The clinical spectrum of tubulointerstitial nephritis
Authors: Asghar Rastegar, Michael Kashgarian
Journal: Kidney International (1998)

acute interstitial nephritis analgesic-induced tubulointerstitial nephritis acetosalicylic acid chronic renal failure computer tomography chronic tubulointerstitial nephritis end-stage renal disease glomerular filtration rate granulomatous interstitial nephropathy human immunodeficiency virus interleukin nonsteroidal anti-inflammatory drugs odds ratio platelet-derived growth factor red blood cells relative risk systemic lupus erythrematosus transforming growth factor-Β tubulointerstitial nephritis white blood cells Tubules and interstitium make up approximately 80% of the renal volume, and occupy the compartment referred to as the tubulointerstitium. The interstitium space takes up 13% of rat and up to 17% of dog and rabbit kidneys, including 7 to 9% of renal cortex, 3 to 5% of outer medulla and 30 to 40% of inner medulla and papillary tip1.Wolgast M.A. Larson M. Nygren K. Functional characteristics of renal interstitium.Am J Physiol. 1981; 241 (Renal Fluid Electrolyte Physiol 10): F105-F111PubMed Google Scholar,2.Lemley K.V. Kriz W. Anatomy of the renal interstitium.Kidney Int. 1991; 39: 370-381Abstract Full Text PDF PubMed Scopus (187) Google Scholar. It is made up of both cellular and matrix components. There are two main cell types. (a) Type I interstitial cells are fibroblast-like cells capable of producing and degrading extracellular matrix. The lipid-rich interstitial cells in the inner medulla, a possible source of prostaglandins, are also considered to be a form of type I interstitial cells. (b) Type II interstitial cells, found in all renal zones, include monocyte derived macrophages with capacity for phagocytosis and dendritic antigen-presenting cells found primarily in the cortex. The matrix is made up of a fibrillar net of interstitial and basement membrane collagens and associated proteoglycans, glycoproteins, and interstitial fluid. The interstitial compartment not only provides structural support for the individual nephrons, but also serves as a conduit for solute transport2.Lemley K.V. Kriz W. Anatomy of the renal interstitium.Kidney Int. 1991; 39: 370-381Abstract Full Text PDF PubMed Scopus (187) Google Scholar. It is also the site of production of several hormones and cytokines such as erythropoietin and prostaglandins. Renal diseases can broadly be classified as glomerular, vascular, tubulointerstitial or obstructive in origin. Diseases of tubulointerstitial compartment may be the result of primary injury to this compartment or secondary to injury to other compartments. Several studies in patients with a variety of renal diseases have shown that changes in the tubulointerstitial compartment are a better predictor of the severity of renal dysfunction and long-term outcome than changes in other compartments3.Striker G.E. Schainuck L.I. Cutler R.E. Benditt E.P. Structural-functional correlations in renal diseases. Part 1: A method for assaying and classifying histophatholgic changes in renal disease.Hum Pathol. 1970; 1: 615-630Abstract Full Text PDF PubMed Scopus (126) Google Scholar, 4.Mujais S. Battle D.C. Functional correlates of tubulo-interstitial damage.Semin Nephrol. 1988; 8: 94-99PubMed Google Scholar, 5.Eknoyan G. Mc Donald M.A. Appel D. Truong L.D. Chronic tubulo-interstitial nephritis: Correlation between structural and functional findings.Kidney Int. 1990; 38: 736-743Abstract Full Text PDF PubMed Scopus (38) Google Scholar, 6.Bohle A. Mackensen-Haen S. Gise H. The consequences of tubulointerstitial changes for renal function in glomerulopathies,.in: Amerio A. Cortelli P. Massry S.E. Tubulo-Interstitial Nephropathies. Kluwer Academic Press, Boston, Dordrecht, London1991: 29-40Crossref Google Scholar, 7.Nath K.A. Tubulointerstitial changes as a major determinant in the progression of renal damage.Am J Kidney Dis. 1992; 20: 1-17Abstract Full Text PDF PubMed Scopus (806) Google Scholar. Recent advances in our understanding of the process of injury and repair in general, and tubulointerstitial compartment in particular, have helped elucidate some of the important pathogenic events leading to tubulointerstitial nephritis (TIN). These advances have been summarized in several excellent reviews8.Wilson C.B. Nephritogenic tubulointerstitial antigens.Kidney Int. 1991; 39: 501-517Abstract Full Text PDF PubMed Scopus (16) Google Scholar, 9.Nielson E.G. Pathogenesis and therapy of interstitial nephritis (clinical conference).Kidney Int. 1989; 35: 1257-1270Abstract Full Text PDF PubMed Scopus (179) Google Scholar, 10.Jones C.L. Eddy A.A. Tubulointerstitial nephritis.Pediatr Nephrol. 1992; 6: 572-586Crossref PubMed Scopus (40) Google Scholar, 11.Dodd S. The pathogenesis of tubulointerstitial disease and mechanisms of fibrosis.Curr Topic Pathol. 1995; 88: 51-67Crossref PubMed Scopus (11) Google Scholar, 12.Eddy A.A. Experimental insights into the tubulointerstitial disease accompanying primary glomerular lesions.J Am Soc Nephrol. 1994; 5: 1273-1287Crossref PubMed Google Scholar and will only be discussed briefly here. This review focuses primarily on clinical aspect of the diseases where the tubulointerstitial compartment is the primary target of the pathogenic process rather than being secondarily involved by damage to the glomerular, vascular compartment or collecting system. The term acute interstitial nephritis was first used a century ago in 1898 by Councilman in describing a group of patients with systemic bacterial infection, primarily scarlet fever and diphtheria. This term was applied to acute inflammation of the kidney characterized by cellular and fluid exudation in the interstitial tissue that was not dependent on the presence of bacteria13.Councilman W.J. Acute interstitial nephritis.J Exp Med. 1898; 3: 303-420Crossref Scopus (97) Google Scholar. For many decades, the term chronic pyelonephritis was used to describe renal diseases associated with chronic injury to interstitum, despite the lack of evidence for the presence of active infection in a majority of the patients. Beginning in early 1950s, the work of Spuhler and Zollinger in Switzerland on the role of analgesics14.Zollinger H. Spuhler O. Die nicht-eitrige chronische interstitielle Nephritis.Scheizerische Zeitschrift fuer Allgemeine Pathologie. 1950; 13: 807-811PubMed Google Scholar,15.Spuhler O. Zollinger H.U. Die chronisch-interstitielle nephritis.Zeitschrift fuer Med. 1953; 151: 1-50Google Scholar, and Henderson and colleagues in Australia on the role of lead in the development of chronic tubulointerstitial nephritis (TIN)16.Henderson D.A. Chronic nephritis in Queensland.Aust Ann Med. 1955; 4: 164-177Google Scholar, provided strong evidence that the so-called chronic pyelonephrits was often not infectious in origin. It is now recognized that TIN represents a group of diseases that are due to a variety of etiologies and pathogenic mechanisms. Given the tight structure-function relationship between glomerular, vascular and tubulointerstitial compartments, a significant overlap exists between the clinical presentation of the diseases initiated in any compartment. In addition, the clinical presentation of TIN depends both on its etiology and the severity of renal dysfunction. Despite this factor, certain findings are more common in these patients than patients with glomerular disease. These include: (1) a lack of significant proteinuria and hypoalbuminemia; (2) the presence of sterile pyuria and white blood cell (WBC) casts rather than hematuria and red blood cell (RBC) casts; (3) the presence of a concentrating defect resulting in polyuria and nocturia; and (4) the presence of other tubular defects such as renal tubular acidosis, salt losing nephropathy and osteomalacia due to long-standing vitamin D deficiency. These differences become increasingly blurred with progression of renal failure. TIN is an important cause of renal failure and end-stage renal disease (ESRD). The incidence of primary TIN varies by geographical area, entry criteria, and mode of diagnosis17.Murray T.G. Goldberg M. Analgesic-associated nephropathy in the USA: Epidemiologic, clinical and pathogenetic features.Kidney Int. 1978; 13: 64-71Abstract Full Text PDF PubMed Scopus (41) Google Scholar, 18.Murray T.G. Stolley P.D. Anthony J.C. Schinnar R. Hepler-Smith E. Jeffreys J.L. Epidemiologic study of abuse of analgesics containing phenacetin.N Engl J Med. 1983; 308: 357-362Crossref PubMed Google Scholar, 19.Pommer W. Glaedke G. Molzahn M. The analgesic problem in the the Federal Republic of Germany: Analgesic consumption, frequency of analgesic nephropathy and regional differences.Clin Nephrol. 1986; 26: 274-278Google Scholar, 20.Pommer W. Bronder E. Greiser E. Helmert U. Jesdinsky H.J. Klimpel A. Borner K. Molzahn M. Regular analgesic intake and the rish of end-stage renal disease.Am J Nephrol. 1989; 9: 403-412Crossref PubMed Scopus (104) Google Scholar, 21.Sandler D.P. Smith J.C. Weinberg C.R. Buckalew JR, V.M. Dennis V.W. Blythe W.B. Burgess W.P. Analgesic use and chronic renal disease.N Engl J Med. 1989; 320: 1238-1243Crossref PubMed Scopus (216) Google Scholar, 22.United States Renal Data System Annual Data Report: II. Incidence and prevalence of ESRD.Am J Kidney Dis. 1996; 28: S34-S47PubMed Google Scholar. While renal biopsy remains the gold standard, nephrologists are less likely to biopsy patients with clinical signs and symptoms of TIN than patients with glomerular disease. Therefore, the diagnosis of TIN is often based on epidemiological, clinical and laboratory evaluations rather than renal biopsy. In an autopsy series the incidence of TIN was reported at 1.7% for acute and 0.2% for chronic TIN23.Zollinger H.U. Mihatsch M.J. Renal Pathology in Biopsy. Springer-Verlas, Berlin1978: 407-410Crossref Google Scholar. In a Finnish study of 314,000 asymptomatic recruits, 174 with hematuria and/or proteinuria were biopsied. Two patients had TIN for a prevalence of 0.7 per 100,000 in this population24.Pettersson G. Vonbonsdorff M. Tomroth T. Lindholm H. Nephritis among young Finnish men.Clin Nephrol. 1984; 22: 217-222PubMed Google Scholar. Murray and Goldberg reported an incidence of 33% among 320 patients admitted to a teaching hospital over a three year period (1969 to 1972) with a diagnosis of CRF and serum creatinine of greater than 1.3 mg%17.Murray T.G. Goldberg M. Analgesic-associated nephropathy in the USA: Epidemiologic, clinical and pathogenetic features.Kidney Int. 1978; 13: 64-71Abstract Full Text PDF PubMed Scopus (41) Google Scholar. The most common causes of TIN were urinary tract obstruction, analgesic abuse, hyperuricemia and nephrocalcinosis. In a similar study from a teaching hospital in North Carolina, TIN was also the most common cause of CRF, accounting for 40.8% of the cases. The most common etiologic diagnosis was analgesic-induced TIN (AITIN), considered as definitive in 26.8% and probable in 14.6% of patients with TIN25.Gonwa T.A. Hamilton R.W. Buckalew V.A. Chronic renal failure and end-stage renal disease in northwest North Carolina: Importance of analgesic associated nephropathy.Arch Intern Med. 1981; 141: 462-465Crossref PubMed Scopus (34) Google Scholar. In both studies the diagnosis of TIN was primarily based on clinicopathological findings and less commonly on renal biopsy. The incidence of TIN among ESRD patients varies from 42.2% in Scotland26.Pendreigh D.M. Howitt L.F. Macdougal A.J. Robson J.S. Heasman M.A. Kennedy A.C. Macleod M. Stewart W.L.D. Survey of chronic renal failure in Scotland.Lancet. 1972; 1: 304-307Abstract PubMed Scopus (35) Google Scholar, 29% in Berlin20.Pommer W. Bronder E. Greiser E. Helmert U. Jesdinsky H.J. Klimpel A. Borner K. Molzahn M. Regular analgesic intake and the rish of end-stage renal disease.Am J Nephrol. 1989; 9: 403-412Crossref PubMed Scopus (104) Google Scholar, and 27.5% in Delaware County, Pennsylvania18.Murray T.G. Stolley P.D. Anthony J.C. Schinnar R. Hepler-Smith E. Jeffreys J.L. Epidemiologic study of abuse of analgesics containing phenacetin.N Engl J Med. 1983; 308: 357-362Crossref PubMed Google Scholar to 25.7% in North Carolina, USA25.Gonwa T.A. Hamilton R.W. Buckalew V.A. Chronic renal failure and end-stage renal disease in northwest North Carolina: Importance of analgesic associated nephropathy.Arch Intern Med. 1981; 141: 462-465Crossref PubMed Scopus (34) Google Scholar. Rostand et al, in a study from Alabama focusing on racial differences in ESRD, calculated an annual incidence per 100,000 population of 2 for TIN, 2.3 for nephrosclerosis, 1.2 glomerulonephritis and 0.8 for diabetes nephropathy27.Rostand S.G. Kirk K.A. Rutsky E.A. Pate B.A. Racial difference in the incidence of treatment of end-stage renal disease.N Engl J Med. 1982; 306: 1276-1279Crossref PubMed Scopus (340) Google Scholar. In a renal biopsy study of 109 patients with unexplained renal failure (GFR < 60 ml/min) and normal size kidney, TIN was the most common diagnosis, and was seen in 29 (27%) of patients28.Farrington K. Levison D.A. Greenwood R.N. Cattell W.R. Baker L.R. Renal biopsy in patients with unexplained renal impairment and normal kidney size.Quart J Med. 1989; 70: 221-233PubMed Google Scholar. The 1996 United States ESRD Registry Data, however, shows an incidence of only 3% among all patients on dialysis22.United States Renal Data System Annual Data Report: II. Incidence and prevalence of ESRD.Am J Kidney Dis. 1996; 28: S34-S47PubMed Google Scholar. If obstructive disease and TIN associated with malignancy is also included, the incidence approaches 7.5%, still significantly lower than the above quoted numbers. This difference may be due to several factors including lack of diagnostic precision, the recent increase in the number of patients with diabetes and other systemic diseases on dialysis, and successful prevention and earlier treatment of tubulointerstitial nephritis. Part of the difference is geographic in nature, reflecting the role of environmental factors in the development of TIN. There is no universally acceptable classification of TIN. The most comprehensive is the WHO classification, which uses a pathogenic and when possible an etiologic approach to these diseases Table 129.Churg J. Cotran R.S. Sakaguchi H. Sobin L.H. Renal Disease Classification and Atlas of Tubulointerstitial Disease. Igaku-Shoin, Tokyo, New York1984Google Scholar. From a practical point of view, we prefer a simpler classification initially dividing TIN into primary and secondary forms, independent of acuity or chronicity of the disease Table 2. Primary TIN is comprised of diseases where the dominant pathogenic process begins in the tubulointerstitial compartment, only secondarily affecting other compartments. Secondary TIN encompasses diseases where the primary pathogenic process begins in vascular, glomerular or collecting system, followed by damage to the tubulointerstitial compartment. This classification is by no mean all encompassing, and does not recognize diseases that affect more than one compartment simultaneously such as systemic vasculitis, systemic lupus erythematosus (SLE), or human immunodeficiency virus (HIV) associated nephropathy.Table 1WHO classification of tubulointerstitial diseaes Open table in a new tab Table 2Classification of tubulointerstitial nephritis (TIN)View Large Image Figure ViewerDownload (PPT) Open table in a new tab Although the tubulointerstitum can only respond in a limited manner to a variety of insults, the pattern of response can help define the acuity of the process, the long-term prognosis and in some patients the pathogenesis and/or etiology of the disorder. The initial division of the histologic pattern of TIN is dependent on the presence or absence of a significant inflammatory infiltrate in the interstitium. In diseases where the infiltrate is predominant, the characteristics of the cellular components of the infiltrate further assist in the differentiating types of TIN with differing pathogenesis. The structural changes of tubular injury include cytopathic changes from sublethal injury to necrosis, alteration in growth including atrophy, hypertrophy and simplification and the accumulation of cast material in the tubular lumina. Interstitial changes include edema, leukocytic infiltration and fibrosis. In predominantly non-inflammatory lesions, the nature of the tubular epithelial changes and the presence of renal tubular pigments, cast material, crystals or other inclusions assist in making these differentiations. Using histological criteria, one can classify tubulointerstitial disease in such a manner as to recognize the wide variety of potential etiologic agents and different pathogenic mechanisms that produce similar or identical morphologic patterns. In acute or active forms of interstitial nephritis the interstitium is edematous and there is a cellular infiltrate that may contain lymphocytes, plasma cells or polymorphonuclear leukocytes, including eosinophils. Invasion of the tubules may be seen to resemble the tubulitis of allograft rejection. In more chronic forms, interstitial fibrosis and tubular atrophy is the most prominent feature that may be accompanied by an infiltrate comprised only of small lymphocytes. Marcussen recently has brought attention to a sequence of events where tubulitis eventually leads to tubular destruction and the development of atubular glomeruli. This process contributes both to the histologic picture and the progressive loss of function seen in chronic interstitial nephritis30.Marcussen N. Atubular glomeruli in chronic renal disease.Curr Topic Pathol. 1995; 88: 145-175Crossref PubMed Scopus (18) Google Scholar. The mechanisms by which various etiologic agents can mediate renal tubulointerstitial injury can either be direct through cytotoxicity or indirect by the induction of systemic inflammatory or immunologic reactions. Direct cytotoxic mechanisms are dose and exposure duration dependent, such as what is seen in analgesic and lead nephropathy. Indirect reactions are often idiosyncratic as occurs in the acute interstitial nephritis associated with nonsteroidal anti-inflamatory agents (NSAIDs). The nature of the injury may be determined to some extent by factors unrelated to the agent such as preexisting renal disease, or extrarenal factors that can affect renal dosage such as abnormal liver function. In addition, the differences in susceptibility of different nephron segments can modify the renal response to these agents, such as with heavy metal exposure. Studies in experimental models and in human disease provide compelling evidence for immune mechanisms of tubulointerstitial disease, and these have been reviewed extensively9.Nielson E.G. Pathogenesis and therapy of interstitial nephritis (clinical conference).Kidney Int. 1989; 35: 1257-1270Abstract Full Text PDF PubMed Scopus (179) Google Scholar,31.Palmer B. The tubules in progression of renal failure.J Invest Med. 1997; 45: 346-361PubMed Google Scholar. These mechanisms are in some instances analogous to immune-mediated glomerular disease involving antibasement membrane antibodies or immune complex deposition. In other instances they are more specific to the structures of the tubulointerstitium and involve antibodies to cell surface antigens, or antigens processed and presented by tubular epithelial or interstitial dendritic cells to the immune system, resulting in cell mediated reactions. In addition, local activation of epithelial, endothelial and interstitial fibroblastic cells results in expression of a variety of cytokines and growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor-Β (TGF-Β), which can contribute to inflamation and fibrogenesis in the tubulointerstitial compartment10.Jones C.L. Eddy A.A. Tubulointerstitial nephritis.Pediatr Nephrol. 1992; 6: 572-586Crossref PubMed Scopus (40) Google Scholar, 12.Eddy A.A. Experimental insights into the tubulointerstitial disease accompanying primary glomerular lesions.J Am Soc Nephrol. 1994; 5: 1273-1287Crossref PubMed Google Scholar, 32.Nath K.A. Reshaping the interstitium by platelet-derived growth factor. Implications for progressive renal disease.Am J Pathol. 1996; 148: 1031-1036PubMed Google Scholar. Diagnosis of TIN should be considered in any patient with unexplained renal failure and/or specific tubular dysfunction. As drugs and toxins are major causes of primary TIN, a complete occupational history, history of drugs ingestion (including over the counter drugs as well as herbal medications) and toxin exposure should be sought. In patients with systemic signs and symptoms known systemic disease, the renal disorder should be considered in the context of a systemic illness. The clinical presentation of TIN reflects the nature of the underlying disease and severity of renal disorder. Although there are significant overlaps between the clinical presentation of glomerular and tubulointerstitial diseases, several features may help differentiate between these two entities. Patients with TIN tend to have less severe systemic hypertension and edema and a slower rate of progression5.Eknoyan G. Mc Donald M.A. Appel D. Truong L.D. Chronic tubulo-interstitial nephritis: Correlation between structural and functional findings.Kidney Int. 1990; 38: 736-743Abstract Full Text PDF PubMed Scopus (38) Google Scholar,33.Cogan M.G. Tubulo-intersitial nephropathies: A pathophysiological approach — Medical Staff Conference, University of California, San Francisco.West J Med. 1980; 132: 134-140PubMed Google Scholar. The initial presentation may be dominated by clinical expression of the tubular defects such as polyuria, nocturia, or abnormal biochemical parameters such as metabolic acidosis and glycosuria33.Cogan M.G. Tubulo-intersitial nephropathies: A pathophysiological approach — Medical Staff Conference, University of California, San Francisco.West J Med. 1980; 132: 134-140PubMed Google Scholar. Urinalysis may provide strong evidence for the presence of tubular disorder with low specific gravity, high pH, and presence of glucose. Twenty-four-hour urine protein levels are rarely greater than 2.5 g and are commonly below 1.0 g5.Eknoyan G. Mc Donald M.A. Appel D. Truong L.D. Chronic tubulo-interstitial nephritis: Correlation between structural and functional findings.Kidney Int. 1990; 38: 736-743Abstract Full Text PDF PubMed Scopus (38) Google Scholar. Urinary sediment varies from bland to active with WBCs and WBC casts rather than RBC and RBC casts. To establish a specific diagnosis, further workup is necessary and should be guided by the clinical history and initial findings. This workup may include specialized imaging, serological, biochemical and toxicological studies and/or renal biopsy. The role of renal biopsy in the diagnosis of TIN has not been systematically examined. In certain circumistances the renal biopsy is carried out to exclude glomerular pathology. In selected patients with possible allergic or granulomatous interstitial nephritis and interstitial nephritis associated with plasma cell dyscrasias, it is often diagnostic. However, in many circumstances such as lithium or lead nephropathy the findings are nonspecific. In summary, the workup of patients suspected of TIN should be guided heavily by the clinical and occupational histories, epidemiology of known diseases, as well as clues offered by the initial workup. The WHO classification Table 1 and our proposed classification Table 2 show that the list of disease categories under TIN is very long. This list includes disorders associated with infection, drugs and toxins, metabolic, hematologic and hereditary disorders. To provide an in-depth review of the spectrum of TIN, we have chosen to discuss four specific disorders that are either common, and therefore clinically important, and/or exemplify a unique type of injury to the tubulointerstitium. These diseases are analgesic-induced TIN, granulomatous interstitial nephritis of sarcoidosis, lead nephropathy, and drug-induced allergic interstitial nephritis. Due to the limitation of space, several other disorders such as lithium associated TIN, interstitial nephritis due to hematologic disorders, and the recently described interstitial nephritis due Chinese herbs are not included in this review. Non-narcotic analgesics are among the most commonly used medications in the world. These drugs, primarily developed in the second half of the nineteenth century, became very popular as single or mixed agents for control of pain. They include salicylates such as aspirin, pyrazolones such as antipyrine, anilides such as phenacetin, and acetoaminophen. Spuhler and Zollinger in the early to mid 1950s reported that 13 of 44 patients in Switzerland with interstitial renal disease habitually consumed analgesics14.Zollinger H. Spuhler O. Die nicht-eitrige chronische interstitielle Nephritis.Scheizerische Zeitschrift fuer Allgemeine Pathologie. 1950; 13: 807-811PubMed Google Scholar,15.Spuhler O. Zollinger H.U. Die chronisch-interstitielle nephritis.Zeitschrift fuer Med. 1953; 151: 1-50Google Scholar. Although the importance of analgesic ingestion as an etiologic factor was not initially clear, these and other reports published from several other countries raised serious questions about a potential association between the use of these medications and development of renal failure. This association is supported by both epidemiological and experimental studies. In this review we will emphasize the epidemiological data linking analgesic use to TIN. The historical prevalence of analgesic-induced tubulointerstitial nephritis (AITIN) in different geographical areas varies widely from 0% in Queenscliff, Australia, 10 to 35% in Switzerland, 33 to 41% in Scandinavia and Wales, to 49% in Brisbane, Australia34.Molzhan M. Pommer W. Analgesic nephropathy,.in: Cameron S. Dawson A.M. Grünfeld J.P. Kerr D. Ritz E. Oxford Textbook of Clinical Nephrology. Oxford Medical Publication, Oxford1992: 803-819Google Scholar,35.Buckalew V.M. Schey H.M. Renal disease from habitual antipyretic analgesic consumption: An assessment of the epidemiologic evidence.Medicine. 1986; 11: 291-303Google Scholar. The prevalence of AITIN in ESRD patients varies from 1.7% in Philadelphia18.Murray T.G. Stolley P.D. Anthony J.C. Schinnar R. Hepler-Smith E. Jeffreys J.L. Epidemiologic study of abuse of analgesics containing phenacetin.N Engl J Med. 1983; 308: 357-362Crossref PubMed Google Scholar, 10% in North Carolina25.Gonwa T.A. Hamilton R.W. Buckalew V.A. Chronic renal failure and end-stage renal disease in northwest North Carolina: Importance of analgesic associated nephropathy.Arch Intern Med. 1981; 141: 462-465Crossref PubMed Scopus (34) Google Scholar to 18% in Belgium33.Cogan M.G. Tubulo-intersitial nephropathies: A pathophysiological approach — Medical Staff Conference, University of California, San Francisco.West J Med. 1980; 132: 134-140PubMed Google Scholar,36.Vanherweghem J.L. Even-Adin D. Epidemiology of analgesic nephropathy in Belgium.Clin Nephrol. 1982; 17: 129-133PubMed Google Scholar and 30% in Queensland, Australia37.Clunie G.J.A. Hartley L.C.J. Ribush N.T. Emmerson B.T. Morgan T.O. An integrated service for treatment of irreversible renal failure.Med J Aust. 1971; 2: 403-408PubMed Google Scholar. In addition to great variability among different countries and different regions of the same country, there is a significant female preponderance in all series, with a female-to-male ratio as high as 6:134.Molzhan M. Pommer W. Analgesic nephropathy,.in: Cameron S. Dawson A.M. Grünfeld J.P. Kerr D. Ritz E. Oxford Textbook of Clinical Nephrology. Oxford Medical Publication, Oxford1992: 803-819Google Scholar. Papillary necrosis is a well known component of both clinical as well as experimental AITIN. Epidemiological data support this association with a close concordance in the incidence of papillary necrosis and AATIN. For example, the autopsy-based incidence of papillary necrosis is only 0.2% in the US compared to 21% in Sydney and Brisbane, Australia32.Nath K.A. Reshaping the interstitium by platelet-derived growth factor. Implications for progressive renal disease.Am J Pathol. 1996; 148: 1031-1036PubMed Google Scholar. The marked variation in the incidence of AITIN and papillary necrosis is best explained by the overall consumption rate of analgesics, especially the combination type containing phenacetin, in a given community35.Buckalew V.M. Schey H.M. Renal disease from habitual antipyretic analgesic consumption: An assessment of the epidemiologic evidence.Medicine. 1986; 11: 291-303Google Scholar. This causal relationship is strengthen by the effect of removal of phenacetin from formulary in many countries beginning in early 1960s38.Noels L.M. Elseviers M.M. De Broe M.E. Impact of legislative measures of the sales of analgesics and the subsequent prevalence of analgesic nephropathy: A comparative study in France, Sweden and Belgium.Nephrol Dial Transplant. 1995; 10: 167-174PubMed Google Scholar. Follow-up reports from Europe39.Norderfeld O. Deaths from renal failure in abusers of phenacetin-containing drugs.Acta Med Scand. 1972; 191: 11-16PubMed Google Scholar, 40.Kasanen A. The effect of restriction of the sale of phenacetin on the incidence of papillary necrosis established at autopsy.Ann Clin Res. 1973; 5: 369-374PubMed Google Scholar, 41.Mabeck C.E. Wichmann B. Mortality from chronic interstitial nephritis and phenacetin consumption in Denmark.Acta Med Scand. 1979; 205: 599-601Crossref PubMed Scopus (12) Google Scholar, Canada42.Wilson D.R. Gault M.H. Declining incidence of analgesic nephropathy in Canada.Can Med Assoc J. 1982; 127: 500-502PubMed Google Scholar, and Australia43.Mc Credie M. Stewart J