Section V. Tubulointerstitial Diseases 313 Acute ... V. Tubulointerstitial Diseases 313 ESSENTIALS OF DIAGNOSIS Acute onset of renal failure. aminoaciduria (proximal tubules), potassium

� 313Section V. Tubulointerstitial Diseases

E SSENT IALS OF D IAGNOS IS

� Acute onset of renal failure.� Fever, skin rash, and peripheral eosinophilia in a minority

of cases.� Mild proteinuria, hematuria, and sterile pyuria; eosin-

ophiluria detected by Hansel's or Wright's stain.� Tubular dysfunction, manifested as glycosuria, aminoac-

iduria, potassium wasting, magnesium wasting.

TUBULOINTERSTITIAL DISEASES

� General ConsiderationsDisease 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 classifi ed as acute or chronic and can present either as primary or secondary (to a systemic disease) pro-cesses. Histopathologically, the presentation can vary from a subtle accumulation of lymphocytes, monocytes, or macro-phages in the interstitium or tubular atrophy or dilation to extensive interstitial fi brosis, which may be accompanied by glomerulosclerosis.

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

Although not commonly performed, a renal biopsy still provides the most defi nitive means of diagnosis. From a practical standpoint, however, the diagnosis is usually based upon a combination of epidemiologic, clinical, and labora-tory fi ndings.

As an example, a simple urinalysis provides a gamut of information on tubulointerstitial diseases. Examina-tion 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 quantifi ed, 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 hypoalbumin-emia. 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 presenta-tion.

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 nonspecifi c symptoms. The classic triad of fever, skin rash, and peripheral eosinophilia is seen in a minority of pa-tients. 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 specifi c for ATIN, as has also been demonstrated in other disease processes such as rapidly progressive glomerulone-phritis 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 suffi ce. Renal tubular aci-dosis 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 defi nitive diagnosis is estab-lished primarily by histopathologic features.

36Acute Tubulointerstitial

Nephritis

Edgar V. Lerma, MD

Chapter 36.indd 313Chapter 36.indd 313 11/22/08 5:53:14 PM11/22/08 5:53:14 PM

� TUBULOINTERSTITIAL DISEASES314 SECTION 5

� PathogenesisThe causes of ATIN are conveniently classifi ed 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).

A. Antibiotic-Induced Acute Tubulointerstitial Nephritis

The prototype agent for antibiotic-induced ATIN is methicil-lin. 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 �-lactam antibiotics (penicillins and cephalosporins) have been associated with ATIN. It can occur from as much as 10–20 days after the fi rst 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. Interest-ingly, case reports of rifampin-induced ATIN have demon-strated the occurrence of circulating antirifampin antibodies and immunoglobulin G (IgG) deposits along the tubular basement membrane as well as casts containing immuno-globulin 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.

B. Nonsteroidal Anti-infl ammatory Drug-Induced Acute Tubulointerstitial Nephritis

Nonsteroidal anti-infl ammatory 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

� Figure 36–1. Mechanisms whereby a drug (or one of its metabolites) can induce acute interstitial nephritis (AIN). A: The drug can bind to a normal component of the tubular basement membrane (TBM) and act as a hapten. B: The drug can mimic an antigen normally present within the TBM or the interstitium and induce an immune response that will also be directed against this antigen. C: The drug can bind to the TBM or deposit within the interstitium and act as a planted (“trapped”) antigen. D: The drug can elicit the production of antibodies and become deposited in the interstitium as circulating immune complexes. (Adapted with permission from Rossert J: Kidney International 2001;60:804.)

Tubular cell

Trappedantigen

Tubule

Immunecomplex

TBM

Hapten Drug-derived Ag

Bloodvessel

Tubule

Endogenous Ag

A B

C D Tubule


ACUTE TUBULOINTERSTITIAL NEPHRITIS CHAPTER 00 � 315CHAPTER 36

Table 36–1. Drugs causing acute tubulointerstitial nephritis (ATIN).

Antimicrobial agents Acyclovir Ampicillin1,2

Amoxicillin Aztreonam Carbenicillin Cefaclor Cefamandole Cefazolin Cephalexin Cephalothin Cefoxitin Cefotaxime Cidofovir Ciprofl oxacin Cloxacillin Colistin Cotrimoxazole2

Erythromycin Ethambutol Foscarnet Gentamicin Indinavir Interferon Isoniazid Lincomycin Methicillin2

Mezlocillin Minocycline Nafcillin Nitrofurantoin2

Norfl oxacin Oxacillin2

Penicillin G2 Piperacillin Polymyxin acid2

Quinine Rifampicin2

Sulfonamides Teicoplanin Tetracycline Vancomycin

NSAIDs including salicylates Alclofenac Azapropazone Aspirin Diclofenac Difl unisal2

Fenclofenac Fenoprofen Ibuprofen Indomethacin

Ketoprofen Mefenamic acid Meloxicam Mesalazine (5-ASA) Naproxen Phenylbutazone Piroxicam Sulfasalazine Sulindac Tolmetin

Anticonvulsants Carbamazepine Diazepam Phenobarbital Phenytoin2 Valproate sodium

Diuretics Chlorthalidone Ethacrynic acid Furosemide2

Hydrochlorothiazide2

Indapamide Triamterene2

Others Allopurinol2

�-Methyldopa Azathioprine Bethanidineb Bismuth salts Captopril2

Chlorpropamide2

Cyclosporine Cimetidine Clofi brate Clozapine D-Penicillamine Fenofi brate2

Gold salts Griseofulvin Interferon Interleukin-2 Omeprazole Phenindione2

Phenothiazine Phenylpropanolamine Probenecid Propranolol Propylthiouracil Ranitidine Streptokinase Sulfi npyrazone Warfarin

1Drugs most commonly involved are shown in italic letters.2Drugs that can induce granulomatous acute interstitial nephritis.

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 sub-jected 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 vol-ume depletion.

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

C. 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.

D. 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 infi ltrate 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 offend-ing proton pump inhibitor are crucial in portending a good prognosis. The majority of affected patients have partial or complete renal recovery.

� Clinical FindingsA. Symptoms and Signs

The main histopathologic feature of ATIN is diffuse or patchy infi ltration of infl ammatory cells within the renal intersti-tial 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 infi ltrate can be T lymphocytes and monocytes, eosinophils, plasma cells, or neutrophils. The particularly type of infl am-matory cell involved depends on the particular culprit causing the reaction. This cellular infi ltrate is eventually replaced by interstitial fi brosis (Figure 36–3).

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



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

Histopathologic fi ndings considered markers of poor prognosis include interstitial granulomas, interstitial fi brosis, and tubular atrophy.

Patients with ATIN usually present with generalized non-specifi c symptoms consistent with acute renal failure, such as oliguria, generalized malaise, nausea and vomiting, or de-creased 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 al-lergic type reaction that consists of the triad of erythema-tous rash, fever, and peripheral eosinophilia. Recent studies, however, have demonstrated the occurrence of such a triad of symptoms in only a minority of cases.

B. 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 con-comitantly.

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. Defi ned as the presence of ��1% eosinophils (out of WBCs) in the urine, it is no longer considered specifi c for ATIN as it has been described in cases of acute cystitis or prostatitis, acute py-elonephritis, 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 eosin-ophiluria was 67% with a specifi city of 83%. Current data suggest that the presence or absence of eosinophiluria neither confi rms 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 de-scribed in those using NSAIDs for a chronic period of time or those with biopsy-proven minimal change disease.

C. Special Tests

Renal ultrasound shows nonspecifi c fi ndings, such as normal to slightly enlarged kidney sizes, with a mild degree of in-creased echogenicity in ATIN. There are, however, no specifi c sonographic features that would reliably distinguish ATIN from other causes of acute renal failure.

Gallium scanning plays an important role in distinguish-ing ATIN from acute tubular necrosis (ATN). A positive

� Figure 36–2. Acute tubulointerstitial nephritis in a 39-year-old male with a history of intake of omeprazole who presented with acute renal failure and a serum creatinine of 5.9 mg/dL. There is interstitial edema, an infl ammatory infi ltrate composed of lymphocytes, mac-rophages, and numerous eosinophils. Tubulitis is also evi-dent (arrow). Hematoxylin and eosin (�400). (Courtesy of Dr. Shane Meehan, Department of Pathology, University of Chicago.)

� Figure 36–3. Acute and chronic tubulointerstitial nephritis in a 14-year-old female with a serum creatinine of 2.0 mg/dL and a history of exposure to amoxicillin. The interstitium has mononuclear infl ammatory cell infi ltrates and increased pink matrix material indicative of collagen deposition. The tubules are shrunken and focal tubulitis is evident (arrow). Hematoxylin and eosin (�200). (Courtesy of Dr. Shane Meehan, Department of Pathology, University of Chicago.)



result is usually indicated by showing diffuse, intense uptake bilaterally, consistent with the interstitial infl ammatory infi l-trate. 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 specifi city and increased occurrence of false-positive results, especially in those with iron overload or advanced liver disease. Gallium has some structural similar-ity to the ferric iron and can bind to transferrin and ferritin.

� Differential DiagnosisAlthough the history and clinical features are truly sugges-tive of ATIN, the defi nitive diagnosis can be arrived at only by performing a renal biopsy and demonstrating the histo-pathologic 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 defi nitely indicated if there is no evidence of recovery or resolution after discon-tinuation of the offending agent, if the patient has rapidly progressed to overt renal failure, or if there is signifi cant uncertainty concerning the actual diagnosis.

For those patients highly suspected of having ATIN who may have a contraindication for renal biopsy, a trial of ste-roids, 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).

� TreatmentThe mainstay of treatment in ATIN is primarily supportive therapy. Once a presumptive diagnosis of ATIN is made, the fi rst step in management is immediate discontinu-ation 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 re-sult in any evidence of improvement in renal function, such as declining serum creatinine.

In 40% of cases there is a persistent elevation in serum cre-atinine despite earlier removal of the culprit agent. In those patients who do not show any signifi cant improvement in renal function within 10–15 days after the withdrawal of the suspected agent, the accepted treatment is pulse methylpred-nisolone followed by oral prednisone, tapered over 4–8 weeks, although this has not always been effective. At present, there is no defi nitive evidence that corticosteroid therapy offers any benefi t 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 bet-ter recovery of renal function. In their study, the etiology of the drug-induced ATIN (antibiotic versus NSAID) did not appear to infl uence the eventual outcome.

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

� PrognosisThe majority of patients with ATIN will have either partial or complete recovery of renal function depending on the un-derlying 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 Nephropathia epidemica is characterized by an acute onset of fever accompanied by abdominal or loin pain, myalgias and arthralgia, and acute myopia with conjunctival injec-tion. Urinalysis reveals proteinuria, microscopic hematuria, and leukocyturia. Transient nonselective glomerular-type proteinuria has been described, implicating a transient lesion involving the glomerular fi ltration barrier. Such an increase in glomerular permeability may be attributed to an immu-nologic response to the viral infection. Antibodies against hantavirus have been demonstrated in affected patients.

Histopathologically, fi ndings consistent with ATIN are seen; some reports have also described concurrent slight glo-merular 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 re-ports suggest that a previous infection with hantavirus may be a risk factor for the development of hypertension.

IDIOPATHIC ACUTE INTERSTITIAL NEPHRITISThere is a subset of patients whose renal biopsies clearly show evidence of AIN, but no medication or infection could be identifi ed 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 immunofl uorescence along the tubular basement membrane.

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



Patient with renal insufficiency, AIN suspected

Withdraw potentially offending medications.

No clinical improvement

Contraindication to renal biopsyor patient refuses biopsy?

Clinical improvement(increased urine output,falling creatinine level,resolution of clinical

symptoms)

Observation, supportivemanagement

Perform renal biopsy

Biopsy diagnostic of AIN?

Treat appropriately orcontinue evaluationfor other causes of

renal failure.

Severe None or minimal

Trial of steroid therapy(prednisone 1mg/kg/day)

Improvement inrenal function?

Continue steroidtherapy (see text).

Continue supportive management; consider trialof alternative immunosuppressive therapy if

not contraindicated.

Resultsconsistentwith AIN

Consider alternativediagnostic study (gallium

67 scan, renal ultrasound)

Results notconsistentwith AIN

Continue evaluationfor other causesof renal failtureContraindication to steroid therapy?

Fibrosis on biopsy

No

No Yes

Yes

Yes

Yes

No

No

� Figure 36–4. Algorithm for the diagnosis and treatment of acute tubulointerstitial nephritis. AIN, acute interstitial nephritis.



Appel GB, Bhat P: Nephrology VIII. Tubulointerstitial diseases. In: ACP Medicine. Dale DC (editor). WebMD, Inc., 2006.

Baker RJ, Pusey CD: The changing profi le of acute tubulointersti-tial nephritis. Nephrol Dial Transplant 2004;19:8.

Brewster UC, Perazella MA: Acute kidney injury following proton pump inhibitor therapy. Kidney Int 2007;71:589.

Clarkson MR et al: Acute interstitial nephritis: clinical features and response to corticosteroid therapy. Nephrol Dial Transplant 2004;19:2778.

González E et al: Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis. Kidney Int 2008;73:940–946.

Kodner CM, Kudrimoti A: Diagnosis and management of acute interstitial nephritis. Am Fam Phys 2003;67(12):2527–2534.

Kshirsagar AV: The signifi cance of urine eosinophils. In: UpToDate 15.3. Rose BD (editor). UpToDate 2008, Waltham, MA.

Kshirsagar AV, Falk RJ: Treatment of acute interstitial nephritis. In: UpToDate 15.3. Rose BD (editor). UpToDate 2008, Waltham, MA.

Miettinen MH et al: Ten-year prognosis of Puumala hantavirus-induced acute interstitial nephritis. Kidney Int 2006;69(11):2043.

Preddie DC et al: Mycophenolate mofetil for the treatment of interstitial nephritis. Clin J Am Soc Nephrol 2006;1:718.

Rose B: NSAIDs: acute renal failure and nephritic syndrome. In: Up-ToDate 15.3. Rose BD (editor). UpToDate 2008, Waltham, MA.

Rose BD, Appel GB: Clinical manifestations and diagnosis of acute interstitial nephritis. In: UpToDate 15.3. Rose BD (editor). UpToDate 2008, Waltham, MA.


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Section V. Tubulointerstitial Diseases 313 Acute ... V. Tubulointerstitial Diseases 313 ESSENTIALS OF DIAGNOSIS Acute onset of renal failure. aminoaciduria (proximal tubules), potassium