Chapter 36. Acute Tubulointerstitial Nephritis

• Acute onset of renal failure.
• Fever, skin rash, and peripheral eosinophilia in a minority of cases.
• Mild proteinuria, hematuria, and sterile pyuria; eosinophiluria detected by Hansel's or Wright's stain.
• Tubular dysfunction, manifested as glycosuria, aminoaciduria, potassium wasting, magnesium wasting.

General Considerations

Disease processes involving the part of the renal parenchyma that consists of the tubules and interstitium are primarily referred to as tubulointerstitial diseases. Tubulointerstitial diseases can be classified as acute or chronic and can present either as primary or secondary (to a systemic disease) processes. Histopathologically, the presentation can vary from a subtle accumulation of lymphocytes, monocytes, or macrophages in the interstitium or tubular atrophy or dilation to extensive interstitial fibrosis, which may be accompanied by glomerulosclerosis.

There are several ways in which injury to the tubulointerstitium can occur, and these can involve either immune-mediated or non-immune-mediated (direct toxicity) mechanisms.

Although not commonly performed, a renal biopsy still provides the most definitive means of diagnosis. From a practical standpoint, however, the diagnosis is usually based upon a combination of epidemiologic, clinical, and laboratory findings.

As an example, a simple urinalysis provides a gamut of information on tubulointerstitial diseases. Examination of the urinary sediment for red blood cells (RBCs), white blood cells (WBCs), and casts is particularly valuable. Dipstick analysis for protein is frequently positive, and when quantified, it is usually <2 g/day. Depending on which part of the tubules is injured, it is possible to observe glucosuria or aminoaciduria (proximal tubules), potassium or magnesium wasting (distal tubules), and salt wasting, as well as urinary concentrating defects or isosthenuria (medullary loop of Henle), manifested by polyuria. Normal anion gap metabolic acidosis is commonly observed, as in the various types of renal tubular acidoses.

Glomerular diseases are a distinct and separate pathologic entity, characterized by heavy or nephrotic-range proteinuria >3.5 g/day, RBC casts on urinalysis, as well as hypoalbuminemia. It is not uncommon, however, for both glomerular and tubulointerstitial disease to occur in a single patient.

Patients are often hypertensive at the time of presentation.

Acute tubulointerstitial nephritis (ATIN) usually presents as an acute rise in blood urea nitrogen (BUN) and creatinine values. The majority of affected patients typically present with nonspecific symptoms. The classic triad of fever, skin rash, and peripheral eosinophilia is seen in a minority of patients. Mild to moderate proteinuria, hematuria, and sterile pyuria are seen in the majority of cases. The occurrence of nephrotic-range proteinuria usually suggests concomitant glomerular disease. It must be noted that eosinophiluria is not specific for ATIN, as has also been demonstrated in other disease processes such as rapidly progressive glomerulonephritis and acute prostatitis as well as atheroembolic renal disease.

Under the microscope, the eosinophilic granules are more clearly demonstrated when Hansel's stain is used, although, in some cases, Wright's stain would suffice. Renal tubular acidosis features, such as glucosuria, aminoaciduria, as well as phosphaturia, indicate tubular injury.

Although the diagnosis of ATIN is usually suspected based on clinical grounds, the definitive diagnosis is established primarily by histopathologic features.

Pathogenesis

The causes of ATIN are conveniently classified into three general categories: Drug-induced ATIN, infection-associated ATIN, and systemic disorders, with immune-mediated mechanisms.

The patient's history is crucial in determining the exact cause of ATIN because the majority of cases have been causally related to medication use, with approximately one-third of such cases being secondary to antibiotic usage.

There are four different mechanisms by which a drug can induce ATIN (Figure 36–1).

Antibiotic-Induced Acute Tubulointerstitial Nephritis

The prototype agent for antibiotic-induced ATIN is methicillin. Because of this it is rarely if ever used in clinical practice today. In fact, it is no longer available in the United States. The list of medications causing ATIN continues to grow (Table 36–1).

All β-lactam antibiotics (penicillins and cephalosporins) have been associated with ATIN. It can occur from as much as 10–20 days after the first exposure to the culprit drug to as little as 2–3 days after reexposure to a drug to which an individual has previously been sensitized. Frequently, ATIN presents as an acute oliguric renal failure.

ATIN has also been noted to occur secondary to drugs that are taken discontinuously, with the classic example being interrupted therapy with rifampin for tuberculosis. Interestingly, case reports of rifampin-induced ATIN have demonstrated the occurrence of circulating antirifampin antibodies and immunoglobulin G (IgG) deposits along the tubular basement membrane as well as casts containing immunoglobulin light chains in tubular lumens similar to that seen in patients with myeloma.

Recently, even the use of proton pump inhibitors has been associated with ATIN.

Note, however, that the development of drug-induced ATIN is not dose dependent.

Nonsteroidal Anti-Inflammatory Drug-Induced Acute Tubulointerstitial Nephritis

Nonsteroidal anti-inflammatory drugs (NSAIDs) produce ATIN with several unique features. It usually occurs after several weeks to months of exposure to the culprit NSAID. In contrast to other causes of ATIN that typically present with mild proteinuria, NSAID-induced ATIN is characterized by the occurrence of nephrotic syndrome (hypoalbuminemia, edema, and nephrotic-range proteinuria). Typically, affected patients tend to be elderly, perhaps because of an increased incidence of painful arthritic conditions. In patients subjected to renal biopsy, features of minimal change disease have been reported, especially in those with concomitant nephrotic-range proteinuria.

It must be emphasized, however, that in the workup of acute renal failure, NSAIDs can cause not only ATIN, but also hemodynamic perturbations of renal perfusion related to its vasoconstrictive properties, especially in the setting of volume depletion.

NSAID-induced ATIN is more likely to cause permanent renal injury as compared to other drugs causing ATIN.

Infection-Induced Acute Tubulointerstitial Nephritis

Infectious disease processes primarily involving the kidneys, such as acute pyelonephritis, have also been associated with ATIN. This topic is discussed in more detail in Chapters 37 and 38.

Other Causes of Acute Tubulointerstitial Nephritis

Recently, proton pump inhibitors have been implicated in the causation of ATIN. The timing from initiation of proton pump inhibitors to presentation with renal involvement varies, with an average of 9–10 weeks. Reexposure after discontinuation of the drug results in a faster onset of kidney damage. Renal biopsy typically shows the presence of an interstitial infiltrate with or without tubulitis. The presence of eosinophils in the tubulointerstitium is seen in the majority of cases. Glomeruli are typically spared (Figure 36–2).

Early recognition and prompt withdrawal of the offending proton pump inhibitor are crucial in portending a good prognosis. The majority of affected patients have partial or complete renal recovery.

Clinical Findings

Symptoms and Signs

The main histopathologic feature of ATIN is diffuse or patchy infiltration of inflammatory cells within the renal interstitial space, accompanied by edema, with particular sparing of the glomeruli and blood vessels; this is accompanied by pathologic changes in the renal tubules. The interstitial infiltrate can be T lymphocytes and monocytes, eosinophils, plasma cells, or neutrophils. The particularly type of inflammatory cell involved depends on the particular culprit causing the reaction. This cellular infiltrate is eventually replaced by interstitial fibrosis (Figure 36–3).

In general, there is a poor correlation between clinical and laboratory findings and the underlying histopathology.

In NSAID-induced ATIN the typical glomerular lesion is that of minimal change disease with normal findings on light microscopy and a demonstration of foot process effacement on electron microscopy. Membranous nephropathy has also been associated with NSAID use in some published reports.

Histopathologic findings considered markers of poor prognosis include interstitial granulomas, interstitial fibrosis, and tubular atrophy.

Patients with ATIN usually present with generalized nonspecific symptoms consistent with acute renal failure, such as oliguria, generalized malaise, nausea and vomiting, or decreased appetite. Typically, the diagnosis is initially suspected in a patient presenting with asymptomatic or symptomatic elevation of BUN and serum creatinine (azotemia) values in the setting of recent infection or usage of medications, in particular antibiotics.

Those with drug-induced ATIN can present with an allergic type reaction that consists of the triad of erythematous rash, fever, and peripheral eosinophilia. Recent studies, however, have demonstrated the occurrence of such a triad of symptoms in only a minority of cases.

Laboratory Findings

Aside from the usual elevation in BUN and serum creatinine, urinalysis shows a predominance of WBCs, some RBCs, and WBC casts. The presence of RBC casts point to underlying glomerular disease, which may be primary or may occur concomitantly.

Eosinophiluria is usually shown with a Hansel's stain, which demonstrates the eosinophilic granules more clearly, in contrast to that of a simple Wright's stain. Defined as the presence of >−1% eosinophils (out of WBCs) in the urine, it is no longer considered specific for ATIN as it has been described in cases of acute cystitis or prostatitis, acute pyelonephritis, as well as postinfectious or rapidly progressive glomerulonephritis, and even renal atheroembolic disease. It has also been seen during transplant rejection. In a recent review of four large series, the estimated sensitivity of eosinophiluria was 67% with a specificity of 83%. Current data suggest that the presence or absence of eosinophiluria neither confirms nor excludes the diagnosis of ATIN, respectively.

Mild proteinuria, usually <1 g/day, is a common occurrence in ATIN. Nephrotic-range proteinuria, >3 g/day, has been described in those using NSAIDs for a chronic period of time or those with biopsy-proven minimal change disease.

Special Tests

Renal ultrasound shows nonspecific findings, such as normal to slightly enlarged kidney sizes, with a mild degree of increased echogenicity in ATIN. There are, however, no specific sonographic features that would reliably distinguish ATIN from other causes of acute renal failure.

Gallium scanning plays an important role in distinguishing ATIN from acute tubular necrosis (ATN). A positive result is usually indicated by showing diffuse, intense uptake bilaterally, consistent with the interstitial inflammatory infiltrate. In one small series, patients with ATIN were shown to have positive gallium scans; this is in contrast to those with ATN who have negative gallium scans. Such utility is limited, however, by its lack of specificity and increased occurrence of false-positive results, especially in those with iron overload or advanced liver disease. Gallium has some structural similarity to the ferric iron and can bind to transferrin and ferritin.

Differential Diagnosis

Although the history and clinical features are truly suggestive of ATIN, the definitive diagnosis can be arrived at only by performing a renal biopsy and demonstrating the histopathologic features discussed above.

In most cases, however, when ATIN is highly suspected, the offending agent is immediately removed or discontinued. If renal function subsequently shows an improving trend in the following days to a week, then no further evaluation or therapy is rendered. A renal biopsy is definitely indicated if there is no evidence of recovery or resolution after discontinuation of the offending agent, if the patient has rapidly progressed to overt renal failure, or if there is significant uncertainty concerning the actual diagnosis.

For those patients highly suspected of having ATIN who may have a contraindication for renal biopsy, a trial of steroids, eg, prednisone 1 mg/kg/day, may be considered. Those who respond to this form of treatment usually improve within 1–2 weeks of initiation of steroid therapy and return to baseline renal function (Figure 36–4).

Treatment

The mainstay of treatment in ATIN is primarily supportive therapy. Once a presumptive diagnosis of ATIN is made, the first step in management is immediate discontinuation of the offending agent or treatment of the underlying infection. The diagnosis should be made promptly as ATIN is usually easily reversible in the earlier stages. However, it may take several days to weeks to see an improvement in renal function (based on serum creatinine) and for it to return to baseline levels.

Pharmacologic therapy should be considered considered in those patients in whom drug discontinuation does not result in any evidence of improvement in renal function, such as declining serum creatinine.

In 40% of cases there is a persistent elevation in serum creatinine despite earlier removal of the culprit agent. In those patients who do not show any significant improvement in renal function within 10–15 days after the withdrawal of the suspected agent, the accepted treatment is pulse methylprednisolone followed by oral prednisone, tapered over 4–8 weeks, although this has not always been effective. At present, there is no definitive evidence that corticosteroid therapy offers any benefit to those with NSAID-induced ATIN. One study, however, suggested that a course of prednisone be tried in those with renal failure that is still persistent 1–2 weeks after the discontinuation of the culprit NSAID.

Recently, Gonzalez, et al reported that “early” initiation of steroid treatment improved the recovery of renal function in patients with drug-induced acute interstitial nephritis. An earlier onset of use of corticosteroids after discontinuing the offending drug (13 versus 34 days) was associated with a better recovery of renal function. In their study, the etiology of the drug-induced ATIN (antibiotic versus NSAID) did not appear to influence the eventual outcome.

Recently, mycophenolate mofetil has been used in the treatment of those patients with ATIN who have been steroid resistant or intolerant. This would include patients with obesity, diabetes, or other conditions that make steroids not an ideal agent.

Prognosis

The majority of patients with ATIN will have either partial or complete recovery of renal function depending on the underlying cause. If recovery of renal function is not achieved after 3 weeks, it is unlikely that there will be any recovery. This is considered to be another negative prognosticator.

Nephropathia epidemica is characterized by an acute onset of fever accompanied by abdominal or loin pain, myalgias and arthralgia, and acute myopia with conjunctival injection. Urinalysis reveals proteinuria, microscopic hematuria, and leukocyturia. Transient nonselective glomerular-type proteinuria has been described, implicating a transient lesion involving the glomerular filtration barrier. Such an increase in glomerular permeability may be attributed to an immunologic response to the viral infection. Antibodies against hantavirus have been demonstrated in affected patients.

Histopathologically, findings consistent with ATIN are seen; some reports have also described concurrent slight glomerular mesangial changes.

Thrombocytopenia is also common. The etiologic agent is believed to be the Puumala hantavirus of the Bunyavirus family that is carried by rodents.

Although spontaneous renal recovery is the rule, some reports suggest that a previous infection with hantavirus may be a risk factor for the development of hypertension.

There is a subset of patients whose renal biopsies clearly show evidence of AIN, but no medication or infection could be identified as the culprit. These patients are labeled as having idiopathic AIN. Although the pathogenesis remains unclear, some cases may demonstrate evidence of an immune-mediated mechanism, ie, circulating antibodies against the tubular basement membrane or linear immunofluorescence along the tubular basement membrane.

Similarly, these patients clinically present with acute renal failure or tubular function abnormalities.