Skip to main content
SpringerLink
Log in

Beneficial effect of triple treatment plus immunoglobulin in experimental nephrotic syndrome

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

Abstract

Combinations of antiproteinurics, including angiotensin I-converting enzyme inhibitors + angiotensin II receptor antagonist + statins, are promising choices in the treatment of steroid-resistant nephrotic syndrome. We aimed to investigate the effects of high doses of immunoglobulin in addition to these combinations in rats with adriamycin-induced nephrosis. The study included 40 rats allocated into five groups: control, nephrotic syndrome without treatment, dual therapy (DT) with enalapril + losartan, triple therapy (TT) with enalapril + losartan + simvastatin, and quadruple therapy (QT) with enalapril + losartan + simvastatin + a high dose of immunoglobulin. The proteinuria levels were not statistically different between DT, TT and QT groups at weeks 5, 8, 12 and 16. At week 16, serum creatinine levels in the QT group were significantly lower than those in the control, DT and TT groups. The glomerulosclerosis index in the DT group was significantly lower than in the TT and QT groups. The scores for interstitial fibrosis and TGF-β staining were similar among treatment groups. In conclusion, we showed that quadruple therapy including immunoglobulin had a beneficial effect on renal function in the late phase, but it had no additional effects in reducing proteinuria or in glomerulosclerosis score in experimental nephrotic syndrome. Further studies with angiotensin I-converting enzyme inhibitors (ACEIs), angiotensin II receptor antagonists (AIIRAs) and immunoglobulin combinations would offer some benefits in the treatment of nephrotic syndrome.

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

Similar content being viewed by others

References

  1. Grond J, Weening JJ, Elema JD (1984) Glomerular sclerosis in nephrotic rats. Comparison of the long-term effects of adriamycin and aminonucleoside. Lab Invest 51:277–285

    CAS  PubMed  Google Scholar 

  2. Sakemi T, Ohtsuka N, Tomiyoshi Y, Morito F (1996) Sex difference in progression of adriamycin-induced nephropathy in rats. Am J Nephrol 16:540–547

    CAS  PubMed  Google Scholar 

  3. Okasora T, Takikawa T, Utsunomiya Y, Senoh I, Hayashibara H, Shiraki K, Kasagi T, Shimizu F (1992) Suppressive effect of superoxide dismutase on adriamycin nephropathy. Nephron 60:199–203

    CAS  PubMed  Google Scholar 

  4. Van den Branden C, Ceyssens B, De Craemer D, Pauwels M, Vanden Houte K, De Bleser P, Hellemans K, Geerts A, Verbeelen D (2000) Renal antioxidant enzymes and fibrosis-related markers in the rat adriamycin model. Nephron 86:167–175

    PubMed  Google Scholar 

  5. Ozen S, Usta Y, Sahin-Erdemli I, Orhan D, Gumusel B, Yang B, Gursoy Y, Tulunay O, Dalkara T, Bakkaloglu A, El-Nahas M (2001) Association of nitric oxide production and apoptosis in a model of experimental nephropathy. Nephrol Dial Transplant 16:32–38

    CAS  PubMed  Google Scholar 

  6. Bricio T, Molina A, Mampaso F (1992) Effect of anti-interleukin-1 administration to rats with adriamycin-induced nephrosis. APMIS 100:401–407

    CAS  PubMed  Google Scholar 

  7. Abbate M, Zoja C, Rottoli D, Corna D, Perico N, Bertani T, Remuzzi G (1999) Antiproteinuric therapy while preventing the abnormal protein traffic in proximal tubule abrogates protein and complement-dependent interstitial inflammation in experimental renal disease. J Am Soc Nephrol 10:804–813

    CAS  PubMed  Google Scholar 

  8. Zoja C, Donadelli R, Corna D, Testa D, Facchinetti D, Maffi R, Luzzana E, Colosio V, Bertani T, Remuzzi G (1997) The renoprotective properties of angiotensin-converting enzyme inhibitors in a chronic model of membranous nephropathy are solely due to the inhibition of angiotensin II: evidence based on comparative studies with a receptor antagonist. Am J Kidney Dis 29:254–264

    CAS  PubMed  Google Scholar 

  9. Perico N, Amuchastegui SC, Colosio V, Sonzogni G, Bertani T, Remuzzi G (1994) Evidence that an angiotensin-converting enzyme inhibitor has a different effect on glomerular injury according to the different phase of the disease at which the treatment is started. J Am Soc Nephrol 5:1139–1146

    CAS  PubMed  Google Scholar 

  10. Taal MW, Brenner BM (2000) Renoprotective benefits of RAS inhibition: from ACEI to angiotensin II antagonists. Kidney Int 57:1803–1817

    CAS  PubMed  Google Scholar 

  11. Kim SI, Kim HJ, Han DC, Lee HB (2000) Effect of lovastatin on small GTP binding proteins and on TGF-b1 and fibronectin expression. Kidney Int 58:S88–S92

    Google Scholar 

  12. Hundt M, Manger K, Dorner T, Grimbacher B, Kalden P, Rascu A, Weber D, Burmester GR, Peter HH, Kladen JR, Schmidt RE (2000) Treatment of acute exacerbation of systemic lupus erythematosus with high-dose intravenous immunoglobulin. Rheumatology 39:1301–1302

    CAS  PubMed  Google Scholar 

  13. Yokoyama H, Goshima S, Wada T, Takaeda M, Furuichi K, Kobayashi K, Kida H (1999) The short- and long-term outcomes of membranous nephropathy treated with intravenous immune globulin therapy. Kanazawa study group for renal diseases and hypertension. Nephrol Dial Transplant 14:2379–2386

    CAS  PubMed  Google Scholar 

  14. Rostoker G, Desvaux-Belghiti D, Pilatte Y, Petit-Phar M, Philippon C, Deforges L, Terzidis H, Intrator L, André C, Adnot S, Bonin P, Bierling P, Rémy P, Lagrue G, Lang P, Weil B (1994) High-dose immunoglobulin therapy for severe IgA nephropathy and Henoch-Schönlein purpura. Ann Intern Med 120:476–484

    CAS  PubMed  Google Scholar 

  15. Jungi TW, Brcic M, Kuhnert P, Spycher MO, Li F, Nydegger UE (1990) Effect of IgG for intravenous use on Fc receptor-mediated phagocytosis by human monocytes. Clin Exp Immunol 82:163–169

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Abe Y, Horiuchi A, Miyake M, Kimura S (1994) Anti-cytokine nature of natural human immunoglobulin: one possible mechanism of the clinical effect of intravenous immunoglobulin therapy. Immunol Rev 139:5–19

    CAS  PubMed  Google Scholar 

  17. Andersson UG, Bjork L, Skansén-Saphir U, Andersson JP (1993) Down-regulation of cytokine production and interleukin-2 receptor expression by pooled human IgG. Immunology 79:211–216

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Basta M, Fries LF, Frank MM (1991) High doses of intravenous Ig inhibit in vitro uptake of C4 fragments onto sensitized erythrocytes. Blood 77:376–380

    CAS  PubMed  Google Scholar 

  19. Dietrich G, Kaveri SV, Kazatchkine MD (1992) Modulation of autoimmunity by intravenous immune globulin through interaction with the function of the immune/idiotypic network. Clin Immunol Immunopathol 62:S73–S81

    CAS  PubMed  Google Scholar 

  20. Blanchette VS, Kirby MA, Turner C (1992) Role of intravenous immunoglobulin G in autoimmune hematologic disorders. Semin Hematol 29:72–82

    CAS  PubMed  Google Scholar 

  21. Toungouz M, Denys CH, De Groote D, Dupont E (1995) In vitro inhibition of tumour necrosis factor-alpha and interleukin-6 production by intravenous immunoglobulins. Br J Haematol 89:698–703

    CAS  PubMed  Google Scholar 

  22. Shalhoub RJ (1974) Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 2:556–560

    CAS  PubMed  Google Scholar 

  23. Yap HK, Cheung W, Murugasu B, Sim SK, Seah CC, Jordan SC (1999) Th1 and Th2 cytokine mRNA profiles in childhood nephrotic syndrome: evidence for increased IL-13 mRNA expression in relapse. J Am Soc Nephrol 10:529–537

    CAS  PubMed  Google Scholar 

  24. Stefanoviç V, Goluboviç E, Mitic-Zlatkovic M, Vlahovic P, Jovanovic O, Bogdanovic R (1998) Interleukin-12 and interferon-gamma production in childhood idiopathic nephrotic syndrome. Pediatr Nephrol 12:463–466

    PubMed  Google Scholar 

  25. Sahali D, Pawlak A, Le Gouvello S, Lang P, Valanciute A, Remy P, Loirat C, Niaudet P, Bensman A, Guellaen G (2001) Transcriptional and post-transcriptional alterations of IκBα in active minimal-change nephrotic syndrome. J Am Soc Nephrol 12:1648–1658

    CAS  PubMed  Google Scholar 

  26. Cao C, Lu S, Dong C, Zhao R (2001) Abnormal DNA-binding of transcription factors in minimal-change nephrotic syndrome. Pediatr Nephrol 16:790–795

    CAS  PubMed  Google Scholar 

  27. Erisir S, Akbas H, Koyun M, Akman S (2006) The efficiency of intraperitoneal high-dose immunoglobulin in experimental nephrotic syndrome. Pediatr Nephrol 21:39–45

    PubMed  Google Scholar 

  28. Okuda S, Oh Y, Tsuruda H, Onoyama K, Fujimi S, Fujishima M (1986) Adriamycin-induced nephropathy as a model of chronic progressive glomerular disease. Kidney Int 29:502–510

    CAS  PubMed  Google Scholar 

  29. Diamond JR, Anderson S (1990) Irreversible tubulointerstitial damage associated with chronic aminonucleoside nephrosis. Amelioration by angiotensin I converting enzyme inhibition. Am J Pathol 137:1323–1332

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Attia DM, Feron O, Goldschmeding R, Radermakers LH, Vaziri ND, Boer P, Balligand JL, Koomans HA, Joles JA (2004) Hypercholesterolemia in rats induces podocyte stress and decreases renal cortical nitric oxide synthesis via an angiotensin II type 1 receptor-sensitive mechanism. J Am Soc Nephrol 15:949–957

    CAS  PubMed  Google Scholar 

  31. Zoja C, Corna D, Rottoli D, Cattaneo D, Zanchi C, Tomasoni S, Abbate M, Remuzzi G (2002) Effect of combining ACE inhibitor and statin in severe experimental nephropathy. Kidney Int 61:1635–1645

    CAS  PubMed  Google Scholar 

  32. Raij L, Azar S, Keane W (1984) Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. Kidney Int 26:137–143

    CAS  PubMed  Google Scholar 

  33. Zoja C, Benigni A, Camozzi D, Corna D, Longaretti L, Todeschini M, Remuzzi G (2003) Combining lisinopril and l-arginine slows disease progression and reduces endothelin-1 in passive Heymann nephritis. Kidney Int 64:857–863

    CAS  PubMed  Google Scholar 

  34. Coa Z, Cooper ME, Wu LL, Cox AJ, Jandeleit-Dahm K, Kelly DJ, Gilbert RE (2000) Blockade of the renin-angiotensin and endothelin systems on progressive renal injury. Hypertension 36:561–568

    Google Scholar 

  35. Wilkinson-Berka JL, Gibbs NJ, Cooper ME, Skinner SL, Kelly DJ (2001) Renoprotective and anti-hypertensive effects of combined valsartan and perindopril in progressive diabetic nephropathy in the transgenic (mRen-2)27 rat. Nephrol Dial Transplant 16:1343–1349

    CAS  PubMed  Google Scholar 

  36. Bos H, Henning RH, De Boer E, Tiebosch AT, De Jong PE, De Zeeuw D, Navis G (2002) Addition of AT1 blocker fails to overcome resistance to ACE inhibition in adriamycin nephrosis. Kidney Int 61:473–480

    CAS  PubMed  Google Scholar 

  37. Zoja C, Corna D, Camozzi D, Cattaneo D, Rottoli D, Batani C, Zanchi C, Abbate M, Remuzzi G (2002) How to fully protect the kidney in a severe model of progressive nephropathy: a multidrug approach. J Am Soc Nephrol 13:2898–2908

    CAS  PubMed  Google Scholar 

  38. Branton MH, Kopp JB (1999) TGF-b and fibrosis. Microbes Infect 1:1349–1365

    CAS  PubMed  Google Scholar 

  39. Khalil A, Tullus K, Bakhiet M, Burman LG, Jaremko G, Brauner A (2000) Angiotensin II type 1 receptor antagonist (losartan) down-regulates transforming growth factor-beta in experimental acute pyelonephritis. J Urol 164:186–191

    CAS  PubMed  Google Scholar 

  40. Goumenos DS, Tsamandas AC, Oldroyd S, Sotsiou F, Tsakas S, Petropoulou C, Bonikos D, El Nahas AM, Vlachojannis JG (2001) Transforming growth factor-b1 in kidney and urine of patients with glomerular disease and proteinuria. Nephron 87:240–248

    CAS  PubMed  Google Scholar 

  41. Taniguchi Y, Yorioka N, Masaki T, Yamashita K, Ito T, Ueda H, Yamakido M (2000) Role of transforming growth factor beta 1 in glomerulonephritis. J Int Med Res 25:71–80

    Google Scholar 

  42. Wasilewska AM, Zoch-Zwierz WM (2004) Transforming growth factor-β1 in nephrotic syndrome treated with cyclosporine and ACE inhibitors. Pediatr Nephrol 19:1349–1353

    PubMed  Google Scholar 

  43. Zhang W, Li Q, Wang L, Yang X (2008) Simvastatin ameliorates glomerulosclerosis in Adriamycin-induced-nephropathy rats. Pediatr Nephrol 23:2185–2194

    PubMed  PubMed Central  Google Scholar 

  44. Adamczak M, Gross ML, Amnn K, Ritz E (2004) Reversal of glomerular lesions involves coordinated restructuring of glomerular microvasculature. J Am Soc Nephrol 15:3063–3072

    PubMed  Google Scholar 

  45. Ma J, Nishimura H, Fogo A, Kon V, Inagami T, Ichikawa I (1998) Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction. Kidney Int 53:937–944

    CAS  PubMed  Google Scholar 

  46. Benchetrit S, Golan E, Podjarny E, Green J, Rashid G, Bernheim J, Hershkovitz R, Bernheim J (2001) Low molecular weight heparin reduces proteinuria and modulates glomerular TNF alpha production in the early phase of adriamycin nephropathy. Nephron 87:155–160

    CAS  PubMed  Google Scholar 

  47. Zima T, Tesar V, Stipek S, Crkovska J, Poledne R, Teminova J, Platenik J, Rychlik I, Merta M, Nemecek K (1997) The influence of cyclosporine on lipid peroxidation and superoxide dismutase in adriamycin nephropathy in rats. Nephron 75:464–468

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by a grant from the Turkish Society of Nephrology and the Scientific Research Fund of Akdeniz University.

Author information

Authors and Affiliations

  1. Department of Pediatric Nephrology, School of Medicine, Akdeniz University, 07070, Antalya, Turkey

    Sema Akman, Mustafa Koyun, Yunus Emre Baysal & Ayfer Gur Guven

  2. Department of Pediatrics, School of Medicine, Akdeniz University, 07070, Antalya, Turkey

    Salih Kalay

  3. Department of Pathology, School of Medicine, Akdeniz University, 07070, Antalya, Turkey

    Bahar Akkaya

  4. Department of Biochemistry, School of Medicine, Akdeniz University, 07070, Antalya, Turkey

    Halide Akbaş

Authors
  1. Sema Akman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Salih Kalay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bahar Akkaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mustafa Koyun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Halide Akbaş
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yunus Emre Baysal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ayfer Gur Guven
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sema Akman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Akman, S., Kalay, S., Akkaya, B. et al. Beneficial effect of triple treatment plus immunoglobulin in experimental nephrotic syndrome. Pediatr Nephrol 24, 1173–1180 (2009). https://doi.org/10.1007/s00467-009-1117-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-009-1117-x

Keywords

Search

Navigation