A randomised controlled unblinded multicentre non-inferiority trial with activated vitamin D and prednisolone treatment in patients with minimal change nephropathy (ADAPTinMCN)

Tilde Kristensen, Henrik Birn, Per Ivarsen, Tilde Kristensen, Henrik Birn, Per Ivarsen

Abstract

Background: Minimal change nephropathy (MCN) is a common cause of nephrotic syndrome in both adults and children. International guidelines recommend treatment with prednisolone 1 mg/kg/day to adults. This dose is derived from an empirically established dose in children, although children generally attain remission faster and relapse more rapidly than adults. Prednisolone is associated with multiple and serious adverse events. Activated vitamin D has been shown to reduce albuminuria in other glomerular renal diseases with a minimum of adverse events. This study tests the hypothesis that a new treatment regimen in MCN combining reduced dose prednisolone and active vitamin D is as efficient in inducing remission and has fewer and less severe adverse events than standard prednisolone. Furthermore, we aim to establish models allowing for more personalized medicine based on assessment of the individual's prednisolone metabolism.

Methods: A randomised controlled multicentre non-inferior unblinded trial including 96 adult, incident patients with biopsy-proven MCN, albuminuria > 3 g/day, and an estimated glomerular filtration rate (eGFR) > 30 ml/min from renal departments in Denmark. Patients are randomised to standard prednisolone (1 mg/kg/day) or reduced prednisolone (0.5 mg/kg/day) and alfacalcidol (0.5 μg/day). The primary outcome is the rate of remissions after 16 weeks and the time from diagnosis to remission. The study will include a saliva test to characterise prednisolone pharmacokinetics and compare them to genetic variations in specific liver enzymes responsible for prednisolone metabolism.

Discussion: Reducing the prednisolone dose is expected to reduce the number of severe adverse events. This study will examine if reduced prednisolone dose with active vitamin D but without additional immunosuppression is feasible in the treatment of MCN and will reduce the number of adverse events. The findings can potentially change current guidelines for treatment of MCN in adults. Additional outcomes on inter-individual pharmacokinetic and metabolic variations may allow for a more personalised treatment strategy.

Trial registration: EudraCT 2017-001206-16, ClinicalTrials.gov NCT03210688 . Registered on June 3, 2017.

Keywords: Activated vitamin D; Adverse events; Minimal change nephropathy; Nephrotic syndrome; Pharmacokinetics; Prednisolone.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

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Participant timeline

References

    1. Hogan J, Radhakrishnan J. The treatment of minimal change disease in adults. J Am Soc Nephrol. 2013;24(5):702–711. doi: 10.1681/ASN.2012070734.
    1. Vivarelli M, Massella L, Ruggiero B, Emma F. Minimal change disease. Clin J Am Soc Nephrol. 2017;12(2):332–345. doi: 10.2215/CJN.05000516.
    1. Vaziri ND. Disorders of lipid metabolism in nephrotic syndrome: mechanisms and consequences. Kidney Int. 2016;90:41–52. doi: 10.1016/j.kint.2016.02.026.
    1. Heaf J, Løkkegaard H, Larsen S. The epidemiology and prognosis of glomerulonephritis in Denmark 1985-1997. Nephrol Dial Transplant. 1999;14(8):1889–1897. doi: 10.1093/ndt/14.8.1889.
    1. Seeger H, Fehr T. Nephrotic syndrome in adult patients--etiology and complications. Praxis (Bern 1994) 2016;105(5):259–267. doi: 10.1024/1661-8157/a002296.
    1. Ordoñez JD, Hiatt RA, Killebrew EJ, Fireman BH. The increased risk of coronary heart disease associated with nephrotic syndrome. Kidney Int. 1993;44(3):638–642. doi: 10.1038/ki.1993.292.
    1. Suri D, Ahluwalia J, Saxena AK, Sodhi KS, Singh P, Mittal BR, et al. Thromboembolic complications in childhood nephrotic syndrome: a clinical profile. Clin Exp Nephrol. 2014;18:803–13.
    1. Kidney Disease Improving Global Outcomes KDIGO Clinical practice guideline for glomerulonephritis. Kidnet Int Suppl. 2012;2(2):1–274.
    1. Raja K, Parikh A, Webb H, Hothi D. Use of a low-dose prednisolone regimen to treat a relapse of steroid-sensitive nephrotic syndrome in children. Pediatr Nephrol. 2017;32(1):99–105. doi: 10.1007/s00467-016-3458-6.
    1. Waldman M, Crew RJ, Valeri A, Busch J, Stokes B, Markowitz G, D'Agati V, Appel G. Adult minimal-change disease: clinical characteristics, treatment, and outcomes. Clin J Am Soc Nephrol. 2007;2(3):445–453. doi: 10.2215/CJN.03531006.
    1. Shinzawa M, Yamamoto R, Nagasawa Y, Oseto S, Mori D, Tomida K, Hayashi T, Izumi M, Fukunaga M, Yamauchi A, Tsubakihara Y, Isaka Y. Comparison of methylprednisolone plus prednisolone with prednisolone alone as initial treatment in adult-onset minimal change disease: a retrospective cohort study. Clin J Am Soc Nephrol. 2014;9(6):1040–1048. doi: 10.2215/CJN.12331213.
    1. Lee H, Yoo KD, Oh YK, Kim DK, Oh K-H, Joo KW, Kim YS, Ahn C, Han JS, Lim CS. Predictors of relapse in adult-onset nephrotic minimal change disease. Medicine (Baltimore). 2016;95(12):e3179. doi: 10.1097/MD.0000000000003179.
    1. Black DA, Rose G, Brewer DB. Controlled trial of prednisone in adult patients with the nephrotic syndrome. Br Med J. 1970;3(August):421–426. doi: 10.1136/bmj.3.5720.421.
    1. Imbasciati E, Gusmano R, Edefonti A, Zucchelli P, Pozzi C, Grassi C, Della Volpe M, Perfumo F, Petrone P, Picca M. Controlled trial of methylprednisolone pulses and low dose oral prednisone for the minimal change nephrotic syndrome. Br Med J. 1985;291(November):1305–1308. doi: 10.1136/bmj.291.6505.1305.
    1. Zhao L, Cheng J, Zhou J, Wu C, Chen J. Enhanced steroid therapy in adult minimal change nephrotic syndrome: a systematic review and meta-analysis. Intern Med. 2015;54(17):2101–2108. doi: 10.2169/internalmedicine.54.3927.
    1. Liu LJ, Lv JC, Shi SF, Chen YQ, Zhang H, Wang HY. Oral calcitriol for reduction of proteinuria in patients with IgA nephropathy: a randomized controlled trial. Am J Kidney Dis. 2012;59(1):67–74. doi: 10.1053/j.ajkd.2011.09.014.
    1. Fishbane S, Chittineni H, Packman M, Dutka P, Ali N, Durie N. Oral paricalcitol in the treatment of patients with CKD and proteinuria: a randomized trial. Am J Kidney Dis. 2009;54(4):647–652. doi: 10.1053/j.ajkd.2009.04.036.
    1. Szeto CC, Chow KM, Kwan BCH, Chung KY, Leung CB, Li PKT. Oral calcitriol for the treatment of persistent proteinuria in immunoglobulin a nephropathy: an uncontrolled trial. Am J Kidney Dis. 2008;51(5):724–731. doi: 10.1053/j.ajkd.2007.12.038.
    1. Mirković K, van den Born J, Navis G, de Borst MH. Vitamin D in chronic kidney disease: new potential for intervention. Curr Drug Targets. 2011;12(1):42–53. doi: 10.2174/138945011793591572.
    1. Agarwal R, Acharya M, Tian J, Hippensteel RL, Melnick JZ, Qiu P, et al. Antiproteinuric effect of oral paricalcitol in chronic kidney disease. Kidney Int. 2005;68(6):2823–2828. doi: 10.1111/j.1523-1755.2005.00755.x.
    1. Deng J, Zheng X, Xie H, Chen L. Calcitriol in the treatment of IgA nephropathy with non-nephrotic range proteinuria: a metaanalysis of randomized controlled trials. Clin Nephrol. 2017;87(1):21–28. doi: 10.5414/CN108915.
    1. Barragry JM, Carter ND, Beer M, Cohen RD, France MW, Auton JA, Boucher BJ. Vitamin-D metabolism in nephrotic syndrome. Lancet. 1977;310(8039):629–632. doi: 10.1016/S0140-6736(77)92498-9.
    1. Li X-H, Huang X-P, Pan L, Wang C-Y, Qin J, Nong F-W, Luo YZ, Wu Y, Huang YM, Peng X, Yang ZH, Liao YH. Vitamin D deficiency may predict a poorer outcome of IgA nephropathy. BMC Nephrol. 2016;17(1):164. doi: 10.1186/s12882-016-0378-4.
    1. Bergmann TK, Barraclough KA, Lee KJ, Staatz CE. Clinical pharmacokinetics and pharmacodynamics of prednisolone and prednisone in solid organ transplantation. Clin Pharmacokinetics. 2012;51:711–741. doi: 10.1007/s40262-012-0007-8.
    1. Miloslavsky EM, Naden RP, Bijlsma JWJ, Brogan PA, Brown ES, Brunetta P, et al. Development of a Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis. Ann Rheum Dis. 2017;76(3):543–6.
    1. Webb SM, Badia X, Barahona MJ. Colao a, Strasburger CJ, Tabarin a, et al. Evaluation of health-related quality of life in patients with Cushing’s syndrome with a new questionnaire. Eur J Endocrinol. 2008;158(5):623–630. doi: 10.1530/EJE-07-0762.
    1. Nelson LM, Forsythe A, McLeod L, Pulgar S, Maldonado M, Coles T, Zhang Y, Webb SM, Badia X. Psychometric evaluation of the Cushing’s quality-of-life questionnaire. Patient. 2013;6(2):113–124. doi: 10.1007/s40271-013-0012-5.
    1. Wight JP, Edwards L, Brazier J, Walters S, Payne JN, Brown CB. The SF36 as an outcome measure of services for end stage renal failure. Qual Heal Care. 1998;7(4):209–221. doi: 10.1136/qshc.7.4.209.
    1. Teeninga N, Guan Z, Freijer J, Ruiter AFC, Ackermans MT, Kist-van Holthe JE, et al. Monitoring prednisolone and prednisone in saliva: a population pharmacokinetic approach in healthy volunteers. Ther Drug Monit. 2013;35(4):485–492. doi: 10.1097/FTD.0b013e3182899ea2.
    1. Teeninga N, Guan Z, Stevens J, Kist-van Holthe JE, Ackermans MT, van der Heijden AJ, et al. Population pharmacokinetics of prednisolone in relation to clinical outcome in children with nephrotic syndrome. Ther Drug Monit. 2016.
    1. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2(1):1–138. doi: 10.1038/kisup.2012.1.
    1. Kim YC, Lee TW, Lee H, Koo HS, Oh KH, Joo KW, Kim S, Chin HJ. Complete remission induced by tacrolimus and low-dose prednisolone in adult minimal change nephrotic syndrome: a pilot study. Kidney Res Clin Pract. 2012;31(2):112–117. doi: 10.1016/j.krcp.2012.04.321.
    1. Li X, Liu Z, Wang L, Wang R, Ding G, Shi W, Fu P, He Y, Cheng G, Wu S, Chen B, du J, Ye Z, Tao Y, Huo B, Li H, Chen J. Tacrolimus monotherapy after intravenous methylprednisolone in adults with minimal change nephrotic syndrome. J Am Soc Nephrol. 2017;28(4):1286–1295. doi: 10.1681/ASN.2016030342.
    1. Gulati A, Sinha A, Sreenivas V, Math A, Hari P, Bagga A. Daily corticosteroids reduce infection-associated relapses in frequently relapsing nephrotic syndrome: a randomized controlled trial. Clin J Am Soc Nephrol. 2011;6(1):63–69. doi: 10.2215/CJN.01850310.
    1. Bergmann TK, Isbel NM, Ostini R, Barraclough KA, Campbell SB, McWhinney BC, et al. Exploratory study of total and free prednisolone plasma exposure and cushingoid appearance, quality of life and biochemical toxicity in adult male kidney transplant recipients. Clin Drug Investig. 2015;35(11):743–750. doi: 10.1007/s40261-015-0334-2.

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