The role of statins in chronic kidney disease: friend or foe?
Dear Editor,
Dr Strippoli and colleagues conducted a meta-analysis to evaluate the
effects of statins in dialysis and transplanted patients as well as in
patients with low glomerular filtration rate (GFR)[1], and concluded that
these drugs modestly reduced proteinuria but did not affect the rate of
decline of GFR. An earlier meta-analysis detected a similar effect of
statins on proteinuria as well as a decrease in the loss of GFR by a mean
of 1.22ml/min/year[2]. Moreover, Douglas and colleagues reported an
antiproteinuric effect of statins[3], while a subgroup analysis of the
Cholesterol and Recurrent Events (CARE) trial showed a beneficial effect
of pravastatin in retarding the decrease in kidney function[4], which was
consonant with the findings of Fried and colleagues[5].
However, these meta-analyses should be interpreted with caution as
most of them mix prospective studies with post-hoc substudies of major
randomized trials, whereas in others, data are relatively sparse, and in
some of them the results are heterogeneous between the examined studies.
Importantly, several lines of preclinical evidence indicate that statins
might be proven harmful in the long-term management of patients with CKD
by favoring the development of renal fibrosis. In that regard, it has been
recently demonstrated that statins are potential stimulators of TGF-â
signaling, through decreasing cholesterol levels[6]. Cholesterol decreases
TGF-â binding to its receptors ALK5 and TâRII, thus effectively
suppressing TGF-â signaling. It is now well established that enhanced TGF-
â signaling is a key pathogenetic mechanism contributing to the
development of renal fibrosis[7, 8]. Intriguingly, other preclinical data
suggest that statins may prevent tubulointerstitial fibrosis in a variety
of progressive renal diseases by inhibiting proliferation of interstitial
fibroblasts and their matrix synthesis[9]. This effect is probably
mediated via inhibition of geranylgeranylated Rho GTPases, whose post-
translational prenylation by the addition of a geranylgeranyl moiety is
critical for their cellular localization and signaling activity[10].
Statins target geranylgeranylated proteins like Rho by depleting the
availability of prenylation substrates[11].
Given the conflicting preclinical data and the limitations of the
aforementioned metanalyses, use of statins as renoprotective medications
in patients with CKD cannot be safely recommended. Well designed
prospective studies including the Prospective Evaluation of Proteinuria
and Renal Function in Non-Diabetic Patients With Progressive Renal Disease
(PLANET II)[12], the Lipid lowering and Onset of Renal Disease (LORD)[13]
and the Study of Heart And Renal Protection (SHARP)[14], will hopefully
elucidate the exact role of statins in CKD.
References
1. Strippoli GF, Navaneethan SD, Johnson DW, Perkovic V, Pellegrini
F, Nicolucci A, et al. Effects of statins in patients with chronic kidney
disease: meta-analysis and meta-regression of randomised controlled
trials. Bmj 2008;336(7645):645-51.
2. Sandhu S, Wiebe N, Fried LF, Tonelli M. Statins for improving
renal outcomes: a meta-analysis. J Am Soc Nephrol 2006;17(7):2006-16.
3. Douglas K, O'Malley PG, Jackson JL. Meta-analysis: the effect of
statins on albuminuria. Ann Intern Med 2006;145(2):117-24.
4. Tonelli M, Moye L, Sacks FM, Cole T, Curhan GC. Effect of
pravastatin on loss of renal function in people with moderate chronic
renal insufficiency and cardiovascular disease. J Am Soc Nephrol
2003;14(6):1605-13.
5. Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the
progression of renal disease: a meta-analysis. Kidney Int 2001;59(1):260-
9.
7. Bottinger EP, Bitzer M. TGF-beta signaling in renal disease. J Am
Soc Nephrol 2002;13(10):2600-10.
8. Kassimatis TI, Giannopoulou I, Koumoundourou D, Theodorakopoulou
E, Varakis I, Nakopoulou L. Immunohistochemical evaluation of
phosphorylated SMAD2/SMAD3 and the co-activator P300 in human
glomerulonephritis: correlation with renal injury. J Cell Mol Med
2006;10(4):908-21.
9. Ikeuchi H, Kuroiwa T, Yamashita S, Hiramatsu N, Maeshima A, Kaneko
Y, et al. Fluvastatin reduces renal fibroblast proliferation and
production of type III collagen: therapeutic implications for
tubulointerstitial fibrosis. Nephron Exp Nephrol 2004;97(4):e115-22.
10. Khwaja A, Sharpe CC, Noor M, Hendry BM. The role of
geranylgeranylated proteins in human mesangial cell proliferation. Kidney
Int 2006;70(7):1296-304.
11. Konstantinopoulos PA, Karamouzis MV, Papavassiliou AG. Post-
translational modifications and regulation of the RAS superfamily of
GTPases as anticancer targets. Nat Rev Drug Discov 2007;6(7):541-55.
12. ClinicalTrials.gov. PLANET II: Prospective Evaluation of
Proteinuria and Renal Function in Non-Diabetic Patients With Progressive
Renal Disease.2008
http://clinicaltrials.gov/ct2/show/NCT00296400?term=planet&rank=1
13. Fassett RG, Ball MJ, Robertson IK, Geraghty DP, Coombes JS. The
Lipid lowering and Onset of Renal Disease (LORD) Trial: a randomized
double blind placebo controlled trial assessing the effect of atorvastatin
on the progression of kidney disease. BMC Nephrol 2008;9:4.
14. Baigent C, Landry M. Study of Heart and Renal Protection (SHARP).
Kidney Int Suppl 2003(84):S207-10.
Competing interests:
None declared
Competing interests:
No competing interests
12 May 2008
Theodoros I Kassimatis
Nephrology fellow
Panagiotis A. Konstantinopoulos (Beth Israel Deaconess Medical Center, Harvard Medical School), Lydia Nakopoulou (Professor of Pathology, Athens Medical School)
Nephrology Department, Evangelismos General Hospital, Athens 10676, Greece
Rapid Response:
The role of statins in chronic kidney disease: friend or foe?
Dear Editor, Dr Strippoli and colleagues conducted a meta-analysis to evaluate the effects of statins in dialysis and transplanted patients as well as in patients with low glomerular filtration rate (GFR)[1], and concluded that these drugs modestly reduced proteinuria but did not affect the rate of decline of GFR. An earlier meta-analysis detected a similar effect of statins on proteinuria as well as a decrease in the loss of GFR by a mean of 1.22ml/min/year[2]. Moreover, Douglas and colleagues reported an antiproteinuric effect of statins[3], while a subgroup analysis of the Cholesterol and Recurrent Events (CARE) trial showed a beneficial effect of pravastatin in retarding the decrease in kidney function[4], which was consonant with the findings of Fried and colleagues[5].
However, these meta-analyses should be interpreted with caution as most of them mix prospective studies with post-hoc substudies of major randomized trials, whereas in others, data are relatively sparse, and in some of them the results are heterogeneous between the examined studies. Importantly, several lines of preclinical evidence indicate that statins might be proven harmful in the long-term management of patients with CKD by favoring the development of renal fibrosis. In that regard, it has been recently demonstrated that statins are potential stimulators of TGF-â signaling, through decreasing cholesterol levels[6]. Cholesterol decreases TGF-â binding to its receptors ALK5 and TâRII, thus effectively suppressing TGF-â signaling. It is now well established that enhanced TGF- â signaling is a key pathogenetic mechanism contributing to the development of renal fibrosis[7, 8]. Intriguingly, other preclinical data suggest that statins may prevent tubulointerstitial fibrosis in a variety of progressive renal diseases by inhibiting proliferation of interstitial fibroblasts and their matrix synthesis[9]. This effect is probably mediated via inhibition of geranylgeranylated Rho GTPases, whose post- translational prenylation by the addition of a geranylgeranyl moiety is critical for their cellular localization and signaling activity[10]. Statins target geranylgeranylated proteins like Rho by depleting the availability of prenylation substrates[11].
Given the conflicting preclinical data and the limitations of the aforementioned metanalyses, use of statins as renoprotective medications in patients with CKD cannot be safely recommended. Well designed prospective studies including the Prospective Evaluation of Proteinuria and Renal Function in Non-Diabetic Patients With Progressive Renal Disease (PLANET II)[12], the Lipid lowering and Onset of Renal Disease (LORD)[13] and the Study of Heart And Renal Protection (SHARP)[14], will hopefully elucidate the exact role of statins in CKD.
References
1. Strippoli GF, Navaneethan SD, Johnson DW, Perkovic V, Pellegrini F, Nicolucci A, et al. Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials. Bmj 2008;336(7645):645-51.
2. Sandhu S, Wiebe N, Fried LF, Tonelli M. Statins for improving renal outcomes: a meta-analysis. J Am Soc Nephrol 2006;17(7):2006-16.
3. Douglas K, O'Malley PG, Jackson JL. Meta-analysis: the effect of statins on albuminuria. Ann Intern Med 2006;145(2):117-24.
4. Tonelli M, Moye L, Sacks FM, Cole T, Curhan GC. Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J Am Soc Nephrol 2003;14(6):1605-13.
5. Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int 2001;59(1):260- 9.
6. Chen CL, Huang SS, Huang JS. Cholesterol modulates cellular TGF- beta responsiveness by altering TGF-beta binding to TGF-beta receptors. J Cell Physiol 2008;215(1):223-33.
7. Bottinger EP, Bitzer M. TGF-beta signaling in renal disease. J Am Soc Nephrol 2002;13(10):2600-10.
8. Kassimatis TI, Giannopoulou I, Koumoundourou D, Theodorakopoulou E, Varakis I, Nakopoulou L. Immunohistochemical evaluation of phosphorylated SMAD2/SMAD3 and the co-activator P300 in human glomerulonephritis: correlation with renal injury. J Cell Mol Med 2006;10(4):908-21.
9. Ikeuchi H, Kuroiwa T, Yamashita S, Hiramatsu N, Maeshima A, Kaneko Y, et al. Fluvastatin reduces renal fibroblast proliferation and production of type III collagen: therapeutic implications for tubulointerstitial fibrosis. Nephron Exp Nephrol 2004;97(4):e115-22.
10. Khwaja A, Sharpe CC, Noor M, Hendry BM. The role of geranylgeranylated proteins in human mesangial cell proliferation. Kidney Int 2006;70(7):1296-304.
11. Konstantinopoulos PA, Karamouzis MV, Papavassiliou AG. Post- translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets. Nat Rev Drug Discov 2007;6(7):541-55.
12. ClinicalTrials.gov. PLANET II: Prospective Evaluation of Proteinuria and Renal Function in Non-Diabetic Patients With Progressive Renal Disease.2008 http://clinicaltrials.gov/ct2/show/NCT00296400?term=planet&rank=1
13. Fassett RG, Ball MJ, Robertson IK, Geraghty DP, Coombes JS. The Lipid lowering and Onset of Renal Disease (LORD) Trial: a randomized double blind placebo controlled trial assessing the effect of atorvastatin on the progression of kidney disease. BMC Nephrol 2008;9:4.
14. Baigent C, Landry M. Study of Heart and Renal Protection (SHARP). Kidney Int Suppl 2003(84):S207-10.
Competing interests: None declared
Competing interests: No competing interests