Nephron Clinical Practice
Original Paper
Does Treatment with Corticosteroids and Cyclosporine Reduce Transglutaminase Type 2 Expression in the Renal Tissue of Patients with Membranous Nephropathy?Papasotiriou M.a · Kalliakmani P.a · Huang L.b · Gerolymos M.a · Goumenos D.S.a · Johnson T.S.baDepartment of Nephrology and Renal Transplantation, University Hospital of Patras, Patras, Greece; bAcademic Unit of Nephrology, Sheffield Kidney Institute, University of Sheffield, Sheffield, UK
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Article / Publication Details
Received: March 21, 2012
Accepted: June 12, 2012
Published online: October 25, 2012
Issue release date: December 2012
Number of Print Pages: 8
Number of Figures: 4
Number of Tables: 1
eISSN: 1660-2110 (Online)
For additional information: https://www.karger.com/NEC
Abstract
Background/Aims: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Transglutaminase type 2 (TG2) contributes to renal scarring through altering extracellular matrix homeostasis. In this study we hypothesized that immunosuppressive treatment would downregulate TG2 expression leading to reduced fibrosis, and subsequently TG2 would have value as a biomarker of progression of MN. Methods: TG2 expression was studied by immunofluorescence in kidney biopsy sections from 32 patients with MN and was compared to control biopsies. All patients were subsequently treated by a combination of cyclosporine and prednisolone for at least 24 months with a repeat biopsy taken in 14 patients. Results: Twenty-two out of 32 patients showed stable renal function, whereas 10 showed doubling of baseline serum creatinine and 5 of them reached end-stage renal disease during the 5-year follow-up. At the end of the follow-up, 22 out of 32 patients were in remission of nephrotic syndrome. TG2 immunostaining was increased in sections from patients with MN compared to healthy controls (p = 0.0002). TG2 at diagnosis was more intense in patients with severer interstitial fibrosis and advanced glomerular sclerosis. TG2 significantly increased in most patients in the repeat biopsies after treatment (p < 0.0001), whereas patients who showed a marked increase in interstitial fibrosis in the repeat biopsy had significantly more TG2 expression in the first biopsy (p = 0.02). Conclusion: TG2 expression is increased in MN patients and continues to increase despite immunosuppressive treatment. However, early detection of TG2 might be of value in MN since increased TG2 production seems to precede extensive interstitial fibrosis.
© 2012 S. Karger AG, Basel
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References
- Haas M: Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976–1979 and 1995–1997. Am J Kidney Dis 1997;30:621–631.
- Maisonneuve P, Agodoa L, Gellert R, et al: Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe, and Australia/New Zealand: results from an international comparative study. Am J Kidney Dis 2000;35:157–165.
- Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, Klein JB, Salant DJ: M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009;361:11–21.
- Cattran DC: Idiopathic membranous glomerulonephritis. Kidney Int 2001;59:1983–1994.
-
Ponticelli C, Passerini P: Can prognostic factors assist therapeutic decisions in idiopathic membranous nephropathy? J Nephrol 2010;23:156–163.
External Resources
- Nangaku M: Mechanisms of tubulointerstitial injury in the kidney: final common pathways to end-stage renal failure. Intern Med 2004;43:9–17.
-
Shweke N, Boulos N, Jouanneau C, et al: Tissue transglutaminase contributes to interstitial renal fibrosis by favoring accumulation of fibrillar collagen through TGF-beta activation and cell infiltration. Am J Pathol 2008;173:631–642.
External Resources
- Douthwaite JA, Johnson TS, Haylor JL, Watson P, El Nahas AM: Effects of transforming growth factor-beta1 on renal extracellular matrix components and their regulating proteins. J Am Soc Nephrol 1999;10:2109–2119.
- Goumenos DS, Tsamandas AC, Oldroyd S, et al: Transforming growth factor-beta(1) and myofibroblasts: a potential pathway towards renal scarring in human glomerular disease. Nephron 2001;87:240–248.
- Griffin M, Casadio R, Bergamini CM: Transglutaminases: nature’s biological glues. Biochem J 2002;368:377–396.
- Johnson TS, Griffin M, Thomas GL, et al: The role of transglutaminase in the rat subtotal nephrectomy model of renal fibrosis. J Clin Invest 1997;99:2950–2960.
- Johnson TS, El-Koraie AF, Skill NJ, et al: Tissue transglutaminase and the progression of human renal scarring. J Am Soc Nephrol 2003;14:2052–2062.
-
Fisher M, Jones RA, Huang L, et al: Modulation of tissue transglutaminase in tubular epithelial cells alters extracellular matrix levels: a potential mechanism of tissue scarring. Matrix Biol 2009;28:20–31.
External Resources
-
Collighan RJ, Griffin M: Transglutaminase 2 cross-linking of matrix proteins: biological significance and medical applications. Amino Acids 2009;36:659–670.
External Resources
- Nunes I, Gleizes PE, Metz CN, Rifkin DB: Latent transforming growth factor-beta binding protein domains involved in activation and transglutaminase-dependent cross-linking of latent transforming growth factor-beta. J Cell Biol 1997;136:1151–1163.
- Johnson TS, Skill NJ, El Nahas AM, et al: Transglutaminase transcription and antigen translocation in experimental renal scarring. J Am Soc Nephrol 1999;10:2146–2157.
-
Kalliakmani P, Koutroulia E, Sotsiou F, Vlachojannis JG, Goumenos DS: Benefit and cost from the long-term use of cyclosporine-A in idiopathic membranous nephropathy. Nephrology 2010;15:762–767.
External Resources
-
Schwartz MM: Membranous GN. Heptinstall’s Pathology of the Kidney, ed 5. Philadelphia, Lippincott-Raven Publishers, 1998, pp 259–307.
- Huang L, Haylor JL, Hau Z, et al: Transglutaminase inhibition ameliorates experimental diabetic nephropathy. Kidney Int 2009;76:383–394.
- Troyanov S, Roasio L, Pandes M, Herzenberg AM, Cattran DC: Renal pathology in idiopathic membranous nephropathy: a new perspective. Kidney Int 2006;69:1641–1648.
- Shiiki H, Saito T, Nishitani Y, et al: Prognosis and risk factors for idiopathic membranous nephropathy with nephrotic syndrome in Japan. Kidney Int 2004;65:1400–1407.
- Goumenos DS, Katopodis KP, Passadakis P, et al: Corticosteroids and ciclosporin A in idiopathic membranous nephropathy: higher remission rates of nephrotic syndrome and less adverse reactions than after traditional treatment with cytotoxic drugs. Am J Nephrol 2007;27:226–231.
- Cattran DC, Appel GB, Hebert LA, et al, North America Nephrotic Syndrome Study Group: Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial. Kidney Int 2001;59:1484–1490.
-
Cattran DC, Greenwood C, Ritchie S, et al: A controlled trial of cyclosporine in patients with progressive membranous nephropathy. Canadian Glomerulonephritis Study Group. Kidney Int 1995;47:1130–1135.
External Resources
- Goumenos DS, Kalliakmani P, Tsakas S, Sotsiou F, Vlachojannis JG: The remission of nephrotic syndrome with cyclosporin treatment does not attenuate the progression of idiopathic membranous nephropathy. Clin Nephrol 2004;61:17–24.
- Alexopoulos E, Papagianni A, Tsamelashvili M, Leontsini M, Memmos D: Induction and long-term treatment with cyclosporine in membranous nephropathy with the nephrotic syndrome. Nephrol Dial Transplant 2006;21:3127–3132.
- Ambalavanan S, Fauvel JP, Sibley RK, Myers BD: Mechanism of the antiproteinuric effect of cyclosporin in membranous nephropathy. J Am Soc Nephrol 1996;7:290–298.
-
Miyamoto Y, Myomoto A, Sakaguchi Y, Yamaguchi-Yamada M, Uchio-Yamda K, Manabe N: Localization of tissue transglutaminase (tTG) in kidney of ICR-derived glomerulonephritis (ICGN) mice. Exp Anim 2009;58:375–382.
External Resources
- Ikee R, Kobayashi S, Hemmi N, et al: Involvement of transglutaminase-2 in pathological changes in renal disease. Nephron Clin Pract 2007;105:139–146.
- Roberts IS, Burrows C, Shanks JH, Venning M, McWilliam LJ: Interstitial myofibroblasts: predictors of progression in membranous nephropathy. J Clin Pathol 1997;50:123–127.
- Johnson TS, Abo-Zenah H, Skill JN, et al: Tissue transglutaminase: a mediator and predictor of chronic allograft nephropathy? Transplantation 2004;77:1667–1675.
Article / Publication Details
Received: March 21, 2012
Accepted: June 12, 2012
Published online: October 25, 2012
Issue release date: December 2012
Number of Print Pages: 8
Number of Figures: 4
Number of Tables: 1
eISSN: 1660-2110 (Online)
For additional information: https://www.karger.com/NEC
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