Acute interstitial nephritis
2010; Elsevier BV; Volume: 77; Issue: 11 Linguagem: Inglês
10.1038/ki.2010.89
ISSN1523-1755
Autores Tópico(s)Nephrotoxicity and Medicinal Plants
ResumoAcute interstitial nephritis (AIN) represents a frequent cause of acute kidney injury, accounting for 15–27% of renal biopsies performed because of this condition. By and large, drug-induced AIN is currently the commonest etiology of AIN, with antimicrobials and nonsteroidal anti-inflammatory drugs being the most frequent offending agents. Pathogenesis is based on an immunologic reaction against endogenous nephritogenic antigens or exogenous antigens processed by tubular cells, with cell-mediated immunity having a major pathogenic role. The characteristic interstitial infiltrates, mostly composed of lymphocytes, macrophages, eosinophils, and plasma cells, experience a rapid transformation into areas of interstitial fibrosis. A significant proportion of AIN has nowadays an oligosymptomatic presentation, although the presence of specific extrarenal symptoms such as fever, skin rash, arthralgias, and peripheral eosinophilia has an important role to orientate clinical diagnosis. Identification and removal of the offending drug are the mainstay of the treatment, but recent studies strongly suggest that early steroid administration (within 7 days after diagnosis) improves the recovery of renal function, decreasing the risk of chronic renal impairment. Delayed steroid treatment, when interstitial fibrosis has taken place, would have a less pronounced or nule therapeutic benefit. Acute interstitial nephritis (AIN) represents a frequent cause of acute kidney injury, accounting for 15–27% of renal biopsies performed because of this condition. By and large, drug-induced AIN is currently the commonest etiology of AIN, with antimicrobials and nonsteroidal anti-inflammatory drugs being the most frequent offending agents. Pathogenesis is based on an immunologic reaction against endogenous nephritogenic antigens or exogenous antigens processed by tubular cells, with cell-mediated immunity having a major pathogenic role. The characteristic interstitial infiltrates, mostly composed of lymphocytes, macrophages, eosinophils, and plasma cells, experience a rapid transformation into areas of interstitial fibrosis. A significant proportion of AIN has nowadays an oligosymptomatic presentation, although the presence of specific extrarenal symptoms such as fever, skin rash, arthralgias, and peripheral eosinophilia has an important role to orientate clinical diagnosis. Identification and removal of the offending drug are the mainstay of the treatment, but recent studies strongly suggest that early steroid administration (within 7 days after diagnosis) improves the recovery of renal function, decreasing the risk of chronic renal impairment. Delayed steroid treatment, when interstitial fibrosis has taken place, would have a less pronounced or nule therapeutic benefit. Acute interstitial nephritis (AIN) is characterized by the presence of inflammatory infiltrates and edema within the interstitium, usually associated with an acute deterioration in renal function. AIN represented 1–3% of all renal biopsies in some studies.1.Cameron J.S. Allergic interstitial nephritis: clinical features and pathogenesis.Q J Med. 1998; 66: 97-115Google Scholar,2.Pettersson E. von Bonsdorff M. Tornroth T. Nephritis among young Finnish men.Clin Nephrol. 1984; 22: 217-222PubMed Google Scholar However, when the analysis was restricted to patients with acute kidney failure, AIN accounted for 15–27% of lesions.3.Haas M. Spargo B.H. Wit E.J. et al.Etiologies and outcome of acute renal insufficiency in older adults: a renal biopsy study of 259 cases.Am J Kidney Dis. 2000; 35: 433-447Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar,4.Farrington K. Levison D.A. Greenwood R.N. et al.Renal biopsy in patients with unexplained renal impairment and normal kidney size.Q J Med. 1989; 70: 221-233PubMed Google Scholar These studies suggest that AIN is a common cause of acute renal dysfunction, but its true incidence might even be underestimated by several reasons. First, a significant number of patients in whom AIN is suspected on clinical grounds is not submitted to a confirmatory renal biopsy because empirical treatment is preferred, particularly in elderly and frail patients. Second, milder forms of AIN can be underdetected, either because of the absence or vagueness of clinical symptoms or because acute renal failure is attributed to other causes of renal injury. As shown in Table 1, the main causes of AIN can be grouped as drug induced, infection related, idiopathic forms (which would include tubulointerstitial nephritis and uveitis syndrome (TINU) and anti-tubular basement membrane (anti-TBM) disease), and AIN associated with sarcoidosis and other systemic diseases (systemic lupus erythematosus, Sjögren, malignancies). Tubulointerstitial lesions that frequently accompany primary glomerulonephritis are usually not included within AIN. Regarding the frequency of these different etiologies, drug-induced AIN currently accounts for more than two-thirds of the cases, infection-related AIN for 15%, idiopathic forms for 10%, and TINU for 4%, the remaining ones being associated with systemic disorders.5.Baker R.J. Pusey C.D. The changing profile of acute tubulointerstitial nephritis.Nephrol Dial Transplant. 2004; 19: 8-11Crossref PubMed Scopus (222) Google Scholar, 6.Buysen J.G. Houthoff H.J. Krediet R.T. et al.Acute interstitial nephritis: a clinical and morphological study in 27 patients.Nephrol Dial Transplant. 1990; 5: 94-99Crossref PubMed Scopus (113) Google Scholar, 7.Schwarz A. Krause P.H. Kunzendorf U. et al.The outcome of acute interstitial nephritis: risk factors for the transition from acute to chronic interstitial nephritis.Clin Nephrol. 2000; 54: 179-190PubMed Google Scholar However, the prevalence of drug-induced AIN could have even increased in the last years: according to our own experience (data not published), drugs were responsible for more than 90% of biopsy-proven AIN occurring during the period 2000–2008.Table 1Etiology of biopsy-proven AINDrugs (>75% of AIN)Antibiotics: ampicillin, cephalosporins, ciprofloxacin, cloxacillin, methicillin, penicillin, rifampicin, sulfonamides, vancomycin. NSAIDs Other: allopurinol, acyclovir, famotidine, furosemide, omeprazole, phenytoinInfections (5–10%)Bacteria: Brucella, Campylobacter, Escherichia coli, Legionella, Salmonella, Streptococcus, Staphylococcus, YersiniaViruses: cytomegalovirus, Epstein–Barr, hantavirus, human immunodeficiency virus, polyomavirus Other: Leptospira, Mycobacterium tuberculosis, Mycoplasma, Rickettsia, Schistosoma, ToxoplasmaIdiopathic (5–10%)Anti-TBM TINUAssociated with systemic diseases (10–15%)Sarcoidosis, Sjögren, systemic lupus erythematosusAbbreviations: AIN, acute interstitial nephritis; NSAID, nonsteroidal anti-inflammatory drug; TBM, tubular basement membrane; TINU, tubulointerstitial nephritis and uveitis syndrome.Most commonly involved causative agents. Open table in a new tab Abbreviations: AIN, acute interstitial nephritis; NSAID, nonsteroidal anti-inflammatory drug; TBM, tubular basement membrane; TINU, tubulointerstitial nephritis and uveitis syndrome. Most commonly involved causative agents. A large and expanding number of drugs has been implicated in causing AIN and it can be stated that any drug can theoretically induce an episode of AIN. However, the majority of cases have been caused by antimicrobial agents and nonsteroidal anti-inflammatory drugs (NSAIDs). Table 1 lists those drugs most commonly involved in AIN. It is generally accepted that the initial event unleashing an AIN episode is the expression of endogenous nephritogenic antigens or exogenous antigens processed by tubular cells. Immunization of rabbits or rats with Tamm–Horsfall protein or megalin (a protein localized in the brush border of proximal tubular cells) induced an AIN,8.Serafini-Cessi F. Malagolini N. Cavallone D. Tamm-Horsfall glycoproteins: biology and clinical relevance.Am J Kidney Dis. 2003; 46: 658-676Abstract Full Text Full Text PDF Scopus (276) Google Scholar thus suggesting a possible pathogenic role of these proteins as endogenous antigens in the development of some human AIN. Other endogenous antigens implicated in AIN have been identified as components of TBM, such as the tubulointerstitial nephritis antigen, a glycoprotein important for TBM integrity and whose molecular composition has been cloned and sequenced.9.Ikeda M. Takemura T. Hino S. et al.Molecular cloning, expression, and chromosomal localization of a human tubulointerstitial nephritis antigen.Biochem Biophys Res Commun. 2000; 268: 225-230Crossref PubMed Scopus (24) Google Scholar Tubulointerstitial nephritis antigen is likely to be the target for some human cases of anti-TBM AIN, an uncommon entity in which circulating anti-TBM antibodies that react specifically with proximal TBM are found. The mechanisms involved in the appearance of such antibodies, as well as the proportion of human idiopathic AIN that are caused by this pathogenic mechanism, remain unknown. Anti-TBM AIN is occasionally manifested in association with membranous nephropathy.10.Katz A. Fish A.J. Santamaria P. et al.Role of antibodies to tubulointerstitial nephritis antigen in human anti-tubular basement membrane nephritis associated with membranous nephropathy.Am J Med. 1992; 93: 691-698Abstract Full Text PDF PubMed Scopus (23) Google Scholar The above-referred antigens are likely to be responsible for most idiopathic types of AIN. The pathogenesis of the more common drug-induced AIN is also believed to have an immunologic basis, as indicated by the relatively common appearance of extrarenal manifestations of hypersensitivity, its dose-independent character, and the recurrence of AIN after re-exposure to the offending drug.11.Rossert J. Drug-induced acute interstitial nephritis.Kidney Int. 2001; 60: 804-817Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar Medications and specific microbial antigens could elicit an immune reaction after their interstitial deposition (planted antigens). Conversely, tubular cells have the capacity to hydrolyze and process exogenous proteins. In this regard, medications can bind to a normal component of TBM, behaving as a hapten, or can mimic an antigen normally present within the TBM, inducing an immune response directed against this antigen (reviewed by Rossert11.Rossert J. Drug-induced acute interstitial nephritis.Kidney Int. 2001; 60: 804-817Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar). Although evidence is not so strong, some microbial antigens could also induce AIN through these mechanisms. The fact that only a minority of patients treated with a particular drug or suffering an infectious process develop AIN indicates that the expression of nephritogenic antigens at renal tubulointerstitium is likely counterbalanced by complex protective mechanisms, mainly involving suppressor T cells.12.Neilson E.G. Pathogenesis and therapy of interstitial nephritis.Kidney Int. 1989; 35: 1257-1270Abstract Full Text PDF PubMed Scopus (179) Google Scholar When these protective mechanisms are surpassed (likely on the basis of a genetically determined susceptibility) and AIN ensues, both experimental studies and cumulative evidence in humans indicate that cell-mediated immunity has the major pathogenic role.12.Neilson E.G. Pathogenesis and therapy of interstitial nephritis.Kidney Int. 1989; 35: 1257-1270Abstract Full Text PDF PubMed Scopus (179) Google Scholar,13.Michel D.M. Kelly C.J. Acute interstitial nephritis.J Am Soc Nephrol. 1998; 9: 506-515PubMed Google Scholar Target antigen, or one cross-reactive with it, is presented to T cells. Activated T-helper cells induce the differentiation of other effector T cells, such as those mediating delayed-type hypersensitivity and cytotoxicity. With the exception of anti-TBM disease and some cases of drug-induced AIN (mainly those related to methicillin), immunofluorescence studies in renal biopsies of patients with AIN are generally negative, indicating the absence of antibody-mediated immunity that has a marginal, if any, pathogenic role. The inflammatory cellular infiltrates that characterize AIN, mainly composed of T lymphocytes and macrophages, are a powerful source of cytokines that increase the production of extracellular matrix and the number of interstitial fibroblasts, and induce an amplification process recruiting more inflammatory cells and eosinophils into the interstitium.12.Neilson E.G. Pathogenesis and therapy of interstitial nephritis.Kidney Int. 1989; 35: 1257-1270Abstract Full Text PDF PubMed Scopus (179) Google Scholar,13.Michel D.M. Kelly C.J. Acute interstitial nephritis.J Am Soc Nephrol. 1998; 9: 506-515PubMed Google Scholar Particularly decisive for the final outcome of renal function is the rapid transformation of these inflammatory lesions into destructive fibrogenesis, a process that can be detected after only 7 days of interstitial inflammation.14.Neilson E.G. Mechanisms of disease: fibroblasts – a new look at an old problem.Nat Rev Nephrol. 2006; 2: 101-107Google Scholar Interstitial fibrosis is marked by the loss of renal tubules and the accumulation of fibroblasts and extracellular matrix proteins (collagens, fibronectin, laminin). There is a number of profibrotic cytokines and growth factors actively synthetized by inflammatory cells that have a crucial role in the progression of interstitial fibrosis, such as transforming growth factor-β, platelet-derived growth factor-BB, endothelin-1, epidermal growth factor, and fibroblast growth factor-2. These mediators are also an important stimulus for local epithelial-to-mesenchymal transition that affects tubular epithelium after injury.14.Neilson E.G. Mechanisms of disease: fibroblasts – a new look at an old problem.Nat Rev Nephrol. 2006; 2: 101-107Google Scholar Fibroblasts derived from epithelial-to-mesenchymal transition have a crucial role in tubulointerstitial fibrosis.15.Kalluri R. Neilson E.G. Epythelial-mesenchymal transition and its implications for fibrosis.J Clin Invest. 2003; 112: 1176-1184Crossref PubMed Scopus (1956) Google Scholar However, some recent studies have cast doubts about the implication of epithelial-to-mesenchymal transition in renal fibrosis.16.Humprheys B.D. Lin S.L. Kobayashi A. et al.Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis.Am J Pathol. 2010; 176: 85-97Abstract Full Text Full Text PDF PubMed Scopus (988) Google Scholar The characteristic inflammatory cell infiltrates of AIN (Figure 1) can be diffuse or patchy. Interstitial edema is a typical finding, whereas glomeruli and vessels are distinctly normal. Interstitial infiltrates are mostly composed of lymphocytes (CD4+ T cells being the most abundant type), macrophages, eosinophils, and plasma cells. Interstitial granulomas can be observed in some cases of drug-induced AIN, but the possibility of sarcoidosis, tuberculosis, and some other infections must be kept in mind when they are found. Results of immunofluorescence studies are negative in most of patients, although granular or linear deposits of IgG or complement along the TBM can occasionally be observed. The rare finding of homogeneous linear deposits of IgG along the TBM is indicative of antibodies directed against TBM antigens, as in anti-TBM disease, but it has also been described in some cases of drug-induced AIN. Electron microscopy reveals nonspecific lesions. In those patients with NSAIDs-induced AIN accompanied by nephrotic syndrome, diffuse effacement of podocyte's foot processes is observed.17.Porile J.L. Bakris G.L. Garella S. Acute interstitial nephritis with glomerulopathy due to nonsteroidal anti-inflammatory agents: a review if its clinical spectrum and effects of steroid therapy.J Clin Pharmacol. 1990; 30: 468-475Crossref PubMed Scopus (47) Google Scholar Fibrotic changes can already be seen within 7–10 days of initiation of the inflammatory process and they progress to advanced interstitial fibrosis accompanied by tubular atrophy (Figure 2) unless rapid withdrawal of offending drug or onset of steroid treatment take place.18.González E. Gutiérrez E. Galeano C. et al.Early steroid treatment improves renal function recovery in patients with drug-induced acute interstitial nephritis.Kidney Int. 2008; 73: 940-946Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar In patients with drug-induced AIN, mean delay between the starting of the offending drug and the appearance of renal manifestations is 10 days,11.Rossert J. Drug-induced acute interstitial nephritis.Kidney Int. 2001; 60: 804-817Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar although the latent period may be as short as 1 day after some antibiotics or as long as several months with NSAIDs. Table 2 shows the clinical and laboratory features at presentation in two large and recently published series of patients with AIN that included a total of 121 cases.18.González E. Gutiérrez E. Galeano C. et al.Early steroid treatment improves renal function recovery in patients with drug-induced acute interstitial nephritis.Kidney Int. 2008; 73: 940-946Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar,19.Clarkson M.R. Giblin L. O'Connell F.P. et al.Acute interstitial nephritis: clinical features and response to corticosteroid therapy.Nephrol Dial Transplant. 2004; 19: 2778-2783Crossref PubMed Scopus (220) Google Scholar Drug-induced AIN accounted for the majority (91%) of the cases (of whom, 44% corresponded to NSAIDs-induced AIN). All the patients presented with an acute worsening of renal function, whose severity led to dialysis requirement in a significant proportion of cases. AIN-related renal failure can be asymptomatic or accompanied by some clinical or laboratory findings that, when present, are very valuable to orientate the diagnosis. The specific clinical findings in drug-induced AIN are related to an allergic-type reaction and their incidence is shown in Table 2: low-grade fever in 36% and maculopapular skin rash in 22% (Figure 3), whereas arthralgias were more frequently reported (45%) in some series.19.Clarkson M.R. Giblin L. O'Connell F.P. et al.Acute interstitial nephritis: clinical features and response to corticosteroid therapy.Nephrol Dial Transplant. 2004; 19: 2778-2783Crossref PubMed Scopus (220) Google Scholar The presence of eosinophilia (35% of patients) is considered as an another expression of this allergic-type reaction. Eosinophilia is significantly less common in NSAIDs-related AIN than in other types of drug-induced AIN.18.González E. Gutiérrez E. Galeano C. et al.Early steroid treatment improves renal function recovery in patients with drug-induced acute interstitial nephritis.Kidney Int. 2008; 73: 940-946Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar Another clinical condition characterized by acute or subacute renal impairment, eosinophilia, and skin lesions is atheroembolic renal disease, which should be considered in the differential diagnosis of AIN, particularly in the elderly.20.Espejo B. Herrero J.C. Torres A. et al.Immunoallergic interstitial nephritis vs. cholesterol atheroembolism. Differentiating characteristics.Nefrologia. 2003; 23: 125-130PubMed Google Scholar Earlier series emphasized the diagnostic importance of the classic triad of fever, rash, and eosinophilia. However, only a minority of patients ( 500 eosinophils per mm3)35%MicrohematuriabData from González et al.1867%Gross hematuriabData from González et al.185%LeukocyturiabData from González et al.1882%Non-nephrotic proteinuria93%Nephrotic-range proteinuria2.5%Complete nephrotic syndrome0.8%a Data from Clarkson et al.19.Clarkson M.R. Giblin L. O'Connell F.P. et al.Acute interstitial nephritis: clinical features and response to corticosteroid therapy.Nephrol Dial Transplant. 2004; 19: 2778-2783Crossref PubMed Scopus (220) Google Scholarb Data from González et al.18.González E. Gutiérrez E. Galeano C. et al.Early steroid treatment improves renal function recovery in patients with drug-induced acute interstitial nephritis.Kidney Int. 2008; 73: 940-946Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar Open table in a new tab Other diagnostic features have also changed after the earliest clinical reports, in which methicillin was the predominant causative agent.21.Galpin J.E. Shinaberger J.H. Stanley T.M. et al.Acute interstitial nephritis due to methicillin.Am J Med. 1978; 65: 756-765Abstract Full Text PDF PubMed Scopus (188) Google Scholar Thus, gross hematuria was reported as a common type of presentation, whereas it is currently a very uncommon initial symptom. Microscopic hematuria, however, is found in almost two-thirds of the patients, although the presence of red blood cell casts is rare. A very common finding (more than 80% of cases) is leukocyturia, frequently accompanied by leukocyte casts. Conversely, in spite of stimulating earlier reports, the search for urinary eosinophils have not conclusively confirmed its diagnostic usefulness.22.Ruffing K.A. Hoppes P. Blend D. et al.Eosinophils in urine revisited.Clin Nephrol. 1994; 41: 163-166PubMed Google Scholar Monitoring of sensitive urinary markers of tubulointerstitial damage, such as neutrophil gelatinase-associated lipocalin, liver-type fatty acid-binding protein, and kidney injury molecule-1, has been suggested as a noninvasive test to evaluate early damage and evolution of interstitial nephritis.23.Waanders F. van Timmeren M.M. Stegeman C.A. et al.Kidney injury molecule-I in renal disease.J Pathol. 2010; 220: 7-16Crossref PubMed Scopus (101) Google Scholar,24.Tuwabara T. Mori K. Mukoyama M. et al.Urinary neutrophil gelatinase-associated lipocalin levels reflect damage to glomeruli, proximal tubules and distal nephrons.Kidney Int. 2009; 75: 285-294Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar However, more investigations are required before translation to clinical practice. A great majority of patients presents moderate, non-nephrotic proteinuria, but the finding of nephrotic-range proteinuria or complete nephrotic syndrome with hypoalbuminemia appears to be rather uncommon, even in those patients with NSAIDs-induced AIN (Table 2). Thus, in two relatively large series recently published,18.González E. Gutiérrez E. Galeano C. et al.Early steroid treatment improves renal function recovery in patients with drug-induced acute interstitial nephritis.Kidney Int. 2008; 73: 940-946Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar,19.Clarkson M.R. Giblin L. O'Connell F.P. et al.Acute interstitial nephritis: clinical features and response to corticosteroid therapy.Nephrol Dial Transplant. 2004; 19: 2778-2783Crossref PubMed Scopus (220) Google Scholar only 3 patients out of a total of 121 showed nephrotic-range proteinuria at presentation, although NSAIDs were the causative drug in 40% of the patients. In patients with AIN secondary to infectious diseases (Table 1), extrarenal manifestations are dominated by the underlying infection. Clinical findings that typically orientate the diagnosis of a patient with acute renal dysfunction toward AIN (maculopapular rash, arthralgias, eosinophilia) are uncommon or absent and the same is true in patients with idiopathic AIN. TINU syndrome is characterized by AIN accompanied by a bilateral anterior uveitis that can precede, concur with, or follow renal dysfunction.25.Sessa A. Meroni M. Battini G. et al.Acute renal failure due to acute tubulointerstitial nephritis and uveitis: ‘TINU syndrome’. Case report and review of the literature.J Nephrol. 2000; 13: 377-380PubMed Google Scholar Several patients with AIN coincidental with autoimmune pancreatitis have been reported.26.Finkelberg D.L. Sahani D. Deshpande V. et al.Autoimmune pancreatitis.N Engl J Med. 2006; 355: 2670-2676Crossref PubMed Scopus (355) Google Scholar,27.Yoneda K. Murata K. Katayama K. et al.Tubulointerstitial nephritis associated with IgG4-related autoimmune disease.Am J Kidney Dis. 2007; 50: 455-462Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar A distinctive feature of this entity is a dense infiltration of IgG4-positive mononuclear cells in renal interstitium. Initial reports, most of them based on series of methicillin-induced cases, depicted drug-induced AIN as a benign condition, with a rapid improvement of renal function after the removal of the inducing agent. However, later studies with a larger number of patients and a longer follow-up revealed that a significant proportion of patients, ranging from 30 to 70%, did not fully recovered their baseline renal function.6.Buysen J.G. Houthoff H.J. Krediet R.T. et al.Acute interstitial nephritis: a clinical and morphological study in 27 patients.Nephrol Dial Transplant. 1990; 5: 94-99Crossref PubMed Scopus (113) Google Scholar, 11.Rossert J. Drug-induced acute interstitial nephritis.Kidney Int. 2001; 60: 804-817Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar, 21.Galpin J.E. Shinaberger J.H. Stanley T.M. et al.Acute interstitial nephritis due to methicillin.Am J Med. 1978; 65: 756-765Abstract Full Text PDF PubMed Scopus (188) Google Scholar, 28.Pusey C.D. Saltissi D. Bloodworth L. et al.Drug associated acute interstitial nephritis: clinical and pathological features and the response to high dose steroid therapy.Q J Med. 1983; 52: 194-211PubMed Google Scholar, 29.Kida H. Abe T. Tomosugi N. et al.Prediction of the long-term outcome in acute interstitial nephritis.Clin Nephrol. 1984; 22: 55-60PubMed Google Scholar, 30.Laberke H.G. Bohle A. Acute interstitial nephritis: correlation between clinical and morphological findings.Clin Nephrol. 1980; 14: 263-273PubMed Google Scholar, 31.Bhaumik S.K. Kher V. Arora P. et al.Evaluation of clinical and histological prognostic markers in drug-induced acute interstitial nephritis.Ren Fail. 1996; 18: 97-104Crossref PubMed Scopus (50) Google Scholar Duration of treatment with the offending drug or duration and severity of renal failure have not shown a clear correlation with the levels of serum creatinine at the end of follow-up. Whereas some studies found a predictive role of diffuse interstitial infiltrates in opposition to patchy ones,30.Laberke H.G. Bohle A. Acute interstitial nephritis: correlation between clinical and morphological findings.Clin Nephrol. 1980; 14: 263-273PubMed Google Scholar other ones have not corroborated these findings.6.Buysen J.G. Houthoff H.J. Krediet R.T. et al.Acute interstitial nephritis: a clinical and morphological study in 27 patients.Nephrol Dial Transplant. 1990; 5: 94-99Crossref PubMed Scopus (113) Google Scholar Conversely, the extent of interstitial fibrosis has shown a clear impact on the risk of chronic renal impairment after a drug-induced AIN in some studies.18.González E. Gutiérrez E. Galeano C. et al.Early steroid treatment improves renal function recovery in patients with drug-induced acute interstitial nephritis.Kidney Int. 2008; 73: 940-946Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar,31.Bhaumik S.K. Kher V. Arora P. et al.Evaluation of clinical and histological prognostic markers in drug-induced acute interstitial nephritis.Ren Fail. 1996; 18: 97-104Crossref PubMed Scopus (50) Google Scholar Regarding the withdrawal of the causative agent, it is important to remark that in some patients with biopsy-proven AIN and in whom clinical and pathological findings strongly point out to a drug-induced form, the offending drug cannot be identified even after meticulous investigations. Reasons for such failure include self-treatment with antibiotic mixtures, polymedication, and the huge and largely uncontrolled consumption of NSAIDs among the general population, the two latter issues being particularly relevant among elderly people. The role of steroids in the treatment of drug-induced AIN remains controversial. Several studies reported a significantly better outcome in patients who were treated with steroids.6.Buysen J.G. Houthoff H.J. Krediet R.T. et al.Acute interstitial nephritis: a clinical and morphological study in 27 patients.Nephrol Dial Transplant. 1990; 5: 94-99Crossref PubMed Scopus (113) Google Scholar, 21.Galpin J.E. Shinaberger J.H. Stanley T.M. et al.Acute interstitial nephritis due to methicillin.Am J Med. 1978; 65: 756-765Abstract Full Text PDF PubMed Scopus (188) Google Scholar, 28.Pusey C.D. Saltissi D. Bloodworth L. et al.Drug associated acute interstitial nephritis: clinical and pathological features and the response to high dose steroid therapy.Q J Med. 1983; 52: 194-211PubMed Google Scholar In some cases, the response to steroids was dramatic, with a rapid recovery of diuresis and serum creatinine decrease. However, the number of patients included in such positive studies was short and other studies failed to found a beneficial influence of steroids in comparison with conservative measures.11.Rossert J. Drug-induced acute interstitial nephritis.Kidney Int. 2001; 60: 804-817Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar,32.Koselj M. Kveder R. Bren A.F. et al.Acute renal failure in patients with drug-induced acute interstitial nephritis.Ren Fail. 1993; 15: 69-72Crossref PubMed Scopus (41) Google Scholar Clarkson et al.19.Clarkson M.R. Giblin L. O'Connell F.P. et al.Acute interstitial nephritis: clinical features and response to corticosteroid therapy.Nephrol Dial Transplant. 2004; 19: 2778-2783Crossref PubMed Scopus (220) Google Scholar performed a retrospective study in a relatively large series of 60 patients with biopsy-proven AIN to define the influence of steroids on this disease. AIN was drug related in 92% of cases and NSAIDs were the most common offending drug, accounting for 44% of cases. Follow-up data were available in 42 patients. Of them, 25 patients (60%) received steroid treatment, whereas the remaining 17 (40%) received only supportive care. No difference in serum creatinine levels was observed between the two groups after 1, 6, and 12 months following AIN. Of note, a significant proportion of patients in both groups showed chronic renal impairments at the end of follow-up. An important aspect of Clarkson's study that should be kept in mind when interpreting its results is the considerable delay between the onset of AIN symptoms and the performance of renal biopsy (median time 3 weeks); steroids were always started after renal biopsy.19.Clarkson M.R. Giblin L. O'Connell F.P. et al.Acute interstitial nephritis: clinical features and response to corticosteroid therapy.Nephrol Dial Transplant. 2004; 19: 2778-2783Crossref PubMed Scopus (220) Google Scholar Whether the timing of treatment initiation might affect the response to steroids was investigated by González et al.,18.González E. Gutiérrez E. Galeano C. et al.Early steroid treatment improves renal function recovery in patients with drug-induced acute interstitial nephritis.Kidney Int. 2008; 73: 940-946Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar for the Grupo Madrileño de Nefritis Intersticiales. This retrospective multicenter study collected 61 patients with biopsy-proven, drug-induced AIN. Antibiotics (56%) and NSAIDs (37%) were the most common inciting drugs. Strengths of the study were the knowledge of the baseline renal function and a follow-up long enough (at least 6 months) to evaluate recovery of renal function in all the patients. A majority of patients (85%) received steroids and their outcome was significantly better than that of the remaining 15% of patients treated conservatively (need of chronic dialysis 3.8 vs 44%). When analyzing the course of those patients treated with steroids more carefully, it was found that 53% of the patients had completely recovered their baseline renal function, whereas in the remaining 47% renal function did not reach the baseline values (final serum creatinine 1.1±0.2 vs 3.2±2.7 mg/dl). There were no significant differences at baseline between both groups of steroid-treated patients regarding clinical characteristics, type of the causative agent, or highest serum creatinine values. Duration and doses of steroids were similar, but those patients who experienced incomplete renal function recovery had a significantly longer interval between withdrawal of the offending drug and start of steroid treatment (34±17 vs 13±10 days). Multivariate regression analysis showed that an interval of >7 days was associated with a more than six times increased risk of experiencing incomplete recovery of renal function. The separate analysis of those patients in whom NSAIDs had been the causative drug yielded similar results: a significant beneficial effect of steroids but only when they had been started shortly after the withdrawal of NSAIDs. The study of González et al.,18.González E. Gutiérrez E. Galeano C. et al.Early steroid treatment improves renal function recovery in patients with drug-induced acute interstitial nephritis.Kidney Int. 2008; 73: 940-946Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar therefore, suggests that steroid treatment is indicated in drug-induced AIN and that it should be started soon or immediately after the diagnosis to diminish the risk of chronic renal impairment. However, it is important to remark that this study consisted of a multicenter and retrospective collection of patients with biopsy-proven drug-induced AIN and that treatment regimens, regarding steroid doses and duration, showed considerable variations between participating centers. Prospective, randomized studies about steroid treatment in AIN are needed to resolve these questions. A prospective randomized study designed to compare early steroid treatment (administered immediately after AIN diagnosis and offending-drug withdrawal) vs late treatment (steroids administered only to those patients who had not started to improve renal function some weeks after offending-drug withdrawal) would give very valuable information about the indication of steroid treatment in AIN and when they should be given. The physiopathological rationale to explain the benefits of early steroid treatment in drug-induced AIN could be related to the rapid transformation of interstitial cellular infiltrates (responsive to high-dose steroids) into areas of irreversible interstitial fibrosis, a process that starts after only 7 days of interstitial inflammation as stated above.14.Neilson E.G. Mechanisms of disease: fibroblasts – a new look at an old problem.Nat Rev Nephrol. 2006; 2: 101-107Google Scholar Early steroid administration would likely reduce the number and extent of inflammatory infiltrates, thus decreasing the risk of subsequent fibrosis. In the study of González et al.,18.González E. Gutiérrez E. Galeano C. et al.Early steroid treatment improves renal function recovery in patients with drug-induced acute interstitial nephritis.Kidney Int. 2008; 73: 940-946Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar a second renal biopsy was performed 4–6 weeks after the first one in three patients who had received a delayed course of steroids; interstitial fibrotic areas that have largely replaced inflammatory infiltrates were observed in all these cases. If the efficacy of steroids relies on the rapid disappearance of interstitial infiltrates, a logical recommendation is to initiate treatment with high doses of steroids followed by a rapid tapering off. Our current therapeutic scheme consists of intravenous pulses of methylprednisolone (250 mg daily for 3 consecutive days) followed by oral prednisone (0.5–1 mg/kg/day) tapering off over 4–6 weeks. The number of side effects when using this protocol is relatively low in our experience. Steroids are the mainstay of treatment in idiopathic AIN, TINU, and AIN associated with systemic diseases, including the recently reported association of AIN with autoimmune pancreatitis.11.Rossert J. Drug-induced acute interstitial nephritis.Kidney Int. 2001; 60: 804-817Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar, 12.Neilson E.G. Pathogenesis and therapy of interstitial nephritis.Kidney Int. 1989; 35: 1257-1270Abstract Full Text PDF PubMed Scopus (179) Google Scholar, 26.Finkelberg D.L. Sahani D. Deshpande V. et al.Autoimmune pancreatitis.N Engl J Med. 2006; 355: 2670-2676Crossref PubMed Scopus (355) Google Scholar, 27.Yoneda K. Murata K. Katayama K. et al.Tubulointerstitial nephritis associated with IgG4-related autoimmune disease.Am J Kidney Dis. 2007; 50: 455-462Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Plasmapheresis and cytotoxics have been used in anti-TBM disease. In patients with idiopathic AIN resistant to steroids, anecdotal reports suggest benefit from cyclophosphamide and cyclosporine.33.Zuliani E. Zwahlen H. Gilliet F. et al.Vancomycin-induced hypersensitivity reaction with acute renal failure: resolution following cyclosporine treatment.Clin Nephrol. 2005; 64: 155-158Crossref PubMed Google Scholar A recent report of eight patients with steroid-dependent, recurrent AIN documented an interesting beneficial effect of mycophenolate mofetil.34.Preddie D.C. Markowitz G.S. Radhakrishnan J. et al.Mycophenolate Mofetil for the treatment of interstitial nephritis.Clin J Am Soc Nephrol. 2006; 1: 718-722Crossref PubMed Scopus (77) Google Scholar In patients with NSAID-induced AIN and nephrotic syndrome, withdrawal of the offending drug has proved to be the most effective treatment, whereas the addition of steroids does not alter the clinical course.17.Porile J.L. Bakris G.L. Garella S. Acute interstitial nephritis with glomerulopathy due to nonsteroidal anti-inflammatory agents: a review if its clinical spectrum and effects of steroid therapy.J Clin Pharmacol. 1990; 30: 468-475Crossref PubMed Scopus (47) Google Scholar AIN represents a frequent cause of acute kidney injury. Drug-induced AIN is currently the commonest etiology of AIN, antimicrobials and NSAIDs being the most frequent offending agents. Pathogenesis is based on a cell-mediated immune response in most patients and removal of the offending drug is the mainstay of the treatment. However, a significant proportion of patients, ranging from 30 to 70%, did not fully recovered their baseline renal function, likely because of the rapid transformation of interstitial cellular infiltrates into large areas of fibrosis. Although prospective randomized trials in AIN are lacking, recent retrospective studies suggest that early steroid treatment (within 7 days after diagnosis) improves the recovery of renal function.
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