12

DRUG-INDUCED TUBULG-INTERSTITIAL NEPHRITIS

P. CORATELLI,G.M.PANNARALE,N.LATTANZI and G. PASSAVANTI

Institute of Nephrology - University of Bari (Italy)

INTRODUCTION

Acute interstitial nephritis (AIN) is by far the most com­

mon pattern of immunologically mediated renal injury and is asso­

ciated with an ever-expanding number of pharmacologic agents (1,2).

Antibiotics, diuretics and nonsteroidal anti-inflammatory agents

(NSAID)are among the more commonly reported drugs responsible for

causing AIN (3, 4, 5).

The incidence of this untoward effect is unknown. Large re­

trospective reviews, indicate that the incidence of drug induced

AIN in the general population is low, being probably 0.8% of all

cases of acute renal failure (ARF)(6). In some series, the inciden­

ce of drug induced AIN was as high as 8% of all cases of ARF (1).

These retrospective analysis, however, tend to understimate the

true incidence of this complications, since they include only the

more serious cases requ; ring further medical attention or renal

biopsy but not the majority of cases with only mild and transitory

rise in serum creatinine.

There are,unfortunately, only few prospective studies ad­

dressing these issues.Kleinknecht et ale (3), recently reported the

results of a national prospective collaborative study on drug-asso­

ciated ARF. 398 patients with drug-associated ARF were registered

in 58 french nephrology units, 18.3% of total patients with ARF ho­

spitalized during the same period. 81 patients underwent a renal

A. Amerio et al. (eds.), Tubulo-Interstitial Nephropathies© Springer Science+Business Media New York 1991

108

biopsy, i.e. 20.4% of total patients with drug-associated ARF. The

incidence of AIN increased in biopsied cases up to 24.7%.

The incidence of this complication appears to be in­

creasing.

CLINICAL FEATURES

The onset of clinical syndrome is usually heralded by fe­

ver, skin rash and hematuria.

The duration of drug exposure before the onset of ne­

phropathy is variable and it is longer (months) in NSAID-AIN than

the 15-day exposure described for drugAIN.

The triad of skin rash, fever, and arthralgias is present

in less than one-third of drug-induced cases (4) and is uncommon in

subjects with AIN secondary to NSAID (7).

Intense lumbar pain has been reported in several patients

with AIN (8).

AIN is seen at a II ages in cont rast to NSAI D-AIN wh i ch is

seen in older patients (64,6 ± 2,1 years) (5).

Eosinophilia (10-40%) appears in 60-80% of cases and is ti­

pically transient. Such a finding is therefore helpful if positive.

Detecting raised serum IgE levels is also useful. Un­

fortunately, only about half the patients with biopsy-proven in­

terstitial nephritis have shown elevated IgE levels, so a negative

result does not exclude the diagnosis (1, 9).

Hematuria is present in 95% and gross hematuria in about o­

ne-third. Urinalysis reveals that more than 30% of the urinary leu­

cocytes are eosinophils in the majority of patients (86% of cases)

(1, 10). Less than 5% of patients with NSAID-AIN, however, have eo­

sinophiluria (7).

Proteinuria is usually mild « 1,5 g/24 hours). Nephrotic

range proteinuria is uncommon, unless interstitital lesions are as-

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sociated with minimal-change glomerulonephritis following the use

of NSAID (7).

ARF occurs frequently; in 20 to 50% oliguria or anuria can

develop. The urinary diagnostic indices have seldom been reported

in this condition (11,12) and in many patients they are similar to

the findings in acute tubular necrosis (ATN) (1,4).

Renal failure is variable in severity and may require hemo­

dialysis in up to 35% of cases (13). In most of the early cases of

drug~AIN reported, the diagnosis was suspected because of the asso­

ciation between acute renal impairment and evidence of an acute al­

lergic reaction.

The predictive value of hypersensitivity signs was assessed

in a multicentric prospective study. Blood hypereosinophi lia was

the best predictive sign for recognizing AIN. The progressive addi­

tion of clini cal signs to blood hypereosinophil ia increased the

sensitivity and the negative predictive value of these features but

lowered consequently their specificity and their positive predicti­

ve value (3).

It is now clear, however, that many or all of these featu­

res many be absent. The differentation between AIN and ATN may, ho­

wever, be very difficuLt, particuLary if signs of sistemic allergic

response are absent, or when renal fai Lure develops insidiously

(15) and is nonoliguric (30-40% of reported cases) (3,9,13).

The diagnosis of allergic interstitial nephritis therefore

may often be missed unLess a renaL biopsy is performed in aLL pa­

tients with acute and unexpLained deterioration in renal function.

PATHOLOGICAL CHANGES

On renal biopsy the interstitial edema is usually diffuse,

involving the entire cortex. The interstitial infiLtrate, moderate

to severe, is predominantLy composed of lympocytes, plasmacells and

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eosinophils. Eosinophilic infiltration tend to occur early but di­

sappears rapidly (16). Since the renal biopsy is often delayed, re­

ports of tissue eosinophilia have been sketchy.

Tubular damage is found with the leukocyte infiltrates, and

the caracteristic lesion has been said to be a single row of small

and medium lymphocytes closely approximated to the outer tubular

profile, with other lymphocytes on the opposite side of the tubular

basement membrane, insinuated between adjacent tubular epithelial

cells, with or without distruption of the tubular basement membra­

ne. A simi lar lesion was described by Ooi et al. (9) and called

"tubulitis".

Interstitial granulomas with giant cells may be present

(17,18) and is believed specific for hypersensivity to drugs (19).

In some series, epithelioid cell granulomas within renal intersti­

tium are present in 25 to 50% of drug-AIN (19,20).

Usually glomeruli and vessels are normal and most of the i­

solated reports of glomerular and vascular lesions may have anteda­

ted the AIN.

IMMUNOFLUORESCENCE STUDIES

In some cases Linear staining for IgC and, occasionaLLy,

for C3 was demonstrated along the tubuLe basement membrane (TBM).

This has been reported only in a few instances of methiciL­

lin, penicillin or phenytoin-induced AIN (17,21,22, 24).

In 3 patients the antibody was associated with a methicil­

lin antigen, dimethoxy-phenyl-penicilloyL (DPO) in a linear pattern

along the TBM (21,22,23), suggesting that a hapten-carrier mechani­

sm may have been respons i b Le for ant i TBM ant i body induct i on in

these patients. A similar mechanism has been suggested in the case

of phenytoin-associated AIN, in which anti-TBM antibodies were pre­

sent and phenytoin was found aLong the TBM (24).

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In most reported cases, however, immunofluorescent studies

of renaL tissue have been LargeLy negative for immunogLobuLins,

compLement and fibrin (1,9,13).

ELECTRON MICROSCOPY

There are a few reports on eLectron microscopy findings in

drug-AIN.

Ooi et aL. (9) found that tubuLar cells were extensiveLy damaged

with striking mitochondrial changes characterized by swelling with

fragmentation ~ the cristae. The rough reticulum was often marke­

dly dilated.Distal tubules were more severeLy affected than proxi­

maL tubuLes. The peritubular basement membrane of cortical tubuLes

were thickened and multilayered. The thickening was due to an in­

crease of basement membrane material or to a reduplication.

The interstitial regions has been described as "chaotic" by

Galpin et al. (13), because subversion in interstitial architectu-

reo

The inflammatory infiLtrate was composed of lymphocytes, plasmacel­

Ls,eosinophils and,to a lesser degree,neutrophils. Lymphocytes were

seen insinuated between epitheliaL ceLLs, or Located between the

basement membrane and tubular cells (9). Glomeruli were normal and

the onLy significant glomerular findings have been foot-process fu­

sion in those patients who have a nephrotic syndrome associated wi­

th the interstitial lesion (25).

PATHOGENESIS

The pathogenesis of drug-induced AIN is not clear and still

remains uncertain.

The evidence strongly suggests that this type of drug- induced in­

jury is immunologically mediated. The smaLL number of patients suf­

fering this adverse drug reaction despite the large number of pa-

112

tients treated with drugs; the lack of correlation with the dose of

drug; the recurrence of the reaction following exposure to the same

or similar drugs all point to an allergic-hypersensitivity reac­

tion.Finally circulating antibodies to the offending drug or in­

creased serum IgE leveLs in some patients (26,27); lymphobLastic

stimulation or inhibition of Leukocyte migration occasionaLly re­

ported (24,28); the renaL histoLogic findings with interstitial eo­

sinophilia, IgE containing pLasmacell(29) and epitheLiaL granuLoma­

ta (17,18) support this mechanism.

There is no satisfactory experimentaL model, so.that evi­

dence is derived from human studies.

At least three factors have to be taken into account in

formulating any hypothesis reLating to the mechanism of renaL inju­

ry. These factors are the presence of 19G and C3 in a Linear pat­

tern along the TBM in occasionaL cases; the deveLopment of eLevated

IgE LeveLs in some patients; and the presence of Large numbers of

mononucLear ceLLs, including Lymphocytes, monocytes and muLtinu­

cLeate giant ceLls in the interstitium of the kidney.

The initiaL step may be the binding of drug hapten to

structuraL protein of the renal interstitium and/or TBMs leading to

the formation of a stabLe hapten-protein conjugate.

Such bound antigen should be able to trigger an anti­

body-mediated reaction, as well as a delayed-type hypersensitivity

reaction. Subsequently either humoraL or cell mediated mechanism of

renal damage may predominate.

Antibodies in the tubulointerstitium probabLy bind as an

in-situ process and may directLy produce inflammatory by activating

complement (30), inducing chemiotaxis (31), invoking tubuLar injury

by direct cytotoxis effects on tubular cells (32), or by acting as

a brigde between antigen and mechanism of antibody-dependent-cel­

l-mediated cytoxicity (ADCC) (33).

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OccasionaLLy the humoraL immune response produces IgE anti­

bodies.The IgE antibody produced then can directLy bind to speciaL

receptors on tissue eosinophiLs, basophiLs and mast ceLLs.Degranu­

Lation of both ceLL types induces the reLease of proteases, hista­

mine, PAF, Leukotrienes, prostagLandins and peroxidases and can di­

rectLy contribute to LocaL injury.

Certain observations can suggest ceLL-mediate immune mecha­

nism in the pathogenesis of drug-AIN. In most cases, a predominan­

tLy mononucLear ceLL infiLtrate, incLuding epitheLioid and muLtinu­

cLeate giant ceLLs, is found without associated immunogLobuLin de­

posits.

It as been postuLated that renaL damage evoLves from simuL­

taneous deposition of the offending drug aLong the TBM and/or the

interstitium and sensitization of Lymphocytes to the agent.Subse­

quent renaL infiLtration by these pernicious ceLLs resuLts in their

release of various lymphokines and mediators which produce tissue

distruction. If, as it seems probabLe, the drug hapten is bound to

the surface of tubular ceLls, they could aLso be targets of T-ceL­

l-mediated lysis or ADCC.

Immunohistologic studies in some patients show that the in­

filtrate contains a preponderance of T-Lymphocytes (25,34).Both

CD4+ and CD8+ T-lymphocyte sUbpopulation usually are present in ac­

tive interstitial infiLtrate.CD8+T celL subset was found more pro­

minent in patients with antibiotic and NSAID-AIN, compared to other

drug-reLated causes of AIN in which CD4+T ceLLs predominate (25,

35-37).

In summary the weight of evidence therefore favours an im­

munologic basis for the occurence of interstitial nephritis due to

drugs, but the exact mechani sm, either humora L or eel Lu Lar, is

still to be elucidated.

Van Ypersele (11) suggests a hypothetical scheme that might

114

integrate the different pathogenic mechanism defined experimentally

with the various immunologic disturbances observed in clinical AIN.

Interstitial accumulation of the drug may result either from a di­

rect toxic effect of the drug on tubular cells with subsequent dif­

fusion through a ruptured TBM, or from its concentration within pe­

ritubular capillaries, or from its combination with the TBM acting

as a hapten.

Once in the interstitium, the drug challenges immunity and

induces either humoral immunization or cellular, delayed hypersen­

sitivity immunization.

Humoral reaction is either systemic, manifested in the for­

mation of circulating antibodies directed against the drug or a­

gainst the TBM, or locaL with infiltration of monocytes, lymphocy­

tes and plasmocytes. These latter celLs are able to synthesize im­

munogLobulins locally and form immune complexes in situ.

Delayed hypersensitivity wi II bring about the invasion of

the interstitium with macrophage-stimulating lymphocytes.

Within this framework, it is conceivable that the same drug

elicits the same tubuLo-interstitiaL lesions through different im­

mune mechanisms, the type of response being provoked by the geneti­

cally determined immune responsiveness of the patient, the degree

of stimulation of immunity, and the characteristics as well as the

quantity of the offending agent.

As far as concern the characteristics of some drugs, like

NSAID, the pathogenesis is difficult to conceptualize because of

the unsuaL combination of glomerular proteinuria, interstitial ne­

phritis and renaL faiLure. NSAID are known to inhibit prostaglan­

dins synthesis. The inhibition of cycLooxygenase may lead to shun­

ting of archidonic acid precursor into the Lipoxygenase pathway,

favoring the production of polyenoic acid, incLuding Leukotrienes

(39). These substances are known to function as lymphokines, lea-

115

ding to the recruitment of T lymphocytes and the perpetuation of

the inflammatory process (40).

In addition lipoxygenase products, known to enhance vascu­

lar permeability (39,41), may contribute to the proteinuria by al­

tering the glomerular-capillary barrier.It is unknown if these li­

poxygenase metabolites could be produced locally by renal parenchi­

mal cells (42) or by infiltrating lymphocytes (43).

It is intriguing to speculate that this metabolic effect of

NSAID administration could act either in concert with a cell-media­

ted hypersensitivity response to NSAID or as an indipendent mecha­

nism to mediate this nephropathy (5).

TREATMENT AND PROGNOSIS

The prognosis for drug-induced interstitial nephritis is

generally favorable, at least in terms of overall mortality. Never­

theless the renal failure may be quite severe and prolonged and he­

modialysis may be required in up to 35% of patients.

Klei nknecht and assoc i ates, ina prospect i ve study, when compared

the main differentiaL feature between patients with drug-induced

ATN and AIN, found that patients with AIN had more frequentLy non­

-oliguric ARF, clinical and biological signs suggesting a hypersen­

sitivity reaction, a prolonged ARF period, and permanent renal da­

mage (3).

The probability of good recovery, however, depends on the

duration of renal faiLure prior to its discovery. Laberke and Bohle

showed that the prognosis for AIN with ARF of three weeks or more

duration was significantly poorer than for patients without ARF an­

d/or with ARF lasting two week or less. The presence of scattered

infiltrates also is associated with the return of normal renal fai­

lure function, whereas diffuse involvement often results in per­

sistent functional damage (14).

116

The type of drug inducing AIN can also influence the lon­

g-term outcome, NSAID being more frequently associated with irre­

versible chronic renal failure.

Prolonged or unrecognized interstitial damage usually leads

to irreversible chronic interstitiaL fibrosis.

Clearly, recognizing the conditions and identifying and wi­

thdrawing the offending drug is often aLL that is required for a

rapid and compLete recovering of renal function.

It is not clear if steroid acceLerate recovery or improve

prognosi s. The evi dence for empLoyi ng predni sone comes onLy from

small uncontrolled nonrandomized studies (1,13, 44) or anedoctal

case report (15).

Controlled data are non availabLe because large, omogeneous

patients populations are difficult to recruit.

Neilson does not consider persistent interstitial nephritis

a particulary benign Lesions and believes that a limited course of

high-dose prednisone generaLly is prudent for biopsy-proven acute

interstitial injury in which renal faiLure has persisted for more

than one week, after withdrawal of ther offending drug. Steroids

can be useful usally after one week of rising serum creatinine, but

before several week of persistent renaL failure. Steroid should be

discontinued if no meaningful response is achieved after 3 to 4

weeks of therapy (38).

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