Top

Published in:

10-01-2023 | IgA Vasculitis | Educational Review

The first randomized controlled trial in pediatric nephrology: the history of the International Study of Kidney Disease in Children (ISKDC)

Authors: William A. Primack, Robert L. Chevalier, Aaron Friedman, Kevin V. Lemley, Victoria F. Norwood, George J. Schwartz, Douglas Silverstein, Frederick Kaskel

Published in: Pediatric Nephrology | Issue 12/2023

Abstract

The International Study of Kidney Disease in Children (ISKDC), begun in 1966, conducted the first international collaborative randomized blinded controlled trial in pediatric nephrology and one of the first in either pediatrics or nephrology. For this trial, the ISKDC developed the criteria, such as those for response and relapse, used today to describe the clinical course of the nephrotic syndrome, and the trial generated the nephropathologic terminology and criteria which largely remain the current standards. Over an approximately 20-year span, the ISKDC followed the natural history and evaluated the therapeutic effectiveness of therapies in over 500 children with the nephrotic syndrome from three continents. It published 14 peer-reviewed studies and several reports and commentaries, many of which helped create current standards of practice for therapy of childhood nephrotic syndrome and consequently remain highly cited today. The ISKDC continues to be an important model for subsequent collaborative studies and was the impetus for the development of regional and national pediatric nephrology societies leading to the recognition and growth of pediatric nephrology as a separate subspecialty.

Graphical abstract

Available only for authorised users

Barnett H (1984) Philosophy and ethics of multicenter international controlled clinical trials in children. In: Brodehl J, Ehrich JHH (eds) Pediatric Nephrology. Springer Verlag, Berlin, pp 30–35CrossRef

West CD (1977) Anticoagulant and immunosuppressive drugs in the treatment of severe glomerulonephritis with coagulopathy. J Pediatr 90:1051–1052. https://doi.org/10.1016/s0022-3476(77)80619-7CrossRefPubMed

Arneil GC (1971) An international cooperative study, societies of paediatric nephrology, and Henry L Barnett. Pediatr Clin North Am 18:349–354. https://doi.org/10.1016/s0031-3955(16)32555-xCrossRefPubMed

International Study of Kidney Disease in Children (1979) International trials and pediatric nephrology. N Engl J Med 300:254–255. https://doi.org/10.1056/NEJM197902013000511CrossRef

Farnsworth EB (1950) Metabolic changes associated with administration of adrenocorticotropin in the nephrotic syndrome. Proc Soc Exp Biol Med 74:60–62. https://doi.org/10.3181/00379727-74-17809CrossRefPubMed

Barnett HL, McNamara H, McCrory W, Forman C, Rapoport M, Michie A, Barbero G (1950) The effects of ACTH and cortisone on the nephrotic syndrome. AMA Am J Dis Child 80:519–520PubMed

Luetscher JA Jr, Deming QB, JohnsonBB HJ, Lew W, Poo LJ (1951) Treatment of nephrosis with pituitary adrenocorticotrophin. J Clin Invest 30:1530–1541. https://doi.org/10.1172/JCI10256

Arneil GC (1961) 164 children with nephrosis. Lancet 2:1103–1110. https://doi.org/10.1016/s0140-6736(61)91026-1CrossRefPubMed

Kohn JL, Gribetz D (1960) Nephrotic syndrome of childhood. Comparison of results of current hormonal therapy with those achieved previously. Am J Dis Child 100:373–376CrossRefPubMed

10.

Barness L, Moll G, Janeway C (1950) Nephrotic syndrome: natural history of the disease. Pediatrics 5:486–503. https://doi.org/10.1542/peds.5.3.486CrossRef

11.

(1978) Nephrotic syndrome in children: prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. A report of the International Study of Kidney Disease in Children. Kidney Int 13:159–165. https://doi.org/10.1038/ki.1978.23

12.

Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, Cook HT, Fervenza FC, Gibson KL, Glassock RJ, Jayne DRW, Jha V, Liew A, Liu ZH, Mejía- Vilet JM, Nester CM, Radhakrishnan J, Rave EM, Reich HN, Ronco P, Sanders JF, Sethi S, Suzuki Y, Tang SCW, Tesar V, Vivarelli M, Wetzels JFM, Lytvyn L, Craig JC, Tunnicliffe DJ, Howell M, Tonelli MA, Cheung M, Earley A, Floege J (2021) Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases. Kidney Int 100:753–779. https://doi.org/10.1016/j.kint.2021.05.015CrossRefPubMed

13.

Michael AF, Vernier RL, Drummond KN, Levitt JI, Herdman RC, Fish AJ, Good RA (1967) Immunosuppressive therapy of chronic renal disease. N Engl J Med 276:817–828. https://doi.org/10.1056/NEJM196704132761501CrossRefPubMed

14.

West CD (1958) Use of combined hormone and mechlorethamine (nitrogen mustard) therapy in lipoid nephrosis. AMA J Dis Child 95:498–515. https://doi.org/10.1001/archpedi.1958.02060050502007CrossRefPubMed

15.

Drummond KN, Hillman DA, Marchessault JH, Feldman W (1968) Cyclophosphamide in the nephrotic syndrome of childhood: its use in two groups of patients defined by clinical, light microscopic and immunopathologic findings. Can Med Assoc J 98:524–531PubMedPubMedCentral

16.

Barratt TM, Soothill JF (1970) Controlled trial of cyclophosphamide in steroid-sensitive relapsing nephrotic syndrome of childhood. Lancet 2:479–482. https://doi.org/10.1016/s0140-6736(70)90108-xCrossRefPubMed

17.

Adams DA, Gordon A, Maxwell MH (1967) Azathioprine treatment of immunological renal disease. JAMA 199:459–463CrossRefPubMed

18.

Barnett HL (1979) International study of kidney disease in children. Nihon Jinzo Gakkai Shi 21:1141–1144PubMed

19.

Spitzer A (1977) Ten years of activity: A report for the International Study of kidney Disease in Children. In: Kluthe R, Vogt A, Botsford (eds) Glomerulonephritis. Wiley, New York, pp 201–210

20.

Abramowicz M, Barnett HL, Edelmann CM Jr, Greifer I, Kobayashi O, Arneil GC, Barron BA, Gordillo-P G, Hallman N, Tiddens HA (1970) Controlled trial of azathioprine in children with nephrotic syndrome: a report for the international study of kidney disease in children. Lancet 1:959–961. https://doi.org/10.1016/s0140-6736(70)91093-7CrossRefPubMed

21.

Churg J, Habib R, White RH (1970) Pathology of the nephrotic syndrome in children: a report for the International Study of Kidney Disease in Children. Lancet 760:1299–1302. https://doi.org/10.1016/s0140-6736(70)91905-7CrossRefPubMed

22.

West CD, Winter S, Forristal J, McConville JM, Davis NC (1967) Evidence for in vivo breakdown of beta-10-globulin in hypocomplementemic glomerulonephritis. J Clin Invest 46:539–548. https://doi.org/10.1172/JCI105555CrossRefPubMedPubMedCentral

23.

Tarshish P, Bernstein J, Tobin JN, Edelmann CM Jr (1992) Treatment of mesangiocapillary glomerulonephritis with alternate-day prednisone–a report of the International Study of Kidney Disease in Children. Pediatr Nephrol 6:123–130. https://doi.org/10.1007/BF00866289CrossRefPubMed

24.

(1974) Prospective controlled trial of cyclophosphamide therapy in children with nephrotic syndrome Report of the International Study of Kidney Disease in Children. Lancet 2:423–427

25.

Barratt TM, Bercowsky A, Osofsky SG, Soothill JF (1975) Cyclophosphamide treatment in steroid-sensitive nephrotic syndrome of childhood. Lancet 1:55–58. https://doi.org/10.1016/s0140-6736(75)91068-5CrossRefPubMed

26.

Tarshish P, Tobin JN, Bernstein J, Edelmann CM Jr (1996) Cyclophosphamide does not benefit patients with focal segmental glomerulosclerosis. A report of the International Study of Kidney Disease in Children. Pediatr Nephrol 10:590–593. https://doi.org/10.1007/s004670050167CrossRefPubMed

27.

ISKDC (1972) International workshop on risk benefit assessment of cyclophosphamide in renal disease. Kidney Int 2:352–353

28.

(1981) The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr 98:561–564. https://doi.org/10.1016/s0022-3476(81)80760-3

29.

Ehren R, Benz MR, Brinkkötter PT, Dötsch J, Eberl WR, Gellermann J, Hoyer PF, Jordans I, Kamrath C, Kemper MJ, Latta K, Müller D, Oh J, Tönshoff B, Weber S, Weber LT, German Society for Pediatric Nephrology (2021) Pediatric idiopathic steroid- sensitive nephrotic syndrome: diagnosis and therapy -short version of the updated German best practice guideline (S2e) - AWMF register no. 166–001, 6/2020. Pediatr Nephrol 36:2971–2985. https://doi.org/10.1007/s00467-021-05135-3CrossRefPubMedPubMedCentral

30.

Churg J, Duffy JL, Bernstein J (1979) Identification of dense deposit disease: a report for the International Study of Kidney Diseases in Children. Arch Pathol Lab Med 103:67–72PubMed

31.

(1981) Primary nephrotic syndrome in children: clinical significance of histopathologic variants of minimal change and of diffuse mesangial hypercellularity. A Report of the International Study of Kidney Disease in Children. Kidney Int 20:765–771. https://doi.org/10.1038/ki.1981.209

32.

(1984) Minimal change nephrotic syndrome in children: deaths during the first 5 to 15 years’ observation. Report of the International Study of Kidney Disease in Children. Pediatrics 73:497–501. https://doi.org/10.1542/peds.73.4.497

33.

Tarshish P, Tobin JN, Bernstein J, Edelmann CM Jr (1997) Prognostic significance of the early course of minimal change nephrotic syndrome: report of the International Study of Kidney Disease in Children. J Am Soc Nephrol 8:769–776. https://doi.org/10.1681/ASN.V85769CrossRefPubMed

34.

(1982) Early identification of frequent relapsers among children with minimal change nephrotic syndrome. A report of the International Study of Kidney Disease in Children. J Pediatr 101:514–518. https://doi.org/10.1016/s0022-3476(82)80692-6

35.

(1979) Nephrotic syndrome in children: a randomized trial comparing two prednisone regimens in steroid-responsive patients who relapse early. Report of the International Study of Kidney Disease in Children. J Pediatr 95:239–243. https://doi.org/10.1016/S0022-3476(79)80658-7

36.

Tarshish P, Bernstein J, Edelmann CM Jr (2004) Henoch-Schönlein purpura nephritis: course of disease and efficacy of cyclophosphamide. Pediatr Nephrol 19:51–56. https://doi.org/10.1007/s00467-003-1315-xCrossRefPubMed

37.

Working Group of the International IgA Nephropathy Network and the Renal Pathology Society, Cattran DC, Coppo R, Cook HT, Feehally J, Roberts IS, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA, D’Agati V, D’Amico G, Emancipator S, Emma F, Ferrario F, Fervenza FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Leung CB, Li LS, Li PK, Liu ZH, Mackinnon B, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H (2009) The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int 76:534–545. https://doi.org/10.1038/ki.2009.243CrossRef

38.

Arneil G, Boda D, Ehrich JH, Fanconi A, Habib R, Hallman N (2007) The founding and early history of the European Society for Paediatric Nephrology (ESPN). Pediatr Nephrol 22(Suppl 1):1–15. https://doi.org/10.1007/s00467-006-0406-xCrossRefPubMed

39.

Chesney RW (2002) The development of pediatric nephrology. Pediatr Res 52:770–778. https://doi.org/10.1203/00006450-200211000-00026CrossRefPubMed

40.

Barnett HL, Edelmann CM Jr (1990) Development of pediatric nephrology. Am J Kidney Dis 16:557–562. https://doi.org/10.1016/s0272-6386(12)81040-7CrossRefPubMed

41.

Brodehl J (1991) The treatment of minimal change nephrotic syndrome: lessons learned from multicentre co-operative studies. Eur J Pediatr 150:380–387. https://doi.org/10.1007/BF02093714CrossRefPubMed

42.

Yoshikawa N, Nakanishi K, Sako M, Oba MS, Mori R, Ota E, Ishikura K, Hataya H, Honda M, Ito S, Shima Y, Kaito H, Nozu K, Nakamura H, Igarashi T, Ohashi Y, Iijima K (2015) Japanese Study Group of Kidney Disease in Children. A multicenter randomized trial indicates initial prednisolone treatment for childhood nephrotic syndrome for two months is not inferior to six-month treatment. Kidney Int 87:225–232. https://doi.org/10.1038/ki.2014.260CrossRefPubMed

43.

Pasini A, Bertulli C, Casadio L, Corrado C, Edefonti A, Ghiggeri G, Ghio L, Giordano M, La Scola C, Malaventura C, Maringhini S, Mastrangelo AP, Materassi M, Mencarelli F, Messina G, Monti E, Morello W, Puccio G, Romagnani P, Montini G, NefroKid Study Group (2021) Childhood idiopathic nephrotic syndrome: does the initial steroid treatment modify the outcome? A multicentre, prospective cohort study. Front Pediatr 9:627–636. https://doi.org/10.3389/fped.2021.627636CrossRef

44.

Gadegbeku CA, Gipson DS, Holzman LB, Ojo AO, Song PX, Barisoni L, Sampson MG, Kopp JB, Lemley KV, Nelson PJ, Lienczewski CC, Adler SG, Appel GB, Cattran DC, Choi MJ, Contreras G, Dell KM, Fervenza FC, Gibson KL, Greenbaum LA, Hernandez JD, Hewitt SM, Hingorani SR, Hladunewich M, Hogan MC, Hogan SL, Kaskel FJ, Lieske JC, Meyers KE, Nachman PH, Nast CC, Neu AM, Reich HN, Sedor JR, Sethna CB, Trachtman H, Tuttle KR, Zhdanova O, Zilleruelo GE, Kretzler M (2013) Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach. Kidney Int 83:749–756. https://doi.org/10.1038/ki.2012.428CrossRefPubMedPubMedCentral

45.

Mariani LH, Bomback AS, Canetta PA, Flessner MF, Helmuth M, Hladunewich MA, Hogan JJ, Kiryluk K, Nachman PH, Nast CC, Rheault MN, Rizk DV, Trachtman H, Wenderfer SE, Bowers C, Hill-Callahan P, Marasa M, Poulton CJ, Revell A, Vento S, Barisoni L, Cattran D, D’Agati V, Jennette JC, Klein JB, Laurin LP, Twombley K, Falk RJ, Gharavi AG, Gillespie BW, Gipson DS, Greenbaum LA, Holzman LB, Kretzler M, Robinson B, Smoyer WE, Guay-Woodford LM, CureGN Consortium (2019) CureGN study rationale, design, and methods: establishing a large prospective observational study of glomerular disease. Am J Kidney Dis 73:218–229. https://doi.org/10.1053/j.ajkd.2018.07.020CrossRefPubMed

46.

Trautmann A, Bodria M, Ozaltin F, Gheisari A, Melk A, Azocar M, Anarat A, Caliskan S, Emma F, Gellermann J, Oh J, Baskin E, Ksiazek J, Remuzzi G, Erdogan O, Akman S, Dusek J, Davitaia T, Özkaya O, Papachristou F, Firszt-Adamczyk A, Urasinski T, Testa S, Krmar RT, Hyla-Klekot L, Pasini A, Özcakar ZB, Sallay P, Cakar N, Galanti M, Terzic J, Aoun B, Caldas Afonso A, Szymanik-Grzelak H, Lipska BS, Schnaidt S, Schaefer F, PodoNet Consortium (2015) Spectrum of steroid- resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort. Clin J Am Soc Nephrol 10:592–600. https://doi.org/10.2215/CJN.06260614CrossRefPubMedPubMedCentral

47.

Trautmann A, Vivarelli M, Samuel S, Gipson D, Sinha A, Schaefer F, Hui NK, Boyer O, Saleem MA, Feltran L, Müller-Deile J, Becker JU, Cano F, Xu H, Lim YN, Smoyer W, Anochie I, Nakanishi K, Hodson E, Haffner D, International Pediatric Nephrology Association (2020) IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 35:1529–1561. https://doi.org/10.1007/s00467-020-04519-1CrossRefPubMedPubMedCentral

48.

Sinha A, Bagga A, Banerjee S, Mishra K, Mehta A, Agarwal I, Uthup S, Saha A, Mishra OP, Expert Group of Indian Society of Pediatric Nephrology (2021) Steroid sensitive nephrotic syndrome: revised guidelines. Indian Pediatr 58:650–666. https://doi.org/10.1007/s13312-021-2217-3CrossRefPubMed

49.

Trautmann A, Boyer O, Hodson E, Bagga A, Gipson DS, Samuel S, Wetzels J, Alhasan K, Banerjee S, Bhimma R, Bonilla-Felix M, Cano F, Christian M, Hahn D, Kang HG, Nakanishi K, Safouh H, Trachtman H, Xu H, Cook W, Vivarelli M, Haffner D, International Pediatric Nephrology Association (2022) IPNA clinical practice recommendations for the diagnosis and management of children with steroid-sensitive nephrotic syndrome. Pediatr Nephrol. https://doi.org/10.1007/s00467-022-05739-3CrossRefPubMedPubMedCentral

50.

Larkins NG, Liu ID, Willis NS, Craig JC, Hodson EM (2020) Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children. Cochrane Database Syst Rev 16(4):CD002290. https://doi.org/10.1002/14651858CrossRef

51.

Hahn D, Samuel SM, Willis NS, Craig JC, Hobson EM (2020) Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev 31:CD001533. https://doi.org/10.1002/14651858CrossRef

52.

Christian MT, Maxted AP (2022) Optimizing the corticosteroid dose in steroid- sensitive nephrotic syndrome. Pediatr Nephrol 37:37–47. https://doi.org/10.1007/s00467-021-04985-1CrossRefPubMed

53.

Hodson E, Hahn D, Craig J (2022) Prednisone for steroid-sensitive nephrotic syndrome. Can we use lower doses for the first presentation in children. Am J Kidney Dis 80:433–435. https://doi.org/10.1053/j.ajkd.2022.05.005CrossRefPubMed

54.

McKay AM, Parekh RS, Noone D (2022) Therapeutic trials in difficult to treat steroid sensitive nephrotic syndrome: challenges and future directions. Pediatr Nephrol 28:1–18. https://doi.org/10.1007/s00467-022-05520-6CrossRef

55.

Horinouchi T, Nozu K, Iijima K (2022) An updated view of the pathogenesis of steroid-sensitive nephrotic syndrome. Pediatr Nephrol 37:1957–1965. https://doi.org/10.1007/s00467-021-05401-4CrossRefPubMedPubMedCentral

56.

Barnett HL, Forman CW, Lauson HD (1952) The nephrotic syndrome in children. Adv Pediatr 5:53–128CrossRefPubMed

Title: The first randomized controlled trial in pediatric nephrology: the history of the International Study of Kidney Disease in Children (ISKDC)
Authors: William A. Primack
Robert L. Chevalier
Aaron Friedman
Kevin V. Lemley
Victoria F. Norwood
George J. Schwartz
Douglas Silverstein
Frederick Kaskel
Publication date: 10-01-2023
Publisher: Springer Berlin Heidelberg
Keywords: IgA Vasculitis
IgA Vasculitis
Azathioprine
Nephrotic Syndrome
Azathioprine
Published in: Pediatric Nephrology / Issue 12/2023
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-022-05838-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The first randomized controlled trial in pediatric nephrology: the history of the International Study of Kidney Disease in Children (ISKDC)

Abstract

Graphical abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Graphical abstract

Please log in to get access to this content

Other articles of this Issue 12/2023

Tidal continuous cycling peritoneal dialysis in children

An unusual cause of diarrhea in a child with nephrotic syndrome: Questions

Tubulointerstitial nephritis and uveitis syndrome and SARS-CoV-2 infection in an adolescent: just a coincidence in time?

Application of GFR estimating equations to children with normal, near-normal, or discordant GFR

Nationwide epidemiology and clinical practice patterns of pediatric urinary tract infections: application of multivariate time-series clustering

Chest configuration in children and adolescents with infantile nephropathic cystinosis compared with other chronic kidney disease entities and its clinical determinants