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`Publi;hed January 2003
`
`

`

`KIDNEY INTERNATIONAL
`Volume 63,
`umber 1, January 2003
`
`Official Journal of the international Society of
`
`ephrology
`
`Le Journal Officiel de la Societe Internationale de Nephrologie
`
`Table of contents
`
`PERSPECTIVES TN RENAL MEDICCNE
`Parathyroid hormone (PT! 1), PT! I-derived peptides, and new PTH assays in renal osteodystrophy. William
`G. Goodman, Harald Jiippner, Isidro 8. Salusky, and Donald J. Sherrard . . . . . . . . . . . . . . . . . . . . . . . .
`
`PERSPECTIVES I BASIC SCIENCE
`Anti-inflammatory and immunomodulatory effects of statins. Luis Miguel Blanco-Colio, Jose Twi6n, Jose
`Luis Martfn-Venwra, and Jesiis Egido... ....... ................... . ......................
`
`GENETIC DJSORDERS - DEVELOPME T
`A novel mutation in the chloride channel gene, CLCNKB, as a cause of Gitelman and Banter syndrome .
`Israel Zeliko11ic, Raymonde Szargel, Ali Hawash, Valentina Labay, lhab Hatib, Nadine Cohen, and Farid
`Nakhoul ..................... . ............................... . ............ . ........
`
`HORMONES - CYTOKINES-SIGNALI G
`Growth factor-mediated phosphorylation of proapoptotic BAD reduces tubule cell death in vitro and in
`vivo. Susan C. Kiley, Barbara A. Thornhill, Shiow-Shih Tang, Julie R. Inge/finger, and Rober/ L. Chevalier
`Therapeutic benefit of pironolactone in experimental chronic cyclosporine A nephrotoxicity. iris Feria,
`Israel Pichardo, Pa1ricia Juarez, ViclOria Ramirez, Marco A . Gonzalez, Norma Uribe, Romeo Garcfa-
`Torres, Fernando L6pe;:,-Casillas, Gerardo Gamba, and Norma A. Bobadilla . . . . . . . . . . . . . . . . . . . . .
`Expres ion of omatostatin receptors 3, 4, and 5 in mouse kidney proximal tubules. Carflon M. Bales,
`Hea1her Kegg, Chris1i11a Pe1re11ski, and Sandy Grady . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`CELL BIOLOGY - IMMU OLOGY - PATHOLOGY
`Renoprotective effects of YPI versus ACEY in normotensive nephrotic rats on different sodium intakes.
`Gozewijn D. La11er111an, Harry van Coor, Robert H. Henning, Paul E. de Jong, Dick de Zeemv, and Gerja11
`Na11is............................... .............. .... ............................
`Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell
`death. Kawhiko Tsuruya, Toshiharu Ninomiya, Masanori TokumolO, Mako10 Hirakawa, Kohsuke MaSLt(cid:173)
`tani, Masatomo Taniguchi, Kyoichi Fukuda, Hidetoshi Kanai, Kenji Kishihara, Hideki Hirakata, and Mi1suo
`Iida . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Adoptive transfer studies demonstrate that macrophages can induce proteinuria and mesangial cell prolifer-
`ation. Yohei lkezumi, L ynetle A. Hum, Takao Masaki, Robert C. Atkins, and David J. Nikolic-Paterson
`
`1
`
`12
`
`24
`
`33
`
`43
`
`53
`
`64
`
`72
`
`83
`
`Cover: Dual-labeling immunofluorescence of S TR3 with Cy3 (red) and AQP-1 (green) showing co-expression in proximal tubules (see
`Bates et al, Fig. 3C, p. 60)
`
`

`

`E\tracellular ignal-regulated kinase inhibition b)
`tatins inhibit neutrophil activation b) A CA. Mira
`Choi, Susanne Rolle, Madhavi Rane, l/er111m111 I/al/er, Friedrich C. Luf1, and Ralph Keuri1z. . . . . . . . . .
`
`96
`
`l lypcrcholcsterolemia is a prerequisite for puromycin inducible damage in mouse kidney. Zlw-Zlw Cheng,
`A1111 Piiliiri, Ka1riina Aal!o-Setiilii, Dmilry Noviko1•, De1/ef Schlondorff. and /lorry llohhofer.. . . . . . . . 107
`Mitotic cell cycle proteins increase in podocytcs despite lack of proliferation. Amd1 r. Pe1er111ann, Jeffrey
`Pippin, Keiju Hiro111ura, Toshi Monkawa, Raghu Durvasula, William G. Co111er, Jeffrey Kopp, and Sruar,
`J. Shankland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
`
`Sepsis syndrome stimulates proximal tubule cholesterol synthesis and suppresse the R-8 I cholesterol
`transporter. Richard A. Zager, Ali CM. Johnson, and Sherry Y. 1/anson ......................... 123
`
`A small molecule C5a receptor antagonist protects kidney from ischemialreperfu ion injur} in rats.
`Thirwna V. Arumugam, Ian A. Shiels, Anna J. S1rachan, Giowmi Abhem1111e, Dawd P. Fairlie, and S1ephen
`M. Taylor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`ro CHA
`ELS - MEMBRA E TRA
`PORT- I TEGRATlVE PHY lOLOGY
`Urate transport via human PAH transporter hOATI and its gene tructure. Kim,yOJhi /chida, Mako10
`llosoyamada, Hiroaki Kimura, Michio Takeda, Yasunori U1suno1111ya, Tatsuo lloso_1·a, and 1/itoshi Endou
`
`Potential importance of glomerular citrate S) ntha e activity in remnant nephropathy. \1ichael £. Ullian,
`Benjamin J. Gan//, Amy K. Ford, Baby G. Tholanikunne/, Eleanor K. Spicer, and Wayne R. Fi1:gibbon
`
`134
`
`143
`
`156
`
`Reverse pharmacological effect of loop diuretics and altered rB Cl expression in rats with lithium
`nephropathy. Mari Michimaw, Sayuri Fujiw, Ts111011111 Araki, Kazultiko Miz11kami, 11.rnro Kazama, Yasuko
`Murama1su, Michiko Suzuki, Tokiltisa Kimura, Sei Sasaki, Ywaka Imai, and Mit.11111ob11 M{//111bara. . . . 165
`
`VASCULAR BIOLOGY -HEMODY AMICS-HYPERTE
`JO
`Glomerular hemodynamics and the rcnin-angiotensin system in patients with ty pc I diabetes mcllitus.
`Norman K. Hollenberg, Deborah A. Price, aomi D.L. Fisher, M. Cecilia La111ang, Bruce Perkins, Michael
`S. Gordon, Gordon H. Williams, and Lori M. B. Laffe/. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
`
`Oxidative stress and dysregulation of superoxide dismutase and ADPH oxidase in renal insufficiency.
`osra1ola D. Va:iri, Michael Dicus,
`{///llln D. Ho, La/eh Boroujerdi-Rad, and Ram K. Sindlw. . . . . . . 179
`
`uperoxide dismutase. catalase, glutathione peroxida e and ADPH oxidase in lead-induced hypertension.
`osra10/a D. Vaziri, Ching-Yi Lin, Farbod Farmand, and Ram K. Si11dh11. . . . . . . . . . . . . . . . . . . . . . . . 186
`
`Effects of diabetes, in ulin and antioxidants on O ynthase abundance and O interaction with reactive
`oxygen species. Ja-Ryong Koo and Nosratola D. Vaziri . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`195
`
`Renal oxygenation defects in the spontaneously hypertensive rat: Role of AT1 receptors. William J. Welch,
`Horst Baumglinl, Dietrich Liihhers, and Christopher S. Wilcox. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
`
`Mycophenolate mofetil prevents the development of glomerular injury in experimental diabetes. Ricardo
`U1imura, Clarice Kazue Fujihara, Ana L1icia Mallar, Denise Maria A vancini Cowa Malheiros, Irene de
`/,mm/es oronha, and Rober10 Zat::. (see Editorial by Meyer, p. 377) . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
`
`CU !CAL EPHROLOGY-EPIDEMIOLOGY-CLI ICAL TRIALS
`odium ferric gluconate complc, in hemodialysis patients. II. Adverse reactions in iron dextran-sensitive
`and dcxtran-tolerant patients. Da111el W. Coyne,
`. Franklin Adkinson, Jr., Allen R. Nissenson, S1even
`Fi.1hba11e, Rajiv Aganl'lll, Joseph W. £.\chhach, Beckie Michael, Vaughn Folkert, Daniel Batlle, J. Richard
`Trour, aomi Dahl, Pamela My,rski, fur S1rohos, and David G. Warnock, for the Fer/ecit In vestigators
`
`217
`
`Development and progre sion of nephropathy in type 2 diabetes: The United Kingdom Prospective
`Diabc tc Study (UK PDS 64). Amanda I. Adler, Richard J. Stevens, Sue£. Manley, Rudy W. Bilous, Carole
`A. Cull, and Rury R. llo/111a11. 011 belwlf of the UKPDS Croup ....... .. ... . ................... 225
`Con1cn1\ continued on next page
`
`

`

`Content, continued
`
`Familial collapsing glomcrulopathy: Clinical, pathological and immunogcnctic features. M. Carmen Avila(cid:173)
`Casado, Gilberto Vargas-Alarcon, Maria E. Soto, Guadalupe /lernandez, Pedro A. Reyes, and Jaime
`Herrera-Acosta. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
`Long-term combined treatment with thiazidc and potassium citrate in nephrolithiasis docs not lead to
`hypokalemia or hypochloremic metabolic alkalosis. Clarira V. Odvina, Glenn M . Preminger, Jill S. Lindberg,
`Orson W. Moe, and Charles Y.C. Pak. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
`The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyper(cid:173)
`parathyroidism. Jill S. Lindberg, Sharon M. Moe, William C. Goodman, Jack W. Coburn, Swart M.
`Sprague, Wei Liu, Peter W. Blaisdell, Robert M. Brenner, Stewart A . Turner, and Kevin J. Martin . . . . . 248
`Urine stone risk factors in nephrolithiasis patients with and without bowel disease. Joan II. Parks, Elaine
`M. Worcester, R. Corey O 'Connor, and Fredric L. Coe........... ...................... .... . . 255
`Severe bone disease and low bone mineral density after juvenile renal failure. Jaap W. Groothoff, Martin
`Offringa, Berthe L.F. van Eck-Smit, Mariken P. Gruppen, Nicole J. van de Kar, Eric D. Wolff. Marc R.
`Lilien, Jean Claude Davin, Hugo S.A. Heymans, and Friedo W. Dekker . . . . . . . . . . . . . . . . . . . . . . . . . 266
`Renal function and outcome of PTRA and stcnting for atherosclerotic renal artery stenosis. Felipe Ramos,
`Carol Kotliar, Daniel Alvarez, Hugo Baglivo, Pablo Rafaelle, I lugo Londero, Ramiro Sanchez, and Christo-
`pher S. Wilcox . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
`impaired K • regulation contributes to exercise limitation in end-stage renal failure. Termboon Sangkabu-
`tra, David P. Crankshaw, Claudia Schneider, Steve F. Fraser, Simon Sostaric, Kim Mason, Caroline M.
`Burge, Sandford L. Skinner, Lawrence P. McMahon, and Michael J. Mc Kenna . . . . . . . . . . . . . . . . . . . . 283
`
`291
`
`DIALYSlS - TRANSPLA TATlON
`Muscle atrophy in patients receiving hemodialysis: Effects on muscle strength, muscle quality, and physical
`function. Kirsten L. Johansen, Tiffany Shubert, Julie Doyle, Brian Soher, Giorgos K. Sakkas, and Jane A.
`Kent-Braun . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Glucose degradation products in PD fluids: Do they di appear from the peritoneal cavity and enter the
`systemic circulation? Martin Zeier, Vedar Sclrwenger, Reinhold Deppisch, Ulrike Haug, Kai Weigel, U.
`. . . . . . . . . . . . . . . . . . . . . 298
`Bahner, Christoph Wanner, H. Schneider, Thomas Henle, and Eberhard Rir:::.
`Inhibition of nuclear factor-KB activation by pyrrolidine dithiocarbamate prevents chronicFK506 nephrop-
`athy. Saroshi Tamada, Tarsuya Nakarani, Toshihiro A sai, Koichiro Tashiro, Toshiyuki Komiya, Tomohiko
`Sumi, Mikio Okamura, Shokei Kim, lliro~hi /woo. Takeroshi Kishimoto, Shinya Yamanaka, and Karsuyuki
`Miura ............ . .......................................... ... ..... .. ............ 306
`Impact of albumin synthesis rate and the acute phase response in the dual regulation of fibrinogen levels
`in hemodialysis patient . George A. Kaysen, Joel A. Dubin, Hans-Georg. Miiller, William E. Mitch, Laura
`Ro.mies, Na1han W. Levin, and tire I/EMO Group (see Editorial by Goodship. p. 314)..... . . ....... 315
`Creation, cannulation and survival of arteriovenous fistulae: Data from the Dialysis Outcomes and Practice
`Patterns Study. I lug/, C Rayner, Ronald L. Pisoni, Brenda W. Gillespie, David A. Goodkin, Takashi
`Akiba, Tadao Akizawa, Akira Saito, Eric W. Young, and Friedric/r K. Pon. . . . . . . . . . . . . . . . . . . . . . . 323
`Affinity adsorption of glucose degradation products impro,es the biocompatibility of conventional perito-
`neal dialysis fluid. Naoyoshi Ishikawa, Toshio Miyata, Yasuhiko Ueda, Reiko lnagi, Yuko lwhara, Hiroko
`Yu;:awa, Hiros/ri Onogi, Makoro Nis/rina, Masaomi Nangaku, Charles van Yp ersele de Strihou, and Kiyoshi
`Kurokawa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Prevention of Staphylococcus aureus biofilm on dialysi catheters and adherence to human cells. Naomi
`Balaban, Yael Gov. Arkady Biller, and Johan R. Boelaerr . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
`Gender differences in outcome of arteriovenow, fistulas in hcmodialy is patients. Chrisroplrer D. Miller,
`Michelle L. Robbin, and Michael Allon. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
`Effects of high-flux hemodialysis on oxidant stress. Richard A. Ward, Rosemary Ousep/r, and Kenneth R.
`!,,/cLeis/r. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`331
`
`353
`
`

`

`Blood pressure reduction with HMG-CoA reductase inhibitors in renal transplant recipients. G. V. Ramesh
`Prasad, Aasia Ahmed, Michelle M. Nash, and Jeffrey S. Zaltzman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
`
`TECHNICAL NOTE
`Morphogenesis during mouse embryo nic kidney explaal culture. Indra Rani GttpLa, Martine Lapointe,
`and Oriana H. Yu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
`
`EDITORIALS
`Immuaosuppression for diabetic g lomerular disease? Timothy W. Meyer. . . . . . . . . . . . . . . . . . . . . . . . . 377
`
`Fibrinogen in hemodialysis: The worst of both worlds? Timothy 11.J. Goodship . . . . . . . . . . . . . . . . . . . 379
`
`LETTERS TO THE EDITOR
`Tumor-suppressive effecl of coanexin 32 in renal cell carcinoma from maintenance hemodialysis patients.
`Tomohiro Yano, Fumio Ito, 1/aruna Sarah, Kiyokau Hagiwara, Hayakazu Nakazawa, Hiroshi Toma, and
`Hiroshi Yamasaki . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
`
`Calcium on trial: Beyond a reasonable doubt? Ca1eri11a Canavese, Daniela Bergamo, Hamido Dib, Fran-
`cesca Bermond, and Manuel Burdese . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
`
`Albert Fournier, Mohamed Be11yahia, Crina Popa Claudia, and Tarek Sadek...................... 382
`
`Mark Cleveland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
`
`Charles R. Nolan and Wajah Y. Quinibi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
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`NEPHROLOGY FORUM
`Light at the end of the TUN EL: HIV-associaled thrombotic microangiopathy. Charles E. Alpers...... 385
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`INTERNATIONAL SOCIETY OF NEPHROLOGY
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`Erratum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400
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`lnstrucrions for Authors 011 page xii
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`
`Kidney lnrernational, Vol. 63 (2003), pp. 217- 224
`
`CLINICAL NEPHROLOGY -EPIDEMIOLOGY -CLINICAL TRIALS
`
`Sodium ferric gluconate complex in hemodialysis patients.
`II. Adverse reactions in iron dextran-sensitive
`and dextran-tolerant patients
`DANIEL w. COYNE, N. FRANKLIN ADKINSON, JR., ALLEN R. N1SSENSON, STEVEN FJSHBANE,
`RAJIV AGARWAL, JosEPH W. EscHBACH, BECKIE M1cHAEL, VAUGHN FoLKERT, DANIEL BATLLE,
`J. RICHARD TROUT, NAOMI DAHL, PAMELA MYIRSKJ, JuR STRooos, and DAvm G. WARNOCK,
`for the FERLECIT® INVESTIGATORS
`
`Washington University School of Medicine, St. Louis, Missouri; Johns Hopkins University, Baltimore, Maryland; UCLA School
`of Medicine, Los Angeles, California; Winthrop University Hospital, Mineola, New York; Indiana University School of
`Medicine, Indianapolis, Indiana; Northwest Kidney Center, Seattle, Washington; Thomas Jefferson University, Philadelphia,
`Pennsylvania; Albert Einstein College of Medicine, New York, New York; Northwestern University, Chicago, Illinois; Rutgers
`University, Trenton, and Watson Laboratories, Morristown, New Jersey; Baltimore, Maryland; Washington, D.C.; and
`University of Alabama at Birmingham, Birmingham, Alabama, USA
`
`Sodium ferric gluconate complex in hemodialysis patients. II.
`Adverse reactions in iron dextran-sensitive and dextran-toler(cid:173)
`ant patients.
`Background. Iron dextran administration is associated with
`a high incidence of adverse reactions including anaphylaxis and
`death. Although dextran, rather than iron, is believed to be the
`cause of these reactions, it is not known whether iron dextran(cid:173)
`sensitive patients can be safely administered another form of
`parenteral iron, sodium ferric gluconate in sucrose (SFGC).
`Methods. In a 69 center, prospective, double-blind, con(cid:173)
`trolled trial of safety and tolerability of SFGC, the rate of
`reactions to SFGC and placebo in 144 iron dextran-sensitive
`patients was compared with 2194 patients who were previously
`tolerant to iron dextran preparations. Serum tryptase levels, a
`marker of mast cell degranulation, also were measured.
`Results. Among 143 iron dextran-sensitive patients exposed
`to SFGC, three (2.1 % ) were intolerant. All three had suspected
`allergic events to SFGC, including one patient with a serious
`reaction (0.7%). One dextran-sensitive patient (0.7%) had a
`suspected allergic reaction after placebo. In contrast, among
`2194 iron dextran-tolerant patients, reactions to SFGC were
`significantly less common , with SFGC intolerance seen in seven
`patients (0.3%; P = 0.020), including five (0.2%) who had
`suspected allergic events (P = 0.010), but none who had serious
`events (0.0%; P = 0.061 ). Two iron dextran-tolerant patients
`(0.09%) had allergic-like reactions following placebo injec(cid:173)
`tions. Two of the three suspected allergic events in the iron
`dextran-sensitive group were confirmed as mast cell dependent
`by a 100% increase in serum tryptase, while there were no
`
`Key words: allergy, drug safety, intravenous iron , renal failure, lryp(cid:173)
`tase, anemia, parenteral iron, hemoglobin.
`
`Received for publication February 28, 2002
`and in revised form July 16, 2002
`Accepted for publication August 7, 2002
`© 2003 by the International Society of Nephrology
`
`confirmed allergic events in the iron dextran-toleranl group.
`Long-term exposure to SFGC in iron dextran-sensitive patients
`resulted in intolerance in only one additional patient and no
`serious adverse events.
`Conclusions. Patients with a history of iron dextran sensitiv(cid:173)
`ity had approximately sevenfold higher rates of reaction to
`both placebo and SFGC compared to iron dextran tolerant
`patients. However, logistic regression analysis, performed lo
`account for the higher reaction rate to placebo, suggests that
`this increased reactivity was not drug-specific nor immunologi(cid:173)
`cally mediated, but represented host idiosyncrasy. These results
`support the conclusions that reactions to SFGC can be attrib(cid:173)
`uted to pseudoallergy, and that SFGC is not a true allergen .
`
`The frequent blood loss associated with dialysis and
`its related procedures is estimated to result in 1 to 3 grams
`of iron loss per year in chronic hemodialysis patients [1 ].
`Regular administration of iron to hemodialysis patients
`increases the percentage of patients in the target hemo(cid:173)
`globin range and reduces requirements for recombinant
`human erythropoietin (epoetin). Guidelines from both
`American and European nephrology groups recommend
`administration of intravenous iron as both repletion and
`maintenance therapy in hemodialysis patients [2, 3] to
`achieve target hemoglobin and ensure efficient use of
`erythropoietin.
`For many years the only form of parenteral iron avail(cid:173)
`able in the United States was iron dextran. Review of
`drug reporting databases by Faich and Strobos identified
`31 deaths reportedly due to administration of iron dex(cid:173)
`tran [4]. Allergic reactions due to iron dextran were
`reported in 8.7 per million doses per year but only in 3.3
`
`217
`
`

`

`218
`
`Coyne et al: Reactions /0 sodium ferric gluco11ate complex
`
`per million doses per year with sodium ferric gluconate
`complex in sucrose (SFGC) [4]. In the same study there
`were 74 "allergic" events related to SFGC administration.
`None of these 74 events associated with SFGC were fatal.
`In contrast, 31 of 196 (15.8%) of the allergic events
`reported for iron dextran resulted in death. While pseudo(cid:173)
`allergic reactions usually occur during the first exposure
`to iron dextran, anaphylactic reactions can follow multi(cid:173)
`ple uneventful exposures [5]. Furthermore, iron dextran
`intolerance (which includes all forms of reactions) is
`common, occurring in approximately 2.5% of iron dex(cid:173)
`tran-na'ive patients [4]. The molecular weight of iron
`dextran also appears to influence the incidence of ana(cid:173)
`phylactic and intolerance reactions, with higher molecu(cid:173)
`lar weight Dexferrum® being associated with a higher
`incidence of reactions than InFeD® [5]. These data have
`called into question the wisdom of using iron dextran
`preparations at all, particularly if safer parenteral iron
`preparations are available [6].
`It is not known whether other forms of parenteral iron
`such as SFGC can be used safely in iron dextran-sensi tive
`patients. We have recently reported on a randomized
`double blind study of SFGC versus placebo in chronic
`dialysis patients in the United States that confirmed the
`safety of SFGC in a large number of patients, the vast
`majority of whom had prior iron dextran tolerance [7].
`Since SFGC does not contain any dextran moieties that
`are thought to be important antigenic determinants, we
`hypothesized that the incidence of drug intolerance and
`adverse reactions to SFGC in those patients who did
`have a history of iron dextran-sensitivity would not ex(cid:173)
`ceed that seen with placebo administration.
`We report here the results of SFGC and placebo ad(cid:173)
`ministration to the 144 patients from the randomized
`double blind study who had a history of prior iron dex(cid:173)
`tran reactions, as well as the results of subsequent admin(cid:173)
`istration of multiple doses of SFGC to a subset of 92 iron
`dextran-sensitive patients who entered an open-label
`study of SFGC. We also determined whether suspected
`allergic reactions following SFGC and placebo were mast
`cell dependent by measuring serum tryptase, a marker
`of mast cell degranulation.
`
`METHODS
`Data were collected for patients with a history of iron
`dextran allergies, known iron dextran tolerance, or sus(cid:173)
`pected allergic reactions to SFGC during a multicenter,
`crossover, randomized, double-blind, placebo controlled
`prospective trial of SFGC performed in 2534 hemodialy(cid:173)
`sis patients [7]. Data also were collected from a subse(cid:173)
`quent open label long-term study of SFGC in 1412 pa(cid:173)
`tients successfully completing the double-blind study.
`Prior dextran sensitivities were classified by each partici(cid:173)
`pating center as mild, drug intolerance, or anaphylactoid,
`
`based on information in the patient record and patient
`history. A predefined secondary end-point of the blinded
`study was to evaluate the cross sensitivity of SFGC and
`iron dextran by comparing patients who previously toler(cid:173)
`ated iron dextran with those patients with prior iron
`dextran intolerance. The federal Food and Drug Admin(cid:173)
`istration (FDA) approved the final study design.
`
`Patient selection
`Patients were enrolled in the double blind study at 69
`centers in the U.S. between August 1999 and October
`2000, and all centers obtained approval from their re(cid:173)
`spective Institutional Review Boards. Patient eligibility
`and exclusion criteria have been reported in detail pre(cid:173)
`viously [7]. Briefly, patients with known sensitivity to
`iron dextran were limited in this trial to avoid over(cid:173)
`enrollment of atopic or multiple drug allergy patients.
`which could bias the overall study toward over-reactions.
`Centers could enroll up to 10% of patients with a history
`of iron dextran intolerance. Patients were excluded from
`the study if they had prior treatment with SFGC, or were
`undergoing acute or chronic therapy with antihistamines
`or corticosteroids, which could mask possible allergic
`reactions. The first 1412 patients completing the double(cid:173)
`blinded study without drug intolerance to SFGC then
`