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Kidney International, Vol. 16 (1979), pp. 751-765

NEPHROLOGY FORUM

Acute oliguric interstitial

PRINCIPAL DISCUSSANT: CHARLES VAN YPERSELE DE STRIHOU

Université Catholique de Louvain and Cliniques Universitaires St-Luc, Bruxelles, Belgique

studies for the following agents were within normal limits or neg- The Nephrology Forum is designed to relate the ative: 16 different serotypes of leptospirosis, toxoplasma, in- principles of basic science to clinical problems fluenza A and B, parainfluenza I, II, and III, adenovirus, Q fe- ver, Eaton Agent, Coxsackie B1 through B5, herpes, cyto- in nephrology. megalovirus, EB virus, and hepatitis B. During the first two hospital days, right lumbar and abdominal pain persisted and the patient vomited once. She was treated with acetylsalicylic acid administered intravenously, but she re- Editors mained febrile. Several cultures obtained were sterile. In JORDAN J. COHEN the evening of the second hospital day, her temperature fell to 37.8° C and remained below 370 C throughout the rest of her hos- JOHN T. HARRINGTON pital course. The patient continued to be anorectic and vomited JEROME P. KASSIRER several times; persistent right lumbar and abdominal pain re- New England Medical Center Hospital quired the administration of pentazosin (Fortal®). Twelve hours after admission, a second urinalysis disclosed slight Boston, Massachusetts (0.2 glliter), 2 to 4 WBC per high power field (HPF), and a few hyaline and granular casts. culture was sterile. During the first 24 hours, urine volume was 1050 ml. The urine contained: Case presentation sodium, 3 mEq; urea, 13.3 g; and , 1185 mg/liter. On A 58-year-old woman was admitted to the Cliniques Universi- the morning of the third hospital day, blood analysis revealed: tajres St-Luc for fever of 4 days duration. The patient, a labora- urea, 113 mg; creatinine, 3.6 mg; hemoglobin, 17 g/dl; WBC tory technician in a medical research unit, uses methyl- count, 14,100 mm3 with 83% neutrophils and no eosinophils. A cholanthrene at regular intervals and without gloves handles rats morning urine sample contained: protein, 19 g; glucose, 0.4 g/ as part of her duties. She had been bitten by rats on several occa- liter; 1 to 3 WBC and 10 to 15 red blood cells (RBC)/HPF. The sions, most recently 8 days earlier. Seven days prior to admis- 24-hour urine volume at that time was only 180 ml and it con- sion while on holiday in France, the patient ate a spoiled pate. tained: sodium, 89 mEq; urea, 2.75 g; and creatinine, 485 mg/ Six days prior to admission, she became anorectic. Three days liter; 24-hour urine protein excretion was 1.9 g. The patient ap- prior to admission, she noticed herpetic vesicles on her lips. On peared to be slightly dehydrated, and 4 liters of saline were ad- the same day, she also developed acute right lumbar pain and her ministered. On the fourth day, however, the patient remained temperature rose to 38.7° C. She treated herself with one tablet oliguric (24-hour urine volume, 110 ml). Blood urea concentra- of cotrimoxazole. During the next 2 days, her temperature re- tion increased to 180 mg, and serum creatinine concentration in- mained between 39.5° and 40.4° C despite the continued use of creased to 6.1 mg/dl. Echography revealed kidneys of normal cotrimoxazole and acetylsalicylic acid. Because of persistent fe- size without evidence of obstruction. ver and right lumbar pain, the patient returned to Belgium and Six days after admission, anuria persisted; blood urea concen- was admitted the following evening. tration was 228 mg, and serum creatinine concentration was 8.8 The physical examination revealed the following data: temper- mg/dl. Intravenous urography revealed a slight but persistent ature, 39.5° C; pulse, 100 beats/mm; blood pressure (supine), nephrogram and a normal pelvicalyceal system visible on late 110/80 mm Hg; chest, no rales; cardiac auscultation, Grade 1/VI films. A percutaneous renal biopsy was obtained immediately early systolic murmur; the tip of the spleen was palpated as well thereafter, and the results will be described later. One week after as the lower pole of the right kidney; the liver was not increased admission, IgA and 1gM levels were elevated at 165 and 321%, in size; the remainder of the examination was unremarkable. respectively. IgE and IgO levels were normal. Serum corn- Laboratory findings revealed the following: blood urea, 43 mg; serum creatinine, 1.4 mg/dl; serum sodium, 131 mEq; serum po- tassium, 3.6 mEq; total carbon dioxide content, 23 mEq/liter; This installment of Nephrology Forum was held at the Univer- hemoglobin, 15.6 g/dl; white blood cell (WBC) count, 52001mm3; site Catholique de Louvain, Bruxelles, Belgique. serum lactate dehydrogenase (LDH), 619 U (normal, 140 to 300 U); creatinine phosphokinase (CPK), 31.5 U (normal, 3 to 65 U); Presentation of the Forum is made possible by grants from serum glutamic oxaloacetic transaminase (SOOT), 36 U (normal, Hoechst-Roussel Pharmaceuticals Inc., Smith Kline & French 6 to 30 U); serum glutamic pyruvic transaminase (SGPT), 16 U/ Laboratories, 0. D. Searle & Co., Warner-Lambert Pharmaceu- liter (normal, 4 to 40 U/liter); serum , 0.5 mgldl. Results tical Division, Burroughs Welicome Company, Geigy Pharma- of urinalysis revealed the following: specific gravity, 1.015; pH, ceuticals Inc., Ciba Pharmaceuticals Inc., and Boehringer Ingel- 5; no proteinuria, glucosuria, or sediment abnormalities, Several heim Ltd. blood cultures and urine cultures, obtained during the first 24 hours, were sterile. ASLO titers were within normal limits. Paul- 0085-2538/79/0016-0093 $03.00 Bunnell, Widal and Wright reactions were negative. Serologic © 1979 by the International Society of Nephrology

751 752 NephrologyForum plement was at the lower limit of normal. Ten days later, the tiously because the patient received cotrimoxazole same observations were made but in addition IgG levels had in- creased to 138%. No specific treatment was given. Two weeks prior to admission. after admission, the urine volume exceeded 400 mllday for the The sudden onset of oligoanuric renal failure in a first time and increased to normal levels thereafter. The patient patient with symmetric, slightly enlarged kidneys underwent hemodialysis three times in the interim. Results of urinalysis 12 days after admission revealed protein content of 5g/ certainly suggests (ATN); liter, 50 WBC/HPF, and 10 RBC/HPF. Sixteen days after admis- the dense, persisting nephrogram observed on i.v. sion, the 24-hour urine volume exceeded I liter, and protein and urography also supports this diagnosis, although in sediment abnormalities disappeared from the urine. Twenty days after admission, serum creatinine concentration was 1 mg and one series of 20 patients both signs were absent in blood urea concentration was 33 mgldl. Results of urinalysis 20% of the patients [1]. Several features, in this pa- were normal. tient, however, are not common in ATN. A causal factor could not be identified: despite a detailed his- tory, no toxic factors were discovered, and al- Discussion though an increase in temperature was seen early in DR. CHARLES VAN YPERSELE DE STRIHOU (Pro- her course, there was no evidence for septic shock. fessor of Medicine, Head, Renal Service, University Slight lumbar pain may be present in ATN, but in- of Louvain Medical School, Cliniques Universi- tense pain, which required potent analgesics in this taires St-Luc, Louvain en Woluwe, Brussels): I patient, is not a usual finding. Lumbar pain is seen should like first to discuss the patient's presentation rarely, however, in toxic nephropathies such as that and the initial physical and laboratory findings. In induced by carbon tetrachloride inhalation. Serum brief, she suffered for 4 days prior to admission analysis failed to disclose any sign of hepatic dys- from intense right lumbar pain and elevated temper- function, rhabdomyolysis, or intravascular hemoly- ature, while not responding to cotrimoxazole thera- sis. Finally, chemical analysis of the urine argues py. Although deterioration of her general condition against a diagnosis of ATN on admission because was the immediate problem on admission, renal fail- the urinary sodium concentration was low, and the ure soon appeared and progressed to oliguria and urine-to-plasma ratios for urea and creatinine were anuria. On admission, the patient appeared to be high. In a recent prospective study, Miller et al ob- slightly dehydrated. Urinary sediment was normal served a urinary sodium concentration below 20 and the urinary concentration of sodium was low, mEq/liter in less than 10% of the patients with non- whereas the urinary concentrations of urea and oliguric ATN [2]. Similarly, a urine-to-plasma ratio creatinine were elevated. Infusion of several liters for creatinine above 40 was observed in less than of saline, however, failed to restore renal function. 10% of these patients. A combination of these two Dehydration can thus be eliminated as the sole indexes, the "renal failure index" [(urinary sodium, cause of renal failure. Urinary tract obstruction, mEq/liter)/(urine-to-plasma creatinine ratio)], was suggested by the right lumbar pain and the lack of below 1 in only 6% of the patients with nonoliguric urinary sediment abnormalities, can be ruled out as ATN, whereas in our patient this index reached 0.6. well because neither echographic examination nor Taken together, these observations lead us to sus- i.v. urography demonstrated any evidence for ob- pect another cause of acute renal failure, namely, struction. acute interstitial nephritis (AIN). The diagnostic process thus inevitably leads to Acute interstitial nephritis is probably less rare primary renal disease as the cause of the severe oh- than is believed currently. In a recent series of 976 guria in this patient. Acute or subacute glomerulo- patients with acute renal failure, Richet et al per- nephritis is unlikely because she did not initially formed renal biopsy in 218 patients in whom the di- have hypertension, edema, proteinuria, or any uri- agnosis was not clear-cut [3]. Pure AIN was ob- nary sediment abnormalities, in particular hema- served in 29 patients—that is, 14%. An almost iden- tuna and red cell casts. It is noteworthy, however, tical proportion has been reported by Wilson [4]. that 3 days after admission, a second urinalysis dis- Over the last few years, we have been more aggres- closed a high protein content and red blood cells, sive in performing renal biopsy in acute renal failure but not casts. Acute ascending pyelo- because the biopsy results provide clues not only to nephritis is also unlikely because (1) the patient did AIN but also to other unsuspected glomerular or not have chills or pyuria, (2) her temperature re- vascular diseases. Richet argues that renal biopsy is mained constant after the second hospital day, and indicated in all patients with acute renal failure un- (3) urine cultures were sterile. The findings of the der the following conditions: (1) when accompanied urine cultures, however, should be interpreted cau- by systemic manifestations such as a cutaneous Acute oliguric interstitial nephritis 753 rash, arthralgias, unexplained temperature, raised immunofluorescent staining failed to reveal IgG, level of blood eosinophils; (2) when the expected IgA, IgE, fibrinogen or the third component of com- diuresis does not occur within the usual time limits; plement (C3). A few plasma cells fixed the anti-IgM (3) when renal failure is subacute and associated antiserum. The electron microscopic examination with atypical urinary features [3]. In his series of revealed a normal glomerulus, interstitial edema, biopsies, Richet reported only a few perirenal he- and well-differentiated tubules. matomas [5]. They were encountered only in vascu- The microscopic study allows us to exclude gb- lar renal diseases and led to nephrectomy in three merular or vascular disease. We are dealing either patients. The frequency of this complication, with ATN or AIN. This differential diagnosis is not though low, justifies a cautious approach to renal always easy for the pathologist since shock-induced biopsy in acute renal failure and requires rigorous ATN with a prominent cellular interstitial reaction control of the hemorrhagic tendency and hyper- and AIN may be histologically similar [6]. Ooi et al tension commonly associated with acute renal fail- [7] have described a tubular lesion named "tubu- ure. Dr. Cosyns, would you report the findings of litis" defined as the infiltration of acute or chronic the renal biopsy? inflammatory cells, or both, in the peritubular re- DR. J. P. COSYNS (Department of Pathology, gions or between the lining epithelial cells, with or Cliniques Universitaires St-Luc, Louvain en Wo- without disruption of the tubular basement mem- luwe, Brussels): The renal tissue obtained by needle brane. This lesion is not specific to AIN since it has biopsy was composed of 25 glomeruli and a large also been observed by the same group in a patient portion of medulla. Except for one hyalinized gb- with ATN following abortion. Furthermore, agents merulus, the glomeruli showed only minimal abnor- such as cephalothin [6, 8] or gentamicin [9] may malities—that is, a few polymorphonuclear neutro- produce either ATN or AIN. It is noteworthy that phils in some capillary lumina and some swelling of the lesions observed as a consequence of adverse the epithelial cells. The vessels were normal. There reaction to certain drugs such as glafenin have been was considerable congestion of the intertubular termed acute tubulo-interstitial lesions [10]. These capillaries with areas of interstitial hemorrhage and lesions seem to be representative of an "inter- there were nucleated cells in the vasa recta. There mediate phase" between ATN, following an epi- was no interstitial fibrosis. There was, however, dif- sode of shock, and AIN. In light of current data, fuse interstitial edema and cellular infiltration pre- observers are questioning whether these lesions dominantly in a large subcapsular area, in the should be classified as ATN with prominent inter- boundary zone nd in the medulla (Fig. I). The infil- stitial cellular infiltration, or more properly as true trating cells were mainly lymphocytes, mononucle- AIN [3]. Nevertheless, in view of the clear findings ar cells, a few plasma cells, and rare polymorphonu- of interstitial cellular infiltration, particularly in the clear neutrophils. There were no eosinophils. The important subcapsular area, I believe this patient tubular architecture was normal except for spotty has AIN. We should remain cognizant, however, tubular loss without atrophy and some dilatation in both of the lack of well-defined histopathobogic cri- the cortex. Some epithelial linings were flattened teria in AIN and of the small sample of renal tissue and showed increased cytoplasmic acidophilia and obtained by needle biopsy, which is not necessarily nuclear density. These findings were obvious in the representative of the whole renal parenchyma [11]. upper medulla, in the midportion of the cortex DR. C. VAN YPERSELE: We and Dr. Cosyns thus where a few mitoses were seen, and in the severely conclude that this patient has AIN. I should like to infiltrated subcapsular area where there was some comment further on a few unusual aspects of this tubular loss and rare atrophic tubules. In this area, patient's course, and then proceed to a discussion the staining of the tubular basement membranes by of the possible cause of AIN in this patient. PAS and PASM was very weak (Fig. 2). No overt Intense lumbar pain has been reported in several rupture was seen. The inflammatory cells were in patients with AIN [12—15]. It is probably due to the close relation with the altered basement mem- distention of the renal capsule by interstitial edema, branes. A few inflammatory cells were visible be- evidenced sometimes by an increase in renal size tween tubular epithelial cells but not in the tubular [16, 17]. Interestingly, in two patients with antibiot- lumen. Rare eosinophilic proteinaceous casts but ic-induced interstitial nephritis [16, 18] the lumbar no granular or pigmented casts were seen. Finally, pain was unilateral, as it was in our patient. A dense rare crystalline deposits resembling calcium oxalate immediate nephrogram has also been observed in were present in the lumen of cortical tubules. Direct another patient with antibiotic-induced interstitial 754 Nephrology Foru,n

Fig. 1. Subcapsular area with considerable degree of interstitial edema and cellular infiltration. There is some tubular loss but no glomerular abnormalities (Trichrome x390). nephritis [19]. These cases viewed together suggest What are the possible causes of AIN in our pa- that i.v. urography does not help in distinguishing tient? Acute interstitial nephritis is a very hetero- between ATN and AIN. genous condition but two major causes have been The "prerenal" characteristics of the urine ob- identified: drugs and infection. Our patient had not served at the onset of renal failure in our patient taken any drugs save acetylsalicylic acid and cotri- continue to be puzzling. Indeed, the limited data moxazole. Acute interstitial nephritis has been attrib- available suggest that the results of chemical urine uted to sulfonamide toxicity [22], and cotrimoxa- analysis in AIN are identical with those seen in zole does contain a sulfonamide derivative. Fur- ATN. It is possible however that at its earliest stage ther, acute reversible deterioration of renal function AIN behaves differently. In acute ureteral obstruc- after administration of cotrimoxazole has been re- tion, it has been demonstrated that the urine sodium ported in 20 patients [23, 24]; in 2 of those patients, concentration decreases, whereas the concentrating renal biopsy showed ATN with an interstitial reac- power of the kidney is preserved [20]. Two patients tion [23]. Two instances of cotrimoxazole-induced with obstructive renal failure in whom the sodium AIN have been reported; one patient had an in- concentration was initially low have been observed creased serum concentration of IgE, and another [21]. It is thus possible that the results in our patient patient had many eosinophils in the urine [18, 25]. indicate an incipient intrarenal obstruction. What- In our patient, however, cotrimoxazole toxicity ever the interpretation, it should be remembered does not seem to be the cause of the disease. In- that when the patient became oliguric, the results of deed, the amount taken was much lower than that in urine chemistries were compatible with ATN. reported observations of acute renal failure from Acute oliguric interstitial nephritis 755 S 7( am - 'Ci '5$ 4 C 3 'y; -1 t St I

Fig. 2. Weakly-stained tubular basement membranes in the interstitial areas infiltrated by chronic inflammatory cells, chiefly by poly- morphonuclear leukocytes (trichrome, x625). Insert shows inflammatory cells (arrow) infiltrating between the tubular epithelial cells and the tubular basement membrane (trichrome, X1560). this agent. Furthermore, the symptoms of fever and causal agent could be identified. Blood and urine lumbar pain antedated intake of the drug. cultures were consistently sterile, antistreptolysin The presence of an infection responsible for the titers were normal, and the antibodies against a fever is suggested by the history, the elevated WBC multitude of microbial species were normal. The count, and the evolution of serum protein changes; spontaneous decrease in temperature suggests a vi- that is, the early increase of 1gM and IgA followed ral infection. This hypothesis is further supported 10 days later by an increase in IgG concentration. by the striking occurrence of acute renal failure in The fact that the serum complement concentration two additional patients, both working in the same remained at the lower limit of normal during this laboratory and manipulating rats, within the 3 inflammatory reaction suggests that complement months preceding this patient's illness. Similarities was consumed by circulating immune complexes. can be seen among all three patients. Dr. Van- The concentration of immune complexes, as mea- denbroucke, would you present briefly the history sured by the Cambiaso method [26],wasinitially at of these other two patients? the upper limit of normal but fell subsequently. DR. J. M. VANDENBROUCKE (Physician, Renal These findings should be interpreted with caution as Service, Cliniques Universitaires St-Luc, Louvain the detection of immune complexes depends very en Woluwe, Brussels): As Dr. van Ypersele men- much on the technique used; results may be nega- tioned, a few weeks prior to admission of the pa- tive with some techniques and positive with others. tient under discussion today, we observed an identi- Although our observations are suggestive of an in- cal clinical picture in two people working in the fectious disease, we must acknowledge that no same laboratory as this patient. The first patient, a 756 NephrologyForum

37-year-old man, works with rats and pigeons. He icologic research was negative, serology was nega- suffered, a few days after his wife, with an in- tive for leptospirosis and toxoplasmosis. Only in the fluenza-like syndrome and was treated with phe- first patient did we observe a rise in titer for the nacetin and doxacycline. Three days later, he had Coxsackie B4 antibodies of questionable signifi- an episode of vomiting, and 2 days later, he had cance—1/128 to 1/5 12 and later 1/128. Immunoglob- chills and a temperature of 390 C. At that time, the ulin studies showed a transient increase in IgA con- patient complained of heavy lumbar pain, pre- centration. dominantly on the right side, and urine volume de- DR. C. VAN YPERSELE: The striking similarity in creased. His physician found proteinuria; the next the courses of these three patients indeed suggests day, urinalysis disclosed the protein content to be the presence of an infectious agent which to date we 17 g/liter with moderate leukocyturia. Serum creati- have not been able to identify. nine concentration reached 6.5 mg/dl and the pa- I should now like to turn to a more in-depth dis- tient was admitted to the hospital. Physical exam- cussion of the pathogenesis of AIN. Heptinstall de- ination revealed hypertension (200/120 mm Hg) and fines AIN as an acute inflammatory lesion of the in- bilateral flank pain. Blood analysis disclosed an ac- terstitium occasionally associated with tubular le- celerated erythrocyte sedimentation rate (E.S.R.) sions but without glomerular involvement [6]. This and an increased concentration of fibrinogen: pathologic picture is observed in a great variety of creatinine concentration was 9.2 mg; blood urea clinical renal disturbances, ranging from simple pro- was 135 mg/dl; enzymes were normal; WBC count teinuria with only slight alterations of the urinary was normal without eosinophils. Results of urinaly- sediment to acute renal failure. It may have various sis revealed: protein content, 0.4 glliter; sediment, 3 immunologic manifestations and may occur in a va- to 6 WBC/HPF, 2 to 4 RBC/HPF; urine culture, riety of circumstances, which suggests that AIN is sterile. An i.v. urogram showed kidneys of in- the common endpoint of diverse diseases acting creased size with parenchymatous edema; excre- through different mechanisms. To the restrictively tion was symmetric but slight; there was no evi- defined AIN of Heptinstall, one should add the dence of obstruction. During the hospital course, acute interstitial lesions that may accompany gb- daily urine volume remained above 1.5 liters; there merular or vascular diseases. It is probable that was no fever, and renal function returned rapidly to AIN, like gbomerulonephritis, will be divided into a normal with no specific treatment. variety of subgroups in the future. Two weeks later, the second patient was referred Experimental acute interstitial nephritis. I plan to to us for treatment of acute renal failure with mas- review the various clinical conditions associated sive proteinuria. The clinical history was similar: in- with AIN, but first I will summarize the experimen- tense lumbar pain, predominantly on the right, at tal immunologic manipulations that may induce the beginning; a few days later, development of fe- AIN. Three different mechanisms have been identi- ver and vomiting; and proteinuria accompanied by fied: the first relies on immune complexes, the sec- . On admission, the patient was febrile, ond on antitubular membrane antibodies, and the normotensive without symptoms of hypervolemia, third on the induction of delayed hypersensitivity. but had hepatosplenomegaly and an enlarged, Two models of AIN demonstrate the first mecha- tender right kidney. Laboratory examination re- nism: The repeated injection of homologous cyto- vealed: an accelerated E.S.R. and increased con- plasmic tubular (HCT) antigens [27] or the repeated centration of fibrinogen in the blood; serum creati- administration of heterobogous bovine albumin nine, 3.4 mg; blood urea, 104 mg!dl; LDH, 764 U; (HBA) [28] in the rabbit result in the development SGOT, 93 U; SGPT, 74 U. Hemogram was normal: of interstitial nephritis characterized by mono- WBC count, 9200/mm3 with monocytosis (15%) but nuclear infiltration and tubular lesions. In the HCT with no eosinophils. Urinary protein was 7.3 g/liter antigen model, the glomeruli are spared, whereas in initially but rapidly decreased; also the HBA model they are involved. On immuno- disappeared rapidly. During the first two hospital fluorescence, granular IgG and C3 deposits are seen days, the patient was oliguric; subsequently the dai- along the tubular membrane. In the HBA model de- ly urine volume increased, exceeding 1.5 liters, with posits are also located along the gbomerular base- a simultaneous decrease in serum creatinine con- ment membrane. The lesions in the HCT antigen centration to normal. model result apparently from the in situ combina- In neither of these two patients did we find an tion of cytoplasmic tubular antigens slowly dif- etiologic factor for the acute renal failure: tox- fusing from tubular cells with circulating antibody Acute oliguric interstitial nephritis 757 brought by blood flow to the basal membrane. In may result in AIN if the stimulating antigen is lo- the HBA model, immune complexes of bovine albu- cated within the kidney. min and antibovine albumin antibodies are carried Clinical acute interstitial nephritis. How can through the circulation into the glomeruli and along these mechanisms intervene in human disease? 1 the tubular basement membrane. From these mod- will comment only briefly on the interstitial lesions els, we may conclude that immune complexes may associated with glomerular diseases. Immune com- provoke acute interstitial reaction whether they are plexes, probably DNA and anti-DNA, are observed formed within the interstitium or are located there along the tubular basement membrane in more than secondarily. half the patients with lupus nephritis [38]. Other im- The second mechanism is demonstrated by ex- mune complexes along the tubular basement mem- periments in which purified rabbit tubular mem- brane have been reported in cryoglobulinemia [38] branes are injected into the guinea pig [29]. Acute and renal transplants [39, 40]. Linear anti-TBM interstitial nephritis develops subsequently and is antibody deposits have been observed in rapidly characterized by cellular infiltration of plasmo- progressive glomerulonephritis with antiglomerular cytes, mononuclear cells, macrophages, and giant basement membrane (anti-GBM) antibodies [38, 40] cells, which provoke tubular lesions. On immuno- and in renal transplants [41, 42]. These observations fluorescent examination, linear deposits of IgG and illustrate the pathogenic role of humoral immunity C3 are observed along the tubular basement mem- in the genesis of AIN. It is noteworthy that in renal brane. This model of AIN is due to the development transplants the same immune challenge may result of circulating antitubular basement membrane (anti- in two different types of lesions. A detailed analysis TBM) antibodies, which have been identified in the suggests that in addition to these two antibody-me- circulation. Furthermore, injection of guinea pig diated lesions some cellular-mediated lesions—de- serum induces the disease in nonimmunized recipi- layed hypersensitivity—are also involved. ents [30]. This reaction requires the activation of In order to review AIN that is unaccompanied by complement, at least through the alternate pathway glomerular lesions, I will follow Richet's classifica- [3 1—33], and probably also requires the presence of tion [43]. This classification is based on the type of intact bone marrow cells in the recipient [34]. When cells infiltrating the kidney: polymorphonuclear or the disease is transferred to a nonimmunized recipi- mononuclear cells. ent, the injected antibody initiates the tubular le- Acute interstitial nephritis with massive infil- sion, but subsequently the recipient develops au- tration of polymorphonuclear cells and formation of toantibodies, thus amplifying the initial reaction microabscesses is induced by septicemias, occa- [35]. From this model, we conclude that anti-TBM sionally of urinary origin. Urinary protein excretion antibodies may provoke interstitial nephritis medi- reaches 2 to 3 g/liter and is accompanied by pyuria. ated by complement activation and marrow cells, Renal insufficiency is usually progressive, may be which might suggest cellular immunization as well. severe, and is only slowly and partially reversible. These anti-TBM antibodies may be generated either No immunoglobulins are seen in the kidney, and by the injection of heterologous TBM or by the lib- circulating anti-TBM antibodies have not been de- eration of autologous hidden tubular membrane an- tected. Resolution of this type of AIN requires a tigens. careful search for the cause of the septicemia and its The third mechanism relies on delayed hyper- prompt treatment [44]. This variety of AIN was ob- sensitivity. Guinea pigs or rats are injected with bo- served in 6% of the 218 patients with acute renal vine gamma globulin (BGG) at a rate appropriate to insufficiency biopsied by Richet [3]. stimulate delayed hypersensitivity [36]. Aggregated Acute interstitial nephritis with mononuclear cell BGG is then injected into the subcortical region of infiltration is more heterogenous and may be pro- the kidney. Immediately, there is an intense mono- voked either by drugs or infection. A drug may be nuclear cell infiltration, which destroys the tubular toxic by itself, as demonstrated by the dose de- components. This type of interstitial reaction is cer- pendency of the lesions. This mechanism has been tainly due to delayed hypersensitivity because it is invoked to account for the important interstitial le- transferable by lymphocytes but not by the serum sions occasionally observed after administration of of the donor. Furthermore, no circulating anti-BGG polymyxin E, cephaloridine, cephalothin, and glafe- antibodies are demonstrated and no immunoglobu- nm [13, 17, 45—47]. Interestingly, the acute renal lins are present in the kidney [37]. This model dem- failure provoked by these substances may be ac- onstrates therefore that delayed hypersensitivity companied solely by minimal tubular lesions with- 758 Nephrology Forum out cellular interstitial infiltration, a picture identi- ministration of methicillin [18, 52, 53] or diuretics cal to that of ATN. [48, 54, 55], in sporadic cases [56, 57], and rarely In other instances, drugs act apparently through after administration of drugs such as rifampin [8], immune mechanisms: AIN is evoked by a normal glafenin [13], or cephalothin [58]. On biopsy, lym- dose of the drug, sometimes simultaneously with phocytes, plasmocytes, and mononuclear cells are extrarenal manifestations of an immunologic con- present in abundance, often but not always accom- flict. The list of incriminated drugs is very long, but panied by eosinophils. In a few patients, epithelioid the most frequently mentioned are: methicillin, phe- cell granulomas with giant cells were observed nytoin, phenindione, rifampin, sulfonamides, and [59-61]. The existence of a humoral immune reac- less frequently, cephalothin, glafenin, and diuretics tion is also suggested by the finding on renal biopsy (see Table 1) [8, 48]. The delay between the admin- of linear IgO and occasionally of C3 deposits along istration of the drug and the onset of renal lesions the tubular basement membrane. This has been re- varies from a few hours to several weeks. ported, however, only in a few instances of methi- The clinical picture is heterogenous. Frequently, cillin-, penicillin-, or phenytoin-induced AIN [52, the onset of renal failure is acute and associated 53, 59, 62]. In these patients, circulating anti-TBM with hematuria, which is sometimes macroscopic, antibodies were also demonstrated [52, 59, 62]. It whereas a few series reveal consistent pyuria with a should be pointed out, however, that these abnor- large number of eosinophils. Occasionally, how- malities are exceptional: indeed, immunoglobulins ever, renal failure develops slowly without urinary were absent in the renal biopsy of the six patients manifestations: the kidney may be increased in size with methicillin-induced AIN reported by Galpin with associated severe lumbar pain, or in some pa- [18]. In a few patients with methicillin-induced AIN tients, the kidneys may be normal in size or only and in one patient with cotrimoxazole-induced slightly enlarged. Renal failure is variable in severi- AIN, increased serum concentrations of IgE were ty and may require hemodialysis. Withdrawal of the observed [25, 63]. In a single patient with phenobar- offending drug is usually accompanied by improve- bitol-induced AIN, plasmocytes filled with IgE ment in renal function, providing further evidence were observed in the interstitium [64]. Usually, for a cause-and-effect relationship. Readministra- however, all of these parameters are normal. Fur- tion of the drug can lead to another episode of renal ther evidence for an antibody-mediated immune re- insufficiency [13, 48]. Total healing is frequent, but action can be found in a positive Coombs reaction occasionally persistent chronic renal failure has been in a few instances of ampicillin-, rifampin-, or glafe- reported [8, 18, 49—51]. nm-induced AIN [8, 65, 66]. Lymphoblastic stimu- The existence of an immunologic conflict is sug- lation or inhibition of leukocyte migration has been gested by systemic clinical manifestations such as occasionally reported in AIN due to methicillin, ri- fever, cutaneous rash, and arthralgias. These are by fampin, glafenin, phenytoin, and phenindione [13, no means always present. An increased number of 61, 62, 67, 68]. But, as mentioned earlier, the tests circulating eosinophils is often observed after ad- are often negative. In summary, these data suggest that the same drugs may evoke AIN through a vari- ety of immune mechanisms, either humoral or cellu- Table1. Prevalenceof drug-induced acute interstitial nephritisa lar as well as produce toxic, dose-dependent renal Frequent Rare lesions. Methicillin Oxacillin The following hypothetical scheme might in- Penicillin Nafcillin tegrate the different pathogenic mechanisms de- Ampicillin Carbenicillin fined experimentally with the various immunologic Rifampin Cephalothin Glafenin Tetracycline disturbances observed in clinical AIN. Interstitial Sulfonamides Thiazide accumulation of the drug may result either from a and cotrimoxazole Furosemide direct toxic effect of the drug on tubular cells with Phenindione Phenylbutazone Phenytoin Aminophenazone subsequent diffusion through a ruptured tubular PAS acid basement membrane, or from its concentration Gold and bismuth salts within peritubular capillaries, or from its combina- Azathioprine Allopurinol tion with the tubular membrane acting as a hapten. Phenobarbital Once in the interstitium, the drug challenges immu- Cephalexin nity and induces either humoral immunization or a Datataken from Refs. 8 and 59. cellular, delayed hypersensitivity immunization. Acute oliguric interstitial nephritis 759

Humoral reaction is either systemic, manifested in Toxoplasmosis [73], mononucleosis [74], and mea- the formation of circulating antibodies directed sles [4] have also been incriminated. No antibodies against the drug or against the tubular membrane, have been identified in situ but the viral antigens or local with infiltration of monocytes, lympho- have been identified in the tubular cells. Virus-in- cytes, and plasmocytes. These latter cells are able duced AIN is well documented in animals. In the to synthesize immunoglobulins locally and form im- fowl, infectious bronchitis virus is able to damage mune complexes in situ. Delayed hypersensitivity tubular cells and induce a mononuclear infiltration will bring about the invasion of the interstitium with of the interstitium [75]. In the dog infected with ca- macrophage-stimulating lymphocytes. Within this nine adenovirus, the virus penetrates into tubular framework, it is conceivable that the same drug cells and destroys them. Focal necrotic material is elicits the same tubular lesions through different im- then surrounded by lymphocytes, macrophages, mune mechanisms, the type of response being de- and plasmocytes that are filled with IgG anticanine termined by the genetically determined immune re- adenovirus antibodies [72]. Under those circum- sponsiveness of the patient, the degree of stimula- stances, however, anti-TBM antibodies have not tion of immunity, and the characteristics as well as been demonstrated. the quantity of the offending agent. The same scheme as used earlier for drugs can Whatever the mechanisms involved, it is quite account for these observations: accumulation in the clear that it is extremely important, both in patients interstitium of bacterial or viral antigens, which ar- with acute renal failure and in those with chronic rive there either through tubular cells or by blood renal insufficiency who have an unexpected decline flow; formation in situ of antibodies secreted by in function, to look for evidence of activation of the plasmocytes; or arrival of delayed hypersensitivity immune system and to suspect a deleterious role for lymphocytes, creating a general inflammatory reac- any drug recently taken by the patient. Detection of tion. Moreover, it has been demonstrated in a pa- increased amounts of eosinophils in the urine may tient with leptospirosis that the infectious agent be helpful. If there is any doubt, renal biopsy should may elicit further the formation of anti-TBM anti- be performed. Immunologic tests for the detection bodies, thus "amplifying" the initial renal lesion of anti-TBM, IgE, Coombs reaction, inhibition of [76]. In addition to AIN generated by drugs or infec- lymphocyte migration, or lymphoblastic transfor- tious agents, there are several reports in which it mation are useful to support the hypothesis of drug- has not been possible to indict either of these agents induced interstitial nephritis. This critical attitude because of the complexity of the situation [17, 77, allowed Lyons et al [48] to modify the apparently 78]. inevitable degradation of renal function observed in At the end of this discussion of the causes of some patients with glomerulonephritis simply by in- AIN, I should reiterate that renal biopsies of many terrupting the administration of diuretics. patients with ATN do show conspicuous interstitial The role of infectious agents in the genesis of infiltration. This occurrence is not unusual; of the AIN with mononuclear infiltration has been demon- 69 patients with ATN reported by Richet [43], 15 strated, although it is less extensively documented had slight interstitial lesions and 9 had severe ones. than drug-induced AIN. The streptococcus has These lesions have also been described by Kim- been implicated in the context of a hyperergic reac- melstiel [79], by Zollinger [80], and more recently tion that is sometimes associated with eosinophilia by Pasternack [81] in patients with ATN. The origin [43, 69, 70] and is reminiscent of AIN following of the infiltration has not been clearly defined: it scarlet fever, described more than a century ago may represent residue of hematogenous bacterial [71]. Leptospirosis may also produce AIN. Its dissemination; it may be due to drug toxicity; or, as mechanism has been delineated in studies per- we suggested earlier, it may be attributable to au- formed in infected dogs [72].Theleptospires are ini- toimmune reactions. tially found in the tubular lumen, but subsequently As already stated, the course of AIN is usually their antigenic material is found in the interstitium, favorable as soon as the offending drug is with- either within macrophages or as discrete granular drawn or the infectious agent destroyed. In a few deposits combined with antileptospire antibodies, patients, however, the response was less favorable which are secreted locally by plasmocytes. An anal- and prednisone has been administered with some ogous lesion has been found in a lepromatous pa- success [16, 18, 48, 54, 77, 78]. Recently, Galpin tient [43]: the Hansen bacilla or its antigenic com- evaluated the effectiveness of steroids in methi- ponent has not been identified, but plasmocytes that cillin-induced AIN [18]. Of the eight patients who produce IgG have been found in the interstitium. were treated with prednisone, serum creatinine re- 760 Nephrology Forum turned to control values in six patients, and stable this patient, you dismissed the hypothesis that she concentrations were obtained after an average of had ATN secondary to dehydration. I believe we only 9 days. In contrast, in the six patients who did should recall that this patient took aspirin in addi- not receive prednisone, serum creatinine returned tion to cotrimoxazole prior to admission, and that to control values in only 2, and stable concentra- she received I g of acetylsalicylic acid intrave- tions were obtained only after 54 days. Although nously just before the episode of dehydration. The these data suggest that prednisone may be effective recent work of Henrich suggests that prostaglandins in MN, the incidence of residual renal functional seem to balance the vasoconstrictive action of an- impairment in the control group was higher than giotension and renal nerves during hypovolemic or that reported elsewhere in the literature. In con- hemorrhagic hypotension [82]. It could be argued clusion, I should like to point out that the more fre- that the degree of dehydration seen in this patient, quent use of renal biopsy in acute renal failure may which would not have evoked ATN, did so here be- be very helpful. This technique discloses unsus- cause of the earlier treatment with acetylsalicylic pected glomerular or vascular disease, allows the acid. identification of AIN as in the patient discussed DR. C. VAN YPERSELE: That is an interesting today, and should make it possible to institute ap- idea, but I believe that hypothesis must remain propriate treatment more promptly. speculative until sufficient data have been collected. Furthermore, this hypothesis does not fit with the Questions and Answers interstitial infiltrate found on biopsy. DR.N. LAMEIRE(instructor in Medicine, Renal DR. P. MIcHIELsEN: There is a study by Torres in Service, Akademisch Ziekenhuis, University of which indomethacin has been shown to aggravate Ghent): We discussed the first patient presented glycerol-induced ATN in rabbits [83]. At one time, today earlier in Ohent, and our tentative diagnosis we gave indomethacin to patients following trans- was salmonella food poisoning with dehydration plantation, but we had to discontinue this practice and possible ATN. That diagnosis was based on the because of the high incidence of ATN in this group history of ingestion of the spoiled pate, the sple- [84]. Thus, these observations support my hypothe- nomegaly, the absence of lymphocytosis, and the sis. pulse rate of only 100 beats/mm despite a temper- DR. C. VAN YPERSELE: 1 think it is an alternative ature of 400 C. Of course, now that the two other possibility. As Dr. Lameire already pointed out, the cases from the same laboratory have been present- similar findings in the two other patients also argue ed, our original hypothesis must be dropped. None- against that explanation. theless, I would return to your comments on the uri- DR.J.P. GODON (Agrégé, University of Liege): nary findings used to distinguish between ATN and To follow up the comments of Dr. Michielsen, we AIN. The first urine tests revealed a low concentra- observed a case of aspirin-induced AIN several tion of sodium and a high concentration of urea. years ago in a woman who had absorbed 9 g of aspi- During the first several days following admission, rin. she received no saline and she was vomiting. That DR. P. MICHIELSEN: The clinical evolution of the suggests to me that she had prerenal acute renal fail- two other patients was much more benign. They ure, which later evolved to ATN simply because of had an acute febrile evolution followed by rapid re- dehydration. covery of renal function. They did not have the pro- DR. C. VAN YPERSELE: On admission renal fail- tracted anuria characteristic of the first patient's ure was already present as evidenced by a serum course. She also had an i.v. urographic procedure creatinine concentration of 1.9 mgldl, but there before the biopsy; do you know when that took were no clinical signs of dehydration and the patient place? was not yet oliguric. Therefore, I do not think that DR.C.VAN YPERSELE: Yes, the i.v. urography the patient initially had prerenal acute renal failure. was performed in preparation for the biopsy, which As to the subsequent progression of renal failure, I was done 2 hours after urography; the patient had have rarely seen prerenal failure from dehydration already been anuric for several days. evolve to ATN without associated severe signs of DR. P. MICHIELSEN: Are there any data that al- hypovolemia, which this patient never had. low us to eliminate the iodine given on urography as DR.P. MICHIELSEN(Professor of Medicine, the cause of some of the interstitial infiltration? The Head, Renal Service, University of Leuven Medical earliest report I know from the literature indicates School, Akademische Ziekenhuis, St-Rafael, Leu- that definite ATN lesions can appear 1 day after the yen): With respect to Dr. Lameire's diagnosis in procedure [85]. Acute oliguric interstitial nephritis 761

DR. J. T. HARRINGTON: While I don't have any DR. C. VAN YPERSELE: In our department we are systematic data regarding this issue, we have per- slightly more conservative than Richet. I would formed many biopsies using fluoroscopy and I don't consider oliguria that lasts beyond 1 month to be a believe we have seen an unanticipated degree of prolonged episode. interstitial infiltration or edema. DR. J. T. HARRINGTON: Earlier, you commented DR. N. LAMEIRE: Performing i.v. urography in a on the difficulty in distinguishing between ATN and dehydrated, anuric patient is certainly not without AIN in the absence of a kidney biopsy. This is a danger, and for this reason we never use this proce- specific example of a more general problem, that of dure preparatory to renal biopsy. Instead, we use making two different diagnoses affecting the same echography prior to biopsy, which gives a very organ system. We had similar difficulties with that good visualization of the kidney even in a patient problem in the patients we described who had di- with anuria. uretic-induced interstitial nephritis [48]. All were pa- DR. C. VAN YPERSELE: I should point out that the tients who had known chronic glomerular disease patient was not dehydrated at the time of the and in whom renal failure slowly progressed over a urographic procedure. Dehydration had been cor- matter of months. The major clue that superim- rected earlier. posed disease was causing the renal failure was the DR. P. MICHIELSEN: Another question, if I may. persistence of normal kidney size. That was the pri- Which kidney did you biopsy? mary reason for repeating the kidney biopsies. Only DR. C. VAN YPERSELE: The right kidney was later, when we carefully perused the clinical rec- biopsied. ords systematically, did we realize that mild inter- DR. P. MICHIELSEN: I am somewhat puzzled by mittent eosinophilia and fleeting skin rashes had of- the occurrence of intense pain on the right side in ten occurred. this patient. DR. G. RORIVE (Established Investigator, Fonds DR. C. VAN YPERSELE: As I mentioned earlier, National de Ia Recherche Scientfique, Head, Renal Hamburger, who has enormous experience in this Hypertension Unit, Hópital de Bavière, University area, reports that diffuse lumbar pain in ATN may of Liege): I am somewhat surprised by the delay be a bit more characteristic on the right side for rea- between the first symptom and renal failure. In my sons that are not clear [86]. experience, the evolution of AIN is more rapid. DR. N. LAMEIRE: If you suspect that the acute DR. C. VAN YPERSELE: The delay between drug episodes of the three patients presented today have ingestion and the onset of renal failure is highly var- a similar etiology, you may have a slight clue to a iable—a few hours in the case of patients who have possible cause in the rise in the antibody titer probably been presensitized, several weeks in other against Coxsackie virus in the second patient. As you know, Coxsackie virus has been associated patients. with the lesions of glomerulonephritis, not inter- DR. G. R0RIVE: I agree that the delay between stitial nephritis [87]. May I have your comments on drug absorption and the first symptoms varies con- this possibility? siderably among patients. Once the clinical signs DR. C. VAN YPERSELE: First, our virologist be- are present, however, the disease has an acute lieves that the small changes in the antibody titer course, and the reduction in renal function is maxi- against Coxsackie virus noted in our patient should mal within a few hours or days. The evolution of not be viewed too rigorously. As I pointed out, I this patient was somewhat slower. think AIN is a very heterogeneous condition in DR. C. VAN YPERSELE: The course of AIN is by which most of the mechanisms that have been im- no means always as acute as you suggest; in diuret- plicated in the development of the several types of ic-induced AIN, for instance, the evolution ob- glomerulonephritis are also involved. I quoted a re- served by Dr. Harrington in his patients [48] ex- port of AIN following measles, and measles has al- tended over a period of several months. so been implicated in the development of glomeru- DR. G. R0RIVE: In five cases of glafenin-induced lonephritis. Thus, I don't think there is an in- AIN, I was struck by the rapidity of the evolution, compatibility—as a matter of fact, it makes things which lasted 3 or 4 days. One patient complained of more interesting. lumbar pain and three had anuria; urine volume re- DR. J. T. HARRINGTON: You mentioned earlier turned to normal rapidly and renal function became Richet's indications for kidney biopsy and stated normal within 4 to 5 days. that one was "prolonged" oliguria. What would you DR. C. VAN YPERSELE: Your observations are in consider to be prolonged oliguria—2 weeks, 3 weeks? agreement with those of many others who have at- 762 Nephrology Forum tributed these signs to an overdose of the drug, thus DR. G. R0RIvE: Would you say the reverse? characterizing the effect as toxic, which is only part Would you say that if you have lymphoblastic trans- of the picture. The possible existence, documented formation, this means that the drug could produce in a few cases, of preformed antibodies should not such an effect? be ignored in evaluating the clinical evolution of DR. P. MASSON: That means that the body is AIN. Once the concentration of glafenin is suf- mounting an immune response against this drug, but ficient in the kidney, an interstitial reaction ensues. it doesn't mean that the mechanism is necessarily DR. G. R0RIvE: I should like to know if you can involved in the pathogenesis of the disease. classify the drugs involved in AIN according to the DR. N. LAMEIRE: Patients with AIN often take type of immune reaction elicited by each agent. one or more drugs. In one case we have seen, the DR. C. VANYPERSELE: Ido not believe that such patient took approximately 20 drugs. In such a pa- a classification can be made. As a matter of fact, tient, it is difficult to determine whether the reaction there is evidence that the same drug may be nephro- is drug related and which drug is responsible. toxic through different mechanisms. For instance, Couldn't you then perform a lymphoblastic trans- in methicillin-induced AIN, anti-TBM antibodies formation test in which all 20 drugs would be tested, have been present in a few patients. Clearly, anoth- eliminate some of them, and conclude that one or er mechanism must be invoked in those patients in another drug may be responsible? whom no anti-TBM antibodies have been demon- DR. P. MASSON: Statistically, you increase your strated. This latter category includes the majority of chances. If you have a lymphoblastic transforma- patients with methicillin-induced AIN [18]. It is also tion with a given drug, of course you have more possible that one mechanism, such as the develop- chance that this drug is involved. I would ask a ment of anti-TBM antibodies, is only a secondary question myself. Is AIN very often associated with response that amplifies the interstitial lesions in- other disorders? You mentioned a positive Coombs duced by another primary reaction. test. What I mean is, for example, is there hemolysis DR. J. T. HARRINGTON: Dr. McCluskey has or thrombocytopenic purpura, or is the disorder re- stated that in 10 patients with drug-induced allergic stricted to the kidney? interstitial nephritis they were unable to find circu- DR. C. VANYPERSELE:Hemolytic anemia has lating anti-TBM antibodies in any patients, yet all been occasionally reported, for instance in associa- had similar histologic findings and clinical histories tion with glafenin-induced AIN. [88]. That observation would relegate anti-TBM DR. G. R0RIvE: Perhaps the most usual hemato- antibodies to secondary importance. logic disorder is eosinophilia. Isn't it? DR. Y. PIRSON (Physician, Renal Service, Clini- ques Universitaires St-Luc, Louvain en Woluwe, DR. C. VANYPERSELE:Yes. If I may go back to Brussels): Dr. Masson, what is the specificity of the the question which was put to Dr. Masson. You different types of immunologic tests that have been said that the lymphoblastic transformation test mentioned in identifying humoral and cellular im- merely shows that some immune stimulation has mune reactions and delayed hypersensitivity? occurred. Whether it reacts in the kidney or not is DR. P. MASSON (Professor of Experimental Medi- another matter. What is your feeling on the specific- cine, University of Louvain Medical School, Lou- ity of the leukocyte migration inhibition test? vain en Woluwe, Brussels): It is impossible, in fact, DR. P. MASSON: Exactly the same. The specifici- to get an immune reaction if there is no lymphoblas- ty is certainly not better than the lymphoblastic tic transformation. Each time an immune response transformation test and personally I would trust the occurs there is a lymphoblastic transformation. lymphoblastic transformation more than the so- Thus, it is impossible on the basis of this test to say called MIF test, which is measuring the migration whether the immune response is either humoral or inhibiting factor. cellular. When the antibody is detected in the DR. C. VANYPERSELE:Why? blood, then of course it is a humoral response, but DR. P. MASSON:Oh,just for technical reasons; on the basis of just a lymphoblastic transformation I the lymphoblastic transformation test is easier to would not dare to say that it was just a cellular one. perform. Personally, I would recommend obtaining The lymphocyte incorporation of thymidine, which an intradermal reaction as soon as you suspect a is used in this test, will be due not only to T lympho- drug; a simple scratch test or an intradermal injec- cytes but also to the B lymphocytes and other cells tion of a small amount of this could be useful and that could be involved. So I would be very careful perhaps be more informative than all of these so- in interpreting it. phisticated tests, which are somewhat fashionable. Acute oliguric interstitial nephritis 763

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