Abstract
Inflammation is highly prevalent in patients with chronic kidney disease (CKD) and is consistently associated with cardiovascular morbidity and mortality. Clinical event rates increase with declining renal function and activation of the acute-phase response. Statins are potent anti-inflammatory drugs that reduce the incidence of cardiovascular events. Owing to the increased prevalence of inflammation in patients with CKD and the potent effect of statins in individuals with elevated levels of C-reactive protein, these drugs should be especially effective in patients with CKD. Whereas data indicate that pravastatin may prevent loss of kidney function to a greater extent in individuals with evidence of increased inflammation than in those who show no inflammation, two large, randomized statin trials in patients on hemodialysis found no benefit of statin therapy, neither in the whole study group nor after stratifying for inflammation. Irrespective of inflammation, guidelines recommend treatment of dyslipidemia in early stages of CKD, which is supported by results from recent meta-analyses, and the Study of Heart and Renal Protection (SHARP), a large, randomized, placebo-controlled trial.
Key Points
-
Levels of C-reactive protein (CRP) increase with failing kidney function and are higher in patients on dialysis than in patients with coronary heart disease or healthy individuals
-
High CRP levels in patients on dialysis reflect underlying comorbidities and are the result of a chronic acute-phase response in various organ systems of the body
-
CRP levels are a predictor of all-cause mortality and cardiovascular events in patients with chronic kidney disease (CKD); however, data regarding CRP and loss of kidney function are not unequivocal
-
Statins have potent anti-inflammatory effects in patients with CKD, with individual statins having different effects on proteinuria and the loss of kidney function
-
At present, no data support an especially beneficial effect of statins in patients on hemodialysis who show evidence of inflammation
-
The primary outcome of SHARP (major atherosclerotic events) was reduced in patients with CKD stages 3–5 who were treated with simvastatin and ezetimibe, supporting guideline recommendations on management of hyperlipidemia in these patients
Similar content being viewed by others
References
Ross, R. Atherosclerosis—an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).
Kaptoge, S. et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 375, 132–140 (2010).
Ridker, P. M. et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N. Engl. J. Med. 359, 2195–2207 (2008).
Abedini, S. et al. Inflammation in renal transplantation. Clin. J. Am. Soc. Nephrol. 4, 1246–1254 (2009).
Fellström, B. C. et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N. Engl. J. Med. 360, 1395–1407 (2009).
Hung, A. M. et al. CRP polymorphisms and progression of chronic kidney disease in African Americans. Clin. J. Am. Soc. Nephrol. 5, 24–33 (2010).
Iseki, K., Tozawa, M., Yoshi, S. & Fukiyama, K. Serum C-reactive protein (CRP) and risk of death in chronic dialysis patients. Nephrol. Dial. Transplant. 14, 1956–1960 (1999).
Krane, V. et al. Effect of atorvastatin on inflammation and outcome in patients with type 2 diabetes mellitus on hemodialysis. Kidney Int. 74, 1461–1467 (2008).
Yeun, J. Y., Levine, R. A., Mantadilok, V. & Kaysen, G. A. C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients. Am. J. Kidney Dis. 35, 469–476 (2000).
Zimmermann, J., Herrlinger, S., Pruy, A., Metzger, T. & Wanner, C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int. 55, 648–658 (1999).
Go, A. S., Chertow, G. M., Fan, D., McCulloch, C. E. & Hsu, C. Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med. 351, 1296–1305 (2004).
Stel, V. S., Kramer, A., Zoccali, C. & Jager, K. J. The 2007 ERA-EDTA Registry Annual Report—a Précis. NDT Plus 2, 514–521 (2009).
Foley, R. N., Parfrey, P. S. & Sarnak, M. J. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am. J. Kidney Dis. 32, S112–S119 (1998).
K/DOQI Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am. J. Kidney Dis. 45, S1–S153 (2005).
Barany, P. Inflammation, serum C-reactive protein, and erythropoietin resistance. Nephrol. Dial. Transplant. 16, 224–227 (2001).
Gupta, R. et al. Statin use and sepsis events [corrected] in patients with chronic kidney disease. JAMA 297, 1455–1464 (2007).
Shlipak, M. G. et al. Cystatin-C and inflammatory markers in the ambulatory elderly. Am. J. Med. 118, 1416 (2005).
Tonelli, M., Sacks, F., Pfeffer, M., Jhangri, G. S. & Curhan, G. Biomarkers of inflammation and progression of chronic kidney disease. Kidney Int. 68, 237–245 (2005).
Sarnak, M. J. et al. Serum C-reactive protein and leptin as predictors of kidney disease progression in the Modification of Diet in Renal Disease Study. Kidney Int. 62, 2208–2215 (2002).
Landray, M. J. et al. Inflammation, endothelial dysfunction, and platelet activation in patients with chronic kidney disease: the chronic renal impairment in Birmingham (CRIB) study. Am. J. Kidney Dis. 43, 244–253 (2004).
Stenvinkel, P. et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int. 55, 1899–1911 (1999).
Ducloux, D., Bresson-Vautrin, C., Kribs, M., Abdelfatah, A. & Chalopin, J. M. C-reactive protein and cardiovascular disease in peritoneal dialysis patients. Kidney Int. 62, 1417–1422 (2002).
Nascimento, M. M., Pecoits-Filho, R., Lindholm, B., Riella, M. C. & Stenvinkel, P. Inflammation, malnutrition and atherosclerosis in end-stage renal disease: a global perspective. Blood Purif. 20, 454–458 (2002).
Pearson, T. A. et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 107, 499–511 (2003).
Sela, S. et al. Primed peripheral polymorphonuclear leukocyte: a culprit underlying chronic low-grade inflammation and systemic oxidative stress in chronic kidney disease. J. Am. Soc. Nephrol. 16, 2431–2438 (2005).
Zoccali, C., Mallamaci, F. & Tripepi, G. Inflammation and atherosclerosis in end-stage renal disease. Blood Purif. 21, 29–36 (2003).
Liu, Y. et al. IL-6 haplotypes, inflammation, and risk for cardiovascular disease in a multiethnic dialysis cohort. J. Am. Soc. Nephrol. 17, 863–870 (2006).
Zoccali, C., Tripepi, G. & Mallamaci, F. Dissecting inflammation in ESRD: do cytokines and C-reactive protein have a complementary prognostic value for mortality in dialysis patients? J. Am. Soc. Nephrol. 17, S169–S173 (2006).
Papanicolaou, D. A., Wilder, R. L., Manolagas, S. C. & Chrousos, G. P. The pathophysiologic roles of interleukin-6 in human disease. Ann. Intern. Med. 128, 127–137 (1998).
Tzoulaki, I. et al. C-reactive protein, interleukin-6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population: Edinburgh Artery Study. Circulation 112, 976–983 (2005).
Snaedal, S. et al. Comorbidity and acute clinical events as determinants of C-reactive protein variation in hemodialysis patients: implications for patient survival. Am. J. Kidney Dis. 53, 1024–1033 (2009).
de Beer, F. C. et al. Low density lipoprotein and very low density lipoprotein are selectively bound by aggregated C-reactive protein. J. Exp. Med. 156, 230–242 (1982).
Zhang, Y. X., Cliff, W. J., Schoefl, G. I. & Higgins, G. Coronary C-reactive protein distribution: its relation to development of atherosclerosis. Atherosclerosis 145, 375–379 (1999).
Zacho, J. et al. Genetically elevated C-reactive protein and ischemic vascular disease. N. Engl. J. Med. 359, 1897–1908 (2008).
Wensley, F. et al. Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. BMJ 342, d548 (2011).
Barreto, D. V. et al. Plasma interleukin-6 is independently associated with mortality in both hemodialysis and pre-dialysis patients with chronic kidney disease. Kidney Int. 77, 550–556 (2010).
Noh, H. et al. Serum C-reactive protein: a predictor of mortality in continuous ambulatory peritoneal dialysis patients. Perit. Dial. Int. 18, 387–394 (1998).
Wang, A. Y. et al. Is a single time point C-reactive protein predictive of outcome in peritoneal dialysis patients? J. Am. Soc. Nephrol. 14, 1871–1879 (2003).
Owen, W. F. & Lowrie, E. G. C-reactive protein as an outcome predictor for maintenance hemodialysis patients. Kidney Int. 54, 627–636 (1998).
Herzig, K. A. et al. Is C-reactive protein a useful predictor of outcome in peritoneal dialysis patients? J. Am. Soc. Nephrol. 12, 814–821 (2001).
Pifer, T. B. et al. Mortality risk in hemodialysis patients and changes in nutritional indicators: DOPPS. Kidney Int. 62, 2238–2245 (2002).
Reddan, D. N. et al. White blood cells as a novel mortality predictor in haemodialysis patients. Nephrol. Dial. Transplant. 18, 1167–1173 (2003).
Menon, V. et al. Relationship between C-reactive protein, albumin, and cardiovascular disease in patients with chronic kidney disease. Am. J. Kidney Dis. 42, 44–52 (2003).
Janssen, U. et al. Activation of the acute phase response and complement C3 in patients with IgA nephropathy. Am. J. Kidney Dis. 35, 21–28 (2000).
Bolton, C. H. et al. Endothelial dysfunction in chronic renal failure: roles of lipoprotein oxidation and pro-inflammatory cytokines. Nephrol. Dial. Transplant. 16, 1189–1197 (2001).
Pereira, B. J. et al. Plasma levels of IL-1 beta, TNF alpha and their specific inhibitors in undialyzed chronic renal failure, CAPD and hemodialysis patients. Kidney Int. 45, 890–896 (1994).
Pecoits-Filho, R. et al. Associations between circulating inflammatory markers and residual renal function in CRF patients. Am. J. Kidney Dis. 41, 1212–1218 (2003).
Stam, F. et al. Impaired renal function is associated with markers of endothelial dysfunction and increased inflammatory activity. Nephrol. Dial. Transplant. 18, 892–898 (2003).
Oberg, B. P. et al. Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. Kidney Int. 65, 1009–1016 (2004).
Shlipak, M. G. et al. Cardiovascular disease risk status in elderly persons with renal insufficiency. Kidney Int. 62, 997–1004 (2002).
Stuveling, E. M. et al. C-reactive protein is associated with renal function abnormalities in a non-diabetic population. Kidney Int. 63, 654–661 (2003).
Menon, V. et al. C-reactive protein and albumin as predictors of all-cause and cardiovascular mortality in chronic kidney disease. Kidney Int. 68, 766–772 (2005).
Sacks, F. M. et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N. Engl. J. Med. 335, 1001–1009 (1996).
Bash, L. D. et al. Inflammation, hemostasis, and the risk of kidney function decline in the Atherosclerosis Risk in Communities (ARIC) Study. Am. J. Kidney Dis. 53, 596–605 (2009).
Erlinger, T. P. et al. Leukocytosis, hypoalbuminemia, and the risk for chronic kidney disease in US adults. Am. J. Kidney Dis. 42, 256–263 (2003).
Keller, C. et al. Inflammatory biomarkers and decline in kidney function in the elderly: the Cardiovascular Health Study. Nephrol. Dial. Transplant. 25, 119–124 (2010).
Fried, L. et al. Inflammatory and prothrombotic markers and the progression of renal disease in elderly individuals. J. Am. Soc. Nephrol. 15, 3184–3191 (2004).
Coll, E. et al. Serum cystatin C as a new marker for noninvasive estimation of glomerular filtration rate and as a marker for early renal impairment. Am. J. Kidney Dis. 36, 29–34 (2000).
Vazquez, M. A., Jeyarajah, D. R., Kielar, M. L. & Lu, C. Y. Long-term outcomes of renal transplantation: a result of the original endowment of the donor kidney and the inflammatory response to both alloantigens and injury. Curr. Opin. Nephrol. Hypertens. 9, 643–648 (2000).
Cottone, S. et al. Inflammation and endothelial activation are linked to renal function in long-term kidney transplantation. Transpl. Int. 20, 82–87 (2007).
Krüger, B. et al. Is inflammation prior to renal transplantation predictive for cardiovascular and renal outcomes? Atherosclerosis 210, 637–642 (2010).
Winkelmayer, W. C. et al. C-reactive protein and body mass index independently predict mortality in kidney transplant recipients. Am. J. Transplant. 4, 1148–1154 (2004).
Krüger, B. et al. No effect of C-reactive protein (CRP) haplotypes on CRP levels and post-transplant morbidity and mortality in renal transplantation. Transpl. Int. 21, 452–458 (2008).
Perez, R. V. et al. Pretransplant systemic inflammation and acute rejection after renal transplantation. Transplantation 69, 869–874 (2000).
Ozdemir, N. F., Elsurer, R., Ibis, A., Arat, Z. & Haberal, M. Serum C-reactive protein surge in renal transplant recipients: link with allograft survival. Transplant. Proc. 39, 934–937 (2007).
van Ree, R. M. et al. Elevated levels of C-reactive protein independently predict accelerated deterioration of graft function in renal transplant recipients. Nephrol. Dial. Transplant. 22, 246–253 (2007).
Morrow, D. A. et al. Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial. Circulation 114, 281–288 (2006).
Ridker, P. M. et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation 98, 839–844 (1998).
Wanner, C. et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N. Engl. J. Med. 353, 238–248 (2005).
Kinlay, S. Low-density lipoprotein-dependent and -independent effects of cholesterol-lowering therapies on C-reactive protein: a meta-analysis. J. Am. Coll. Cardiol. 49, 2003–2009 (2007).
Chang, J. W. et al. Effects of simvastatin on high-sensitivity C-reactive protein and serum albumin in hemodialysis patients. Am. J. Kidney Dis. 39, 1213–1217 (2002).
Danesh, J. et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N. Engl. J. Med. 350, 1387–1397 (2004).
Ichihara, A. et al. Fluvastatin prevents development of arterial stiffness in haemodialysis patients with type 2 diabetes mellitus. Nephrol. Dial. Transplant. 17, 1513–1517 (2002).
Vernaglione, L., Cristofano, C., Muscogiuri, P. & Chimienti, S. Does atorvastatin influence serum C-reactive protein levels in patients on long-term hemodialysis? Am. J. Kidney Dis. 43, 471–478 (2004).
Ridker, P. M., Rifai, N., Pfeffer, M. A., Sacks, F. & Braunwald, E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 100, 230–235 (1999).
Arabul, M. et al. Effect of fluvastatin on serum prohepcidin levels in patients with end-stage renal disease. Clin. Biochem. 41, 1055–1058 (2008).
Sezer, M. T. et al. Short-term effect of simvastatin treatment on inflammatory parameters in peritoneal dialysis patients. Scand. J. Urol. Nephrol. 41, 436–441 (2007).
Malyszko, J., Malyszko, J. S., Hryszko, T. & Mysliwiec, M. Increased soluble CD40L levels are reduced by long-term simvastatin treatment in peritoneally dialyzed patients. Blood Coagul. Fibrinolysis 15, 463–467 (2004).
Kumar, S., Raftery, M., Yaqoob, M. & Fan, S. L. Anti-inflammatory effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors (statins) in peritoneal dialysis patients. Perit. Dial. Int. 27, 283–287 (2007).
Di Lullo, L. et al. Effects of fluvastatin treatment on lipid profile, C-reactive protein trend, and renal function in dyslipidemic patients with chronic renal failure. Adv. Ther. 22, 601–612 (2005).
Sawara, Y. et al. Effects of lipid-lowering therapy with rosuvastatin on atherosclerotic burden in patients with chronic kidney disease. Intern. Med. 47, 1505–1510 (2008).
Verma, A., Ranganna, K. M., Reddy, R. S., Verma, M. & Gordon, N. F. Effect of rosuvastatin on C-reactive protein and renal function in patients with chronic kidney disease. Am. J. Cardiol. 96, 1290–1292 (2005).
Goicoechea, M. et al. Effects of atorvastatin on inflammatory and fibrinolytic parameters in patients with chronic kidney disease. J. Am. Soc. Nephrol. 17, S231–S235 (2006).
Panichi, V. et al. In vivo and in vitro effects of simvastatin on inflammatory markers in pre-dialysis patients. Nephrol. Dial. Transplant. 21, 337–344 (2006).
Bayes, B. et al. Effect of low doses of atorvastatin on adiponectin, glucose homeostasis, and clinical inflammatory markers in kidney transplant recipients. Transplant. Proc. 37, 3808–3812 (2005).
Holdaas, H. et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 361, 2024–2031 (2003).
Ridker, P. M. et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N. Engl. J. Med. 344, 1959–1965 (2001).
Ridker, P. M. et al. C-reactive protein levels and outcomes after statin therapy. N. Engl. J. Med. 352, 20–28 (2005).
Arici, M. & Walls, J. End-stage renal disease, atherosclerosis, and cardiovascular mortality: is C-reactive protein the missing link? Kidney Int. 59, 407–414 (2001).
Ridker, P. M. et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 373, 1175–1182 (2009).
Nissen, S. E. et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N. Engl. J. Med. 352, 29–38 (2005).
Mega, J. L. et al. Cholesterol, C-reactive protein, and cerebrovascular events following intensive and moderate statin therapy. J. Thromb. Thrombolysis 22, 71–76 (2006).
Ridker, P. M. et al. Relative efficacy of atorvastatin 80 mg and pravastatin 40 mg in achieving the dual goals of low-density lipoprotein cholesterol <70 mg/dl and C-reactive protein <2 mg/l: an analysis of the PROVE-IT TIMI-22 trial. J. Am. Coll. Cardiol. 45, 1644–1648 (2005).
Ridker, P. M., MacFadyen, J., Cressman, M. & Glynn, R. J. Efficacy of rosuvastatin among men and women with moderate chronic kidney disease and elevated high-sensitivity C-reactive protein: a secondary analysis from the JUPITER (Justification for the Use of Statins in Prevention-an Intervention Trial Evaluating Rosuvastatin) trial. J. Am. Coll. Cardiol. 55, 1266–1273 (2010).
Strippoli, G. F. et al. Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials. BMJ 336, 645–651 (2008).
Navaneethan, S. D. et al. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database of Systematic Reviews, Issue 2. Art. No.: CD007784. doi:10.1002/14651858.CD007784 (2009).
Baigent, C. et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 376, 1670–1681 (2010).
Tonelli, M., Moye, L., Sacks, F. M., Cole, T. & Curhan, G. C. Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J. Am. Soc. Nephrol. 14, 1605–1613 (2003).
Tonelli, M., Moye, L., Sacks, F. M., Kiberd, B. & Curhan, G. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann. Intern. Med. 138, 98–104 (2003).
Tonelli, M. et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation 110, 1557–1563 (2004).
Tonelli, M. et al. Effect of pravastatin on rate of kidney function loss in people with or at risk for coronary disease. Circulation 112, 171–178 (2005).
Tonelli, M. et al. Effect of pravastatin in people with diabetes and chronic kidney disease. J. Am. Soc. Nephrol. 16, 3748–3754 (2005).
Sandhu, S., Wiebe, N., Fried, L. F. & Tonelli, M. Statins for improving renal outcomes: a meta-analysis. J. Am. Soc. Nephrol. 17, 2006–2016 (2006).
Navaneethan, S. D. et al. HMG CoA reductase inhibitors (statins) for dialysis patients. Cochrane Database of Systematic Reviews, Issue 3. Art. No.: CD004289. doi:10.1002/14651858.CD004289.pub4 (2009).
Navaneethan, S. D. et al. HMG CoA reductase inhibitors (statins) for kidney transplant recipients. Cochrane Database of Systematic Reviews, Issue 2. Art. No.: CD005019. doi:10.1002/14651858.CD005019.pub3 (2009).
Huskey, J. et al. Effect of simvastatin on kidney function loss in patients with coronary heart disease: findings from the Scandinavian Simvastatin Survival Study (4S). Atherosclerosis 205, 202–206 (2009).
Holdaas, H., Wanner, C., Abletshauser, C., Gimpelewicz, C. & Isaacsohn, J. The effect of fluvastatin on cardiac outcomes in patients with moderate to severe renal insufficiency: a pooled analysis of double-blind, randomized trials. Int. J. Cardiol. 117, 64–74 (2007).
Rahman, M. et al. Progression of kidney disease in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin versus usual care: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am. J. Kidney Dis. 52, 412–424 (2008).
Kendrick, J. et al. Effect of lovastatin on primary prevention of cardiovascular events in mild CKD and kidney function loss: a post hoc analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study. Am. J. Kidney Dis. 55, 42–49 (2010).
Athyros, V. G. et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J. Clin. Pathol. 57, 728–734 (2004).
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360, 7–22 (2002).
de Zeeuw, D. Different renal protective effects of atorvastatin and rosuvastatin in diabetic and non-diabetic renal patients with proteinuria. Results of the PLANET trials. Presented at the XLVII ERA-EDTA Congress 2010.
Del Vecchio, L., Pozzoni, P., Andrulli, S. & Locatelli, F. Inflammation and resistance to treatment with recombinant human erythropoietin. J. Ren. Nutr. 15, 137–141 (2005).
KDOQI & National Kidney Foundation. II. Clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease in adults. Am. J. Kidney Dis. 47, S16–S85 (2006).
Locatelli, F. et al. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol. Dial. Transplant. 19 (Suppl. 2), ii1–ii47 (2004).
Owen, W. F. & Lowrie, E. G. C-reactive protein as an outcome predictor for maintenance hemodialysis patients. Kidney Int. 54, 627–636 (1998).
Bárány, P., Divino Filho, J. C. & Bergström, J. High C-reactive protein is a strong predictor of resistance to erythropoietin in hemodialysis patients. Am. J. Kidney Dis. 29, 565–568 (1997).
Gunnell, J., Yeun, J. Y., Depner, T. A. & Kaysen, G. A. Acute-phase response predicts erythropoietin resistance in hemodialysis and peritoneal dialysis patients. Am. J. Kidney Dis. 33, 63–72 (1999).
Beguin, Y. et al. Early prediction of response to recombinant human erythropoietin in patients with the anemia of renal failure by serum transferrin receptor and fibrinogen. Blood 82, 2010–2016 (1993).
Kalantar-Zadeh, K. et al. Effect of malnutrition-inflammation complex syndrome on EPO hyporesponsiveness in maintenance hemodialysis patients. Am. J. Kidney Dis. 42, 761–773 (2003).
Kwack, C. & Balakrishnan, V. S. Managing erythropoietin hyporesponsiveness. Semin. Dial. 19, 146–151 (2006).
Locatelli, F. et al. Nutritional-inflammation status and resistance to erythropoietin therapy in haemodialysis patients. Nephrol. Dial. Transplant. 21, 991–998 (2006).
Macdougall, I. C. & Cooper, A. C. Hyporesponsiveness to erythropoietic therapy due to chronic inflammation. Eur. J. Clin. Invest. 35 (Suppl. 3), 32–35 (2005).
Malyszko, J., Malyszko, J. S., Hryszko, T., Pawlak, K. & Mysliwiec, M. Is hepcidin a link between anemia, inflammation and liver function in hemodialyzed patients? Am. J. Nephrol. 25, 586–590 (2005).
Casadevall, N. Cellular mechanism of resistance to erythropoietin. Nephrol. Dial. Transplant. 10 (Suppl. 6), 27–30 (1995).
Weiss, G. & Goodnough, L. T. Anemia of chronic disease. N. Engl. J. Med. 352, 1011–1023 (2005).
Himmelfarb, J., Stenvinkel, P., Ikizler, T. A. & Hakim, R. M. The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int. 62, 1524–1538 (2002).
Nemeth, E. et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090–2093 (2004).
Delaby, C., Pilard, N., Goncalves, A. S., Beaumont, C. & Canonne-Hergaux, F. Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin. Blood 106, 3979–3984 (2005).
Miller, C. B., Jones, R. J., Piantadosi, S., Abeloff, M. D. & Spivak, J. L. Decreased erythropoietin response in patients with the anemia of cancer. N. Engl. J. Med. 322, 1689–1692 (1990).
Khankin, E. V. et al. Soluble erythropoietin receptor contributes to erythropoietin resistance in end-stage renal disease. PLoS ONE 5, e9246 (2010).
Jelkmann, W., Pagel, H., Wolff, M. & Fandrey, J. Monokines inhibiting erythropoietin production in human hepatoma cultures and in isolated perfused rat kidneys. Life Sci. 50, 301–308 (1992).
de Francisco, A. L., Stenvinkel, P. & Vaulont, S. Inflammation and its impact on anaemia in chronic kidney disease: from haemoglobin variability to hyporesponsiveness. NDT Plus 2, i18–i26 (2009).
Sirken, G., Kung, S. C. & Raja, R. Decreased erythropoietin requirements in maintenance hemodialysis patients with statin therapy. ASAIO J. 49, 422–425 (2003).
Tsouchnikas, I. et al. Beneficial effect of atorvastatin on erythropoietin responsiveness in maintenance haemodialysis patients. Nephrology (Carlton) 14, 560–564 (2009).
Chiang, C. K. et al. Atorvastatin increases erythropoietin-stimulating agent hyporesponsiveness in maintenance hemodialysis patients: role of anti-inflammation effects. Am. J. Nephrol. 29, 392–397 (2009).
Macdougall, I. C., Lilienthal, J., Krane, V., Drechsler, C. & Wanner, C. Atorvastatin does not improve ESA responsiveness in haemodialysis patients: a post hoc analysis from the 4D randomised controlled trial [abstract]. American Society of Nephrology Renal Week SA-PO2404 (2009).
Tleyjeh, I. M. et al. Statins for the prevention and treatment of infections: a systematic review and meta-analysis. Arch. Intern. Med. 169, 1658–1667 (2009).
Aikawa, M. et al. An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 103, 276–283 (2001).
Niessner, A. et al. Simvastatin suppresses endotoxin-induced upregulation of toll-like receptors 4 and 2 in vivo. Atherosclerosis 189, 408–413 (2006).
Kwak, B., Mulhaupt, F., Myit, S. & Mach, F. Statins as a newly recognized type of immunomodulator. Nat. Med. 6, 1399–1402 (2000).
Weitz-Schmidt, G. et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat. Med. 7, 687–692 (2001).
Istvan, E. S. & Deisenhofer, J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science 292, 1160–1164 (2001).
Cines, D. B. et al. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91, 3527–3561 (1998).
Jain, M. K. & Ridker, P. M. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat. Rev. Drug Discov. 4, 977–987 (2005).
Laufs, U. & Liao, J. K. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J. Biol. Chem. 273, 24266–24271 (1998).
Catron, D. M. et al. Salmonella enterica serovar Typhimurium requires nonsterol precursors of the cholesterol biosynthetic pathway for intracellular proliferation. Infect. Immun. 72, 1036–1042 (2004).
del Real, G. et al. Statins inhibit HIV-1 infection by down-regulating Rho activity. J. Exp. Med. 200, 541–547 (2004).
Potena, L. et al. Hydroxymethyl-glutaryl coenzyme a reductase inhibition limits cytomegalovirus infection in human endothelial cells. Circulation 109, 532–536 (2004).
Gyetvai, A. et al. Lovastatin possesses a fungistatic effect against Candida albicans, but does not trigger apoptosis in this opportunistic human pathogen. FEMS Yeast Res. 6, 1140–1148 (2006).
US Renal Data System. 2009 ADR Reference Tables [online], (2009).
Wanner, C. On statin treatment to prevent sepsis in dialysis patients. Am. J. Kidney Dis. 50, 700–702 (2007).
Jonathan, E. et al. C-reactive protein concentration and the vascular benefits of statin therapy: an analysis of 20,536 patients in the Heart Protection Study. Lancet 377, 469–476 (2011).
Sharp Collaborative Group. Study of Heart and Renal Protection (SHARP): randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease. Am. Heart J. 160, 785–794 (2010).
Kidney Disease Outcomes Quality Initiative (K/DOQI) Group. K/DOQI clinical practice guidelines for management of dyslipidemias in patients with kidney disease. Am. J. Kidney Dis. 41, S1–S91 (2003).
Burmeister, J. E., Miltersteiner, D. R. & Campos, B. M. Rosuvastatin in hemodialysis: short-term effects on lipids and C-reactive protein. J. Nephrol. 22, 83–89 (2009).
Ford, I. et al. Reduced glomerular filtration rate and its association with clinical outcome in older patients at risk of vascular events: secondary analysis. PLoS Med. 6, e16 (2009).
Panichi, V. et al. C-reactive protein and interleukin-6 levels are related to renal function in predialytic chronic renal failure. Nephron 91, 594–600 (2002).
Woloshin, S. & Schwartz, L. M. Distribution of C-reactive protein values in the United States. N. Engl. J. Med. 352, 1611–1613 (2005).
Ramirez, R. et al. Stress-induced premature senescence in mononuclear cells from patients on long-term hemodialysis. Am. J. Kidney Dis. 45, 353–359 (2005).
Tsirpanlis, G. et al. Serum oxidized low-density lipoprotein is inversely correlated to telomerase activity in peripheral blood mononuclear cells of haemodialysis patients. Nephrology (Carlton) 11, 506–509 (2006).
Tsirpanlis, G. et al. Telomerase activity is decreased in peripheral blood mononuclear cells of hemodialysis patients. Am. J. Nephrol. 26, 91–96 (2006).
Boxall, M. C., Goodship, T. H., Brown, A. L., Ward, M. C. & von Zglinicki, T. Telomere shortening and haemodialysis. Blood Purif. 24, 185–189 (2006).
Tsirpanlis, G. Cellular senescence, cardiovascular risk, and CKD: a review of established and hypothetical interconnections. Am. J. Kidney Dis. 51, 131–144 (2008).
Carrero, J. J. et al. Telomere attrition is associated with inflammation, low fetuin-A levels and high mortality in prevalent haemodialysis patients. J. Intern. Med. 263, 302–312 (2008).
Asselbergs, F. W. et al. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 110, 2809–2816 (2004).
Nakamura, H. et al. Pravastatin and cardiovascular risk in moderate chronic kidney disease. Atherosclerosis 206, 512–517 (2009).
Lemos, P. A. et al. Long-term fluvastatin reduces the hazardous effect of renal impairment on four-year atherosclerotic outcomes (a LIPS substudy). Am. J. Cardiol. 95, 445–451 (2005).
Ruggenenti, P. et al. Effects of add-on fluvastatin therapy in patients with chronic proteinuric nephropathy on dual renin-angiotensin system blockade: the ESPLANADE trial. Clin. J. Am. Soc. Nephrol. 5, 1928–1938 (2010).
Collins, R., Armitage, J., Parish, S., Sleigh, P. & Peto, R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 361, 2005–2016 (2003).
Baigent, C. et al. First United Kingdom Heart and Renal Protection (UK-HARP-I) study: biochemical efficacy and safety of simvastatin and safety of low-dose aspirin in chronic kidney disease. Am. J. Kidney Dis. 45, 473–484 (2005).
Landray, M. et al. The second United Kingdom Heart and Renal Protection (UK-HARP-II) Study: a randomized controlled study of the biochemical safety and efficacy of adding ezetimibe to simvastatin as initial therapy among patients with CKD. Am. J. Kidney Dis. 47, 385–395 (2006).
Armitage, J. et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 376, 1658–1669 (2010).
Shepherd, J. et al. Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study. Clin. J. Am. Soc. Nephrol. 2, 1131–1139 (2007).
Shepherd, J. et al. Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study. J. Am. Coll. Cardiol. 51, 1448–1454 (2008).
Koren, M. J. et al. Focused atorvastatin therapy in managed-care patients with coronary heart disease and CKD. Am. J. Kidney Dis. 53, 741–750 (2009).
Colhoun, H. M. et al. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am. J. Kidney Dis. 54, 810–819 (2009).
Fassett, R. G., Robertson, I. K., Ball, M. J., Geraghty, D. P. & Coombes, J. S. Effect of atorvastatin on kidney function in chronic kidney disease: a randomised double-blind placebo-controlled trial. Atherosclerosis 213, 218–224 (2010).
Holme, I. et al. Cardiovascular outcomes and their relationships to lipoprotein components in patients with and without chronic kidney disease: results from the IDEAL trial. J. Intern. Med. 267, 567–575 (2010).
Harris, K. P., Wheeler, D. C. & Chong, C. C. A placebo-controlled trial examining atorvastatin in dyslipidemic patients undergoing CAPD. Kidney Int. 61, 1469–1474 (2002).
Stegmayr, B. G. et al. Low-dose atorvastatin in severe chronic kidney disease patients: a randomized, controlled endpoint study. Scand. J. Urol. Nephrol. 39, 489–497 (2005).
Holmberg, B. et al. Safety and efficacy of atorvastatin in patients with severe renal dysfunction. Scand. J. Urol. Nephrol. 39, 503–510 (2005).
Han, S. H. et al. Combined vascular effects of HMG-CoA reductase inhibitor and angiotensin receptor blocker in non-diabetic patients undergoing peritoneal dialysis. Nephrol. Dial. Transplant. doi:10.1093/ndt/gfr108.
Holdaas, H. et al. Effect of fluvastatin on acute renal allograft rejection: a randomized multicenter trial. Kidney Int. 60, 1990–1997 (2001).
Kasiske, B. L. et al. The effects of lipid-lowering agents on acute renal allograft rejection. Transplantation 72, 223–227 (2001).
Schmidt, W. M., Spiel, A. O., Jilma, B., Wolzt, M. & Muller, M. In-vivo effects of simvastatin and rosuvastatin on global gene expression in peripheral blood leucocytes in a human inflammation model. Pharmacogenet. Genomics 18, 109–120 (2008).
Acknowledgements
C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape, LLC-accredited continuing medical education activity associated with this article.
Author information
Authors and Affiliations
Contributions
V. Krane and C. Wanner contributed equally to researching data for the article, discussion of content, writing, and reviewing and editing the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Table 1
Lists studies including more than 10 participants with CKD on statins. (DOC 238 kb)
Rights and permissions
About this article
Cite this article
Krane, V., Wanner, C. Statins, inflammation and kidney disease. Nat Rev Nephrol 7, 385–397 (2011). https://doi.org/10.1038/nrneph.2011.62
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrneph.2011.62
- Springer Nature Limited
This article is cited by
-
Biomarker and genomic analyses reveal molecular signatures of non-cardioembolic ischemic stroke
Signal Transduction and Targeted Therapy (2023)
-
International practice patterns of dyslipidemia management in patients with chronic kidney disease under nephrology care: is it time to review guideline recommendations?
Lipids in Health and Disease (2023)
-
Management of gout in chronic kidney disease: a G-CAN Consensus Statement on the research priorities
Nature Reviews Rheumatology (2021)
-
Epicardial adipose tissue radiodensity is associated with all-cause mortality in patients undergoing hemodialysis
Scientific Reports (2021)
-
Circulating fatty acid profiles are associated with protein energy wasting in maintenance hemodialysis patients: a cross-sectional study
Scientific Reports (2021)