CORRESPONDENCE: LETTER TO THE EDITOR
Statins in Patients With Chronic Kidney Disease: A Double-Edged Sword?
Theodoros I. Kassimatis, MD, PhD* and
Panagiotis A. Konstantinopoulos, MD, PhD
* Department of Nephrology, "Evangelismos" General Hospital, Freiderikou Tsentner 11, Athens 10676, Greece (Email: tkassimatis{at}yahoo.gr).
In their recent article, Harper and Jacobson (1) reviewed the management of dyslipidemia in chronic kidney disease (CKD) and discussed the potential renoprotective effects of statins. We would like to quote further data regarding the renoprotective effects of statins, but also refer to existing pre-clinical evidence suggesting potential harmful effects of statins in CKD, a perspective that was largely overlooked by the authors.
A recent meta-analysis in CKD, dialysis, and transplanted patients concluded that statins modestly reduced proteinuria but did not affect the rate of decline of glomerular filtration rate (GFR) (2). Similarly, Douglas et al. (3) reported an antiproteinuric effect of statins, while a contemporary meta-analysis detected a congener effect of statins on proteinuria and a decrease in the rate of GFR reduction by a mean of 1.22 ml/min/year (4). Pravastatin was proven to be beneficial in retarding the decrease in kidney function in a subgroup analysis of the CARE (Cholesterol and Recurrent Events) trial (5), which was consonant with the findings of Fried et al. (6). However, these meta-analyses should be interpreted with caution; most of them mix prospective studies with post-hoc substudies of major randomized trials, in others, data are relatively sparse, and in some of them, the results are heterogeneous between the examined studies.
Importantly, several lines of pre-clinical evidence indicate that statins may favor the development of renal fibrosis and, therefore, might be harmful in the long-term management of patients with CKD. In that regard, it has been recently demonstrated that statins are potential stimulators of transforming growth factor (TGF)-β signaling through decreasing cholesterol levels (7). Cholesterol decreases TGF-β binding to its receptors ALK5 and TβRII, thus effectively suppressing TGF-β signaling. It is now well established that enhanced TGF-β signaling is a key pathogenetic mechanism contributing to the development of renal fibrosis (8,9). The known immunomodulatory effects of statins should also be considered in the management of CKD patients who are known to be relatively immunodeficient. Statins may worsen certain infectious diseases that are not uncommon in CKD or dialysis patients, including human immunodeficiency virus, hepatitis B virus, and hepatitis C virus infections, by increasing regulatory T cells concentration (10).
Given the absence of prospective randomized controlled studies that directly address the role of statins in CKD as well as the limitations of the aforementioned meta-analyses, use of statins as renoprotective medications in CKD should be carefully monitored and always individualized. Physicians should be well aware of the potential harmful effects of statins in CKD, which have been suggested in pre-clinical studies and may emerge when well designed prospective studies directly addressing the role of statins in CKD are completed. These studies, including the PLANET II (Prospective Evaluation of Proteinuria and Renal Function in Non-Diabetic Patients With Progressive Renal Disease) trial (11), the LORD (Lipid lowering and Onset of Renal Disease) trial (12), and the SHARP (Study of Heart And Renal Protection) trial (13), will hopefully elucidate the exact role of statins in CKD and, most importantly, define the subgroups of patients that derive benefit or harm from them.
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1. Harper CR, Jacobson TA. Managing dyslipidemia in chronic kidney disease J Am Coll Cardiol 2008;51:2375-2384.[Abstract/Free Full Text]2. Strippoli GF, Navaneethan SD, Johnson DW, et al. Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials BMJ 2008;336:645-651.[Abstract/Free Full Text] 3. Douglas K, O'Malley PG, Jackson JL. Meta-analysis: the effect of statins on albuminuria Ann Intern Med 2006;145:117-124.[Abstract/Free Full Text] 4. Sandhu S, Wiebe N, Fried LF, Tonelli M. Statins for improving renal outcomes: a meta-analysis J Am Soc Nephrol 2006;17:2006-2016.[Abstract/Free Full Text] 5. 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;14:1605-1613.[Abstract/Free Full Text] 6. Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the progression of renal disease: a meta-analysis Kidney Int 2001;59:260-269.[CrossRef][Web of Science][Medline] 7. 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;215:223-233.[CrossRef][Web of Science][Medline] 8. Bottinger EP, Bitzer M. TGF-beta signaling in renal disease J Am Soc Nephrol 2002;13:2600-2610.[Abstract/Free Full Text] 9. 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;10:908-921.[CrossRef][Web of Science][Medline] 10. Goldstein MR, Mascitelli L, Pezzetta F. The double-edged sword of statin immunomodulation Int J Cardiol 2008In press. 11. 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 2008 ClinicalTrials.gov. Accessed September 18, 2008. 12. 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.[CrossRef][Medline] 13. Baigent C, Landry M. Study of Heart and Renal Protection (SHARP) Kidney Int Suppl 2003;63:S207-S210.[CrossRef]
Related Article
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- Charles F. Harper and Terry A. Jacobson
J. Am. Coll. Cardiol. 2008 52: 1680.
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