Skip to main content
SpringerLink
Log in

Pioglitazone enhances proteinuria reduction in complicated pediatric nephrotic syndrome

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Background

Nephrotic syndrome (NS) is a common pediatric kidney disease, yet current treatments for complicated NS are only partially effective and have significant toxicity. There is no Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-approved safe and effective treatment for NS. Thiazolidinediones (TZDs) have been shown to reduce proteinuria in both diabetic and non-diabetic kidney disease and in preclinical studies to directly protect podocytes from injury and reduce proteinuria. Here, we report on the potential utility of the addition of the TZD pioglitazone (PIO) to enhance proteinuria reduction in 8 children and young adults with steroid dependent NS and steroid resistant NS.

Methods

Clinical data were analyzed in comparable time periods before and after the addition of PIO to their medical regimens. Eight NS patients with minimal change NS (n = 2), focal segmental glomerulosclerosis (FSGS) (n = 4), or collapsing FSGS (n = 2) were evaluated.

Results

Prior to PIO initiation, all children and young adults had already received multiple immunosuppressive medications (mean = 3.75). Five of eight patients (63%; “Responders”) had notable proteinuria reduction within 1 month of PIO initiation (62% reduction; P = 0.04) and normalization within 6 months (97% reduction; P = 0.04). PIO-related benefits among the responders included notable increases in serum albumin (2.5 to 3.7 g/dl; P = 0.08), dramatic reductions in hospitalizations for IV albumin infusions and diuresis (11 to 0; P < 0.01), and considerable reduction in total immunosuppression (43% reduction; P > 0.1). Importantly, no patients experienced any adverse events attributable to PIO during a total of 136 patient-months of treatment.

Conclusions

While confirmatory safety and efficacy studies are needed, these findings suggest pioglitazone (a non-immunosuppressive drug) may be useful to enhance proteinuria reduction in some children and young adults with complicated NS.

Graphical Abstract

A higher resolution version of the Graphical abstract is available as Supplementary information

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Noone DG, Iijima K, Parekh R (2018) Idiopathic nephrotic syndrome in children. Lancet 392:61–74

    Article  PubMed  Google Scholar 

  2. Wang CS, Greenbaum LA (2019) Nephrotic syndrome. Pediatr Clin North Am 66:73–85

    Article  CAS  PubMed  Google Scholar 

  3. Ruth EM, Landolt MA, Neuhaus TJ, Kemper MJ (2004) Health-related quality of life and psychosocial adjustment in steroid-sensitive nephrotic syndrome. J Pediatr 145:778–783

    Article  PubMed  Google Scholar 

  4. Gipson DS, Tarnoff J, Lee L et al (2001) A pediatric gateway initiative for glomerular disease: introducing PIONEER. Kidney Int 99:515–518

    Article  Google Scholar 

  5. Barisoni L, Barratt J, Campbell K et al (2021) Innovating and invigorating the clinical trial infrastructure for glomerular diseases. Kidney Int 99:519–523

    Article  PubMed  Google Scholar 

  6. Iwamoto Y, Kuzuya T, Matsuda A et al (1994) Effect of new oral antidiabetic agent CS-045 on glucose tolerance and insulin secretion in patients with NIDDM. Diabetes Care 14:1083–1086

    Article  Google Scholar 

  7. Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J (1994) Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 331:1188–1193

    Article  CAS  PubMed  Google Scholar 

  8. Nakamura T, Ushiyama C, Shimada N, Hayashi K, Ebihara I, Koide H (2000) Comparative effects of pioglitazone, glibenclamide, and voglibose on urinary endothelin-1 and albumin excretion in diabetes patients. J Diabetes Complications 14:250–254

    Article  CAS  PubMed  Google Scholar 

  9. Sarafidis PA, Stafylas PC, Georgianos PI, Saratzis AN, Lasaridis AN (2010) Effect of thiazolidinediones on albuminuria and proteinuria in diabetes: a meta-analysis. Am J Kidney Dis 55:835–847

    Article  CAS  PubMed  Google Scholar 

  10. Kincaid-Smith P, Fairley KF, Farish S, Best JD, Proietto J (2008) Reduction of proteinuria by rosiglitazone in non-diabetic renal disease. Nephrology (Carlton) 13:58–62

    Article  CAS  PubMed  Google Scholar 

  11. Shahidi S, Pakzad B, Mortazavi M et al (2011) Reduction of proteinuria by pioglitazone in patients with non-diabetic renal disease. J Res Med Sci 16:1459–1465

    PubMed  PubMed Central  Google Scholar 

  12. Sharma A, Bourey RE, Edwards JC, Brink DS, Albert SG (2020) Nephrotic range proteinuria associated with focal segmental glomerulosclerosis reversed with pioglitazone therapy in a patient with Dunnigan type lipodystrophy. Diabetes Res Clin Pract 172:108620

    Article  PubMed  Google Scholar 

  13. Kanjanabuch T, Ma LJ, Chen J et al (2007) PPAR-gamma agonist protects podocytes from injury. Kidney Int 71:1232–1239

    Article  CAS  PubMed  Google Scholar 

  14. Benigni A, Zoja C, Tomasoni S et al (2006) Transcriptional regulation of nephrin gene by peroxisome proliferator-activated receptor-gamma agonist: molecular mechanism of the antiproteinuric effect of pioglitazone. J Am Soc Nephrol 17:1624–1632

    Article  CAS  PubMed  Google Scholar 

  15. Agrawal S, Chanley MA, Westbrook D et al (2016) Pioglitazone enhances the beneficial effects of glucocorticoids in experimental nephrotic syndrome. Sci Rep 6:24392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Platt C, Coward RJ (2017) Peroxisome proliferator activating receptor-gamma and the podocyte. Nephrol Dial Transplant 32:423–433

    CAS  PubMed  Google Scholar 

  17. Agrawal S, Guess AJ, Benndorf R, Smoyer WE (2011) Comparison of direct action of thiazolidinediones and glucocorticoids on renal podocytes: protection from injury and molecular effects. Mol Pharmacol 80:389–399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sonneveld R, Hoenderop JG, Isidori AM et al (2017) Sildenafil prevents podocyte injury via PPAR-gamma-mediated TRPC6 inhibition. J Am Soc Nephrol 28:1491–1505

    Article  CAS  PubMed  Google Scholar 

  19. Schwartz GJ, Munoz A, Schneider MF et al (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ng DK, Schwartz GJ, Schneider MF, Furth SL, Warady BA (2018) Combination of pediatric and adult formulas yield valid glomerular filtration rate estimates in young adults with a history of pediatric chronic kidney disease. Kidney Int 94:170–177

    Article  PubMed  PubMed Central  Google Scholar 

  21. Levey AS, Stevens LA, Schmid CH et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150:604–612

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ahmadian M, Suh JM, Hah N et al (2013) PPARγ signaling and metabolism: the good, the bad and the future. Nat Med 19:557–566

    Article  CAS  PubMed  Google Scholar 

  23. Nesto RW, Bell D, Bonow RO et al (2004) Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 27:256–263

    Article  CAS  PubMed  Google Scholar 

  24. Guan Y, Breyer MD (2001) Peroxisome proliferator-activated receptors (PPARs): novel therapeutic targets in renal disease. Kidney Int 60:14–30

    Article  CAS  PubMed  Google Scholar 

  25. Nakamura T, Ushiyama C, Suzuki S et al (2001) Effect of troglitazone on urinary albumin excretion and serum type IV collagen concentrations in type 2 diabetic patients with microalbuminuria or macroalbuminuria. Diabet Med 18:308–313

    Article  CAS  PubMed  Google Scholar 

  26. Sarafidis PA, Bakris GL (2006) Protection of the kidney by thiazolidinediones: an assessment from bench to bedside. Kidney Int 70:1223–1233

    Article  CAS  PubMed  Google Scholar 

  27. Pourshabanan P, Momeni A, Mahmoudnia L, Kheiri S (2019) Effect of pioglitazone on decreasing of proteinuria in type 2 diabetic patients with nephropathy. Diabetes Metab Syndr 13:132–136

    Article  PubMed  Google Scholar 

  28. Zhou Y, Huang Y, Ji X, Wang X, Shen L, Wang Y (2020) Pioglitazone for the primary and secondary prevention of cardiovascular and renal outcomes in patients with or at high risk of type 2 diabetes mellitus: a meta-analysis. J Clin Endocrinol Metab 105:dgz252

    Article  PubMed  Google Scholar 

  29. Joy MS, Gipson DS, Dike M et al (2009) Phase I trial of rosiglitazone in FSGS: I. Report of the FONT Study Group. Clin J Am Soc Nephrol 4:39–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu HF, Guo LQ, Huang YY et al (2010) Thiazolidinedione attenuate proteinuria and glomerulosclerosis in adriamycin-induced nephropathy rats via slit diaphragm protection. Nephrology (Carlton) 15:75–83

    Article  CAS  PubMed  Google Scholar 

  31. Miglio G, Rosa AC, Rattazzi L et al (2011) The subtypes of peroxisome proliferator-activated receptors expressed by human podocytes and their role in decreasing podocyte injury. Br J Pharmacol 162:111–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nakamura T, Ushiyama C, Osada S, Hara M, Shimada N, Koide H (2001) Pioglitazone reduces urinary podocyte excretion in type 2 diabetes patients with microalbuminuria. Metabolism 50:1193–1196

    Article  CAS  PubMed  Google Scholar 

  33. Bhayana SAS, Chanley MA, Waller AP, Wolfgang KJ, Wijeratne S, Fitch J, White P, Kerlin BA, Smoyer WE (2020) Glomerular transcriptomic analysis of glucocorticoid- and pioglitazone-treated nephrotic syndrome. J Am Soc Nephrol 31:617

    Google Scholar 

  34. Agrawal S, He JC, Tharaux PL (2021) Nuclear receptors in podocyte biology and glomerular disease. Nat Rev Nephrol 17:185–204

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Mandy Root Thompson for her expert medial illustration services and for preparing the figures for this manuscript. The authors would also like to thank Dr. Ben Brouhard and Dr. John Mahan for their critical reviews of the manuscript.

Author information

Author notes

  1. Tracy E. Hunley and Guillermo Hidalgo contributed equally to this work.

Authors and Affiliations

  1. Monroe Carell Jr. Children’s Hospital at Vanderbilt, Vanderbilt University School of Medicine, Nashville, TN, USA

    Tracy E. Hunley

  2. Department of Pediatrics, Brody School of Medicine, East Carolina University, Greenville, NC, USA

    Tracy E. Hunley, Guillermo Hidalgo & Hostensia M. Beng

  3. K. Hovnanian Children’s Hospital, HMH School of Medicine, Neptune, NJ, USA

    Guillermo Hidalgo

  4. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore

    Kar Hui Ng

  5. Tokyo Women’s Medical University, Tokyo, Japan

    Yoko Shirai, Kenichiro Miura & Motoshi Hattori

  6. East Carolina University, Greenville, NC, USA

    Qiang Wu

  7. Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA

    William E. Smoyer

  8. Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA

    William E. Smoyer

Authors
  1. Tracy E. Hunley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guillermo Hidalgo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kar Hui Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoko Shirai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenichiro Miura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hostensia M. Beng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qiang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Motoshi Hattori
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. William E. Smoyer
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Study design: TEH, GH, and WES; data collection: TEH, GH, KHN, YS, KM, HMB, and MH; data analysis: TEH, GH, QW, and WES; statistical analysis: TEH, GH, QW, and WES; manuscript preparation and editing: TEH, GH, KHN, YS, KM, HMB, QW, MH, and WES.

Corresponding author

Correspondence to William E. Smoyer.

Ethics declarations

Competing interests

TEH, GH, KHN, YS, KM, HMB, QW, and MH have no financial interests. WES is a co-founder of NephKey Therapeutics, Inc., and is on the Board of Directors of NephCure Kidney International and receives no compensation as a member of the Board of Directors. TEH is on the Editorial Board of Frontiers in Pediatrics and receives no compensation as a member of the Board.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file 1

(PDF 249 KB)

Graphical abstract

(PPTX 54 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hunley, T.E., Hidalgo, G., Ng, K.H. et al. Pioglitazone enhances proteinuria reduction in complicated pediatric nephrotic syndrome. Pediatr Nephrol 38, 1127–1138 (2023). https://doi.org/10.1007/s00467-022-05637-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-022-05637-8

Keywords

Search

Navigation