Drug-induced acute interstitial nephritis

Patient 1 A 68-year-old man was referred to another hospital because of fever and a cutaneous infection of the right elbow. On admission, his temperature was 39.5°C; heart rate, 120 beats/min; and blood pressure, 110/75 mm Hg. The hemoglobin was 15 g/dL. The white blood cell count was 20,000/mm3, with 88% polymorphonuclear leukocytes, 7% lymphocytes, and 5% monocytes. Serum creatinine was 80 μmol/L (0.9 mg/dL), and blood urea was 5 mmol/L. Seven blood cultures were positive for Staphylococcus aureus, and treatment with methicillin (12 g/day) was initiated. After 12 days of treatment, the fever resumed, his renal function deteriorated, and he was transferred to the renal unit of Hôpital Tenon. On admission, his temperature was 39°C. The physical examination was normal except for the cutaneous lesion of the right elbow. The serum creatinine was 320 μmol/L (3.6 mg/dL); blood urea was 27 mmol/L. Urinalysis disclosed macroscopic hematuria and 200 white cells/mm3. Proteinuria was 1 g/day. The white blood cell count was 12,000/mm3, with 12% eosinophils. Renal biopsy disclosed an infiltration of the interstitium by numerous lymphocytes and macrophages that was associated with severe tubular lesions. Glomeruli and blood vessels were normal. Immunofluorescent studies showed linear deposits of IgG along the tubular basement membranes. Methicillin was replaced by pristinamycin. Hematuria, pyuria, and proteinuria quickly resolved, and his renal function progressively returned to baseline values. Patient 2 A 42-year-old man was referred to a department of respiratory medicine because of persistent cough, anorexia, and asthenia. He was a heavy smoker but had no pertinent medical history and was taking no medication. His temperature was 38°C, and his blood pressure was 110/70 mm Hg. He had lost 5 kg over the previous two months, and he weighed 46 kg. Physical examination was normal. Hemoglobin was 10.5 g/dL. The white blood cell count was 12,000/mm3, with 80% polymorphonuclear leukocytes, 1% eosinophils, 10% lymphocytes, and 9% monocytes. The serum creatinine was 55 μmol/L (0.6 mg/dL); and blood urea was 2 mmol/L. Liver function tests were normal. Tests for HIV infection were negative. A chest radiograph was suggestive of pulmonary tuberculosis, and this diagnosis was confirmed by the identification of numerous acid-fast bacilli in sputum smears. The patient was given rifampicin (600 mg/day), isoniazid (250 mg/day), and pyrazinamide (1500 mg/day). Three weeks later, he had gained 3 kg and was feeling less tired. Routine laboratory tests were unchanged; in particular, the serum creatinine was still 55 μmol/L (0.6 mg/dL). Four weeks later, the patient had gained two more kg and his general status seemed to be improving, but laboratory tests showed that the serum creatinine was 150 μmol/L (1.7 mg/dL) and the blood urea 10 mmol/L. The patient was referred to our renal unit. On admission, he had no complaints. His blood pressure was 105/70 mm Hg; heart rate, 80 beats/min; and temperature, 37°C. Physical examination was normal. The serum creatinine was 200 μmol/L (2.4 mg/dL), and blood urea was 12 mmol/L. Urinalysis revealed less than one white blood cell/mm3, and less than one red blood cell/mm3. Proteinuria was 0.5 g/day. A stain for urinary eosinophils was negative. Hemoglobin was 11 g/dL, and the white blood cell count was 10,700/mm3, with 72% polymorphonuclear leukocytes, 7% eosinophils, 12% lymphocytes, and 9% monocytes. Eosinophilia subsequently increased to 1,000/mm3. Renal sonography was normal. Rifampicin administration was stopped. Renal biopsy disclosed extensive inflammatory infiltrates within the interstitium that were composed of lymphocytes and macrophages; granulomas were not seen. The inflammatory infiltrates were associated with interstitial edema, focal tubular lesions ranging from mild to severe, and in some places slight fibrosis. All 22 glomeruli were normal. Immunofluorescent examination of the biopsy specimen revealed no immune deposits. No anti-rifampicin antibody could be detected. After stopping rifampicin, his renal function progressively improved, but two years after this episode, the serum creatinine remains 130 μmol/L (1.5 mg/dL), which corresponds to a calculated creatinine clearance of 50 mL/min. Dr. Jérôme Rossert (Department of Nephrology and INSERM U489, Hôpital Tenon; and Professor of Nephrology, University of Paris VI, Paris, France): The two patients presented today, but who were seen more than 20 years apart, both had acute interstitial nephritis (AIN). Acute interstitial nephritis is a rather uncommon disease that has occurred at a relatively stable rate over the years. In three large series published between 1988 and 1998, AIN represented 2% to 3% of all renal biopsies1.Cameron J.S. Allergic interstitial nephritis: Clinical features and pathogenesis.Q J Med. 1988; 66: 97-115PubMed Google Scholar, 2.Buysen J.G.M. Houtlhoff H.J. Krediet R.T. Arisz L. Acute interstitial nephritis: A clinical and morphological study in 27 patients.Nephrol Dial Transplant. 1990; 5: 94-99Crossref PubMed Scopus (113) Google Scholar, 3.Davison A.M. Jones C.H. Acute interstitial nephritis in the elderly: A report from the UK MRC glomerulonephritis register and a review of the literature.Nephrol Dial Transplant. 1998; 13: 12-16https://doi.org/10.1093/ndt/13.1.12Crossref PubMed Scopus (9) Google Scholar. Nevertheless, the clinical presentation of drug-induced AIN has changed since the time when methicillin-induced AIN was prototypical of this entity. After briefly discussing the pathophysiology of drug-induced AIN, and in particular the links between AIN and interstitial fibrosis, I will review the clinical spectrum of drug-induced AIN, the diagnostic tools that can be used besides renal biopsy, and the prognosis and treatment of this disease. Four arguments strongly suggest that drug-induced AIN is secondary to immune reactions in humans. First, AIN occurs only in a small percentage of individuals taking the drug. Second, AIN is not dose-dependent. Third, drug-induced AIN is associated with extrarenal manifestations of hypersensitivity. Four, AIN usually recurs after accidental re-exposure to the drug or to a closely related agent. It is thus tempting to draw a parallel between drug-induced AIN and immune-mediated experimental AIN, and to use these experimental models to understand the pathophysiology of drug-induced AIN. Two main categories of antigens can induce experimental AIN: (1) endogenous renal antigens, which can be either non-collagenous components of the tubular basement membrane (TBM) or proteins synthesized by tubular cells but which are not part of the TBM, and (2) non-renal antigens reviewed in4.Wilson C.B. Study of the immunopathogenesis of tubulointerstitial nephritis using model systems.Kidney Int. 1989; 35: 938-953Abstract Full Text PDF PubMed Scopus (34) Google Scholar,5.Neilson E.G. Pathogenesis and therapy of interstitial nephritis.Kidney Int. 1989; 35: 1257-1270Abstract Full Text PDF PubMed Scopus (179) Google Scholar. The ability of renal antigens to induce AIN has been extensively studied since the first description of this model in 19716.Steblay R.W. Rudofsky U. Renal tubular disease and autoantibodies against tubular basement membrane induced in guinea pigs.J Immunol. 1971; 107: 589-594PubMed Google Scholar. Immunization of some strains of guinea pigs (such as strain XIII), of rats (such as Brown-Norway rats), or of mice (such as SJL mice) with heterologous TBM can induce AIN reviewed in4.Wilson C.B. Study of the immunopathogenesis of tubulointerstitial nephritis using model systems.Kidney Int. 1989; 35: 938-953Abstract Full Text PDF PubMed Scopus (34) Google Scholar,5.Neilson E.G. Pathogenesis and therapy of interstitial nephritis.Kidney Int. 1989; 35: 1257-1270Abstract Full Text PDF PubMed Scopus (179) Google Scholar. Similarly, animals immunized with endogenous renal proteins that are not part of the TBM can develop AIN. Immunization of rabbits or rats with Tamm-Horsfall protein, or injection of rats with antisera to Tamm-Horsfall protein can induce AIN reviewed in4.Wilson C.B. Study of the immunopathogenesis of tubulointerstitial nephritis using model systems.Kidney Int. 1989; 35: 938-953Abstract Full Text PDF PubMed Scopus (34) Google Scholar. Immunization of Lewis rats with megalin induces a membranous nephropathy, which has been associated with tubular lesions and interstitial inflammatory infiltrates reviewed in4.Wilson C.B. Study of the immunopathogenesis of tubulointerstitial nephritis using model systems.Kidney Int. 1989; 35: 938-953Abstract Full Text PDF PubMed Scopus (34) Google Scholar. These models suggest that drugs responsible for AIN induce an immune reaction directed against endogenous renal antigens. The drug or one of its metabolites could serve as a hapten and modify the immunogenicity of native renal proteins Figure 1a, or it could mimic renal antigens and induce an immune reaction that also will be directed against components of the TBM Figure 1b. Experimental AIN also can be induced by promoting immune reactions against extrarenal proteins that have become trapped within the kidney (“planted” antigen). The lesion can be induced by injecting rabbits daily with bovine serum albumin, or by injecting aggregated bovine gamma globulins under the renal capsule of pre-sensitized rats or guinea pigs reviewed in4.Wilson C.B. Study of the immunopathogenesis of tubulointerstitial nephritis using model systems.Kidney Int. 1989; 35: 938-953Abstract Full Text PDF PubMed Scopus (34) Google Scholar. In the former case, the AIN is associated with a glomerulonephritis and is characterized by granular deposits of immunoglobulins, C3, and antigen along the TBM, in the interstitium, and in the basal area of interstitial capillaries. In the latter case, aggregated bovine gamma globulins induce delayed-type hypersensitivity reactions within the interstitium. These two animal models could correspond to human AIN induced by drugs that trigger an immune reaction and become deposited within the interstitium. The drug could first be trapped in the interstitium and then become the target of an immune reaction, as exemplified by the second model Figure 1c. It could also form circulating immune complexes, which then deposit in the interstitium, as might be the case in the first model Figure 1d. Studies of experimental models of AIN have shown that their induction can involve either cell-mediated immunity or antibody-mediated immunity, and that in some cases the same antigen can even trigger either type of immune response depending on the species reviewed in4.Wilson C.B. Study of the immunopathogenesis of tubulointerstitial nephritis using model systems.Kidney Int. 1989; 35: 938-953Abstract Full Text PDF PubMed Scopus (34) Google Scholar,5.Neilson E.G. Pathogenesis and therapy of interstitial nephritis.Kidney Int. 1989; 35: 1257-1270Abstract Full Text PDF PubMed Scopus (179) Google Scholar. For example, immunization of strain XIII guinea pigs with heterologous TBM induces an AIN associated with linear deposits of IgG along the TBM and mediated by antibodies. The lesion can be transferred with antibodies but not with immune cells, and guinea pigs are protected from the disease by “decomplementation” or by injection of anti-idiotypic antibodies7.Rudofsky U.H. Pollara B. Studies on the pathogenesis of experimental autoimmune renal tubulointerstitial disease in guinea pigs: Passive transfer of renal lesion by antitubular basement autoantibody and non-immune bone-marrow cell to leukocyte-depleted recipients.Clin Immunol Immunopathol. 1976; 6: 107-114Crossref PubMed Scopus (13) Google Scholar, 8.Rudofsky U.H. Steblay R.W. Pollara B. Inhibition of experimental autoimmune renal tubulointerstitial disease in guinea pigs by depletion of complement with cobra venom factor.Clin Immunol Immunopathol. 1975; 3: 396-407Crossref PubMed Scopus (27) Google Scholar, 9.Brown C.A. Carey K. Colvin R.B. Inhibition of autoimmune tubulointerstitial nephritis in guinea pigs by heterologous anti-sera containing anti-idiotype antibodies.J Immunol. 1979; 123: 2102-2107PubMed Google Scholar. In contrast, immunization of SJL mice with heterologous TBM induces a purely cell-mediated AIN. This AIN can be induced by injection of a T-cell clone that mediates delayed-type hypersensitivity but it cannot be transferred by anti-TBM antibodies10.Neilson E.G. Phillips S.M. Murine interstitial nephritis. I. Analysis of disease susceptibility and its relationship to pleiomorphic gene products defining both immune-response genes and a restrictive requirement for cytotoxic T cells at H-2K.J Exp Med. 1982; 155: 1075-1085Crossref PubMed Scopus (40) Google Scholar,11.Zakheim B. McCafferty E. Phillips S.M. et al.Murine interstitial nephritis. II. The adoptive transfer of disease with immune T lymphocytes produces a phenotypically complex interstitial lesion.J Immunol. 1984; 133: 234-239PubMed Google Scholar. In humans, most drug-induced AIN probably involves cell-mediated immunity, as renal biopsies usually do not disclose any immune deposits. This hypothesis is reinforced by the fact that interstitial infiltrates usually contain a considerable percentage of T-cells and that they sometimes form granulomas. Nevertheless, deposition of anti-TBM antibodies or immune complexes can be observed occasionally on renal biopsies, as in the methicillin-induced AIN in today's first patient. In these cases, antibody-mediated immunity might play a role in the induction of the disease. Analyses of human renal biopsy tissue and of kidneys taken from animals with experimental AIN have shown that acute interstitial inflammatory reactions are associated with damage to tubular cells. These tubular lesions probably play a key role in the pathogenesis of acute renal failure associated with AIN. The lesions are multifactorial and are due to direct interactions between inflammatory cells and tubular epithelial cells, to the release of soluble molecules by inflammatory cells, or to activation of the complement cascade. Nevertheless, tubular cells are not only a target for inflammatory lesions, they also can actively interact with infiltrating cells to increase interstitial inflammation. Analyses of renal biopsies, studies of kidneys from animals with experimental nephritides, and co-culture experiments have shown that in response to an insult tubular cells can become activated and produce pro-inflammatory molecules such as cytokines, growth factors, adhesion molecules, or chemokines reviewed in12.Ong A.C. Fine L.G. Tubular-derived growth factors and cytokines in the pathogenesis of tubulointerstitial fibrosis: Implications for human renal disease progression.Am J Kidney Dis. 1994; 23: 205-209Abstract Full Text PDF PubMed Scopus (101) Google Scholar,13.Segerer S. Nelson P.J. Schlondorff D. Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies.J Am Soc Nephrol. 2000; 11: 152-176PubMed Google Scholar. For example, analyses of renal biopsies from patients with AIN or from Brown-Norway rats immunized with heterologous TBM have disclosed an overexpression of chemokines by tubular cells14.Grandaliano G. Gesualdo L. Ranieri E. et al.Monocyte chemotactic peptide-1 expression in acute and chronic human nephritides: A pathogenetic role in interstitial monocyte recruitment.J Am Soc Nephrol. 1996; 7: 906-913PubMed Google Scholar,15.Tang W.W. Feng L. Mathison J.C. Wilson C.B. Cytokine expression, upregulation of intercellular adhesion molecule-1, and leukocyte infiltration in experimental tubulointerstitial nephritis.Lab Invest. 1994; 70: 631-638PubMed Google Scholar, and co-culture experiments have shown that, in vitro, T-cells can induce chemokine production by tubular epithelial cells16.Kuroiwa T. Schlimgen R. Illei G.G. et al.Distinct T cell/renal tubular epithelial cell interactions define differential chemokine production: Implications for tubulointerstitial injury in chronic glomerulonephritides.J Immunol. 2000; 164: 3323-3329Crossref PubMed Scopus (78) Google Scholar. Similarly, in a mouse model of spontaneous acute interstitial nephritis, tubular cells overexpress the osteopontin gene, which encodes an adhesion molecule17.Sibalic V. Fan X. Loffing J. Wuthrich R.P. Upregulated renal tubular CD44, hyaluronan, and osteopontin in kdkd mice with interstitial nephritis.Nephrol Dial Transplant. 1997; 12: 1344-1353https://doi.org/10.1093/ndt/12.7.1344Crossref PubMed Scopus (82) Google Scholar. In some cases, acute interstitial inflammatory reactions induce an accumulation of extracellular matrix that leads to permanent impairment of renal function. Experimental studies and analyses of renal biopsies have shown that macrophages, lymphocytes, and activated tubular cells can produce many cytokines that can induce a proliferation of fibroblastic cells, and/or increase the production of extracellular matrix by these cells in vitro reviewed in2.Buysen J.G.M. Houtlhoff H.J. Krediet R.T. Arisz L. Acute interstitial nephritis: A clinical and morphological study in 27 patients.Nephrol Dial Transplant. 1990; 5: 94-99Crossref PubMed Scopus (113) Google Scholar,18.Rossert J. Garrett L.A. Regulation of type I collagen synthesis.Kidney Int. 1995; 47: S34-S38Google Scholar. For example, inflammatory cells can produce transforming growth factor-β (TGF-β), interleukin (IL)-1, IL-4, and lipid peroxidation products, which increase the production of extracellular matrix proteins by fibroblastic cells in vitro. Similarly, tubular cells can synthesize TGF-β, insulin-like growth factor-1 (IGF-1), endothelin-1 (ET-1), and lipid peroxidation products, which stimulate the production of extracellular matrix components by fibroblastic cells in vitro. Nevertheless, in vivo only three of these molecules induce fibrotic reactions within the renal interstitium: TGF-β, ET-1, and platelet-derived growth factor-BB (PDGF-BB). A potent anti-inflammatory molecule, TGF-β1 is probably the most important profibrotic factor identified so far. It is produced by many cells, including monocytes/macrophages, lymphocytes, fibroblasts, endothelial cells, and tubular cells. After being activated, TGF-β1 binds to its receptors and acts mostly by inducing the phosphorylation of Smad proteins reviewed in19.Massagué J. Wotton D. Transcriptional control by the TGF-β/Smad signaling system.EMBO J. 2000; 19: 1745-1754https://doi.org/10.1093/emboj/19.8.1745Crossref PubMed Google Scholar. The profibrotic properties of TGF-β1 are explained by its ability to be chemotactic for fibroblasts, to induce a proliferation of fibroblastic cells, to increase the transcription of genes encoding proteins of the extracellular matrix and the stability of the corresponding mRNAs, to inhibit the production of metalloproteinases, and to increase the production of tissue inhibitors of metalloproteinases (TIMPs), which are their natural inhibitors reviewed in20.Massagué J. The transforming growth factor-β family.Annu Rev Cell Biol. 1990; 6: 597-641Crossref PubMed Scopus (2949) Google Scholar. Nevertheless, some of these profibrotic properties might be indirect and mediated by increased production of a cysteine-rich protein called connective tissue growth factor21.Duncan M.R. Frazier K.S. Abramson S. et al.Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: Down-regulation by cAMP.FASEB J. 1999; 13: 1774-1786Crossref PubMed Scopus (558) Google Scholar. The ability of TGF-β1 to induce renal interstitial fibrosis has been shown by an analysis of the phenotype of transgenic mice, which produce high levels of active TGF-β1. Transgenic mice, which express a cDNA encoding mature TGF-β1 under the control of the albumin enhancer/promoter, have elevated circulating levels of TGF-β1, and progressively develop fibrosis of different organs, including liver and kidney22.Sanderson N. Factor V. Nagy P. et al.Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions.Proc Natl Acad Sci USA. 1995; 92: 2572-2576Crossref PubMed Scopus (587) Google Scholar. Analysis of the corresponding kidneys shows that they display glomerular immune deposits, glomerulosclerosis, and interstitial fibrosis23.Kopp J.B. Factor V.M. Mozes M. et al.Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease.Lab Invest. 1996; 74: 991-1003PubMed Google Scholar. Similarly, transgenic mice that harbor a cDNA encoding active TGF-β1 under the control of rat phosphoenolpyruvate carboxykinase regulatory sequences develop renal interstitial fibrosis, glomerulosclerosis, and fibrosis of the liver and adipose tissue24.Clouthier D.E. Comerford S.A. Hammer R.E. Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-beta-1-transgenic mice.J Clin Invest. 1997; 100: 2697-2713Crossref PubMed Scopus (236) Google Scholar. In vivo, ET-1 also can induce renal interstitial fibrosis. The predominant isoform of endothelin, ET-1 is produced by endothelial cells, vascular smooth muscle cells, and tubular cells reviewed in25.Hirata Y. Endothelin peptides.Curr Opin Nephrol Hypertens. 1996; 5: 12-15Crossref Scopus (19) Google Scholar. Its production can be induced by a variety of stimuli, including hypoxia, angiotensin II, and TGF-β. In vivo, the profibrotic properties of endothelin have been demonstrated by the analysis of transgenic animals overexpressing either ET-1 or ET-2, and by the beneficial effects of endothelin inhibitors in various experimental models of fibrosis involving organs such as kidney, liver, or lung. For example, Hocher et al generated transgenic mice using a 16 kb fragment of human genomic DNA that contained the ET-1 gene, about 8 kb of 5′ flanking sequence, and 1.5 kb of 3′ flanking sequence26.Hocher B. Thone-Reineke C. Rohmeiss P. et al.Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension.J Clin Invest. 1997; 99: 1380-1389Crossref PubMed Scopus (358) Google Scholar. These mice overexpress ET-1 predominantly in lung, brain, and kidney, are normotensive, and progressively develop glomerulosclerosis, renal interstitial fibrosis, and pulmonary fibrosis26.Hocher B. Thone-Reineke C. Rohmeiss P. et al.Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension.J Clin Invest. 1997; 99: 1380-1389Crossref PubMed Scopus (358) Google Scholar,27.Hocher B. Schwarz A. 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The third molecule that induces fibrosis in the renal interstitium, PDGF-BB, is a potent growth factor. It induces renal interstitial fibrosis in vivo: continuous infusion of PDGF-BB to rats induces not only a proliferation of interstitial myofibroblastic cells, but also an accumulation of extracellular matrix within the renal interstitium33.Tang W.W. Ulich T.R. Lacey D.L. et al.Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast formation and tubulointerstitial fibrosis.Am J Pathol. 1996; 48: 1169-1180Google Scholar. Nevertheless, the profibrotic effects of PDGF-BB are probably indirect and mediated by an overproduction of TGF-β134.Pierce G.F. Mustoe T.A. Lingelbach J. et al.Platelet-derived growth factor and transforming growth factor-beta enhance tissue repair activities by unique mechanisms.J Cell Biol. 1989; 109: 429-440Crossref PubMed Scopus (452) Google Scholar. In recent years, much attention has focused on angiotensin II as a profibrotic molecule, because of beneficial effects of angiotensin I converting enzyme inhibitors on the progression of chronic renal diseases reviewed in35.Klahr S. Morrissey J.J. The role of vasoactive compounds, growth factors and cytokines in the progression of renal disease.Kidney Int. 2000; 57: S7-S14Abstract Full Text Full Text PDF Scopus (174) Google Scholar. Nevertheless, data suggest that the effects of angiotensin II on extracellular matrix production are indirect, mediated through an increased production of growth factors such as TGF-β or PDGF, and of other molecules such as thrombospondin-l reviewed in35.Klahr S. Morrissey J.J. The role of vasoactive compounds, growth factors and cytokines in the progression of renal disease.Kidney Int. 2000; 57: S7-S14Abstract Full Text Full Text PDF Scopus (174) Google Scholar. Methicillin-induced AIN has long been considered prototypical of drug-induced AIN. About 100 cases of methicillin-induced AIN have been described in the English literature, and analysis of these case reports shows that the corresponding clinical picture was quite monomorphic Figure 2 reviewed in36.Ditlove J. Weidmann P. Bernstein M. Massry S.G. Methicillin nephritis.Medicine (Baltimore). 1977; 56: 483-490Crossref PubMed Scopus (65) Google Scholar, 37.Nolan C.M. Abernathy R.S. Nephropathy associated with methicillin therapy.Arch Intern Med. 1977; 137: 997-1000Crossref PubMed Scopus (28) Google Scholar, 38.Galpin J.E. Shinaberger J.H. Stanley T.M. et al.Acute interstitial nephritis due to methicillin.Am J Med. 1978; 65: 756-764Abstract Full Text PDF PubMed Scopus (188) Google Scholar. Renal symptoms typically developed about two weeks after the patients started taking methicillin. Hematuria was present in 90% of cases. It was macroscopic in about 80% of cases and was never associated with red blood cell casts. Pyuria was almost always present and often was associated with leukocyte casts. Renal failure, which occurred in only 50% of adults and 15% of children, was oliguric in 20% of the cases. Approximately 33% of the patients with abnormal renal function required dialysis. The most common extrarenal symptom was fever, which was present in about 80% of patients, could be as high as 40°C, and usually lasted 7 to 10 days after discontinuation of methicillin. A generalized cutaneous rash was observed in only 25% of patients, and arthralgias were uncommon. Eosinophilia was present in about 80% of patients, ranging from 500 to 5000/mm3. After the methicillin was discontinued, hematuria and pyuria usually resolved within a few days, but renal failure, when present, could last much longer and its mean duration was 1.5 months. Nevertheless, complete recovery of renal function was the rule, and serum creatinine returned to normal levels in about 90% of reported patients. Besides methicillin, many other drugs can induce AIN Table 1, but the clinical presentation of AIN induced by these drugs is often incomplete and less suggestive of the diagnosis, as illustrated by the second patient presented today. To try to get a global view of this entity, we reviewed more than 150 case reports, as well as our own unpublished cases Figure 2. This analysis showed that renal manifestations develop within three weeks after starting the inciting drug in about 80% of patients, with an average delay of about ten days. The clinical presentation most suggestive of the diagnosis is that of a sudden impairment of renal function associated with mild proteinuria and abnormal urinalysis in a patient with flank pain, normal blood pressure, and no edema. Nevertheless, such a clinical picture is observed in less than one-fourth of cases. Analysis of the different manifestations showed that renal failure is almost constant, and that dialysis is required in about one-half of patients. The presentation is usually that of parenchymal renal failure, but patients with a low fractional excretion of sodium occasionally have been reported. Hematuria and pyuria are each present in only about 50% of patients. Flank pain, reflecting distension of the renal capsule, is also observed in about the same percentage of cases, and it can be the main complaint on admission. Ultrasonography usually discloses an increased cortical echogenicity (comparable to or higher than that of the liver), but as far as we know, the diagnostic value of this finding has not been assessed39.Hi