4 worldwide [2, 3]. However, clinical studies with sirolimus are scant and showed controversial results with other causes of glomerulonephritis. For example, while some studies reported a rapid decline in renal function with worsening proteinuria in patients with primary focal and segmen- tal glomerulosclerosis [55, 56], others showed beneﬁcial anti-proteinuric eﬀects in this disease [39, 40]. However, with respect to mesangioproliferative glomerulonephritis and low-dose rapamycin, an interesting and provocative manuscript has recently been published. In this clinical study which included 25 subjects (15 on rapamycin), it has been shown that low-dose rapamycin plus angiotensin- converting enzyme inhibition (enalapril 5 mg/day) and sta- tins (atorvastatin 10 mg/day) stabilized renal function and reduced glomerular proliferation in subjects with stage 3 chronic kidney disease measured with 51Cr-EDTA technique due to IgA nephropathy with proteinuria >1 g/day. At 1 year, according to Oxford classiﬁcation rapamycin treatment was associated with a signiﬁcant reduction of mesangial and endocapillary proliferation. Moreover, patients receiving only angiotensin-converting enzyme inhibition and statins lost 8 mL/min/1.73 m2, whereas those under rapamycin improved by 5 mL/min/1.73 m2 (P = 0.03). However, scle- rosis, chronic biopsy lesions, and proteinuria decreased similarly in both study groups [57]. With respect to pro- teinuria, baseline values dropped from 2.9 ± 1.8 to 2.0 ± 0.9 g/day at one year, compared with the respective decrease in the control group from 3.7 ± 1.6 to 2.8 ± 1.4 g/day. The dose of rapamycin employed was 1 mg/day with through levels between 4 and 8 ng/mL, as it is usually used in renal transplantation. Nevertheless, authors consider this rapamycin approach as a low-dose regime, as they compare it with a previous work by Fervenza et al. in which diﬀerent classes of glomerulonephritis with proteinuria >1 g/day and creatinine clearance >20 mL/min were treated with rapamycin 5 mg/day to seek through levels between 7 and 10 ng/mL [23]. However, in this work renal function was measured with Cockcroft-Gault equation, only 5 of the 11 subjects included had IgA nephropathy, 6 developed acute renal failure presumably due to not-adjusted rapamycin levels according to renal function, and no data regarding initial or ﬁnal proteinuria are oﬀered [23]. Therefore, we believe both studies are not comparable, and the human “low-dose” mTORi for mesangioproliferative is still to be determined. Finally, mTORi are not recommended in the trans- planted patient when proteinuria exceeds approximately 800 mg/day. However, proteinuric mechanisms in this setting are not related to mesangial proliferation, which is the main culprit in mesangioproliferative glomerulonephritis. In addition, low dose of everolimus or rapamycin in human is to be determined. We believe that rapamycin and everolimus must not be considered indistinctly as therapeutic alternatives in glomerular diseases. Human doses have not been established, and randomized trials in humans are required before rec- ommendations are made. Whether preferentially early versus late, low-versus-high doses of mTORi eﬀects on proteinuria in mesangioproliferative GNs are due to VEGF reduced International Journal of Nephrology expression, to podocin-nephrin protection, and/or to inter- ventions in the adiponectin-PDGF binomium, among many other possibilities, is a novel, interesting, and a promising ﬁeld of research to assess treatment of acute mesangioprolif- erative glomerulonephritis, for which no speciﬁc immuno- suppressive standardized therapy exists. References [1] United States Renal Data System, Annual Data Report, vol. 1, chapter 1, 2011. [2] J. Floege, “Evidence-based recommendations for immunosup- pression in IgA nephropathy: handle with caution,” Nephrol- ogy Dialysis Transplantation, vol. 18, no. 2, pp. 241–245, 2003. [3] B. A. Julian and J. Novak, “IgA nephropathy: an update,” Current Opinion in Nephrology and Hypertension, vol. 13, no. 2, pp. 171–179, 2004. [4] G. D’Amico, E. Imbasciati, G. Barbiano di Belgiojoso et al., “Idiopathic IgA mesangial nephropathy. Clinico-histologic study in 374 patients,” Medicine, vol. 64, pp. 49–57, 1985. [5] D. Goumenas, M. Ahuja, J. Shortland, and C. Brown, “Can immunosuppressive drugs slow down the progression of IgA nephropathy?” Nephrology Dialysis Transplantation, vol. 10, pp. 1173–1181, 1995. [6] E. Alamartine, J. C. Sabatier, C. Guerin, J. M. Berliet, and F. Berthoux, “Prognostic factors in mesangial IgA glomeru- lonephritis: an extensive study with univariate and multivari- ate analyses,” American Journal of Kidney Diseases, vol. 18, no. 1, pp. 12–19, 1991. [7] O. Bogenschutz, A. Bohle, C. Batz et al., “IgA nephritis: on the importance of morphological and clinical parameters in the long-term prognosis of 239 patients,” American Journal of Nephrology, vol. 10, no. 2, pp. 137–147, 1990. [8] J. S. Cameron, “The long-term outcome of glomerular dis- ease,” in Diseases of the Kidney, R. Schrier and C. Gottschalk, Eds., pp. 1914–1916, Little Brown, Boston, Mass, USA, 5th edition, 1993. [9] R. Glassock, A. Cohen, and S. Adler, “Primary glomerular disease,” in The Kidney, B. Brenner, Ed., pp. 1414–1421, W.B. Saunders, Philadelphia, Pa, USA, 5th edition, 1995. [10] C. Ponticelli and R. Glassock, “Other primary glomerular diseases,” in Primary Glomerular Diseases, C. Ponticelli and R. Glassock, Eds., pp. 453–460, Oxford University Press, Oxford, UK, 2nd edition, 2009. [11] W. A. Border and N. A. Noble, “Transforming growth factor β in tissue ﬁbrosis,” New England Journal of Medicine, vol. 331, no. 19, pp. 1286–1292, 1994. [12] S. Klahr, G. Schreiner, and I. Ichikawa, “The progression of renal disease,” New England Journal of Medicine, vol. 318, no. 25, pp. 1657–1666, 1988. [13] S. Kramer, T. Loof, S. Martini et al., “Mycophenolate mofetil slows progression in anti-thy1-induced chronic renal ﬁbrosis, but is not additive to a high dose of enalapril,” American Journal of Physiology, vol. 289, pp. F359–F368, 2005. [14] G. Remuzzi and T. Bertani, “Pathophysiology of progressive nephropathies,” New England Journal of Medicine, vol. 339, no. 20, pp. 1448–1456, 1998. [15] G. Wolf and E. Ritz, “Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications,” Kidney International, vol. 67, no. 3, pp. 799–812, 2005.