasive AIN. These include Epstein-Barr virus (EBV), legionella, mycoplasma, cytomegalovirus, adenovirus, and the ricketsial Rocky Mountain spotted fever. Leptospirosis is a classic example of invasive AIN. The spirochete enters the bloodstream through the skin or mucosa, and it transiently invades glomerular capillaries before migrating into the tubulointerstitum. Once in this compartment, the organism induces inflammation and direct tubular injury that, over time, manifests as large, edematous kidneys. In addition, ischemic ATN may coexist with AIN in patients who develop septic shock from overwhelming leptospiral infection. Eradication of infection is associated with recovery of kidney function.
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Hantavirus is an RNA virus associated with interstitial edema with infiltration of polymorphonuclear leukocytes, eosinophils, and monocytes. Interstitial hemorrhage accompanies renal inflammation and is associated with gross or microscopic hematuria. Candidemia has been associated with an interstitial inflammatory reaction initially limited to the renal cortex. With time, large fungus balls can form, obstruct the collecting system, and cause AKI as a result of obstructive uropathy.
NONINVASIVE INFECTIONS Even without direct invasion of the kidney, infectious agents have been associated with AIN. Historically, streptococcal infections were commonly associated with AIN. The clinical syndrome associated with AIN develops early in the course of infection (9 to 12 days). Given the rapidity with which streptococcal infections are treated currently, infectionrelated AIN has disappeared as a clinical entity.
SYSTEMIC DISEASES The classic lesions of acute tubulointerstitial inflammation may also complicate a variety of systemic diseases. Whereas rheumatologic diseases primarily cause immune-mediated glomerular disease, they can also induce AIN. Metabolic diseases and malignancy are also associated with interstitial inflammation and AKI.
TUBULOINTERSTITIAL NEPHRITIS WITH UVEITIS Tubulointerstitial nephritis with uveitis (TINU) is a rare condition of unclear etiology that presents most frequently in adolescent girls, but may appear in adulthood. Weight loss, fever, anemia, and hyperglobulinemia occur before ocular and kidney manifestations. Fanconi syndrome with glucosuria, proteinuria, and aminoaciduria is the initial kidney manifestation, followed by a tubulointerstitial infiltrate, sometimes with granulomas. Certain infections such as toxoplasmosis, Epstein-Barr infection, and giardiasis have been associated with TINU. However, there is no clearly elucidated immune or genetic cause. Steroids are the mainstay of therapy for both the ocular and kidney manifestations of the disease. Fortunately, the prognosis is good in treated patients.
IMMUNOLOGIC DISEASES The vast majority of rheumatologic diseases complicated by AKI have underlying glomerular disease from anti- glomerular basement membrane (GBM) antibody disease (i.e., Goodpasture disease), immune deposition diseases (lupus or IgA nephropathy among others), or antineutrophil cytoplasmic antibody (ANCA)-related pauci-immune vasculitides. However, there are some rheumatologic ailments, such as Sjögren or sarcoid, which may present with tubulointerstitial inflammation in the absence of glomerular involvement. In the right clinical scenario, these causes of AIN should remain high on the differential diagnosis of kidney injury. Immune-related injury in a transplanted kidney (cellular rejection) manifests primarily as tubulointerstitial
inflammation with or without vascular involvement. The workup and classification of this interstitial disease can be found in Chapter 62.
MALIGNANCY Patients with underlying cancer are at high risk for AKI because of the malignancy itself or therapies used in its management. Primary lymphoma of the kidney is a rare cause of AKI, whereas non-Hodgkin’s lymphoma and acute lymphoblastic leukemias commonly invade the kidney parenchyma. Although it is seen on rare occasions in Hodgkin’s lymphoma, infiltrates are usually bilateral and diffuse, and kidneys may appear enlarged on imaging. Multiple myeloma and the plasma cell dyscrasias cause kidney injury when filtered light chains coalesce and obstruct tubular lumens. These obstructive “casts” are accompanied by varying degrees of tubular injury, necrosis, and an interstitial inflammatory reaction on kidney biopsy that resembles classic interstitial nephritis.
TREATMENT Treatment of AIN depends on the underlying disease that is driving the inflammatory reaction. When the pathologic process is associated with an underlying disease such as a malignancy, therapy is directed at the identified cause. In rheumatologic disease, treatment of the inflammatory condition often improves kidney function as well. In the setting of infection-related interstitial nephritis, eradication of the infection is often associated with kidney recovery. Treatment of drug-induced AIN is more complicated and controversial. The most important intervention is early recognition of disease and drug discontinuation. This can be a complicated endeavor in patients taking multiple essential medications, making it challenging to identify the culprit drug. Careful scrutiny of the medication record for exposure dates and history of previous drug treatment may point to the offending agent. When a drug is suspected, it should be immediately discontinued and replaced, if necessary, with an agent from a different class. A drug-free trial should be undertaken to determine if kidney function recovers without further intervention. If no improvement is noted after a period of observation (3 to 5 days), or if kidney function is declining rapidly, a trial of corticosteroids is reasonable. Prognosis appears to depend on the timing of diagnosis and drug withdrawal. In general, earlier is better with data supporting a 1- to 2-week time frame. Despite this, a substantial proportion of patients (up to 35%) may develop CKD. The data published on use of corticosteroids for AIN are incomplete. Assuming the offending drug is withdrawn, steroids improved the rate of kidney recovery in several small studies (fewer than 20 patients). A review of seven nonrandomized retrospective studies including up to 100 patients showed no benefit of steroids in recovery of kidney function or prevention of CKD. However, many of the retrospective studies were biased against steroids as more severely affected patients were treated, confounding the results. Early steroid therapy, initiated 1 to 2 weeks after diagnosis, is more likely to improve kidney function compared to those started later. In addition, it is reasonable to offer steroids to
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those with severe AIN where renal replacement therapy is or will likely be required in the absence of rapid kidney recovery. Steroid therapy is recommended for 4 to 6 weeks with a slow taper. If there is no substantial improvement in kidney function after 3 to 4 weeks, response is unlikely, and steroids should be discontinued. There are limited data available on other forms of immunosuppression. In a small case series of eight patients, mycophenolate mofetil (MMF) improved or stabilized kidney function in patients with steroid-dependent or steroid-resistant AIN. As a result, MMF may offer an alternative therapy to corticosteroids, but more data are required before this agent can be recommended. BIBLIOGRAPHY Baldwin DS, Levine BB, McCluskey RT, et al: Renal failure and interstitial nephritis due to penicillin and methicillin, N Engl J Med 279:12451252, 1968. Brewster UC, Perazella MA: Proton pump inhibitors and the kidney: critical review, Clin Nephrol 68:65-72, 2007. Clarkson MR, Giblin L, O'Connell FP, et al: Acute interstitial nephritis: clinical features and response to corticosteroid therapy, Nephrol Dial Transplant 19:2778-2783, 2004.
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Councilman WT: Acute interstitial nephritis, J Exp Med 3:393-420, 1898. González E, Gutiérrez E, Galeano C, et al: Early steroid treatment improves the recovery of renal function in patients with druginduced acute interstitial nephritis, Kidney Int 73:940-946, 2008. Ivanyi B, Hamilton-Dutoit SJ, Hansen HE, et al: Acute tubulointerstitial nephritis: phenotype of infiltrating cells and prognostic impact of tubulitis, Virchows Arch 428:5-12, 1996. Michel DM, Kelly CJ: Acute interstitial nephritis, J Am Soc Nephrol 9:506515, 1998. Nielson EG: Pathogenesis and therapy of interstitial nephritis, Kidney Int 35:1257-1270, 1989. Perazella MA, Markowitz GS: Drug-induced acute interstitial nephritis, Nat Rev Nephrol 6:461-470, 2010. Praga M, González E: Acute interstitial nephritis, Kidney Int 77:956-961, 2010. Preddie DC, Markowitz GS, Radhakrishnan J, et al: Mycophenolate mofetil for the treatment of interstitial nephritis, Clin J Am Soc Nephrol 1:718-722, 2006. Rossert J: Drug-induced acute interstitial nephritis, Kidney Int 60:804817, 2001. Ruffing KA, Hoppes P, Blend D, et al: Eosinophils in urine revisited, Clin Nephrol 41:163-166, 1994. Spanou Z, Keller M, Britschgi M, et al: Involvement of drug-specific T cells in acute drug-induced interstitial nephritis, J Am Soc Nephrol 17:2919-2927, 2006.
Acute Interstitial Nephritis Ursula C. Brewster | Asghar Rastegar
In 1898, W.T. Councilman defined acute interstitial nephritis (AIN) as “an acute inflammation of the kidney characterized by cellular and fluid exudation in the interstitial tissue, accompanied by, but not dependent on, degeneration of the epithelium; the exudation is not purulent in character, and the lesions may be both diffuse and focal.” This was seen on postmortem examination of patients with scarlet fever and, less commonly, other systemic infectious diseases that had no evidence for direct bacterial invasion of the kidney parenchyma. More than a century later, definitive diagnosis of AIN requires the pathologic findings of interstitial edema and infiltration with acute inflammatory cells including polymorphonucleocytes (PMNs), eosinophils, and lymphocytes. In the years since Councilman’s description, the causes of AIN have changed dramatically with pharmacologic agents the most common etiology (more than 75%). In this chapter we will focus primarily on acute tubulointerstitial inflammation, while briefly covering direct parenchymal invasion by infectious agents. The incidence of AIN varies greatly depending on the clinical scenario. An incidence of 0.7% is seen in asymptomatic patients with proteinuria or hematuria, whereas hospitalized patients with acute kidney injury (AKI) of unknown etiology experience an incidence of 10% to 15%. Although AIN can occur in all age groups, it is more common in the elderly. In one report, biopsy-proven AIN was seen in 3.0% of the elderly compared to 1.9% of younger subjects. This may reflect greater exposure of elderly patients to drugs and other inciting factors.
CLINICAL PRESENTATION The presenting symptoms of AIN include an acute or subacute decline in kidney function, often in patients exposed to multiple drugs. Although the “classical” presentation of skin rash, arthralgia, and eosinophilia is occasionally seen, this triad occurs in only 5% to 10% of unselected patients. This presentation is more commonly seen in association with certain drugs, such as penicillin derivatives, in comparison to nonsteroidal antiinflammatory drugs (NSAIDs). Fever, the most common clinical sign, is present in up to 50% of patients with drug-induced AIN but only in 30% of unselected patients. Skin rash is reported in one third of patients and is usually maculopapular. No clinical symptom or sign is sensitive or specific enough to establish a definitive diagnosis. Nonoliguric AKI usually accompanies AIN, but oliguric AKI with rapid rise in creatinine also occurs. Increasingly, AIN develops in patients with underlying chronic kidney disease (CKD) and multiple comorbidities,
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which makes a diagnosis challenging. AIN should therefore be considered in any patient with acute or subacute decline in kidney function with no clear inciting factor.
LABORATORY FINDINGS Common laboratory findings in AIN are summarized in Table 35.1. The most common abnormality is a slow and steady rise in blood urea nitrogen and serum creatinine concentration. Rapid and fulminant presentation of AIN occurs less often. Other major laboratory findings include eosinophilia, eosinophiluria, and abnormal urinary sediment. Eosinophilia is common in β-lactam antibiotic associated AIN, reported in up to 80% of cases, where only a third of other drug-induced AIN cases develop eosinophilia. Hyperkalemia, with or without hyperchloremic metabolic acidosis, is occasionally seen. Urinalysis and examination of the urine sediment are often the most useful laboratory tests. Low-grade proteinuria (1-2+) and positive leukocyte esterase are noted on urine dipstick in most patients. Quantitative proteinuria measurements are usually less than 1 g/day. Macroscopic hematuria is rare, whereas microscopic hematuria is present less than 50% of the time. Leukocytes are present on urine microscopy in virtually all cases of methicillin-induced AIN, but they may be absent in as many as 50% of patients with AIN due to other drugs. The absence of leukocyturia, therefore, should not eliminate this diagnosis from the differential. Classically, urine microscopy will show hematuria, leukocyturia, leukocyte casts, and renal tubular epithelial (RTE) cells (Fig. 35.1). Cellular casts are seen in most cases of methicillin-associated AIN and in up to 50% of patients with AIN resulting from other etiologies. Eosinophiluria, once thought to be hallmark of this disease, is both insensitive and nonspecific and should not be used to make a diagnosis. This test has a sensitivity of 67% and a specificity of 83% in patients with AKI. The techniques used to stain urine for eosinophils (Wright stain and Hansel stain) have proven unreliable and cumbersome. In addition, other disease states such as cystitis, pyelonephritis, atheroembolic kidney disease, and rapidly progressive glomerulonephritis may present with eosinophiluria, making the test nonspecific in diagnosing AIN.
IMAGING Kidney ultrasound in the setting of AIN typically shows normal to enlarged kidneys with normal echogenicity. However,
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Table 35.1 Laboratory Findings in Acute Interstitial Nephritis Eosinophilia Eosinophiluria Urinary sediment Protein excretion Fractional excretion of sodium (FeNa) Proximal tubular defect Distal tubular defect Medullary defect
Inconsistent finding seen more commonly in drug-induced AIN Sensitivity 63% to 91%, specificity 52% to 94% Hematuria, leukocyteuria, leukocyte casts, RTE cells, and RTE casts Less than 1 g/24 h Greater than 1% Glycosuria, phosphaturia, bicarbonaturia, aminoaciduria Hyperkalemia, distal RTA, sodium wasting Nephrogenic diabetes insipidus
AIN, Acute interstitial nephritis; RTA, renal tubular acidosis; RTE, renal tubular epithelial.
Figure 35.1 Urine microscopy showing a white blood cell cast (arrow) and surrounding white blood cells and red blood cells (×60).
these findings are also nonspecific and may be seen with other forms of kidney disease. Although Gallium-67 scan was initially reported as highly sensitive in AIN, this has not been supported over time, and its only role may be to differentiate AIN from acute tubular necrosis (ATN) in those patients who cannot undergo a kidney biopsy. Positron emission tomography has shown diagnostic promise in several AIN cases, but needs further evaluation before widespread use.
PATHOLOGY Although suspicion of AIN is based on clinical clues, definitive diagnosis often requires a kidney biopsy. Major pathologic findings include interstitial edema, inflammation, and tubulitis without glomerular or vascular involvement (Fig. 35.2). Interstitial infiltration may be diffuse but is often patchy in nature and consists of lymphocytes, mononuclear cells, eosinophils, neutrophils, and plasma
Figure 35.2 Kidney biopsy showing acute interstitial nephritis. A diffuse interstitial infiltrate is present (arrows) along with severe tubular injury and tubulitis (arrowhead) where lymphocytes have crossed the tubular basement membrane. Also present are eosinophils (curved arrows). (Hematoxylin and eosin ×200.)
cells. T lymphocytes are primarily composed of CD4 and CD8 cells. The number of eosinophils is highly variable and is more prominent in drug-induced AIN. Granulomas are uncommon but occasionally seen, especially with sarcoidosis and drug-induced AIN. Tubulitis, characterized by the invasion of inflammatory cells though the tubular basement membrane, results in tubular injury and is often seen in association with severe inflammation. Severity of interstitial inflammation, however, does not always correlate with clinical outcome. Poor prognosis is more directly related to the degree of interstitial fibrosis and tubular atrophy. Immunofluorescence and electron microscopic studies are usually unrevealing. NSAID-associated AIN is sometimes associated with glomerular changes of minimal change disease or membranous nephropathy. In contrast to isolated AIN, full-blown nephrotic syndrome accompanies AKI in these cases.
PATHOGENESIS The clinical and histopathologic findings summarized earlier strongly point to an immune-mediated mechanism initiating and sustaining tubulointerstitial damage. The immunologic basis of injury is supported by the low frequency of AIN in persons exposed to a drug, lack of dose dependency, presence of systemic symptoms in some patients, and recurrence of AIN upon reexposure. The antigens initiating the immune-mediated injury could be of endogenous origin (Tamm-Horsfall protein, megalin, and tubular base membrane components) or exogenous, such as drugs and chemicals. Exogenous antigens may be trapped directly or may circulate as immune complexes that are deposited in the kidney interstitium. They may bind to a tubular antigen acting as a hapten, or mimic a normal tubular or interstitial antigen, thereby triggering an immune reaction. In animal models, both cell-mediated and humoral immunity is involved. The injury is initiated by the presentation of endogenous or exogenous antigens to antigen-presenting
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lymphocytes resulting in the activation of T cells. These cells induce differentiation and proliferation of other T cells responsible for delayed hypersensitivity and cytotoxicity. The resultant inflammatory infiltrates within the interstitium produce a variety of fibrinogenic cytokines and chemokines, such as transforming growth factor-β (TGF-β), platelet-derived growth factor-BB (PDGF-BB), epidermal growth factor (EGF), and fibroblast growth factor-2 (FGF2). The fibroblasts invading the interstitium are the product of epithelial-to-mesenchymal transition. Ultimately, this inflammatory process results in the accumulation of extracellular matrix, interstitial fibrosis, and tubular loss.
CAUSES OF ACUTE INTERSTITIAL NEPHRITIS There are multiple causes of AIN, but pharmacologic agents are the most common (Table 35.2). Diagnosis of AIN should trigger a review of the medication list to identify culpable agents and limit further drug exposure. In addition to various drugs, certain infectious agents may induce AIN. Although less common in the antibiotic era, infectious agents must be considered when the clinical scenario is consistent. Finally, systemic diseases, primarily rheumatologic, are associated with the pathologic finding of AIN. These diseases are usually evident from the clinical presentation (Table 35.3).
Table 35.2 Common Drugs Associated With Acute Interstitial Nephritis Drug Class
Examples
Antibiotics
β-lactams, sulfonamides, fluoroquinolones, rifampin, vancomycin, erythromycin, ethambutol, chloramphenicol Acyclovir, atazanavir, abacavir, indinavir NSAIDs, selective COX-2 inhibitors PPIs, H2-receptor blockers, 5-aminosalicylates Phenytoin, carbamazepine, phenobarbital Hydrochlorothiazide, furosemide, triamterene, chlorthalidone Allopurinol, Chinese herbs
Antivirals Analgesics GI medications Anticonvulsants Diuretics Others
COX-2, Cyclooxygenase-2; GI, gastrointestinal; NSAIDs, nonsteroidal antiinflammatory drugs; PPIs, proton pump inhibitors.
Table 35.3 Common Diseases Associated With Acute Interstitial Nephritis Bacterial infection Viral infection Autoimmune
DRUG-ASSOCIATED INTERSTITIAL NEPHRITIS
Neoplastic diseases
Legionella, Staphylococcus, Streptococcus, Yersinia Hantavirus, CMV, EBV, HIV, herpes simplex, Hep C Systemic lupus erythematosis, Sjögren syndrome, sarcoidosis Lymphoproliferative disorders, plasma cell dyscrasias
ANTIBIOTICS β-LACTAM ANTIBIOTICS Methicillin and other β-lactam antibiotics are the most common agents associated with AIN. Methicillin is immunogenic and leads to a hypersensitivity syndrome more often than other drugs, including those in the β-lactam class. The time course is variable, but AIN usually develops approximately 10 to 14 days following drug exposure, unless the patient was previously sensitized. Patients with β-lactam–induced AIN frequently manifest systemic symptoms of fever, rash, arthralgias, and eosinophilia along with AKI. These symptoms may be fleeting or nonexistent, making them unreliable clinical tools for diagnosing AIN. Urinalysis and urine microscopy demonstrate low-grade proteinuria, hematuria, and leukocyturia in approximately 75% of cases (see Fig. 35.1). Because of its association with AIN, methicillin is rarely used thanks to the availability of other β-lactam agents. Cephalosporins may cause a similar clinical presentation of AIN; however, this is less common than with traditional penicillins. On withdrawal of the drug, kidney function usually recovers, although CKD may persist in some. NON β-LACTAM ANTIBIOTICS Rifampin-induced AIN can be severe and appears to occur more frequently with intermittent dosing as compared to continuous dosing regimens. AIN develops in a dosedependent fashion in most but not all patients, and, at
CMV, Cytomegalovirus; EBV, Epstein-Barr virus; Hep C, hepatitis C virus; HIV, human immunodeficiency virus.
times, circulating antibodies to rifampin may be detected. Systemic manifestations include fever, chills, abdominal pain, and myalgia. Laboratory abnormalities include liver function test disturbances, hemolytic anemia, and thrombocytopenia. Renal histopathology demonstrates interstitial inflammation with invasion of mononuclear cells and occasional eosinophils. Tubular epithelial cell injury and tubular necrosis related to vasomotor injury may also occur. Patients with a history of a severe reaction should not be reexposed to the agent because of the potential risk of hemodynamic collapse. Sulfonamides are widely used antibiotics associated with kidney injury. When these drugs were introduced in the first half of the twentieth century, the most common kidney injury was tubular obstruction from crystalline deposition of insoluble drug and/or metabolite. Currently AIN is the most common cause of kidney injury reported with these agents. Patients exposed to these drugs often present with an acute hypersensitivity syndrome characterized by fever, rash, and eosinophilia. Patients with human immunodeficiency virus (HIV) infection, kidney transplant recipients, or those with underlying CKD appear to be more susceptible to an allergic reaction, but the increased use of agents such as trimethoprim-sulfamethoxazole in these
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populations may account for this observation. Patients who are slow acetylators of sulfonamides may be at higher risk because of drug accumulation, even with routine dosing schedules. Fluoroquinolones, particularly ciprofloxacin, may cause kidney injury by several mechanisms; however, AIN is the most common kidney complication. It often pre sents with a slowly progressive decline in kidney function despite the absence of a hypersensitivity syndrome. Other agents in this class have been associated with AIN, but ciprofloxacin, based on its widespread use, is most commonly described. Azithromycin, erythromycin, ethambutol, gentamicin, nitrofurantoin, tetracycline, vancomycin, and multiple antiviral agents have all been associated with AIN. No drug is beyond suspicion, and every agent must be considered in the evaluation.
NONSTEROIDAL ANTIINFLAMMATORY AGENTS Nonsteroidal antiinflammatory agents are widely used by patients including those with chronic illness and chronic pain. Both NSAIDs and the selective cyclooxygenase-2 (COX-2) inhibitors are associated with AIN. Given the high frequency of NSAID use, AIN remains a relatively rare event, supporting an idiosyncratic drug reaction. NSAIDs cause several renal syndromes (see Chapter 37), marked by hemodynamic AKI, electrolyte/acid-base disturbances, and nephrotic syndrome. AIN associated with NSAIDs presents more insidiously than that seen with antibiotics. It often occurs months after starting therapy, with an average onset time of 6 to 18 months. Classically, patients do not develop a hypersensitivity syndrome, and fever, eosinophilia, and rash are rare. An interstitial infiltrate, which is less intense and has fewer eosinophils than seen with other culprit agents, and tubulitis are noted on renal histopathology. Despite multiple classes of NSAIDs with a variety of chemical structures, the pattern of kidney injury is remarkably similar across all agents, arguing against a single epitope-induced immune response. By their mechanism of action, which is inhibition of the conversion of arachidonic acid into its derivatives, NSAIDs may blunt the formation of inflammatory intermediates and the degree of kidney injury. Interestingly, this effect may modulate immune function and alter the clinical presentation, making the diagnosis of AIN more difficult.
GASTROINTESTINAL AGENTS Proton pump inhibitors (PPIs) have emerged as perhaps the most frequent cause of AIN worldwide. In many countries, these agents are available over the counter, further increasing their use. Since omeprazole became available in the early 1990s, the number of prescriptions for PPIs continues to increase. The mean time to AIN diagnosis from drug initiation is approximately 11 weeks, although it can occur after months of therapy. Only 10% of patients with PPI-induced AIN will present with the classic hypersensitivity syndrome of fever, rash, and eosinophilia, and therefore symptoms are either absent or very mild and nonspecific. Early recognition and treatment of AIN is associated with a relatively good prognosis and rare need
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for renal replacement therapy, although CKD does occur in some patients. 5-Aminosalicylates are the mainstay of therapy for patients with inflammatory bowel disease. Most patients require long-term treatment and many years of drug exposure. Kidney impairment is rare with these drugs, occurring in 1 in 200 to 500 patients on therapy. A hypersensitivity reaction can occur and cause AIN. In the absence of early recognition, CKD from chronic interstitial fibrosis may develop. This reaction usually occurs within the first year of therapy, but it can develop at any time in a nondose-dependent fashion.
DIURETICS Diuretic-induced AKI is almost always related to kidney hypoperfusion from decreased intravascular volume. There are, however, multiple case reports of diuretic-induced AIN from furosemide, hydrochlorothiazide, chlorthalidone, and triamterene. AIN is relatively rare despite widespread use of these drugs. In published reports, most patients experience systemic symptoms including fever, rash, and eosinophilia, suggesting a hypersensitivity syndrome. Drug discontinuation generally leads to renal recovery.
INFECTIONS INVASIVE INFECTIONS In the preantibiotic era, streptococcal and diphtheria infections caused inflammatory reactions in the kidney in the absence of direct tissue invasion. However, infection-related AIN diminished in frequency after antibiotics became readily available. Now, when AKI develops in the setting of an infection treated with antibiotics, the drug is assumed to be the culprit. If AKI persists despite antibiotic withdrawal, an acute postinfectious glomerulonephritis or AIN should be considered. Tubulointerstitial injury can occur either from direct invasion by an organism as in pyelonephritis or indirectly by an immune-mediated mechanism. Unlike AIN, pyelonephritis is usually confined to one pyramid in the kidney. In the setting of urinary obstruction, it becomes more diffuse, resulting in AKI. Although clinical history and symptoms usually differentiate the two conditions readily, CT imaging showing a wedge-shaped area of inflammation supports a diagnosis of pyelonephritis rather than AIN. A number of infectious agents have been linked with invasive AIN. These include Epstein-Barr virus (EBV), legionella, mycoplasma, cytomegalovirus, adenovirus, and the ricketsial Rocky Mountain spotted fever. Leptospirosis is a classic example of invasive AIN. The spirochete enters the bloodstream through the skin or mucosa, and it transiently invades glomerular capillaries before migrating into the tubulointerstitum. Once in this compartment, the organism induces inflammation and direct tubular injury that, over time, manifests as large, edematous kidneys. In addition, ischemic ATN may coexist with AIN in patients who develop septic shock from overwhelming leptospiral infection. Eradication of infection is associated with recovery of kidney function.
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Hantavirus is an RNA virus associated with interstitial edema with infiltration of polymorphonuclear leukocytes, eosinophils, and monocytes. Interstitial hemorrhage accompanies renal inflammation and is associated with gross or microscopic hematuria. Candidemia has been associated with an interstitial inflammatory reaction initially limited to the renal cortex. With time, large fungus balls can form, obstruct the collecting system, and cause AKI as a result of obstructive uropathy.
NONINVASIVE INFECTIONS Even without direct invasion of the kidney, infectious agents have been associated with AIN. Historically, streptococcal infections were commonly associated with AIN. The clinical syndrome associated with AIN develops early in the course of infection (9 to 12 days). Given the rapidity with which streptococcal infections are treated currently, infectionrelated AIN has disappeared as a clinical entity.
SYSTEMIC DISEASES The classic lesions of acute tubulointerstitial inflammation may also complicate a variety of systemic diseases. Whereas rheumatologic diseases primarily cause immune-mediated glomerular disease, they can also induce AIN. Metabolic diseases and malignancy are also associated with interstitial inflammation and AKI.
TUBULOINTERSTITIAL NEPHRITIS WITH UVEITIS Tubulointerstitial nephritis with uveitis (TINU) is a rare condition of unclear etiology that presents most frequently in adolescent girls, but may appear in adulthood. Weight loss, fever, anemia, and hyperglobulinemia occur before ocular and kidney manifestations. Fanconi syndrome with glucosuria, proteinuria, and aminoaciduria is the initial kidney manifestation, followed by a tubulointerstitial infiltrate, sometimes with granulomas. Certain infections such as toxoplasmosis, Epstein-Barr infection, and giardiasis have been associated with TINU. However, there is no clearly elucidated immune or genetic cause. Steroids are the mainstay of therapy for both the ocular and kidney manifestations of the disease. Fortunately, the prognosis is good in treated patients.
IMMUNOLOGIC DISEASES The vast majority of rheumatologic diseases complicated by AKI have underlying glomerular disease from anti- glomerular basement membrane (GBM) antibody disease (i.e., Goodpasture disease), immune deposition diseases (lupus or IgA nephropathy among others), or antineutrophil cytoplasmic antibody (ANCA)-related pauci-immune vasculitides. However, there are some rheumatologic ailments, such as Sjögren or sarcoid, which may present with tubulointerstitial inflammation in the absence of glomerular involvement. In the right clinical scenario, these causes of AIN should remain high on the differential diagnosis of kidney injury. Immune-related injury in a transplanted kidney (cellular rejection) manifests primarily as tubulointerstitial
inflammation with or without vascular involvement. The workup and classification of this interstitial disease can be found in Chapter 62.
MALIGNANCY Patients with underlying cancer are at high risk for AKI because of the malignancy itself or therapies used in its management. Primary lymphoma of the kidney is a rare cause of AKI, whereas non-Hodgkin’s lymphoma and acute lymphoblastic leukemias commonly invade the kidney parenchyma. Although it is seen on rare occasions in Hodgkin’s lymphoma, infiltrates are usually bilateral and diffuse, and kidneys may appear enlarged on imaging. Multiple myeloma and the plasma cell dyscrasias cause kidney injury when filtered light chains coalesce and obstruct tubular lumens. These obstructive “casts” are accompanied by varying degrees of tubular injury, necrosis, and an interstitial inflammatory reaction on kidney biopsy that resembles classic interstitial nephritis.
TREATMENT Treatment of AIN depends on the underlying disease that is driving the inflammatory reaction. When the pathologic process is associated with an underlying disease such as a malignancy, therapy is directed at the identified cause. In rheumatologic disease, treatment of the inflammatory condition often improves kidney function as well. In the setting of infection-related interstitial nephritis, eradication of the infection is often associated with kidney recovery. Treatment of drug-induced AIN is more complicated and controversial. The most important intervention is early recognition of disease and drug discontinuation. This can be a complicated endeavor in patients taking multiple essential medications, making it challenging to identify the culprit drug. Careful scrutiny of the medication record for exposure dates and history of previous drug treatment may point to the offending agent. When a drug is suspected, it should be immediately discontinued and replaced, if necessary, with an agent from a different class. A drug-free trial should be undertaken to determine if kidney function recovers without further intervention. If no improvement is noted after a period of observation (3 to 5 days), or if kidney function is declining rapidly, a trial of corticosteroids is reasonable. Prognosis appears to depend on the timing of diagnosis and drug withdrawal. In general, earlier is better with data supporting a 1- to 2-week time frame. Despite this, a substantial proportion of patients (up to 35%) may develop CKD. The data published on use of corticosteroids for AIN are incomplete. Assuming the offending drug is withdrawn, steroids improved the rate of kidney recovery in several small studies (fewer than 20 patients). A review of seven nonrandomized retrospective studies including up to 100 patients showed no benefit of steroids in recovery of kidney function or prevention of CKD. However, many of the retrospective studies were biased against steroids as more severely affected patients were treated, confounding the results. Early steroid therapy, initiated 1 to 2 weeks after diagnosis, is more likely to improve kidney function compared to those started later. In addition, it is reasonable to offer steroids to
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those with severe AIN where renal replacement therapy is or will likely be required in the absence of rapid kidney recovery. Steroid therapy is recommended for 4 to 6 weeks with a slow taper. If there is no substantial improvement in kidney function after 3 to 4 weeks, response is unlikely, and steroids should be discontinued. There are limited data available on other forms of immunosuppression. In a small case series of eight patients, mycophenolate mofetil (MMF) improved or stabilized kidney function in patients with steroid-dependent or steroid-resistant AIN. As a result, MMF may offer an alternative therapy to corticosteroids, but more data are required before this agent can be recommended. BIBLIOGRAPHY Baldwin DS, Levine BB, McCluskey RT, et al: Renal failure and interstitial nephritis due to penicillin and methicillin, N Engl J Med 279:12451252, 1968. Brewster UC, Perazella MA: Proton pump inhibitors and the kidney: critical review, Clin Nephrol 68:65-72, 2007. Clarkson MR, Giblin L, O'Connell FP, et al: Acute interstitial nephritis: clinical features and response to corticosteroid therapy, Nephrol Dial Transplant 19:2778-2783, 2004.
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