Inflammation in Renal Disease

Inflammation in Renal Disease Donald G. Vidt, MD Inflammation is a component of the major modifiable risk factors in renal disease. Elevated high-sensitivity C-reactive protein (hs-crp) levels have been shown to predict all-cause and cardiovascular mortality in patients dependent on dialysis and to predict worsening renal function in subjects without overt renal disease. Levels of hs-crp are also predictive of hypertension, a major risk factor for renal disease, across all levels of blood pressure in subjects without initial hypertension. Many of the treatments used in patients with renal disease exert anti-inflammatory activities that constitute or contribute to their therapeutic effects. A number of studies have indicated that statin therapy exerts a renoprotective effect that is possibly mediated by anti-inflammatory activities. 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;97[suppl]:20A 27A) The acute-phase reactant C-reactive protein (CRP) is a marker of systemic inflammation that also appears to have direct effects on endothelial dysfunction and atherosclerosis progression. Elevated levels of high-sensitivity CRP (hs- CRP) are an independent predictor of cardiovascular disease (CVD) and have been shown to add prognostic information to cardiovascular risk at all levels of Framingham risk assessment, as well as to risks associated with the metabolic syndrome and all blood pressure levels. Measurement of hs-crp has also been shown to have value in predicting cardiovascular mortality in renal disease and in predicting worsening of renal function in individuals without diabetes. Evidence is accumulating to indicate that statin therapy has a beneficial effect on renal function that appears to be mediated by anti-inflammatory activities. Cardiovascular Risk and High-Sensitivity C-Reactive Protein Levels of hs-crp have been shown to predict cardiovascular risk in a large number of studies. For example, assessment of baseline hs-crp levels among 27,939 apparently healthy women in the Women s Health Study showed linear increases in cardiovascular risk (myocardial infarction, stroke, coronary revascularization, cardiovascular death) across the full range of hs-crp values. 1 Figure 1 shows crude relative risk across hs-crp values and risk adjusted for Framingham risk score. Relative risks were also found to increase linearly with increasing hs-crp levels within Framingham 10-year risk categories of 10% and 10% to 20% (Figure 1). Department of Nephrology and Hypertension, The Cleveland Clinic Foundation, Cleveland, Ohio, USA. Address for reprints: Donald G. Vidt, MD, Department of Nephrology and Hypertension, The Cleveland Clinic Foundation, 9500 Euclid Avenue, A51, Cleveland, Ohio 44195. E-mail address: vidtd@ccf.org. Association of High-Sensitivity C-Reactive Protein with Increased Mortality Risk in End-Stage Renal Disease Atherosclerotic events are the leading cause of death in patients with end-stage renal disease (ESRD). In addition to classic risk factors for atherosclerosis, patients with ESRD can have both uremia-related and dialysis-related conditions that result in release of proinflammatory cytokines and other inflammatory factors and cause endothelial dysfunction as well as acute and long-term systemic inflammatory responses, including elevated levels of hs-crp and other proatherothrombotic substances (Figure 2). 2 Elevated levels of hs-crp are found in a substantial proportion of patients with ESRD (20% to 65%). A number of studies have documented an association between elevated hs-crp levels and cardiovascular risk in patients with ESRD. In a study performed by Wanner et al 3 in 280 stable patients undergoing hemodialysis, 44% died over a follow-up period of 4 years, with 60% of these dying from cardiovascular causes. Figure 3 shows all-cause and cardiovascular mortality by quartiles of hs-crp at baseline in the study population. Patients in the highest hs-crp quartile had a 2.4-fold higher risk for all-cause mortality and a 1.7-fold higher risk for cardiovascular mortality (both p 0.0001) compared with those in the lowest quartile. On multivariate analysis, hs-crp was among the strongest predictors of mortality, along with age and preexisting CVD. Association of High-Sensitivity C-Reactive Protein with Risk of Decreasing Renal Function Other studies have shown an association of elevated hs-crp with decreasing renal function in populations without overt renal disease. In a study of 7,317 subjects without diabetes, hs-crp levels were significantly correlated with risk for diminished renal filtration according to both crude risk assessment and multivariate models (Table 1). 4 It is of interest that 0002-9149/06/$ see front matter 2006 Elsevier Inc. All rights reserved. www.ajconline.org doi:10.1016/j.amjcard.2005.11.012

Vidt/Inflammation in Renal Disease 21A Figure 1. (Top) Relative risk (RR) of future cardiovascular (CV) events according to baseline high-sensitivity C-reactive protein (hs-crp) level on crude analysis and adjusted for Framingham risk score (FRS) in subjects in the Women s Health Study. Low, moderate, and high risk indicate current risk break points for hs-crp. (Bottom) Relative risk by hs-crp level among subjects with 10-year Framingham risk 10% (left) or 10% to 20% (right). (Reproduced with permission from Circulation. 1 ) the highest hs-crp quartile was associated with a significant odds ratio (1.9; 95% confidence interval, 1.3 to 2.9) for high glomerular filtration rate (GFR; hyperfiltration), an early sign of altered renal function. Although much of this risk appeared to be explained by increased body mass index, there is evidence that an increased presence of inflammatory markers early in renal injury signals a worsening of renal function. In the setting of decreased nephron mass, there is increased filtration of plasma proteins (resulting in proteinuria) that produces excessive tubular reabsorption of proteins. Excessive tubular protein reabsorption can result in fibrogenesis, either by promoting transdifferentiation of tubular cells to myoblasts or via a pathway whereby increased transforming growth factor results in tubular cell hypertrophy and increased expression of type IV collagen. Excessive reabsorption also induces nuclear signaling for nuclear factor- B dependent genes, leading to release of vasoactive and inflammatory substances into the interstitium, recruitment of inflammatory cells into the interstitium, cytokine and growth factor release, and fibroblast proliferation, ultimately resulting in fibrogenesis, renal scarring, and reduced renal function. 5 Thus, there is evidence of a significant inflammatory response, even in early renal dysfunction, that appears to contribute to progressive deterioration in function.

22A The American Journal of Cardiology (www.ajconline.org) Vol 97 (2A) January 16, 2006 Figure 2. Risk factors for atherosclerosis in patients with end-stage renal disease. CRP C-reactive protein; LDL-C low-density lipoprotein cholesterol. (Reproduced with permission from Kidney Int. 2 ) Association of High-Sensitivity C-Reactive Protein with Hypertension Hypertension is a major risk factor for progressive renal disease. A role for inflammation in hypertension is indicated by the findings that inflammation correlates with both endothelial dysfunction and increased activity of the renin angiotensin system, including increased angiotensin II activity and, as indicated by recent trials, suggesting upregulation of angiotensin I receptor activity. Elevated hs-crp levels are observed in patients with hypertension, and it has been shown that increased hs-crp levels are correlated with risk of developing hypertension. In a study of 20,525 women in the Women s Health Study with initially normal blood pressure ( 140/ 90 mm Hg), 5,365 women developed incident hypertension over a median follow-up period of 7.8 years. 6 Relative risks for developing hypertension increased in a significant linear manner across all hs-crp levels on both crude models and in models adjusting for coronary risk factors. Overall, hs-crp was significantly associated with an increased risk of developing hypertension in all prespecified subgroups evaluated, including subjects with very low blood pressure and those with no traditional coronary risk factors. As shown in Figure 4, hs-crp levels of 1 to 3 mg/l and 3 mg/l conferred additional risks of developing systolic hypertension, both at initially normal levels ( 120 mm Hg) and at prehypertension levels ( 130 mm Hg; p 0.001 for interaction). A similar additive effect was observed for diastolic blood pressure, although the interaction was not statistically significant. Statins, Inflammation, and Renal Function Major modifiable risk factors for progression of renal disease include hypertension, proteinuria, and hyperglycemia. Reduction in blood pressure reduces proteinuria and slows the progression of loss of renal function. Similarly, reduction in proteinuria can stabilize renal function. Control of hyperglycemia in the diabetic state can reduce the risk of vascular disease affecting the kidney. There are accumulating data indicating that dyslipidemia is also a major modifiable risk factor in renal disease. Recent findings indicate that statin treatment can slow the deterioration of renal function and also suggest that these agents exert antihypertensive effects. A number of treatments that are commonly used in patients with renal disease exert anti-inflammatory effects that either are the primary therapeutic activity of the treatment or potentially contribute to the beneficial effects of the treatment. For example, aspirin has antithrombotic and antiinflammatory effects. Inhibitors of the renin angiotensin system, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, exhibit antioxidant effects, improve nitric oxide availability, inhibit cell growth effects mediated by angiotensin II, and inhibit or reverse collagen remodeling. Statins have been reported to suppress cytokine expression, inhibit fibrosis, inhibit low-density lipoprotein (LDL) stimulation of vasoactive angiotensin II and endothelin, and improve availability of nitric oxide. Recent data suggest that they may also improve vasodilation by inhibiting calcium entry into smooth muscle cells. A study reported several years ago by Spósito et al 7

Vidt/Inflammation in Renal Disease 23A Figure 3. Kaplan-Meier estimates of all-cause mortality (top) and cardiovascular mortality (bottom) in hemodialysis patients according to baseline high-sensitivity C-reactive protein (hs-crp) quartile. (Reproduced with permission from Kidney Int. 3 )

24A The American Journal of Cardiology (www.ajconline.org) Vol 97 (2A) January 16, 2006 Table1 Odds ratio (OR) for diminished filtration according to baseline quartile of hs-crp in subjects without diabetes hs-crp Quartile 1 ( 0.54 mg/l) 2 (0.54 1.20 mg/l) 3 (1.22 2.76 mg/l) 4 ( 2.76 mg/l) Model 1: crude OR OR (95% CI) 1.0 1.3 (0.9 1.9) 1.6 (1.1 2.4) 1.8 (1.2 2.6) p value NS 0.01 0.005 Model 2: adjusted for age, sex OR (95% CI) 1.0 1.4 (0.9 2.1) 1.9 (1.3 2.8) 2.1 (1.4 3.2) p value NS 0.005 0.005 Model 3: adjusted for model 2 plus body mass index, systolic and diastolic blood pressures, antihypertensive use, cholesterol, lipid-lowering therapy, albuminuria groups, smoking OR (95% CI) 1.0 1.3 (0.8 2.0) 1.7 (1.1 2.5) 1.9 (1.3 2.9) p value NS 0.05 0.005 CI confidence interval; hs-crp high-sensitivity C-reactive protein; NS not significant. Adapted from Kidney Int. 4 Figure 4. Relative risk and 95% confidence interval (CI) for developing hypertension by initial systolic blood pressure (SBP), diastolic blood pressure (DBP), and initial high-sensitivity C-reactive protein (hs-crp) level in women in the Women s Health Study. (Reproduced with permission from JAMA. 6 ) indicated that statin treatment could produce additional reductions in blood pressure beyond those achieved with antihypertensive treatment. After a 3-month dietary phase, 70 patients with total cholesterol levels of 6.2 mmol/l (240 mg/dl) and diastolic pressure between 95 and 120 mm Hg received lisinopril or enalapril to reduce diastolic pressure to 95 mm Hg; half of the patients received either lovastatin 20 mg or pravastatin 10 mg, with the dose adjusted to reduce total cholesterol to 5.2 mmol/l (200 mg/dl) in the statin plus diet group, and half of the patients received no statin treatment in the diet-only group. After 16 weeks, blood pressure had decreased from 153/100 to 130/81 mm Hg in the statin plus diet group and from 149/102 to 137/87 mm Hg in the diet-only group. The statin plus diet group (mean doses, lovastatin 38.8 mg and pravastatin 25.9 mg) had a greater reduction in diastolic pressure (19% vs 15%) that was significantly associated with changes in total cholesterol level. Systolic pressure was also reduced more in the statin plus diet group (15% vs 8%), with the reduction not being significantly correlated with the reduction in total cholesterol. The statin-treated group had a significantly greater reduction in mean blood pressure (18%

Vidt/Inflammation in Renal Disease 25A Figure 5. Percent change in urine protein excretion (UPE; top) and in creatinine clearance (CrCl; bottom) during run-in phase and during study phase according to treatment with atorvastatin (group A) or no atorvastatin treatment (group B) during study phase. (Reproduced with permission from Am J Kidney Dis. 8 ) vs 12%, p 0.05) and a significantly lower mean arterial blood pressure (97 vs 104 mm Hg, p 0.05) after 16 weeks. In a study by Bianchi et al, 8 56 patients with chronic renal disease (idiopathic chronic glomerulonephritis) who had received 1 year of treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and other antihypertensive drugs (run-in phase) were randomized to receive atorvastatin or no statin treatment while continuing on their prior therapy for 1 year. Atorvastatin was titrated to a maximum of 40 mg to achieve LDL cholesterol levels of 3.1 mmol/l (120 mg/dl) or a 40% reduction in LDL cholesterol from baseline. After 1 year, urine protein excretion had decreased from 2.2 to 1.2 g per 24 hours ( 45.5%, p 0.01) in the atorvastatin group and from 2.0 to 1.86 g per 24 hours ( 10%, p not significant) in the no-treatment group. As shown in Figure 5, the percent decrease in protein excretion from the beginning of the run-in phase was significantly greater in the atorvastatin group after 6, 9, and 12 months. Creatinine clearance decreased slightly from 0.85 ml/sec (51 ml/min) to 0.83 ml/sec (49.8 ml/min) in the atorvastatin group ( 2.0%, p not significant) and significantly from 0.83 ml/sec (50 ml/min) to 0.74 ml/sec (44.2 ml/min) in the no-treatment group ( 11.6%, p 0.01). As shown in Figure 5, the

26A The American Journal of Cardiology (www.ajconline.org) Vol 97 (2A) January 16, 2006 Table 2 Change in glomerular filtration rate (GFR) during rosuvastatin treatment in short-term controlled trials and in long-term open-label treatment ( 96 wk) GFR (ml/min per 1.73 m 2 ) Change in GFR (ml/min per 1.73 m 2 ) Dose N Baseline, Mean (SD) [Range] On-Treatment, Mean (SD) [Range] Mean (SD) Median 5th to 95th Percentile Short-term, controlled clinical trials 5 mg 637 65 (12) [29 125] 67 (12) [30 137] 2 (6)* 0 7 to 11.5 10 mg 2,909 66 (12) [28 158] 67 (13) [25 147] 2 (8)* 0 9.5 to 13 20 mg 1,432 68 (14) [26 155] 70 (14) [16 140] 2 (8)* 0 10 to 16 40 mg 2,107 70 (13) [27 114] 71 (13) [27.5 137] 2 (8)* 0 10 to 14 Placebo 371 67 (14) [24 123] 67 [14] [27 118] 0 (7) 0 11 to 10 Long-term (open-label) treatment 5 mg 263 64 (11) [36 95] 68 (13) [36 114] 4 (8)* 6 9 to17 10 mg 893 64 (10) [29 122] 69 (12) [21 122] 5 (8)* 6 7 to18 20 mg 119 64 (11) [42 95] 68 (12) [33 105] 4 (8)* 5 9 to17 40 mg 109 64 (11) [35 97] 69 (13) [37 106] 4 (8)* 6 7 to16 *p 0.001 versus baseline. SD standard deviation. Adapted from Cardiology. 9 decrease in creatinine clearance was significantly greater in the no-treatment group at 12 months. These findings suggest that atorvastatin can reduce proteinuria and delay progression of renal dysfunction. Similarly, long-term assessment of renal function in 10,000 patients receiving rosuvastatin suggested that this treatment also exerts a renoprotective effect. 9 As shown in Table 2, short-term (median duration, about 8 weeks) controlled clinical trials of rosuvastatin at the approved dose range revealed small but significant mean increases (p 0.001) in GFR at all doses, with no change in placebo-treated patients. Examination of patients receiving longer-term open-label rosuvastatin treatment ( 96 weeks) showed greater mean and median increases (p 0.001) in GFR. These changes were accompanied by decreases in serum creatinine levels. Assessment of changes according to degree of renal function at baseline indicated that greater increases in GFR during rosuvastatin treatment occurred in patients with lower initial rates. Patients with positive dipstick results for proteinuria during longer-term treatment had no change or increases in GFR and overall group result, similar to those with no positive dipstick findings during treatment. These findings suggest that, as with other statins, rosuvastatin may arrest the progression of renal disease. In the secondary prevention Greek Atorvastatin and Coronary-Heart-Disease Evaluation (GREACE) study, patients with coronary artery disease received structured care consisting of follow-up at a university center plus atorvastatin treatment (10 to 80 mg, titrated to achieve National Cholesterol Education Program [NCEP] Adult Treatment Panel III [ATP III] LDL cholesterol goals) or usual care consisting of follow-up by specialists or general practitioners, of the patient s choosing, and including lifestyle changes and any lipid-lowering or other drug treatment deemed necessary. Effects of treatment on renal function were evaluated in 783 patients receiving atorvastatin (mean dose, 24 mg) in the structured care group (structured care/on atorvastatin), 17 patients in the structured care group who withdrew from the atorvastatin arm because of side effects or personal reasons (structured care/no atorvastatin), 97 patients who received statin therapy in the usual care group (usual care/on statins), and 703 patients in the usual care group not receiving a statin (usual care/no statins); all patients had plasma creatinine values of 115 mol/l at baseline. 10 As shown in Figure 6, estimated creatinine clearance increased in patients receiving atorvastatin and decreased in those not receiving atorvastatin during 4 years of follow-up, with the greatest increase occurring in the structured care/on atorvastatin group. Over the 4 years, mean estimated creatinine clearance decreased by 5.3% (from 1.28 ml/sec [77 ml/min] to 1.20 ml/sec [72 ml/min]) in the usual care/no statins group (p 0.0001), increased by 4.9% (from 1.30 ml/sec [78 ml/ min] to 1.37 ml/sec [82 ml/min]) in the usual care/on statins group (p 0.003), decreased by 4.9% (from 1.27 ml/sec [76 ml/min] to 1.22 ml/sec [73 ml/min]) in the structured care/no statins group (p 0.02), and increased by 12% (from 1.27 ml/sec [76 ml/min] to 1.40 ml/sec [84 ml/min]) in the structured care/on statins group (p 0.0001). As in the rosuvastatin analysis, the beneficial changes were more prominent in those patients with poorer renal function at baseline. Conclusion Inflammation is part of the pathophysiology of renal disease, and it is associated with all of the recognized major modifiable risk factors in renal dysfunction. Many of the therapies currently used in patients with renal dysfunction or at risk for worsening renal function exert anti-inflammatory effects that contribute to the preservation of function. Most recently, statin therapy has been found to exert a renoprotective effect that may be mediated by anti-inflammatory

Vidt/Inflammation in Renal Disease 27A Figure 6. Change in estimated creatinine clearance (CrCl) in usual care/no statins, structured care/no atorvastatin, usual care/on statins, and structured care/on atorvastatin groups in the secondary prevention Greek Atorvastatin and Coronary-Heart-Disease Evaluation (GREACE) trial. Asterisks indicate the time at which changes from baseline became statistically significant in each group. (Reproduced with permission from J Clin Pathol. 10 ) activities of these agents. This potential benefit of effective statin therapy requires prospective evaluation in clinical trials. 1. Ridker PM, Cook N. Clinical usefulness of very high and very low levels of C-reactive protein across the full range of Framingham risk scores. Circulation 2004;109:1955 1959. 2. Arici M, Walls J. End-stage renal disease, atherosclerosis, and cardiovascular mortality: is C-reactive protein the missing link? Kidney Int 2001;59:407 414. 3. Wanner C, Zimmermann J, Schwedler S, Metzger T. Inflammation and cardiovascular risk in dialysis patients. Kidney Int 2002;61(suppl 80): S99 S102. 4. Stuveling EM, Hillege HL, Bakker SJ, Gans RO, De Jong PE, De Zeeuw D. C-reactive protein is associated with renal function abnormalities in a non-diabetic population. Kidney Int 2003;63:654 661. 5. Remuzzi G, Ruggenenti P, Perico N. Chronic renal diseases: renoprotective benefits of renin-angiotensin system inhibition. Ann Intern Med 2002;136:604 615. 6. Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM. C-reactive protein and the risk of developing hypertension. JAMA 2003;290:2945 2951. 7. Spósito AC, Mansur AP, Coelho OR, Nicolau JC, Ramires J. Additional reduction in blood pressure after cholesterol-lowering treatment by statins (lovastatin or pravastatin) in hypercholesterolemic patients using angiotensin-converting enzyme inhibitors (enalapril or lisinopril). Am J Cardiol 1999;83:1497 1499. 8. Bianchi S, Bigazzi R, Caiazza A, Campese VM. A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am J Kidney Dis 2003;41:565 570. 9. Vidt DG, Cressman MD, Harris S, Pears JS, Hutchinson HG. Rosuvastatin-induced arrest in progression of renal disease. Cardiology 2004;102:52 60. 10. Athyros VG, Mikhailidis DP, Papageorgiou AA, Symeonidis AN, Pehlivenidis AN, Bouloukos VI, Elisaf M. 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 2004; 57:728 734.