REVIEW ARTICLE I I

INTERSTITIAL NEPHRITIS

Interstitial Nephritis A Brief Review Robert H. Heptinstall, MD

OVER THE PAST 20 y-ears or so, great progress has been made in understandinig x-arious forms of renal disease. This is partictilarl- trte in

the case of primar glomerular disease, where observations using immunofluorescence techniques and electron microscopy, coupled with experimental studies, have completely transformed the dismal picture of former years. On the other hand, there is still considerable confusion over certain entities-this is particularly true in cases where there is no primary glomerular disease but where the main changes are in the interstitium and the tubular system. To this group, the name interstitial nephritis has been given, and although exception can be taken to this term because of its lack of precision, it remains a useful one to retain until such time as its constituents become unraveled. The main characteristics are the presence in the interstitium of variable numbers of inflammatorv cells (usually mononuclears, lymphocytes, and plasma cells, with smaller numbers of eosinophils in some instances and pool-morphonuclear leukocvtes in others), accompanied by variable degrees of tubular atrophy or loss. The interstitium is edematous in some cases and fibrous in others. Acute and chronic forms are recognized. It must be admitted at the outset that this is a motley group. with numerous etiologies and doubtless many pathogenetic mechanisms. It is the failure to recognize that the kidney has a limited number of wa-s in which to respond to a large number of stimuli that has caused so much confusion over the diagnosis of chronic pvelonephritis-for example, because the end result of bacterial infection of the kidney is onlv one of the conditions contributing to the picture of the chronic form of interstitial nephritis. It must also be added that, -hereas the term interstitial nephritis is reserved for those cases in which there is no primarv glomerular damage, From the Department of Pathology. The Johns Hopkins U niversity School of \Medicine and Hospital. Baltimore. Mlary land Supported b! Grant HL-07S:35 from the L-S Public Health Serx ice Address reprint reqluests to Dr Robert H Heptinstall. Departmenit o)f Patholuos. Johns tiopkilnl Hospital. Baltimore. MD 21205.

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there is frequently a conspicuous interstitial reaction in patients w-ith glomerulonephritis. Indeed it is from such cases that manv of the notions on the pathogenesis of interstitial nephritis are derived. Acute Interstitial Nephritis

It is a measure of our ignorance that difficulties are encounitere(I w-hen w-e attempt to define the acute variety. Traditionally. acute iiiterstitial nephritis was used to describe the renal picture in patients dying from acute infectious diseases such as diphtheria and scarlet fever, and it "-as ty pified by the presence of lymphocytes and plasma cells in the interstitium.' Thus, in spite of the name applied to the condition, the tissue reactioni w-as not one with acute inflammatorv cells as the predominanit ty pe. It could be argued that the use of the m-ord acute describes better the clinical state, indicating the rapidity of onset, rather than the character of the tissue reaction. This is also true for those examples attending advxerse drug reactions, X here pol-morphonuclear leukocytes may be scanty in the presence of a dramatic acute onset %vith fever and oliguria. Interstitial edema is verv commonly present in the acute cases and is probably the most constant pathologic feature. Fibrosis is not present, m-hereas it is common in the chronic variety. Acute interstitial nephritis occurs in a variety of situations. In the first place it occurs w-ith acute bacterial infections such as acute pvelonephritis of either the ascending or blood-borne types. In these instances there are large numbers of polymorphonuclear leukocytes in the interstitium, but these rapidly give wax to chronic inflammatorv cells, a transformation that can occur within very- fe- days in experimental models.2 Large numbers of polymorphonuclear leukocytes are seen in the interstitium in septicemic states, particularly those in which Group A streptococci and coagulase-positive staphylococci are involved. In these tw-o instances an acute glomerulonephritis max also be found. An acute interstitial reaction has also been described in brucellosis;3 in this particular patient, a repeat biopsy revealed a nonspecific chronic interstitial nephritis, providing a further example of the conversion of an acute to a chronic form. The greatest numbers of cases of acute interstitial nephritis are seen as part of an adverse reaction to therapeutic agents. Among the first compounds to be implicated were the sulfonamides,4- but these are nowexceeded in frequency bv antibiotics such as cephalothin,7 rifampin,8 penicillin,"'1 ampicillin,'2.13 and in particular methicillin.' 114-17 Such drugs as phenindione,18- diphenylhvdantoin," thiazides,29 furosemide,29 phenazone," and azathioprine3' are also associated with renal involvement. To give some idea of the frequency of these reactions, there

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are 60 cases recorded with methicillin (20 w ith renal histology availal)le). 10 with ampicillin, and 20 with rifampin.17 Sraer et al.27 reported that histologic studies of 13 cases associated with phenindione had been described up to 1972. The numbers are probably much greater because many cases are unrecorded. The usual story- with a drug reaction is that a patient w-ho is being treated -ith the drug in question develops fe-er. morbilliform skiin rasl. eosinophilia, hematuria, and rising serum urea nitrogen or creatinine levels. Acute oliguric renal failure max- occur, and proteinuria is cornmonlx- observed. The interval betw-een onset of adv erse reaction aindi initiation of therapy is variable: for instance it extends from 3 (lax-s to . w-eeks in recorded cases of adverse reactions to methicillin. Recomery is the rule, but there may be permanent impairment of renal function; 24,T sometimes death occurs. The picture on renal biopsx is similar irrespective of the causative agent. There is edema of the interstitium which also show s variable numbers of polymorphonuclear leukocytes, eosinophils, lymphocytes, mononuclear cells, and plasma cells. Glomeruli appear normal, and the tubules show abnormalities which include necrosis, regeneration, or atrophy. The distribution of the tubular changes is patchy. A hypersensitivity reaction appears to be the most likely pathogenetic mechanism because the adverse reaction is not usuallv dose related, is often accompanied by fever, skin rash, and eosinophilia, and mav be attended by circulating antibodies to the drug that is used. It must be admitted howvever that direct evidence for an immunohlgic pathogenesis is available in only xen fe- of the cases described. From a pathogenetic point of view-' the renal lesion arising from methicillin therapy is the best studied. An immunologic mechanism has been suggested on the basis of twvo studies. 11l4 In these, renal biopsy show-ed infiltration of the interstitium by lymphocy tes. mononuclear cells, plasnma cells, eosinophils, and smaller numbers of polI morphonuclear leukocx-tes. Marked tubular degeneration was present; regeneration was seen in some tubules, but glomeruli show'ed no conspicuous changes. With immunofluorescence techniques, there w,as a linear pattern along tubular basement membranes w-ith antibody directed against IgG and dimethoxyphenylpenicilloyl (DPO), the penicilloyl haptenic group of methicilliin. In one study. C:3 w-as also present in the same distribution.14 and in the otler. DPO and IgG w-ere also seen along glomerular capillary wvalls." Anti-tubular basement membrane antibodies (anti-TB\.I) %vere demoinstrated in the circulation bv indirect immunofluorescence techniques.'4 It w'as suggested that conjugates of penicilloyl hapten wvith TBM protein w%-ere formed w-hich led to an immune response. resulting in the formation

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of anti-TBM antibodies. The resultant damage to the tubular basement membrane presumably was responsible for the changes which took place, including the interstitial cellular reaction and the functional derangement. More will be said of the part played by anti-TBM antibodies in the production of interstitial nephritis later in this article. A third case 15 involving methicillin has been briefly reported in which a conspicuous granulomatous reaction was present in the interstitium of a 68-year-old man. Anti-TBM antibodies were stated to be present in the serum on the basis of uptake of radiolabeled TBM; complement levels in the serum were low. Another case 17 in which there was a similar but less conspicuous granulomatous reaction has also been described. In this case, direct immunofluorescence techniques revealed no immunoglobulins along glomerular or tubular basement membranes, and indirect immunofluorescence testing for anit-TBM antibodies in the serum was negative. Raised levels of IgE have been reported in the serum of patients with drug-induced interstitial nephritis,-" and this immunoglobulin has been described in plasma cells in the interstitial infiltrate on biopsy.vU The significance of these observations is not apparent at the moment, but the possibilitv of allergen-reaginic antibody complexes in the pathogenesis of the renal lesion is raised. It is obvious that there are considerable gaps in our understanding of the pathogenesis of acute interstitial nephritis associated with drugs. It seems that primarv damage to the tubule and a secondary reaction in the interstitum is the most likely sequence, although the paucity of changes in tubules in some cases must give rise to certain reservations. The disordered physiology, too, is not understood and is rendered difficult by the inconstancy of the physiologic abnormalities. Certain cases for example have an anuric or oliguric acute renal failure, whereas others show no such decrease in urine formation. Chronic Interstfital Nephritis In chronic interstitial nephritis, there is still the predominant interstitial reaction seen in the acute form, but the polymorphonuclear cell population is lacking and instead of edema there is fibrous tissue. In addition, secondarv glomerular changes of the so-called obsolescent type, or periglomerular fibrosis, mav make their appearance. The picture is seen in a wide variety of conditions including: ischemia, obstruction to urinarv outflow, chronic infection, vesicoureteral reflux, papillarv necrosis, irradiation, uremic medullanr cvstic disease, and the so-called Balkan nephritis. There are other rarer causes, and many for which no explanation can be provided. The likely role of immunologic mechanisms will be consid-

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ered in the section on experimental approaches. Undoubtedly some examples of chronic interstitial nephritis have passed through an acute stagebacterial infections are the best example of this. As mentioned earlier, brucellosis has been described as showing this transition,3 and a case of acute renal failure due to phenindione 2' with sequential biopsies also demonstrated this change. Other conditions however, such as the ischemic kidnev would not show the acute picture during their evolution. Chronic interstitial nephritis is important because it is a nonspecific parenchvmal reaction to a large number of stimuli and one that frequently poses problems for the pathologist, particularly in the interpretation of renal biopsies. In a short article of this type, it is impossible to deal wvith all the conditions leading to chronic interstitial nephritis. However, because of the misconceptions attending them, chronic pyelonephritis and papillary necrosis wvith consequent cortical changes will be considered in further detail. Chronic Pyeonephritis Chronic pvelonephritis, by definition, is the end result of a bacterial infection of the kidney. For practical purposes, it can be differentiated into obstructive and nonobstructive forms. Kidneys with obstructive disease present few difficulties from either a conceptual or diagnostic point of view, for the pelvis and calyces are uniformly dilated and the parenchymal reduction affects both poles and the central part of the kidney. In contrast, the nonobstructive type of renal lesion-so-called because no overt obstructive lesion can be demonstrated-in its purest form shows dilatation of onlv some of the calvceal systems. Those affected are usually in the polar regions, and sometimes the changes are confined to a solitary system. Overlying the dilated calyces are large U-shaped scars, deeper than those caused by ischemia. The rest of the calvces are not dilated and have no overlxing scars. The affected kidnev mav be small, and a likely explanation is that the presence of scars interferes with the growth of the kidney. This explanation is supported by the fact that scar formation frequently occurs in infancy or early childhood, that is, during the growth period of the kidney. As will be described later, patients with severe vesicoureteral reflux and urinary tract infection sometimes develop a more generalized calyceal dilatation, but little information is available on the pathologic changes of this type. Chronic nonobstructive pyelonephritis is a potent cause of chronic renal failure and/or hypertension in childhood; it is not commonlI found outside this age group, especially as a cause of renal failure. The develop-

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ment of the lesion has been a subject of considerable controversy, b)ut clinical and experimental obserxations over the past fevx s-ears haxe greatlx clarified the picture. In the first place, it is noxv accepted that in most cases of acute pyelonephritis, the infection reaches the kidnex- from the lomver urinary tract. This takes place through vesicoureteral reflux-a phenomenon wvell described over 30 years ago n--in x-hich urine is actively propelled up one or both ureters during micturition. Reflux is frequently diagnosed during infancy. Rolleston et al.35 in a study of 1 73 infants with urinarv tract infection found reflux on one or both sides in 49' of cases. It wvas bilateral in 44 cases and unilateral in 42. In a later studv of 350 infants, most of X hom had urinarv tract infections, the same authors noted a 42% incidence. It is obvious from these figures that vesicoureteral reflux is a common phenomenon. Reflux is of various degrees of severity. Gross reflux is the most dangerous 36 because of the concomitant intrarenal reflux that mav occur and because there is less likelihood of spontaneous cure than in the milder cases. In the latter, there is a tendency for vesicoureteral reflux to disappear with time without any surgical intervention.3'537'- For example, Smellie et al.-" observed 73 children up to the age of 12 y-ears for 18 months to 10 x-ears. At the initial examination, vesicoureteral reflux occurred in 121 ureters-it was unilateral in some children-but at follom -up it was no longer present in 62 ureters (over 3Vc0 ). In addition, there -was a decrease in severitv of reflux in other children. Cessation or improvement X as greatest in childretn X ith mild degrees of reflux, but it also occurred in those wvith moderate anid gross degrees. Rolleston et al." observed cessation of reflux in the group with moderate reflux (66%c ) in infants followved for up to 5 years; in the case of gross reflux, only one of eight ureters ceased refluxing over the same time period. Reflux up the ureters sometimes occurs along wxith congenital defects of the urinary tract, but it is often seen as an isolated phenomenon.39 In later age groups, it is found in patients with bladder tumors, enlargement of the prostate, and stone formation.' It is common in patients with paraplegia 41 and is probably responsible for the lhigh incidence of renal damage in that state.'2 The association between chronic pyelonephritis-as judged by the presence of scarring of the kidney- on intraxvenous py elography-and vesicoureteral reflux is a very real one."43" In their most receint paper, Smellie and her colleagues 3 describe renal scarring in 83 children from 0 to 12 x-ears of age with no overt lower urinarx tract obstruction: scarrinlg w-as unilateral in 59 and bilateral in the remainder of these children, the majority of -hom were girls. Vesicoureteral reflux 'was preseInt in oxer 90% of the scarred kidnevs. These authors also point out that in published

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series, between 30 and 60%F of children with vesicoureteral reflux will exhibit renal scarring, the higher figure being quoted from surgical clinics-presumably7 because patients with severe degrees of reflux are referred there for correction-and the lower from medical clinics. Renal scarring is most frequently associated with the more severe forms of vesicoureteral reflux but may be associated with the less severe degrees and, indeed, in patients without reflux.-" It should be remembered that there is a natural tendency for reflux to stop, and those patients with scarring and no reflux at the time of examination may have had reflux in the past. Such an explanation is rendered more plausible by the observations of Smellie et al.'" that in children with scarred kidneys on both sides, unilateral reflux was sometimes found, suggesting that reflux had already stopped on one side; further, cessation of reflux was sometimes observed on the second side during follow-up. It is assumed that infected urine is propelled up the ureter to the kidney, where an acute infection is initiated which eventually destroys renal parenchyma with the formation of the characteristic scars. Until recently, it has not been clear how the infected urine reached the renal parenchyma once it had been transported to the pelvicalyceal system. It is now apparent that one of the ways by which this takes place is intrarenal or calicotubular reflux, a phenomenon demonstrated both in man 47-w and experimentally in the pig.51 In man, it has been shown during the performance of micturating cystograms that radioopaque material may course out from the calyces into the kidney. This occurs with a fan-shaped distribution, the contrast material presumably gaining access to the ducts of Bellini at the papillary tip, from whence it spreads outwards along the collecting tubules. It has been demonstrated that intrarenal reflux occurs in those children with severe and moderate grades of vesicoureteral reflux." Follow-up studies of these children " revealed that progressive renal damage occurred only in those with severe vesicoureteral reflux. Further it was found that the areas of scarring that developed did so in areas corresponding to those in which the contrast material had been observed during the radiologic studies. Hodson 52 has also described such a relationship in 1 patient. Experimentallv, Hodson 5 has demonstrated intrarenal reflux in the miniature pig-an animal with a multipapillary system-by performing puncture cystograms in animals in which the anterior wall of the intramural ureter was slit on one side, coupled with the placement of a silver ring around the proximal urethra. The slitting of the ureter rendered the vesicoureteral "valve" incompetent; the modestly constricted urethra stimulated hvpertrophv of the bladder wall to an extent sufficient to

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propel urine up the ureter during micturition with a force comparable to that in patients with severe reflux. As in man, the contrast material spread outwards in the kidney in a fan-shaped manner from the papillanr tip. Intrarenal reflux took place only when a pressure exceeding 35 mm Hg was attained in the pelvicalyceal system. It was further observed over the ensuing months that the pigs developed scars in the renal parenchyma and that these scars occurred in the same sites as those in which reflux t(xok place. These observations are of considerable interest for several reasons. In the first place thev demonstrate most convincingly the phenomenon of intrarenal reflux. Second, they confirm the findings in man of the identical sites of reflux and scar formation. Third, they show that scars may form in the absence of infection of bladder urine; the urine in these experiments was cultured weeklv and found to be sterile. The last of these points is important because it lends support to the idea that vesicoureteral refluxeven of sterile urine-can cause renal scarring, a suggestion made by Hodson and Edwards " many years ago. Cases of scar formation without urinarv tract infections are difficult to document in man with absolute certaintv because such a claim would require virtually continuous monitoring for sterility. Cases have been recorded of renal damage occurring with apparent sterile reflux,'" but it should be stated that the kidney in this situation often shows diffuse blunting of the calyces and generally thinning of the parenchyma, rather than the focal scars of the pyelonephritic kidney. The question of obstructive atrophy in such a situation is discussed bv Williams.55 In contrast to the claims of the damaging effect of sterile reflux are the experiences of Stephens 3" and Smellie et al.," Stephens comments that he has seen reflux without urinary infection acting for more than 10 years with no deterioration of excretorv pyelograms in children. Moreover, there was no interference with the growth of these kidneys. Smellie et al." record that they have seen no development or extension of renal scarring in 150 children with all grades of reflux-which had persisted from 2 to 10 years-in whom the urine had remained sterile during conservative treatment. Assuming that reflux of sterile urine can in certain circumstances cause damage to the parenchyma with ultimate scar formation, it is not clear at the moment how this occurs. Another point that requires clarification is the site of the scar in nonobstructive pyelonephritis. The distribution of the scars is predominantly polar, and this is also true for the site of maximal incidence of intrarenal reflux. It is conceivable that the upper pole is frequently involved by its position in line with the refluxing jet of urine, but this rather simple explanation would not hold for the lower pole. A more likelv explanation has been provided by a recent studv on piglets," in which it was shown

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that in the larger compound papillae of the upper and lower poles the orifices of the ducts of Bellini cannot be occluded by a rise in pressure in the calyx. This is in contrast to the midzonal papillae, where the orifices close readily in the presence of vesicoureteral reflux." In summarv: Vesicoureteral reflux is a phenomenon that, with the exception of such a condition as paraplegia, usually occurs in infancy and early childhood. It provides a mechanism whereby organisms can be delivered to the pelvicalyceal system of the kidney. In the severe cases, intrarenal reflux also occurs and provides the means whereby bacteria can gain access to the renal substance; this sets up infection with the eventual production of the large polar scar of chronic nonobstructive pyelonephritis. Also, it appears that in the pig under experimental conditions, intrarenal reflux of sterile urine can cause formation of scars similar to those caused by infected urine. If the damage inflicted is sufficiently great, the combination of scarring and the concomitant inhibition of renal growth can give rise to chronic renal failure and/or hypertension. In the less severely scarred kidneys, the damaged area may act as a source of bacteriuria and account for some of the cases of persistent asymptomatic bacteriuria diagnosed during screening tests or during prenatal examinations. The problem of chronic nonobstructive pyelonephritis has been a bothersome one, but we are now beginning to see it in better perspective. The previously quoted high incidence in an autopsy population has had to be revised, and when strict criteria are used, it is found to be a relatively uncommon condition once childhood has been passed. The overdiagnosis was undoubtedly due to a failure to recognize the nonspecific nature of the parenchymal reaction of chronic infection, the various figures quoted being those of chronic interstitial nephritis of diverse origins. Certain troublesome aspects remain. In human studies in which there have been severe grades of vesicoureteral reflux,"'" and in the experimental studies in the pig,51 the kidneys may show a generalized blunting of the renal papillae. No extensive descriptions of the pathology have been given in the case of the human kidneys with severe reflux because the two studies quoted have been based on radiologic appearances. In the case of the experimental lesions in pigs, it was stated that in addition to the blunting of the papillae and generalized narrowing of the cortex, coarse polar scars were also present. If the same holds for man, it should still be possible to separate chronic pyelonephritis from purely obstructive lesions with generalized papillary blunting and cortical thinning by the additional presence of coarse scars. Vesicoureteral reflux is clearly a most important phenomenon, and the

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suggestion has been made that we dispense with the term pyeloneplritis and substitute reflux nephropathy.57 While there is merit to this, it means the introduction of vet another new term into an alreadv confused field, and mv own personal feeling is that we should retain the term chrontic pyelonephritis until more information is available, particularly on the abilitv of sterile reflux to cause discrete scars in man. The issue of continuing renal damage in chronic pyelonephritis is an interesting one. In the presence of infected urine it has been noted that fresh scar formation can take place, and it is likely that continuing vesicoureteral reflux is one of the major factors. This has been best documented bv Smellie et al." in children with kidneys that were normal initiallyr bv radiologic criteria and in children with already damaged kidnevs. In these cases there was invariably a definite infection preceding the appearance of the scars. Similar new scar formation wvith the combination of infection and vesicoureteral reflux has also been reported by others.-"-',-" Certain observations have suggested that continuing renal damage can occur in chronic pyelonephritis in the apparent absence of bacterial infection.59 Some patients give no evidence of ever having had urinar% tract infections, whereas others may have had evidence of infection in the past but no positive urinary cultures recently. Clearly one of the possibilities in the former group is that the patient does not have chronic pvelonephritis according to the criteria we have adopted but instead has a chronic interstitial nephritis of undetermined etiology. Accepting that infection has been responsible for the initial renal injury, -hat are the likely explanations for continuing damage? First there is the pxssibilitv of continued vesicoureteral reflux; as mentioned earlier, this has the potential for causing renal damage in the absence of infected urine. Second, there may be persisting occult bacterial infection in the kidney." In such patients there are some periods when there is bacteriuria but others w hen there is merelv sterile pyuria; consequently, erroneous conclusions wvould be drawn if urine samples were taken during the sterile phases. The role of protoplast or L-forms of bacteria as a cause of progressive renal destruction has been considered in a patient of Davies et al.6" In this 39-year-old woman there was a persistent sterile pyuria but no evidence of obstruction and no vesicoureteral reflux; excretory urography showed progressive bilateral loss of renal substance and mounting nitrogen retention. L-forms of S. faecalis were cultured, and after treatment wvith erythromvcin and ampicillin, the pvuria disappeared and L-forms could no longer be isolated. The isolation of protoplasts has also been achieved by others.62 63 It should be emphasized that there is little evidence for the idea that

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protoplasts can cause renal damage without their reverting to their original form. Third, an obstructive factor could develop and contribute to the renal damage. Fourth, hypertension if present could cause progressive damage by producing narrowing of the arteries. And, fifth, there are various possible immunologic mechanisms. The development of autoantibodies to kidney structures is one of the possible immunologic mechanisms. Kovats " has demonstrated that endotoxins can alter tissue antigenicitv, so it would be theoretically possible for autoantibodies to be produced against this altered tissue. Further, Holmgren et al." found that Serotvpes 0-2, 0-14, and 0-22 of E. coli and renal tissue shared a common antigenic determinant, so that antibody to these various types could theoretically react with renal antigen and provide the basis for a damaging immunologic reaction. As Andersen et al." have pointed out, only a limited number of cases could be explained in this wav; the 3 cases in which thev tested this possibility showed antiboxd directed against Serotvpe 0-8. In man and laboratory animals the evidence for the production of autoantibodies directed against the kidney is not good. This problem was investigated by Kalmanson and Guze67 in a group of 183 middle-aged and elderly men with bacterial counts in their urine exceeding 100,000 bacteria/ml. This figure is one that is c-onsidered to denote a significant bacteriuria, although it should be observed that it simplv refers to the number of organisms in the urine wmithout specifying the source of the bacteria in the urinary tract. In this particular studv, there was proof of the kidnev being infected in many of the patients, but in spite of this there was no evidence of antihuman kidney antibod'ies in the serum using an indirect tanned erythrocyte hemagglutination technique. Miller et al." produced pyelonephritis experimentally in the rabbit using E. coli, and then attempted at various time intervals to determine if antibody svnthesized locally in the kidnev was directed against infected or normal kidney tissue. They found such antibody in only 2 of 8 animals, and even in those 2 the antibodv accounted for only 15 of the lgG synthesized. They concluded that their studies did not support the idea of an autoimmune process contributing to the progression of the pathologic process in "sterile" chronic pyelonephritis. As will be described later, it is possible to produce antitubular basement membrane (anti-TBNI) antibodies in Brown Norway rats by the injection of a suspension of rat kidney in adjuvant. Utilizing this fact," Cotran produced pvelonephritis in Brown Norway rats and looked for linear fluorescence against IgG along tubular basement membranes. This would indicate anti-TBNI antibo)dy formation which could act as a possible mechanism for renal damage in chronic pyelonephritis. No staining was present in rats with chronic Protetus or

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chronic enterococcal infections. It therefore appears that there is i10 evidence for anti-TBMI antibodies playing a pathogenic role in these tw o forms of experimental pyelonephritis. Schwartz and Cotran 70 also failed to demonstrate staining for IgG and C3 in tubular basement membranes in twelve human kidnevs from patients with pyelonephritis, thus failiing to support the idea of anti-TBNI antibodies playing a part in prodducing renal damage. In contrast to these various observations is the %ork of LOSSe et al.7' in which a unilateral pvelonephritis was produced in the rab)bit X ith E. coli. Antibodies directed against a kidney specific antigen and antibodies against an antigen present in liver and kidne- were demonstrated, supporting the notion of an autoimmune mechanism. How ever, the paper omits some important details such as information on histologic changes in the contralateral kidney. If these antibodies had been of any consequence in producing renal damge, changes would have been anticipated in the opposite kidney. There has been speculation about the part that bacterial antigenic residues play in perpetuating renal damage. These antigenic residues can be demonstrated in the kidneys of laboratory animals for several %-eeks or months after induction of acute pvelonephritis, and they may be found long after it is impossible to culture bacteria from the kidneVs.72-74 it is considered that they do not play any significant role in causing further renal damage, but it is likely they may act as a stimulus for local antibody synthesis by the kidney. Finally, the importance of cell-mediated immunity in the kidney must be considered. NMost of the work to date has been concerned x -ith glomerulonephritis, both experimental 75and human,76'77and has used such tests as inhibition of cellular migration and rosette formation. Kalmansonl et al.78 have studied the role of cell-mediated immunity in pyelonephritis using parabiosis. Bilateral pvelonephritis was induced in Fischer rats byan intravenous injection of S. faecalis. The infection was treated mvith penicillin and kanamycin; treatment w%as started 12 weeks after induction and was continued for 16 weeks. Viable bacteria were thereby eliminated. At this time interval, one kidney w-as removed from the recipient, and the remaining kidney of the recipient and those of the donor wvere removed at later intervals. Kidneys were examined histologically and cultured for bacteria. It was found that the kidneys of the recipient rats developed parenchymal lesions that were qualitatively similar to those of the donor; the lesions consisted of superficial scars, tubular atrophy with thickeniing of the basement membranes, mononuclear cell infiltration, and periglomerular fibrosis in the more severely affected areas. Because in previous experiemnts these workers had show n there was no humoral an-

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tibody to kidney antigens, they concluded that cell-mediated immunity was responsible for the renal lesions in the parabiosed rats. Kalmanson et al.79 have also demonstrated inhibition of migration of peritoneal macrophages from rats w-ith experimental enterococcal pyelonephritis on exposure to kidney antigen. The inhibition appears to be tissue specific, as it ,was not found with either muscle or liver antigens. Cotran " has referred to the difficulties experienced in the macrophage inhibition test in the rat and has instead used lvmphocvte transformation as a test for cell-mediated immunitv. He used Brown-Norway rats wvith enterocKccal pvelonephritis and was able to demonstrate that their lymphocytes could be stimulated by bacterial antigen but not by renal antigen. The results were regarded as preliminarv, but they did suggest that rats with pyelonephritis developed a delayed hypersensitivity reaction to the infecting bacteria but not to the homologous kidney antigens. It could not be ascertained -whether the cell-mediated immunity to bacteria contributed to either the composition of the cellular infiltrate in the renal lesion or the progression of the lesion. The evidence for cell-mediated immunity contributing to the lesion of chronic pvelonephritis is therefore rather conflicting, and because of the paucity of studies, judgment should be reserved at the present time. It is difficult to determine which of the various factors discussed is responsible for the progression of the chronic pvelonephritic lesion in the apparent absence of persisting infection. An obvious characteristic of pvelonephritis must always be taken into account when generalized phenomena (such as immunologic entities) are being considered; this characteristic is the focal nature of pyelonephritis. Except in the minute atrophic pyelonephritic kidnevs-and the infective origin of many of these must be in doubt-it is usual to see areas of uninvolved parenchyma Xwith relatively normal glomeruli and tubules. Also, unilateral cases undoubtedlv exist in man, and certainl1 unilateral pyelonephritis may be produced experimentally. It is, therefore, difficult to conceive of an immunologic mechanism playing a meaningful role in the progression of the pyelonephritic lesion because such a mechanism would be expected to involve all of a given infected kidney and the opposite kidney in the case of unilateral infections.

Papillary Necrosis In discussing papillary necrosis, it is necessary to consider the chronlic interstitial nephritis found in the cortex in the more chronic forms. Papillary necrosis (ocurs in an acute form in both diabetes and obstruction to urinary outflow. More chronic forms occur as a result of overindulgence in

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analgesics and in patients with sickling disorders. The acute forms are usuallv terminal and will not be considered here. Overindulgence in analgesics is probably the most common cause of the more chronic forms of papillary necrosis. The historical aspects have been treated elsewhere 7 and will not be repeated here. It was formerly believed that the initial lesion was in the cortex, taking the form of tubular loss and atrophy, with fibrosis of the interstitium which contained variable numbers of chronic inflammatorv cells; papillarv necrosis was considered to be of secondary importance. With greater experience of the condition, the importance of papillary necrosis became better appreciated, but there was still an adherance to the primacy of the cortical lesion, particularly among European authors. Largely because of the Australian studies,8" it became apparent that papillarv necrosis was the primary and predominant lesion in the analgesic-injured kidney and that the cortical changes were secondary to this. The interesting fact was noted that the portion of the cortex affected was that part directly- overlying the papilla, whereas the cortex in the columns of Bertin was frequently normal and, in particular, free of interstitial nephritis. A similar distribution is found in experimental papillary necrosis " in which tubular atrophy with interstitial change takes place predominantly in that part of the cortex overlying the necrotic papilla, with less severe changes in the perihilar cortex-the homolog of the columns of Bertin. It is, therefore, clear that such cortical changes as occur are the consequence of the papillary necrosis rather than an independent or a concomitant lesion. Thev are probably produced by interference with the continuity of the tubular svstem. The reasons for the sparing of the columns of Bertin in man and its homolog in the rat are not apparent, but it is possible that the cortical changes are a function of interference with the long loops of Henle-which arise only from the deeper glomeruli such as are situated in the juxtamedullary region overlying the papilla-rather than interference with the collecting ducts which drain all nephrons irrespective of their position of origin in the kidnev. Although most cases of analgesic abuse have been recorded in Switzerland, Scandinavia, and Australia, the North American continent is not exempt."- Murray and Goldberg,8" in an analysis of the causative factors in 101 patients with interstitial nephritis seen in Philadelphia, found that 20 were abusers of analgesics. Taking into account the total poxl of patients from which these figures were obtained, these authors calculated that analgesic abuse accounted for some 7% of cases of chronic renal disease. The pathogenesis of papillary necrosis in analgesic abuse is not under-

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stood, but the two main alternatives are: a) an interference with the blood

supply to the papilla u'" and b) a poisoning of the papillary structures." In patients with sickling disorders it is common to find small areas of chronic interstitial nephritis in the cortex, which on serial sectioning can be traced back to old infarcts in the papilla. Larger infarcts with considerable cortical change are also seen, but these are less frequent. Expeimenal Approache and Possibl Human Countrparts

Apart from the studies on pyelonephritis referred to earlier, little experimental work had been done on interstitial disease until recent years. Serious efforts are now being made to understand interstitial inflammatory disease; the immunologic aspects in particular are being actively studied. Andres and McCluskey 9' have recently reviewed the immunologic aspects of tubular and interstitial renal disease. The tubular aspect is considered because interstitial inflammatory changes are usually associated with tubular damage, and it is often impossible to determine which is the primary event. Most of the experiments have utilized tubular components as the antigenic agent, and basement membrane in particular has been utilized. Anti-tubular basement membrane antibody disease (anti-TBM disease) was first produced by Steblay and Rudofskv,91 who injected guinea pigs with preparations of rabbit tubular basement membrane mixed with Freund's adjuvant. Tubular damage took place which was accompanied bv mononuclear and giant cells appearing in the interstitium. There was a linear fluorescence along tubular basement membranes with antibody directed against guinea pig IgG. The guinea pig model has also been studied by Lehman et al." using immunization with a variety of bovine renal basement membrane preparations; all 28 animals used showed linear fluorescence for IgG along tubular basement membranes, and 13 of them also showed linear fluorescence along glomerular capillary basement membranes. Elution of renal-bound IgG revealed antibodies against both TBM and glomerular basement membrane (GBM), although anti-GBM activity was usually not detectable at low concentrations of IgG in the eluates. Deposition of C3 by direct immunofluorescence was demonstrable in the guinea pig immunized with the basement membrane fraction containing the greatest proportion of cortical TBM. It was not demonstrable in guinea pigs treated with other fractions, even though tissue injury took place in these animals. It is therefore possible that histologic injury may occur independently of detectable complement deposition, and this is supported by the demonstration that the disease can be produced in guinea pigs deficient in C4.' Tubular damage with a pronounced interstitial inflammatory reaction can

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also be produced in the rat, but up to the present it has only been possible to do this in the Brown Norway or Lewis-Brown Norway F, strains,'' presumably because they are the only strains possessing the necessary TBM antigen. In one of these studies the rats were injected with suspensions of rat kidney (Sprague-Dawley strain), Freund's adjuvant, and pertussis vaccine; in the other the rats were injected with bovine tubular basement membrane plus adjuvant containing pertussis vaccine. The former of these studies " was complicated at a late date by autologous immune complex glomerulonephritis. However, the initial lesion in the first study and the only lesion in the other" was a considerable interstitial reaction of polymorphonuclear leukocytes and mononuclear cells. Tubular loss and interstitial fibrosis took place at a later time. Linear fluorescence along the tubular basement membranes and the presence of antiTBM antibodies in kidney eluates and serum were demonstrated. While these various experiments are examples of primary tubular damage with the interstitial reaction acting as a reaction to it, they do provide a start in a search for the factors concerned in interstitial nephritis. Certain cases have been described in man in which there is an interstitial nephritis and in which anti-TBM antibodies have been shown to be present. Reference has already been made to methicillin hypersensitivity and the part played by anti-TBM antibodies."14'1'` In addition to these, there is a case report of a 6-year-old boy " who underwent renal biopsy because of polydipsia, polyuria, microscopic hematuria, proteinuria, aminoaciduria, and glucosuria. Histologic study of the tissue obtained revealed severe loss and atrophy of proximal and distal tubules, with a markedly fibrotic interstitium with foci of round cells and occasional lymphoid follicles. Glomeruli were either normal, showed periglomerular fibrosis, or were completely hyalinized. Linear fluorescence was present along tubular basement membranes with antisera against IgG and C3, but no fluorescence was seen in glomeruli. Linear fixation of rabbit complement to tubular basement membrane was found, and anti-TBM antibody was demonstrated in the patient's serum. No anti-GBM antibodies were detected in the serum. It is, therefore, likely that anti-TBM antibodies were responsible for the tubular damage and the associated interstitial reaction. However, the authors were careful to point out that antibody formation could have followed tubular injury and release of tubular antigens. Other examples of interstitial nephritis on the basis of anti-TBM antibodies in man are available, but in these there is evidence of preceding or concomitant glomerular disease. A patient studied by Morel-Maroger et al.,'7 on whom several biopsies were done over a 28-week period, showed in the first two biopsies (2 and 7 weeks after onset) a severe post-

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streptococcal glomerulonephritis wvith granular deposits of lgC ain(l :3 in the glomeruli but no staining in the tubules. In the third andi fourtlh biopsies (17 and 28 weeks after onset), there was progressive glomerular sclerosis with diminishing amounts of immunoglobulins and C3 but Xvith the appearance, in the fourth biopsy, of linear staining along the tubular basement membranes for IgG. Anti-TBN1 antibodies X vere demoinstratedc in the serum at that time. At the time of the fourth biopsy the interstitium mvas extensively sclerosed and contained numerous lymphocytes aild plasma cells. It is tempting to suggest that the interstitial changes were a consequence of the action of anti-TBM antibodies on tubular basement membranes, but the authors were careful to point out that histologic sigIns of tubular and interstitial change preceded the accumulation of Ig(G along tubular basement membranes. Tung and Black" also described a case of glomerulonephritis complicated by the development of anti-TBM anitibodies some 2 months after renal biopsy; this w as a membranous glomerulonephritis. When the glomerulonephritis was diagnosed it vvas not possible to demonstrate anti-TBM antibodies, either by direct imnmunofluorescence in the biopsied tissue or in the serum, vet at this time tlhere ,was an interstitial nephritis \-ith "heavy infiltrates of inflammatory cells. The interstitial cells Xvere lymphocytes, plasma cells, monocytes, andi occasional eosinophils. It is. therefore, doubtful whether this case cani be claimed as an interstitial reaction secondarv to tubular damage by antiTBM antibodies. A unique feature of the case wvas the presence of electron-dense deposits in tubular basement membranes w-hich reacted with antibody to IgG, IgMN, IgA, and C3 using immunofluorescence techniques. It is conceivable that these could have initiated the sequence of events leading to the interstitial reaction, particularly in light of the comments that w%ill be made on tubular and interstitial immune complex diseases in the next few pages. Anti-TBNI antibodies have also been demonstrated as part of diseases caused by anti-GBN1 antibodies; most of the patients in w hom the co)mbination has been encountered have Goodpasture's syndrome,"`101 although apparently it can occur in patients w ith glomerulonephritis and no lung lesion.","101 This is another demonstration of the cross reactivity of GBM and TBNI that is brought out so clearly in the wvork of Lehman et al." In addition, Klassen et al.'02 and Wilson et al. 03 have described antiTBM antibodies in renal allografts. Immune complexes may also play a part in the production of interstitial nephritis, and complexes situated in tubular basement membranes have been described in rabbits "," and rats .6 In brief, these experiments consisted of the injection of homologous renal tissue with adjuvant into

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the species under study. Interstitial fibrosis and mononuclear cells were found along with damage to the tubules, with only minor changes in glomeruli, at least in the early stages. Granular fluorescence with antisera to IgG and C3 was present along tubular basement membranes anid intertubular capillaries. It was suggested that autoantibodies were formed against cytoplasmic antigens of the tubular cells and that deposits wvere formed locallv as a result of antigen "leaking" out of the tubular c-ells and reacting with antibody as if diffused out of the peritubular capillaries. There are parallel situations in man, but up to the present, most of the patients in whom immune complexes have been found in the tubular basement membranes have had immunologic glomerular disease. Klassen et al.10" have described complexes in patients with svstemic lupus erythematosus, rapidly progressive glomerulonephritis, membranoproliferative glomerulonephritis, lipoid nephrosis and in a patient with idiopathic interstitial and tubular disease. With electron microscopy these complexes appear as discrete electron-dense deposits in the tubular basement membranes and intertubular capillary walls. Large ribbon-like dense deposits may also be seen in tubular basement membranes, Boxwman's capsule, and glomerular capillary walls in the so-called dense deposit disease.10',' These are probablv not antigen-antibody complexes, and although the pathogenesis of this condition is not understood, it is likely that the properdin pathway rather than the classic pathw ay of complement activation is involved.'09 The high incidence of dense deposit disease in patients with partial lipodystrophy is of note.10F112 Whereas both immune complexes and antitubular basement membrane antibodies play a part in the production of the interstitial reaction of glomerulonephritis, their role in producing a primary interstitial nephritis is not clear. Morel-MNaroger et al.97 have stated that in 1800 renal biopsy specimens studied by immunofluorescence techniques they have not seen a single example of linear staining of tubules with the exception of the case referred to earlier. By analogy with the experience of Sugisaki et al." in the experimental model, it is possible that linear fluorescence along tubules could disappear once the interstitial reaction had been initiated.

Conclusiwis Interstitial nephritis is a common condition, wvhich in spite of a relativelv constant pathologic picture has different etiologic agents and pathogenetic mechanisms. Failure to appreciate this, particularly in the chronic group, has led to considerable confusion and has been largelx responsible for the overdiagnosis of chronic pyelonephritis. Although we are still largely ignorant of the causes of interstitial nephritis, it is no,%

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possible to define many of them. While experimental studies have not made spectacular contributions to our understanding, an attempt is now being made to develop appropriate models, and we hope these w%ill enable us to still further clarify our understanding of other entities. References 1. Councilman WT: Acute interstitial nephritis. J Exp Med :3:393-420, 1898 2. Heptinstall RH, Gorrill RH: Experimental pyelonephritis and its effect on the blood pressure. j Pathol Bacteriol 69:191-198, 1955 3. Muehrcke RC: Acute Renal Failure: Diagnosis and Management. St. Louis. C.N. NMosby, Co., 1969 4. French AJ: Hspersensitivity in the pathogenesis of the histopathologic changes associated with sulfonamide chemotherapy. Am J Pathol 22:679-701, 1946 5. More RH, McMillan GC, Duff GL: The pathology of sulfonamide allergy in mani. Am J Pathol 22:703-735, 1946 6. Robson M, Levi J, Dolberg L, Rosenfeld JB: Acute tubulo-interstitial nephritis following sulfadiazine therapy. Isr j Med Sci 6:561-566, 1970 Heptinstall RH: Pathology of the Kidney, Second edition. Boston. Little. Brown & Co. 1974 8. Decroix G, Pujet JC, Homberg JC, Feldman A, Kleinknecht D: Insuffisance r&nale aigue due d la rifampicine. Nouv Presse Med 2:2093-2095, 197:3 9. Schrier RW, Bulger Rj, VanArsdel PPJr: Nephropathy associated mvith penicillin and homologues. Ann Intem Med 64:116-127, 1966 10. Plafker J: Penicillin-related nephritis and myocarditis: A case report. South Med J

64:852-84, 191I 11. Baldwin DS, Levine BB, McCluskey RT, Gallo GR: Renal failure and interstitial nephritis due to penicillin and methicillin. N Engl J Med 279:1245-12.2. 1968 12. Tannenberg AM, Wicher Kj. Rose NR: Ampicillin nephropathy. JAMA 218:449. 197i 1 13. Woodroffe AJ, W-eldon MI, Meadows R. Lawrence JR: Acute interstitial nephritis following ampicillin hypersensitivity. Med j Aust 1:6548, 197:5 14. B)rder WA, Lehman DH, Egan JD, Sass HJ. Glode JE, Wilson CB: Antitubular basement-membrane antibodies in methicillin-associated interstitial nephritis. N EngI J Med 291:381-38, 1974 15. Mavaud C, Kanfer A, Kourilsky 0, Sraer JD: Interstitial nephritis after methicillin. N EngI J Med 292:1132-113.3, 1975 16. Sanjad SA, Haddad GG, Nassar VH: Nephropathy an underestimated co)mplication of methicillin therapy. j Pediatr 84:873-877. 1974 17. \M&y JP. Morel-Maroger L: Acute interstitial nephritis: A hypersensitity reaction to drugs. Proceedings of the Sixth International Congress of Nephrology, Florence. 1975. Basel, S. Karger (In press) 18. Kirkebv K: Agranulocytosis following treatment with pheny lindanedione. Lancet 2:580-581, 1954 19. Galea EG, Young LN, Bell JR: Fatal nephropathy due to phenindione sensitivity. Lancet 1:920-9'22, 1963 20. Baker SBdeC, Williams RT: Acute interstitial nephritis due to drug sensitivity. Br Med J 1:1655-1658, 1963 21. Lee HA, Holden CEA: Phenindione nephropathy with recovery: Studies of morphology and renal function. Postgrad Med J 40:326-3:31. 1964

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Rapin NM, Amstutz Ph, Gorce F. Barois A, Goulon NI: Anurie par n&phropathie interstitielle aigue au decours d'un traitement prolong, par la phenindione. Presse Med 72:2279-2284, 1964 Turiaf NMj, Basset F, Battesti JP: HWpaton6phrite aigue mortelle due au ph6nylindanedione. Bull Soc Med Hop Paris 116:9-23, 1965 Smith K: Acute renal failure in phenindione sensitivity. Br Mted j 2:24-26, 1965 Guedon J, Corbin JL, Vaugnat P, Chapman A: Nephropathie interstitielle aigui avec anurie transitoire secondaire d un intolerance a li phenindione. J Urol Nephrol 72:901-908, 1966 Nicholls M G, Heale WF: Phenindione sensitivity and acute renal failure. NZ Ned j 7 1:214-216, 1970 Sraer JD, Beufils P, Morel-Maroger L, Richet G: Nephrite interstitielle chroni(lue: Due a la phenylindanedione faisant suite a une insuffisance renale aigue. Nouv Presse NMed 1:193-196, 1972 N'an W%?vk JJ, Hoffmann CR: Periarteritis nodosa: A case of fatal exfoliative dernatitis resulting from "'Dilantin sodium" sensitization. Arch Intern Ned 81:605461 1, 1948 Lyons H, Pinn VW, Cortell S, Cohen JJ, Harrington JT: Allergic interstitial nephritis causing reversible renal failure in four patients with idiopathic'nephrotic syndrome. N Engl J NMed 288:124-128, 1973 Ortuilo J, Botella J: Recurrent acute renal failure induced by phenazone hypersensitivitv. Lancet 2:1473-1476, 1973 Sloth K, Thomsen AC: Acute renal insufficiency during treatment with azathioprine. Acta Med Scand 189:145-148, 1971 Ooi BS, First MR, Pesce AJ, Pollak VF, Bemstein IL, Jao W': IgE levels in interstitial nephritis. Lancet 1:1254-1256, 1974 Faarup P, Christensen E: IgE-containing plasma cells in acute tubulointerstitial nephropathy. Lancet 2:718, 1974 Young HH, Frontz WA, Baldwin JC: Congenital obstruction of the posterior urethra. J Urol 3:289-365, 1919 Rolleston GL, Shannon FT. Utley WLF: Relationship of infantile vesicoureteric reflux to renal damage. Br M1ed J 1:460-463, 1970 Rolleston GL, Shannon FT, Utley WFL: Followv-up of vesico-ureteric reflux in the newbom. Kidney Int 8:S59-S64, 19735 Stephens FD: Urologic aspects of recurrent urinary tract infection in children. J Pediatr 80: 725-737, 1972 Smellie J, Edwards D, Hunter N, Normand ICS, Prescod N: 'Vesico-ureteric reflux and renal scarring. Kidney Int 8:S65-S72, 1975 Edwards D: Significance of vesico-ureteric reflux in childhood. Urinarv 1ract Infection. Edited by F O'Grady, W Brumfitt. London, OxfoFd University Press,

1968, pp 104-107 40. Amar AD, Singer B, Lewis R, Nocks B: Veisocureteral reflux in adults: A twelveyear study of 122 patients. Urology 3:184-189, 1974 41. Hutch JA: Etiology and incidence of reflux in children. Proceedings of a Workshop on Ureteral Reflux in Children. Edited by JF Glenn. Washington, DC., National Academy of Sciences, 1967, pp 135-140 42. Tribe CR: Causes of death in the early and late stages of paraplegia. Paraplegia 1:1947, 1963 4.3. Hodson, CJ, Edwards D: Chronic pyelonephritis and vesico-ureteric reflux. Clii Radiol 11:219-2.31, 1960 44. Rosenheim ML: Problems of chronic pyelonephritis. Br NMed j 1:14.3-1440, 196:3 4.5. Smellie JNI, Hodson CJ, Edwvards D, Normand ICS: Clinical and radiological features of urinary infection in childhoxod. Br Med j 2:1222-1226, 1964

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46. Scoctt JES. Stansfeld J\1: Lreteric reflux and kidnev scarrinig in children. Arch Dis (hild 4:3468-470. 1968 47. Kohler R: Investigations on backflow- in retrograde pyelograph\: A roentgenological and clinical study. Acta Radiol (Suppl) 99:7-92, 1953 48. Brodeur AE. (Go(er RA. MIelick W: A potential hazard of barium cystographb. Radiology V:1080-1084. 1965 49. AAmar AD: Calicotubular backflowv ith vesic()ureteral reflux: Relation to pyelonephritis. JAMIA 213:29:3-294. 197-0 .50. Rolleston (;L. Mlaling TM1J. Hodson CJ: Intrarenal reflu.x and the searred kidne\. Arch Dis Child 49:531-539. 1974 31. H(udson J. Maling TMJ. MlcManamon PJ. Le is MG: Reflux nephropath\. Kidnew Ilot 8:50-S.8. 1975 32. Hodsoin CJ: The mechanism of scar formation in chronic pyelomephritis. Relal Infection and Renal Scarring. Edited by P Kincaid-Smith, KF Fairlev. Melbourne. Mercedes. 1970. pp :327-_329 5:3. Hutch JA. Smith DR: Sterile reflux: Report of 24 cases. LUrol Int24:460-465. 1 9 .54. Stickler GB. Kelalis PP. Burke EC. Segar WE: Primars- interstitial nephritis s\ith refluix: A cause of hypertension. Am J Dis Child 122:144-148, 1971 55. Williams DI: The ureter. the urologist and the paediatrician. Proc R Soc Med 63:595-.602. 1970 .56. Ransle\ PG. Risdon RA: Renal papillae and intrarenal reflux in the pig. Lancet 2:1114, 1974 57. Bailes- RR: The relationship of vesico-ureteric reflux to urinary tract infection and( chronic pyelonephritis-reflux nephropathy. Clin Nephrol 1:132-141. 197:3 .58. Penn IA. Breidahl PD: Ureteric reflux and renal damage. Aust NZ J Siurg 3: 16:3-168. 1967 .59. Angell ME. Relman AS. Robbins SL: Active chronic pyelonephritis without evidence of bacterial infection. N Engl J Med 278:1:303-1308, 1968 60. Fairlev KF. Butler HM: Sterile pyuria as a manifestation of (ocult bacterial pyelonephritis with special reference to intennittent bacterituria.'2 pp 51-67 61. Davies .AG. McLachlan M SF. Asscher AW: Progressise kidney damage after nonobstructive urinarv tract infection. Br Med J 4:406-407. 1972 62. Kalmanson GM. Guze LB: Pyelonephritis: Isolation of protoplasts from human kidnex tissue. Microbial Protoplasts. Spheroplasts and L-Forms. Editedl by LB Guze. Baltimore. Williams & Wilkins Co.. 1968. pp 406-414 63. Turck M. Gutman LT. Wedgwood Rj. Petersdorf RG: Significance of b)acterial variants in urinarv tract infections.62 pp 413-421 64. Kovats TG: The role of endotoxin in autoimmune processes. Naturwissenschaften 48:572-57 ;3. 1961 65. Holmgren J, Hanson LA. Holm SE. Kaijser B: An antigenic relationship betwveen kidnev and certain Escherichia coli strains. Iiit Arch Allergy Appl Immunol 41:46:3-4 4. 1971 66. Andersen HJ. Jacobsson B, Larsson H. WVinberg J Hy pertension. asy mmetric renal parenchymal defect, sterile urine, and high E. coli antitbold titre. Br Med J :14-18. 197,3 67. Kalmanison GM. Guze LB: Pv-elonephritis: An attempt to demoilstrate anti-kidnte\ antibo)ds in the sera of patients w ith chronic bacteriuria. .m J Med Sci 246:532-5.36. 1963 68. \Miller TE. Smith JW. Lehmann JW. Sianford JP- .utoinmmunits in chronic exjx'rimenital pvelonephritis. J Infect Dis 122:191-195. 1970 69. Cotran RS: Pathogenesis of chronic pyelonephfitis: The role of humoral and cell-mediated reactionis to bacterial and renal antigen.' (In press) 70. Schwartz MM. Cotran RS: Common enterobacterial antigen in human clroniic

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and interstitial nephritis: An immunofluorescenit stud%. N Engi Med 289:830-8:35. 1973 Losse H, Intorp HXV. Lison AE. Funke C: Exidence of ani autoimmurne metianism in pyelonephritis. Kidney- Int 8:S44-S49. 1973 Sanford JP. Hunter BW%'. Donaldson P: Localization and fate of E.scherichia coli in hematogenous pyelonephritis. J Exp Med 116:285-294. 19642 Cotran RS: Retrograde proteus pyelonephritis in rats: Localization of anltigen and(l antiboxdv in treated sterile pyelonephritic kidne!s. j Exp Med I17:813-_22. 1963 (,otran RS. V-ivaldi E. Zangwill DP. Kass EH: Retrograde proteus pyelonephritis in rats: Bacteriologic. pathologic and fluorescent-antibod% studies. Am J Pathol 4:3:1-31. 196:3 Crupe WE: An in vitro demonstration of cellular sensitivit\ in experimetntal ;autoimmune nephrosis in rats. Proc Soc Exp Biol Med 127:121 -1222 1968 Rocklin RE. Lewvis EJ. David JR: In vitro evidence for cellular hypersensitivit\ to glomerular-basement-membrane antigens in human glomerulonephritis. N Engl J Med 28:3:497-301. 1970 Mlahieu P. Dardenne M. Bach JF: Detection of humoral and cell-mediated immunitv to kidnex basement membranes in human renal diseases. Am J \led 5:3:1VD-192 1972 Kalmanson GM. Classock RJ. Montgomerie JZ. Guze LB: Pxelonephritis transferred b! parabiosis. Proc Soc E.xp Biol Med 146:1097-1100. 1974 Kalmanson GM. Glassock RJ. Harwick HJ. Guze LB: Cellullar immunit\ in experimental pyelonephritis. Kidney Int 8:S35-S43. 1973 Daw-born JK. Fairley KF. Kincaid-Smith P. King WVE: The associationi of peptic ulceration, chronic renal disease. and analgesic abuse. Q J Med 33:69-8:3. 1966 Sanerkin NG: Chronic phenacetin nephropathy (mvith particular reference to the relationship between renal papillarx necrosis and "chronic interstitial nephritis Br J U-rol 38:361-370. 1966 Burn AF: The evolution of analgesic nephropathy. Nephron 5:185-201. 19S Kincaid-Smith P: Pathogenesis of the renal lesion associated \vith the abtuse of analgesics. Lancet 1 :59-862. 1967 Murrav GC. Wllie RG. Hill GS. Ramsden PWV. Heptinstall RH Experimelntal papillary necrosis of the kidney. 1. Morphologic and functional data Am J Pathol 67:2V3-30'2. 1972 Galt M H. Rud\-al TC. Engles ND. Dossetor JB: Syndrome associated with the abuse of analgesics. Ann Intern Med 68:906-923. 1968 Fellner SK. Tuttle EP: The clinical syndrome of analgesic abuse. Arch Intern Med 124:379-4382. 1969 \urray T. Goldberg MI: Chronic interstitial nephritis: Etiologic factors. Ann Intern Med 82:4,5:3-439. 1973 Lagergren C. Ljungqvist A: The intrarenal arterial pattern in renal papillar\ necrosis: A micro-angiographic and histologic study. Am J Pathol 41 :63:3-643. 1962 Kincaid-Smith P. Saker BM. McKenzie IFC. Muriden KD: Lesions in the bl(od supply of the papilla in experimental analgesic nephropathy. Med J Aust 1:20:3-206. 1968 Andres GA. McCluskey RT: Tubular and interstitiai renal disease due to immunologic mechanisms. Kidney Int 7:271-289. 1973 Steblav RNV, Rudofskv U: Renal tubular disease and autioantiblxdies againist tutbular basement membrane induced in guinea pigs. J Immunol 107:389-394. 197 1 Lehman DH. Marquardt H, WN ilson CB. Dixon FJ: Specificity of autoantibodies to tubular and glomerular basement membranes induced in guinea pigs. J Immunol 112:241-248. 1974 Rudofskv UH. McMaster PRB. Ma WS. Steblav RW. Pollara B Experimental

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autoimmune renal cortical tubulointerstitial disease in guinea pigs lacking the fourth component of complement (C4). J Immunol 112:1387-1393, 1974 Sugisaki T, Klassen J, Milgrom F, Andres GA, McCluskey RT: Immunopathologic study of an autoimmune tubular and interstitial renal disease in Brown Norwav rats. Lab Invest 28:658-67 1, 1973 Lehman DH, Wilson CB, Dixon FJ: Interstitial nephritis in rats immunized with heterologous tubular basement membrane. Kidney Int 5:187-195, 1974 Bergstein J, Litman N: Interstitial nephritis with anti-tubular-basement-membrane antibody. N Engl J Med 292:875-878, 1975 NMorel-M1aroger L, Kourilsky 0, Mignon F, Richet G: Antitubular basement membrane antibodies in rapidly progressive poststreptococcal glomerulo-nephritis: Report of a case. Clin Immunol Immunopathol 2:185-194, 1974 Tung KSK, Black WC: Association of renal glomerular and tubular immune complex disease and antitubular basement membrane antibody. Lab Invest 32:696-700, 1975 Koffler D, Agnello V., Carr RI, Kunkel HG: Variable patterns of immunoglobulin and complement deposition in the kidneys of patients with systemic lupus er%thematosus. Am J Pathol 56:305-316, 1969 McPhaul JJ Jr, Dixon FJ: Characterization of human anti-glomerular basement membrane antibodies eluted from glomerulonephritic kidneys. J Clin Invest 49:308-317, 1970 Wilson CB, Dixon FJ: Anti-glomerular basement membrane antibody-induced glomerulonephritis. Kidney Int 3:74-89, 1973 Klassen J, Kano K, Milgrom F, Menno AB, Anthone S, Anthone R, Sepulveda NM. Elwood CM, Andres GA: Tubular lesions produced by autoantibodies to tubular basement membrane in human renal allografts. Int Arch Allergy 45:675-689, 1973 Wilson CB, Lehman DH, McCoy RC, Gunnells JC Jr, Stickel DL: Antitubular basement membrane antibodies after renal transplantation. Transplantation 18:447-452, 1974 Unanue ER, Dixon FJ, Feldman JD: Experimental allergic glomerulonephritis induced in the rabbit with homologous renal antigens. j Exp Med 125:163-176, 1967 Klassen J, McCluskey RT, Milgrom F: Nonglomerular renal disease produced in rabbits by immunization with homologous kidney. Am J Pathol 63:333-358, 1971 Klassen J, Sugisaki T, Milgrom F, McCluskey RT: Studies on multiple renal lesions in Heymann nephritis. Lab Invest 25:577-585, 1971 Klassen J, Andres GA, Brennan JC, McCluskey RT: An immunologic renal tubular lesion in man. Clin Immunol Immunopathol 1:694-3, 1972 Berger J, Galle P: Dep6ts denses au sein des membranes basales du rein: Etude en microscopies optique et electronique. Presse Med 71:2351-2354, 1963 Habib R, Gubler MC, Loirat C, Maiz HB, Levy M: Dense deposit disease: A variant of membranoproliferative glomerulonephritis. Kidney Int 7:204-215, 19715 Hamza M, Levy M, Brover M, Habib R: Deux cas de glomerulo-nephrite membrano-prolifkrative avec lipodvstrophie partielle de type faciotronculaire. J Urol Nephrol (Paris) 56:1032-1042, 1970 Eisinger AJ, Shortland JR, Moorhead PJ: Renal disease in partial lipodvstrophy. Q J Med 41:34,3-354, 1972 Peters DK, Williams DG, Charlesworth JA, Boulton-jones JM, Sissons JGP, Evans DJ, Kourilsky 0, Morel-Maroger L: Mesangiocapillary nephritis, partial lipodystroph%, and hy-pocomplementaemia. Lancet 2:535-538, 1973