tmational Socie
`Nephrology
`
`ESTON LIBRARY
`MAY 0 3 2002
`J5/120 CUN CA .. s.; ~"-lCE CENTER
`600 HIGHLAND AV'E. MAD SON WI 53792
`
`

`

`KIDNEY INTERNATIONAL
`Volume 61,
`umber 5. May 2002
`
`Official Journal of the International Society of Nephrology
`
`Le Journal Officiel de la Societe Internationale de
`
`ephrologie
`
`Table of contents
`
`PERSPECTIVES fN RENAL MEDICINE
`Methodological issues in studying the epidemiology of mild Lo moderate chronic renal insufficiency. Chi-
`Yuan Hsu, Glenn M. Cherto1v, and Gary C. Cur/,an . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1567
`
`GENETIC DISORDERS - DEVELOPMENT
`Gene expression profile of renal proximal tubules regulated by proteinuria. Hideaki Nakajima, Masarn
`Takenaka, Jun- Ya Kaimori, Yasuyuki Nagasawa, A/sushi Kosugi, Sl1011ko Kawamoto, Enyu Imai, Masat-
`sugu Hori, and Kousaku Okubo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1577
`
`A complete mutation screen of the ADPKD genes by DHPLC. Sandro Rosse1ti, Dominique Chauveau,
`Denise Walker, Anand Saggnr-Malik, Christopher G. Winearls, Vice111e £. Torres, and Peter C. Harris. . 1588
`
`HORMO ES-CYTOKINES-SIGNALING
`High protein-induced glomerular hypertrophy is va cular endothelial growth factor-dependent. Bieke F.
`Schrijvers, Rurh Rasch, Ronald G. Tilton, and Allan F/yvbjerg. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1600
`
`Angiotensin 11 activation of the JAK/STAT pathway in mesangial cells is altered by high gluco e. Farhad
`Amiri, Sean Shaw, Xiaodan Wang, lie Tang, Jennifer L. Waller, Douglas C. Eat0n, and Mario 8 . Marrero 1605
`
`ATP release in human kidney cortex and its mitogenic effects in visceral glomerular epithelial cells. Oliver
`Vonend, Vims Oberhauser, Ivar vo11 Kiigelge11, Thomas W. Apel, Kersrin Amann, Eberhard Ri1z, and Lars
`Christian Rump . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1617
`
`Mechanisms of the regulation of EGF receptor gene expression by calcitriol and parathyroid hormone
`in UMR 106-01 cells. £s1her A. Gon zalez. Sinee Disthabanchong, Rodney Kowalewski, and Kevin J. Martin 1627
`
`Effect of combining ACE inhibitor and Latin in severe experimental nephropalhy. Carla Zoja, Daniela
`Coma, Daniela Rouoli, Dario Ca11aneo, Cristina Zanchi, Susanna Tomasoni, Mauro Abbate, and Giuseppe
`Renw zzi . .......................................................................... 1635
`
`CELL BIOLOGY - IMMU OLOGY - PATHOLOGY
`Monitoring changes in gene expression in renal ischemia-reperfu ion in the rat. Takwni Yoshida, Manjula
`Kurel/a, Francisca Beato, Hyumuk Min, Julie R. Inge/finger, Robin L. Stears, Rita D. Swinford, Steven R.
`Gui/ans, and Shio1v-Shih Tang. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1646
`
`Cover: Masson·s Trichrome staining of unilateral ureteral obstructed kidney 10 days after surgery treated with a specific ROCK inhibitor.
`Y-27632 (see agatoya el al, Fig. 2A. p. 1688).
`
`Contents continued on next page
`
`

`

`Content~ continued
`
`Transferrin up-regulates chemokine ynthesis by human proximal tubular epithelial cells: Implication on
`mechanism of tubuloglomerular communication in glomerulopathic proteinura. Sydney Tang, Joseph CK.
`Leung, Anita W.L. Tsang, Hui Yao Lan, fak Mao Chan, and Kar , eng l.ai . . ....... .... ........ . 1655
`Human antiglomerular basement membrane autoantibody disea e in XenoMouse II. Kevin E.C. Meyers,
`Juanita Allen, Jeffrey Gehret, Aya Jacob01•its, Michael Callo, Eric C. eilson, l/e/111ut llopfer, Raghu
`Kal/uri, and Michael P. Madaio (see Editorial b) Borza and Hud\on, p. I 905) . . . . . . . . . . . . . . . . . . . . 1666
`Altered cholesterol localization and caveolin expression during the evolution of acute renal failure. Richard
`A. Zager, Ali Johnson, Sherry Hanson, and Vil'ian de/a Rosa. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1674
`Y-27632 prevents tubulointerstitial fibrosis in mou e kidneys with unilateral ureteral obstruction. Katsuy11ki
`agatoya, Toshiki Moriyama, oriraka Kall'ada. Ma.wnobu Takeji, S11m1n11 Oseto, Takahiro Murozono,
`Akio Ando, Enyu Imai, and Masarsug11 llori . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1684
`Renal ischemia-reperfusion increases endothelial VEGFR-2 without increasing VEGF or VEGFR-1
`expre ion. John Kanellis, Kathy Paizis, Alison J. Cox, Steven A. Stacker, Richard E. Cilber/, Mark £.
`Cooper, and David A. Power . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1696
`'itric oxide increase adrenomedullin receptor function in rat mesangial cells. Jorg Dorsch, Ellen Schoof,
`Harald 0 . Schock/mann, Bernhard Briine, Ina Knerr, Rei,wld Repp, and Wolfgang Rascher ..... . .. . . 1707
`Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Frank Srrurz, Michael
`Zeisberg, Fttad N. Ziyadeh, Chang-Qing Yang, Ragh11 Kafluri, Gerhard A. Miiller, and Eric C. eilson,
`wirh the technical assistance of A. Renzieha11sen and Z. Sisic ............................. . .. . . 1714
`Hyaluronan increases glomerular cyclooxygenase-2 protein expre~sion in a p38 MAP-kinase-dependent
`process. Marjorie E. Dunlop and Evelyne £. Muggli. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1729
`JON CHANN ELS - MEMBRA E TRA SPORT - I TEGRATfVE PHY IOLOGY
`Putative subunits of the rat mesangial KArP: A type 28 sulfonylurea receptor and an inwardly rectifying
`K + channel. Bahi~~ Szammfalvi, Pedro Cortes, Rebecca Alviani, Kenichiro Asano, Bruce I,. Riser, Cary
`Zas111va, and Jerry Yee ... ........... . .............................. .. ............. . .. . 1739
`Chronic Laurine treatment ameliorates reduction in saline-induced diure is and natriuresis. Mah111ood S.
`Mo:affari and Stephen W. Schaffer .......................... .... .. . .................... . 1750
`Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney. Tm11eo Deguchi,
`Swnio Ohrsuki, Masaki Oragiri, lliro111i Takanaga, Hiroshi Asaba, Shinobu Mori, and Ters11ya Terasaki 1760
`Up-regulation of acyl-coen1ymc A:cholestcrol acyltransferase (ACAT) in nephrotic syndrome. Nosratola
`D. Va~iri and Kai/111i Liang. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1769
`VASCULAR BIOLOGY - HEMODY AMJCS - HYPERTENSION
`Proteinuria is preceded by decreased nitric oxide synthesis and prevented by a O donor in cholesterol-
`fed rats. Diana M. A11ia, %he11111i11 N. Ni, Peter Boer, Mahmoud A. Allia, Roel Coldsc/11neding, 1/ein I\.
`Koomans, osratola D. Va ;:,iri, and Jaap A. Joles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1776
`Renal bemodynamic effects of somatostatin are not related to inhibition of endogenous insulin release.
`Alice Sch111idr, Johanne.\ Pleiner, Georg Schaller, Michael Roden, Susanne Dallinger, Cert Mayer, Leopold
`Schme11erer, and Michael Wolzr. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1788
`Increased genetic ~usceptibility to renal damage in the stroke-prone spontaneously hypertensive rat. Paul
`C. Churchill, Monique C. Churchill, Karen A. Griffin, Maria Picken, Robert Clinton Webb, Theodore \V.
`Kurt~, and Anil K. Bidani . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179-l
`
`

`

`Content, continued
`
`CLINICAL NEPH RO LOGY - EPIDEMIOLOGY -CLINICAL TRIALS
`Ri~k factor~ for cyclosporine-induced tubuloin terstitial lesions in children with minimal change nephrotic
`syndrome. Kawmo/o liji111a, Kiyoshi I lamahira, Ryojiro Tanaka, Akiko Kobayashi, Ka11dai Nozu, llajime
`Nnknmura, n11d Noris!tige Yoshikawa . ................................................... 180 1
`
`Kidney cancer in the Swedish Family Cancer Databa e: Familial risks and second primary malignancie .
`Kamila C::,ene and Kari I l<!mminki . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1806
`
`Bone mineral density is not diminished by mild lo moderate chronic renal insufficiency. Chi-yuan l/s11,
`Steven R. Cummings, Charles E. McCulloch, and Glenn M. Chertotv . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1814
`
`Reduced crystallization inhibition by urine from women with nephrolithiasis. John R. Asplin, Joan ff.
`Park:.~ Yasl111shi Nakagaiva, and Fredric L. Coe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1821
`
`Sodium ferric gluconate complex in hemodialysi patients: Adverse reactions compared to placebo and
`iron dextran. Beckie Michael, Daniel W. Coyne, S1even Fi.1hba11e, Vaughn Folken, Robert Lynn, Allen R.
`Nissenson, Rajiv Agarwal, Joseph W. Eschbach, S1ephe11 Z. Fadem, Richard Trout, Jur S1robos, and David
`C. Warnock, for the Ferrleci1 Publication Co111mi11ee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1830
`
`Renal aplasia is the predominant cause of congenital solitary kidneys. Masahiro lliraoka, 1-/irokaw
`Tsukalwra, Y1111sei Ohshima, Ke11ko11 Kasuga, Yoshi11ori Ishihara, and Mit.wf11111i Mayumi ... . ....... 1840
`
`AM3 (lnmunoferon"') as an adjuvant to hepatitis B vaccination in hemodialysis patients. Rafael Perez(cid:173)
`Garcfa, Alfonso Pere::.-Garcia, Dierik Verbeelen, Erica D. Bernstein. Vicente G. Villarrubia, and Melchor
`Alvarez-Mon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1845
`
`Role of uteroglobin G38A polymorphism in the progression of lgA nephropathy in Japanese patients.
`lchiei Narita, Noriko Saito, Shin Goto, Song Jin, Ke111aro Omori, Mi11oru Sakatsume, and Fu111irake Gejyo 1853
`
`DIALYSIS - TRANSPLANTATION
`Increased cortisol metabolites and reduced activity of 1113-hydroxy tcroid dehydrogenase in patients on
`hemodialysis. Verena N'Gankam, Dominik Uehlinger, Bernhard Dick, Brigi//e M. Frey, and Felix J. Frey 1859
`
`Persistent rejection of peritubular capillaries and tubules is as ociated with progressive interstitial fibrosis.
`Akira Shimiw, Kazuhiko Yamada, David fl. Sachs, and Roberr B. Cofrin . . . . . . . . . . . . . . . . . . . . . . . 1867
`
`Acute graft pyelonephritis and long-term kidney allograft outcome. Magali Gira/, Giovani Pascuariello,
`Georges Karam, Maryvonne Hourmant, Diego Camarovich, lacquer Da111al. Gilles Blancho, S1ephanie
`Coupe/, Regis l osien, Pascal Dagui11, Sandra Mechineau, and Jean Paul S011lillou . . . . . . . . . . . . . . . . . . 1880
`
`Hypocholesterolemia is a significant predictor of death in a cohort of chronic hemodialysis patients.
`K1111iroshi lseki, Masanobu Yama zaro, Masahiko Tozatva, and Sllllic/1i Takishi1a. . . . . . . . . . . . . . . . . . . 1887
`
`Influence of mycophenolic acid and tacrolimus on homocysteine metaboli m. Mihaela C. lgna1esc11, Josef
`Klerzmayr, Manuela Fodinger, Chrisria11 Bieglmayer, Wafter fl. I/or/, and Gere S1111der-Plassma11n . . . . . 1894
`
`Value of static venous pressure for predicting arteriovenous graft thrombosis. Laura M. Dember, Erika
`F. llolmherg, and James S. Kaufman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1899
`
`EDITORIAL
`Of mice and men: Murine models of anti-GBM antibody nephritis. Dorin-Bogdan Borza and Billy C.
`1/11{/Sol/ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . [ 905
`
`Contents continued on next page
`
`

`

`Contents continued
`
`LETTERS TO THE EDITOR
`Dietary protein intake significantly affects the serum ereatinine concentration. Lavjay Butani, Martin S.
`Polinsky, Bruce A. Kaiser, and H. Jorge Baluane. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1907
`
`The homocysteine confusion: Now, more is heller? Ca1erina Canavese, Alessandra Mess11erotti, Roberta
`Fenoglio, Paola Mesiano, Paola Massare11ti, Danie/ti Pa11le110, Giuseppe Ai1110, and Gabriella Priolo . . . 1907
`
`Dai ly hemodialysis and nutritional status. Eric Coffin, Yolande Pirard, Julie Fra11car1, Mercedes Vignioble,
`Tony Goovaerts, Annie Robel'/, and Yves Pirson. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1909
`
`Moderate hyperhomocysteinemia and oxidative stress. Barbara Frick, Gabriele eurawer, and Dietmar
`Fuchs ............................................................................. 1910
`
`NEPHROLOGY FORUM
`Treatment of chronic tubulointer titial disease: A new concept. Kei1h A. lfruska . . . . . . . . . . . . . . . . . . 1911
`
`INTERNATIONAL SOCIETY OF NEPHROLOGY
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`
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`Atlanta, GA 30322
`Email: rmccicr@'cmory.edu
`
`

`

`Saulo Klahr. M.D ..
`Edi1or. Kidnev lntemntional
`Washing1on U1mcrsi1y School of Medicine
`at Barnes-Jewish Ho,p,tal (Norih Campus)
`Dcpar1men1 of Medicine. Su11c 4300
`216 S. King,highwa) Boulc"ard
`St. Lou,,, MO 63110-1092. USA
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`Mrs. Patricia Morrissey
`Via telephone: 3 I 4-454-89 I 9
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`For manuscripts after acceptance please contact:
`Ms. Shellie r.
`cwcll
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`

`

`Kidney lmernational, Vol. 61 (2002) , pp. 1830-1839
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Sodium ferric gluconate complex in hemodialysis patients:
`Adverse reactions compared to placebo and iron dextran
`BECKIE MICHAEL, DANIEL w. COYNE, STEVEN F1SHBANE, VAUGHN FOLKERT, ROBERT LYNN,
`ALLEN R. N1ssENSON, RAJIV AGARWAL, JosEPH W. EscH~ACH, STEPHEN Z. FADEM,
`J. RICHARD TROUT, JuR STROBos, and DAVID G. WARNOCK, for the FERRLECtT®
`PUBLICATION CoMMITTEE 1
`
`Thomas Jefferson University, Philadelphia, Pennsylvania; Washington University School of Medicine, St. Louis, Missouri;
`Winthrop University Hospital, Mineola, and Montefiore Medical Center and Bronx Dialysis Center, New York City,
`New York; UCLA School of Medicine, Los Angeles, California; Indiana University, Indianapolis, Indiana; Northwest
`Kidney Center, Seaule, Washington; Houston Kidney Center, Houston, Texas; Rutgers University, New Brunswick,
`New Jersey; Washington, D.C.; and University of Alabama at Birmingham, Birmingham, Alabama, USA
`
`Sodium ferric gluconate complex in hemodialysis patients:
`Adverse reactions compared to placebo and iron dextran.
`Background. Parenteral iron is often required by hemodial(cid:173)
`ysis patients to maintain adequate iron stores. Until recently,
`the only available form of intravenous iron was iron dextran,
`which is associated with significant adverse reactions, including
`anaphylaxis and death. Sodium (erric gluconate complex (SFGC)
`was recently approved for use in the U.S. under FDA's priority
`drug review. This Phase IV study was designed to evaluate the
`safety of a single dose of intravenous SFGC as compared to pla(cid:173)
`cebo and a historical iron dextran control.
`Methods. This multicenter, crossover, randomized, double
`blind, placebo-controlled prospective comparative study was
`performed in hemodialysis patients requiring at least 125 mg
`of elemental iron. The historical control was obtained from a
`meta-analysis of four publications examining outcomes in pa(cid:173)
`tients exposed to iron dextran. SFGC na'ive patients were ad(cid:173)
`ministered SFGC without a test dose, undiluted. at a rate of
`
`125 mg over 10 minutes, and compared to placebo comprising
`bacteriostatic saline.
`Results. A total of 2534 patients were enrolled. The inci(cid:173)
`dence of drug intolerance (an adverse event precluding re(cid:173)
`exposure) was significantly less (0.44% , confidence interval
`(CI) 0.21 to0.71 % ] after SFGC as compared to the iron dextran
`control (2.47% , CI 1.87 to 3.07%, P < 0.0001). but higher than
`after placebo (0.1 %, P = 0.02). There was no difference found
`between SFGC and placebo in serious adverse events. A single
`life-threatening event occurred after SFGC (0.04% , Cl 0.00 to
`0.22 % ), which was significantly less than following iron dextran
`(0.61 %, CT 0.36 to 0.86%), P = 0.0001.
`Conclusion. SFGC is well tolerated when given by intrave(cid:173)
`nous push without a test dose. SFGC has a significantly lower
`incidence of drug intolerance and life-threatening events as
`compared to previous studies using iron dextran. The routine
`use of iron dextran in hemodialysis patients should be discon·
`tinued.
`
`'Other members of the Ferrlecit® Publication Committee. all of whom
`contributed equally to the preparation of this manuscript include: N.
`Franklin Adkinson (Joh11s Hopki11s U11iversily, Baltimore.MD); Daniel
`Batlle (Northwestern U11iversity Medical School. Chicago. IL); Jose
`Cangiano (San Juan Ba111ista School of Medicine, San Juan , Puerto
`Rico): Jorge Diego (University of Miami, Miami, FL) ; Pam Myirski
`(Baltimore, MD); Chamberlain Obialo (Morehouse School of Medi(cid:173)
`cine, Atlanta, GA) ; Chika Oguagha (Nephrology Fo1111dation of Brook(cid:173)
`lyn, New York City, NY); S. Noor Rahman (University of Texas at
`Houswn, Housto11, TX): Steven Rosenblatt (San Amonio Kidney Dis•
`eases Cemer, San Antonio, TX); Andrea J. Shaer (Medical Universiry
`of South Carolina, Charleston. SC): and Marcia R. Silver (MetroHealth
`Medical Cenrer, Case Wesrem Reserve University, Cleveland, 0/-1). Ad(cid:173)
`ditional participants are listed in the Appendix.
`Key words: anaphylactoid reactions. Declaration of Helsinki, iron de•
`ficiency. hemodialysis. iron dextran, parenteral iron. Phase IV study
`design.
`
`Received for publication July 20, 2001
`and in revised form November 26. 2001
`Accepted for publication December 12, 2001
`© 2002 by the International Society of Nephrology
`
`The increase in hemoglobin resulting from the use of
`erythropoietin in hemodialysis patients can be restricted
`by iron deficiency (1 ]. Blood loss from the extracorporeal
`hemodialysis circuit, vascular access complications, low(cid:173)
`grade gastrointestinal bleeding and periodic phlebotomy
`has been estimated to be 2 to 4 liters per patient per
`year [2]. The concomitant iron loss, approximately 1500
`mg annually, generally exceeds dietary iron absorption
`[3], resulting in a nearly universal need for supplemental
`iron therapy. In the majority of hemodialysis patients
`the use of oral iron is problematic, due to difficulties in
`patient compliance [4], and intestinal transport of iron
`that may be inadequate to meet epoetin-driven synthetic
`demands [5].
`Parenteral iron has played an increasingly important
`role in anemia management in hemodialysis. Improve(cid:173)
`ments in hemoglobin levels in dialysis patients over the
`
`1830
`
`

`

`Michael et al: Safety of sodium f erric gluconate complex
`
`1831
`
`past five years appear to be due in part to the more
`widespread use of parenteral iron [6]. The use of paren(cid:173)
`teral iron in hemodialysis patients is endorsed by the
`National Kidney Foundation's Kidney Disease Out(cid:173)
`comes Quality Initiative (K/DOQI) (7). K/DOQI guide(cid:173)
`lines for anemia management recommend the use of
`parenteral iron not only for absolute iron deficiency, but
`also for functional iron deficiency, where iron stores are
`present but cannot be mobilized rapidly enough to main(cid:173)
`tain maximal epoetin-driven erythrogenesis [7]. In the
`United States (U.S.), the increased use of parenteral iron
`has come at a price: the only preparation available until
`February 1999, iron dextran, can cause anaphylaxis and
`death. Life-threatening anaphylactoid reactions occur in
`approximately 0.7% of iron dextran treated hemodialysis
`patients [8], and serious drug intolerance that precludes
`further administration occurs in at least 2.5% of patients
`[8-10]. Since 1976 at least 30 deaths in the U.S. have
`been attributed to iron dextran use [ 11 ). While a test
`dose of iron dextran is recommended prior to initiating
`full therapy, deaths have occurred subsequent to the test
`dose itself, before a course of iron dextran treatment
`[12, 13]. The antigen that induces anaphylaxis in iron
`dextran is thought to be the dextran molecule rather
`than the iron moiety. Dextran is composed of glucose
`polymers of varying size and its early use, as a volume
`expander, was associated with anaphylaxis (14]. Alterna(cid:173)
`tive intravenous iron preparations, which do not contain
`dextran, have been used for many years outside of the
`U.S. Sodium ferric gluconate in sucrose injection (so(cid:173)
`dium ferric gluconate complex: SFGC) is widely used in
`Europe. There have been no reported fatalities due to
`SFGC, with a European usage estimated to be similar,
`in terms of total doses administered, as that of iron dex(cid:173)
`tran in the U.S. [11]. While hypersensitivity reactions
`have been anecdotally associated with SFGC, serious
`reactions have rarely been reported.
`Sodium ferric gluconate complex was approved in the
`U.S. in 1999 under the Food and Drug Administration's
`(FDA's) priority review program, with a requirement
`for an extensive Phase IV safety analysis. The clinical
`data compiled before FDA approval included only 385
`prospective patient experiences from two controlled
`studies and published reports (15-19]. While these data
`were supplemented by many years of European clinical
`experience in which the incidence of spontaneous ad(cid:173)
`verse events was not significant (16), international con(cid:173)
`sensus guidelines recommend a minimum prospective
`drug exposure experience in 1500 patients before ap(cid:173)
`proval (20). Priority review approval has often been
`based on small study populations and, thus, may lack
`comprehensive long-term efficacy and safety data. To
`address these concerns, FDA requires Phase IV post(cid:173)
`approval studies to increase patient exposure experience,
`study the effects of concomitant medications, evaluate
`
`risks in