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Cholesterol, blood viscosity, chronic kidney disease and statins.
- Les O. Simpson (7 March 2008)
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Cardiovascular disease in patients on renal replacement therapy
- Kaushik Guha (25 March 2008)
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The role of statins in chronic kidney disease: friend or foe?
- Theodoros I Kassimatis, Panagiotis A. Konstantinopoulos (Beth Israel Deaconess Medical Center, Harvard Medical School), Lydia Nakopoulou (Professor of Pathology, Athens Medical School) (12 May 2008)
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Les O. Simpson, retired medical research worker Dunedin, New Zealand, 9077
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A rather surprising feature of the meta-analysis of the effects of statins in patients with chronic renal disease by Strippoli et al (1) is the failure to mention or to recognise the considerable literature which shows that the major pathogenic feature of hypercholesterolemia is that it contributes to blood viscosity. In addition, there are many reports which note that when serum levels of cholesterol are elevated, the cholesterol content of the red blood cell membrane is increased, with the result that the cell becomes poorly deformable. Although statins reduce the blood levels of cholesterol, they may not influence other blood viscosity factors, and for that reason statin therapy may have little impact on the kidney dysfunction associated with increased blood viscosity. Therefore it is not surprising that Strippoli et al should note that the reno-protective effects of statins are uncertain. The effect of blood viscosity on kidney function was a topic for debate more than 25 years ago. There is general acceptance that polycythemia is accompanied by raised blood viscosity. In 1981 we found that the proteinuria of a patient with polycythemia fell by 90% when venesection lowered his haematocrit from 61% to 45%. That observation was consistent with the hypothesis that increased blood viscosity was a cause of proteinuria.(2) Basically, it was proposed that hyperviscous blood in the afferent glomerular arteriole would influence glomerular filtration so that the filtrate could be abnormal in both volume and content. But more importantly, the haemoconcentrating effect of glomerular filtration would render the blood in the efferent arteriole hyperviscous, and impair blood flow in the peritubular plexus with consequent impairment of tubular function. In 1983 (3) we described the development of hyperproteinemic proteinuria in mice which were injected i.p. daily with 1ml of saline containing 250mg of human serum albumin. At 24 hours the mice were excreting albumin plus a 170,000 dalton protein and at 72 hours this was joined by a 225,000 protein. By the third day after the last i.p. injection, only albumin was present in the urine and it vanished on the fourth day. Others have commented on the association of blood viscosity and kidney dysfunction. McGinley et al(4) concluded that, " We suggest that increased blood viscosity and plasma viscosity may play a role in the vascular complications of the nephrotic syndrome." The interactions of central obesity with hyperviscosity and microproteinuria have been reported (5) and a study of the renal complications of cyanotic heart disease concluded, " This observation supports the hypothesis that impaired peritubular blood flow with increased intraglomerular blood pressure may add to chronic glomerular dysfunction."(6) Maybe there would be a better outcome if instead of using statins, fish oil or pentoxifylline was used to reduce blood viscosity in patients with chronic renal disease. References. 1. Strippoli GFM,et al. Efects of statins in patients with chronic kidney disease:meta-analysis of randomised controlled trials. BMJ.doi.10.1136/bmj.39472.580984 AE. 2. Simpson LO. A hypothesis proposing increased blood viscosity as a cause of proteinuria and increased glomerular permability. Nephron 1982;31:89-93. 3. Simpson LO, Shand BI. The implications of the changes in the nature of the urinary proteins whch occur in albumin overload-induced proteinuria in normal mice. Br J Exp Pathol 1983;64:6-14. 4. McGinley E, Lowe GD, Boulton-Jones M. et al. Blood viscosity and haemostasis in the nephrotic syndrome. Thromb Haemost 1983;49:155-7. 5. Solerte SB, Fioravanti M, Pezza N, et al. Hyperviscosity and microproteinuria in central obesity:relevance to cardiovascular risk. Int J Obes Relat Metab Disord 1997;21:417-23. 6. Dittrich S, Kurschat K, Lange PE. Abnormal rheology in cyanotic congenital heart disease - a factor in non-immune nephropathy. Scand J Urol Nephrol 2001;35:411-5. Competing interests: None declared |
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Kaushik Guha, ST2 Cardiology Royal Brompton Hospital, Royal Brompton & Harefield NHS Trust, Sydney Street, London, SW3 6NP
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Dear Editor, Strippoli et al have conducted a thought-provoking meta analysis. (1) The authors have focused all potential aspects of statin usage within populations with renal disease. The conclusions derived though, from the cardiovascular disease perspective are contentious. The cardiovascular mortality in patients on renal replacement therapy and should not be underestimated. Over fifty percent of deaths within patients on renal replacement therapy (RRT) and transplant recipients are attributable to cardiovascular disease. (2,3) As alluded to, in the accompanying editorial, cardiovascular risk factors in this population do not only comprise traditional pro-atherogenic risk factors but others such as anaemia, hyperparathyroidism (with subsequent calcification of the vascular tree), oxidative stress and a generalised pro-inflammatory response. Due to this immense disease burden within these populations, one would want to control all of these risk factors, to reduce the propensity of cardiovascular disease. The management of these allied risk factors is continuously improving and being revised. E.g the management of renal anaemia and the usage of erythropoietin stimulating agents. The studies incorporated into the meta analysis include studies from 1997-2005 for patients on RRT and 1996-2005 for renal transplant patients. The care offered to these patients would differ widely and there is no mention of their control of confounding variables such as the target haemoglobin within the RRT population. It is questionable, whether there would have been aggressive management of the confounding variables within the earlier studies. The impact of renal disease on the circulation can be divided into both macro and micro vascular disease with a putative target of endothelial dysfunction. (4) Statins are recognized to have both anti-lipid and anti-inflammatory actions.(5) This raises the possibility that statins, especially within this population exert their beneficial effect in an as yet unmeasurable manner. In terms of patients with Stage I to III chronic kidney disease, cardiovascular risk profiling is of use. However one should bear in mind the potential aetiologies of chronic kidney disease. Within the Western populations, the three main causes consist of hypertension, diabetes mellitus and renovascular disease. These are all pro-atherogenic and therefore should be aggressively treated to retard progression to stage IV disease. Though this is the current position, we eagerly await the provisional and confirmed findings of the SHARP trial. 1. Strippoli GF, Navaneethan SD, Johnson DW, Perkovic V, Pelligrini F, Nicolucci A & Craig JC. BMJ; 2008;336;645-650. 2. Foley RN, Parfrey PS, Sarnak MJ. Clinical Epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis;1998;32(5) Suppl 3:S112 -119. 3. Wheeler DC & Steiger J. Evolution & aetiology of cardiovascular diseases in renal transplant recipients. Transplantation;2000;70(11):SS41-SS45. 4. Luke RG. Chronic renal failure- a vasculopathic state. New Eng J Med; 1998;339(12):841-843. 5. Sotiriou CG & Cheng JW. Beneficial effects of statins in coronary artery disease- beyond lowering cholesterol. Ann Pharmacother;2000;34:1432-9. Competing interests: None declared |
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Theodoros I Kassimatis, Nephrology fellow Nephrology Department, Evangelismos General Hospital, Athens 10676, Greece, Panagiotis A. Konstantinopoulos (Beth Israel Deaconess Medical Center, Harvard Medical School), Lydia Nakopoulou (Professor of Pathology, Athens Medical School)
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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 |
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