Calcineurin inhibitors in the treatment of primary nephrotic syndrome in children
S.L. MOROZOV1, 2, T.S. KURSOVA1, O.R. PIRUZIEVA1, V.V. DLIN1
1Veltischev Research and Clinical Institute for Pediatrics and Pediatric Surgery, Moscow
2Pirogov Russian National Research Medical University, Moscow
Contact details:
Morozov S.L. — PhD (medicine), Leading Researcher of the Department of Hereditary наследственных и приобретённых болезней почек named after Prof. M.S. Ignatova, Associate Professor of the Department of Hospital Pediatrics No. 2 of Pediatrics Faculty
Address: 2 Taldomskaya Str., Moscow, Russian Federation, 125412, tel.: +7-903-138-77-32, e-mail: mser@list.ru
In pediatric nephrology, idiopathic nephrotic syndrome is the most common glomerular disease. It is now known that about 70% of children with idiopathic nephrotic syndrome develop relapses of the disease, while about 10% of patients are resistant to steroid therapy. In recent decades, calcineurin inhibitors, cyclosporine A and tacrolimus have been used in the treatment of steroid-resistant and steroid-dependent nephrotic syndrome as the first line of immunosuppressive therapy, forming the basis of the treatment of nephrotic syndrome, with more than 70% of patients achieving complete or partial remission of the disease with a favorable long-term prognosis for kidney function. This review discusses the mechanisms of calcineurin inhibitors action and their advantages and disadvantages. Varied therapeutic responses to calcineurin inhibitors prompt further investigation of population pharmacokinetics and pharmacodynamics in order to subsequently consider and possibly develop personalized treatment regimens through the use of therapeutic drug monitoring.
Key words: children, nephrotic syndrome, glomerulonephritis, cyclosporine, tacrolimus, pharmacodynamics.
REFERENCES
- Trautmann A. et al. IPNA clinical practice recommendations for the diagnosis and management of children with steroid-sensitive nephrotic syndrome. Pediatr Nephrol, 2023, vol. 38 (3), pp. 877–919.
- Dlin V.V., Morozov S.L. Nephrotic Syndrome: Is Personalized Therapy Possible? Review. Pediatriya. Vostochnaya Evropa, 2023, vol. 11, no. 1, pp. 65–76 (in Russ.).
- Ignatova M.S., Dlin V.V. Nephrotic syndrome: past, present and future. Rossiyskiy vestnik perinatologii i pediatrii, 2017, vol. 62, no. 6, pp. 29–44 (in Russ.).
- Morozov S.L., Dlin V.V. On the issue of steroid therapy for primary nephrotic syndrome in children. Prakticheskaya meditsina, 2020, vol. 18, no. 3, pp. 26–31 (in Russ.).
- Morozov S.L., Aksenova M.E. Primary nephrotic syndrome in children. Prospects for personalized therapy. Prakticheskaya meditsina, 2018, no. 8 (in Russ.).
- Morozov S.L., Dlin V.V., Sadykov A.R., Voronkova A.S., Sukhorukov V.S. Mechanisms of resistance to immunosuppressive therapy in patients with nephrotic syndrome. Rossiyskiy vestnik perinatologii i pediatrii, 2017, vol. 62, no. 4, pp. 19–24 (in Russ.).
- Li H.-Y. et al. Efficacy and safety of cyclosporine a for patients with steroid-resistant nephrotic syndrome: a meta-analysis. BMC Nephrol, 2019, vol. 20 (1), p. 384.
- Lee J.M. et al. Current understandings in treating children with steroid-resistant nephrotic syndrome. Pediatr Nephrol, 2021, vol. 36 (4), pp. 747–761.
- Morozov S.L., Dlin V.V., Sukhorukov V.S., Voronkova A.S. Molecular nephropathology: new possibilities for diagnosing kidney diseases. Rossiyskiy vestnik perinatologii i pediatrii, 2017, vol. 62 (3), pp. 32–36 (in Russ.).
- Sachdeva S. et al. Management of Steroid-Resistant Nephrotic Syndrome in Children. Cureus, 2021.
- Farouk S.S., Rein J.L. The Many Faces of Calcineurin Inhibitor Toxicity — What the FK? Advances in Chronic Kidney Disease, 2020, vol. 27 (1), pp. 56–66.
- Periman L.M., Mah F.S., Karpecki P.M. A Review of the Mechanism of Action of Cyclosporine A: The Role of Cyclosporine A in Dry Eye Disease and Recent Formulation Developments. OPTH, 2020, vol. 14, pp. 4187–4200.
- Gao J. et al. Mitochondrial Permeability Transition Pore in Inflammatory Apoptosis of Human Conjunctival Epithelial Cells and T Cells: Effect of Cyclosporin A. Invest. Ophthalmol. Vis. Sci, 2013, vol. 54 (7), p. 4717.
- Matsuda S., Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology, 2000, vol. 47 (2–3), pp. 119–125.
- Pflugfelder S.C. et al. Aqueous Tear Deficiency Increases Conjunctival Interferon-γ (IFN-γ) Expression and Goblet Cell Loss. Invest. Ophthalmol. Vis. Sci, vol. 56 (12), pp. 7545.
- Uhlig K. et al. Recommendations for kidney disease guideline updating: a report by the KDIGO Methods Committee. Kidney International, 2016, vol. 89 (4), pp. 753–760.
- Shapiro R. et al. A pilot trial of tacrolimus, sirolimus, and steroids in renal transplant recipients. Transplantation Proceedings, 2002, vol. 34 (5), pp. 1651–1652.
- Bieber T. Topical tacrolimus (FK 506): A new milestone in the management of atopic dermatitis. Journal of Allergy and Clinical Immunology, 1998, vol. 102 (4), pp. 555–557.
- Kavukçu S., Soylu A., Türkmen M., Kasap B., Gümüştekin M., Gülay H. Two-hour post-dose cyclosporin A levels in adolescent renal transplant recipients in the late post-transplant period. Pediatric Nephrology, 2004, vol. 19 (6), pp. 667–671.
- Midtvedt K. Therapeutic drug monitoring of cyclosporine. Transplantation Proceedings, 2004, vol. 36 (2), pp. S430–S433.
- Wu Q. et al. Mechanism of cyclosporine A nephrotoxicity: Oxidative stress, autophagy, and signalings. Food and Chemical Toxicology, 2018, vol. 118, pp. 889–907.
- Dai Y. et al. Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro. Drug Metab Dispos, 2006, vol. 34 (5), pp. 836–847.
- Kolars J.C. et al. First-pass metabolism of cyclosporin by the gut. Lancet, 1991, vol. 338 (8781), pp. 1488–1490.
- Alak A.M., Moy S. Biological activity of tacrolimus (FK506) and its metabolites from whole blood of kidney transplant patients. Transplant Proc, 1997, vol. 29 (5), pp. 2487–2490.
- Copeland K.R., Yatscoff R.W., McKenna R.M. Immunosuppressive activity of cyclosporine metabolites compared and characterized by mass spectroscopy and nuclear magnetic resonance. Clin Chem, 1990, vol. 36 (2), pp. 225–229.
- Barbarino J.M. et al. PharmGKB summary: cyclosporine and tacrolimus pathways. Pharmacogenet Genomics, 2013, vol. 23 (10), pp. 563–585.
- Hubbard P.A. et al. NADPH-cytochrome P450 oxidoreductase. Structural basis for hydride and electron transfer. J Biol Chem, 2001, vol. 276 (31), pp. 29163–29170.
- Anglicheau D. et al. Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. J Am Soc Nephrol, 2003, vol. 14 (7), pp. 1889–1896.
- Tang H.-L. et al. Lower tacrolimus daily dose requirements and acute rejection rates in the CYP3A5 nonexpressers than expressers. Pharmacogenet Genomics, 2011, vol. 21 (11), pp. 713–720.
- Amirimani B. et al. Increased transcriptional activity of the CYP3A4*1B promoter variant. Environ Mol Mutagen., 2003, vol. 42 (4), pp. 299–305.
- Thorp M. et al. The effect of conversion from cyclosporine to tacrolimus on gingival hyperplasia, hirsutism and cholesterol. Transplantation, 2000, vol. 69 (6), pp. 1218–1220.
- Niaudet P. Treatment of childhood steroid-resistant idiopathic nephrosis with a combination of cyclosporine and prednisone. The Journal of Pediatrics, 1994, vol. 125 (6), pp. 981–986.
- Larkins N.G. et al. Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children. Cochrane Database of Systematic Reviews / ed. Cochrane Kidney and Transplant Group, 2020.
- for Japanese Study Group of Renal Disease in Children et al. Morbidity in children with frequently relapsing nephrosis: 10-year follow-up of a randomized controlled trial. Pediatr Nephrol, 2015, vol. 30 (3), pp. 459–468.
- Tunçay S., Mir S., Hakverdi G. What is The Best Choice in Steroid-Dependent Nephrotic Syndrome: Mycophenolate Mofetil Plus Dexamethasone or Cyclosporine A. Saudi J Kidney Dis Transpl, 2021, vol. 32 (4), p. 1019.
- Ishikura K. et al. Effective and safe treatment with cyclosporine in nephrotic children: A prospective, randomized multicenter trial. Kidney International, 2008, vol. 73 (10), pp. 1167–1173.
- Fujinaga S. et al. A prospective study on the use of mycophenolate mofetil in children with cyclosporine-dependent nephrotic syndrome. Pediatr Nephrol, 2007, vol. 22 (1), pp. 71–76.
- Jacobson P. et al. Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation. Bone Marrow Transplant, 1998, vol. 22 (3), pp. 217–225.
- Evans W.E., McLeod H.L. Pharmacogenomics — Drug Disposition, Drug Targets, and Side Effects. N Engl J Med, 2003, vol. 348 (6), pp. 538–549.
- Roberti I., Vyas S. Long-term outcome of children with steroid-resistant nephrotic syndrome treated with tacrolimus. Pediatr Nephrol, 2010, vol. 25 (6), pp. 1117–1124.
- Ahmed H.M. Tacrolimus can induce remission in cyclosporine and mycophenolate mofetil resistant pediatric onset nephrotic syndrome. Iran J Kidney Dis, 2019, vol. 13 (5), pp. 322–327.
- Hoyer P.F., Brodehl J. Initial Treatment of Idiopathic Nephrotic Syndrome in Children: Prednisone versus Prednisone Plus Cyclosporine A: A Prospective, Randomized Trial. Journal of the American Society of Nephrology, 2006, vol. 17 (4), pp. 1151–1157.
- Gellermann J. et al. Mycophenolate Mofetil versus Cyclosporin A in Children with Frequently Relapsing Nephrotic Syndrome. Journal of the American Society of Nephrology, 2013, vol. 24 (10), pp. 1689–1697.
- Dötsch J. et al. Is tacrolimus for childhood steroid-dependent nephrotic syndrome better than ciclosporin A? Nephrology Dialysis Transplantation, 2006, vol. 21 (7), pp. 1761–1763.
- Wang X. et al. Population pharmacokinetics and dosage optimization of tacrolimus in pediatric patients with nephrotic syndrome. CP, 2019, vol. 57 (3), pp. 125–134.