Is There a Role for Mammalian Target of Rapamycin Inhibition in Renal Failure due to Mesangioproliferative Nephrotic Syndrome?

Hernán Trimarchi,Pablo Young,Romina Iriarte,Fernando Lombi,Mariano Forrester,Vanesa Pomeranz,María Soledad Raña

doi:10.1155/2012/427060

Hernán Trimarchi, Pablo Young + Show 5 more

Open Access

https://doi.org/10.1155/2012/427060

Copy DOI

Abstract

Primary glomerulonephritis stands as the third most important cause of end-stage renal disease, suggesting that appropriate treatment may not be as effective as intended to be. Moreover, proteinuria, the hallmark of glomerular damage and a prognostic marker of renal damage progression, is frequently resistant to thorough control. In addition, proteinuria may be the common end pathway in which different pathogenetic mechanisms may converge. This explains why immunosuppressive and nonimmunosuppressive approaches are partly not sufficient to halt disease progression. One of the commonest causes of primary glomerulonephritis is mesangioproliferative glomerulonephritis. Among the triggered intracellular pathways involved in mesangial cell proliferation, the mammalian target of rapamycin (mTOR) plays a critical role in cell growth, in turn regulated by many cytokines, disbalanced by the altered glomerulopathy itself. However, when inhibition of mTOR was studied in rodents and in humans with primary glomerulonephritis the results were contradictory. In light of these controversial data, we propose an explanation for these results, to dilucidate under which circumstances mTOR inhibition should be considered to treat glomerular proteinuria and finally to propose mTOR inhibitors to be prospectively assessed in clinical trials in patients with primary mesangioproliferative glomerulonephritis, for which a satisfactory standard immunosuppressive regimen is still pending.

Highlights

The universal and growing impact of chronic diseases is undoubtedly high
Mesangioproliferative glomerulonephritis, mostly IgA nephropathy, is the most frequent primary glomerular disorder worldwide, and progressive mesangioproliferative nephropathy constitutes a major cause of end-stage renal disease [2, 3]
The studies in anti-thy1 acute and chronic renal disease unanimously indicate that unaffected mammalian target of rapamycin (mTOR) signaling is critical for the very early and marked mesangial cell proliferation and subsequent normal glomerular repair of acute anti-thy1 glomerulonephritis [36, 44, 45]

Summary

Introduction

The universal and growing impact of chronic diseases is undoubtedly high. While there has been little attention paid to kidney disease on a public health level, the reality is that many countries hardly bear the costs of providing endstage renal disease care through renal replacement therapy. Platelet-derived growth factor (PDGF) has been recognized as a major mitogen and one of the most important growth factors, which mediates multiple cellular activities such as cell proliferation, hypertrophy, and extracellular matrix protein synthesis in various types of cells including mesangial cells, and plays an important role in the changes in glomerular morphology in diabetic nephropathy [25, 26] and mesangioproliferative glomerulonephritis, mainly IgAN [27] (Figure 1).

Results

Conclusion