Epidemiology of cardiovascular risk in chronic kidney disease patients: the real silent killer

doi:10.31083/j.rcm.2019.04.548

Reviews in Cardiovascular Medicine

2019, Vol. 20

Issue (4): 209-220 DOI: 10.31083/j.rcm.2019.04.548

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Epidemiology of cardiovascular risk in chronic kidney disease patients: the real silent killer

Michele Provenzano¹, Giuseppe Coppolino^1,^*(

), Teresa Faga¹, Carlo Garofalo², Raffaele Serra³, Michele Andreucci¹

¹ Department of Health Sciences, Renal Unit, "Magna Graecia" University, 88100 Catanzaro, Italy
² Department of Scienze Mediche e Chirurgiche Avanzate, Renal Unit, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
³ Interuniversity Center of Phlebolymphology (CIFL), “Magna Graecia” University, 88100 Catanzaro, Italy

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Abstract:

Chronic kidney disease is a growing public health problem, as its prevalence and incidence have almost doubled over the last three decades. Chronic kidney disease is defined as the presence of an estimated glomerular filtration rate < 60 ml/min/1.73 m² and/or proteinuria ≥ 0.150 g/24 h. It has been demonstrated that both proteinuria and reduction in estimated glomerular filtration rate can predict the development of fatal and non-fatal cardiovascular events, regardless of traditional cardiovascular risk factors, namely blood pressure, smoking habit, cholesterol, age, gender. This relationship is found in the general population, high-risk cohorts and in patients referred to Nephrologists (tertiary care). The accuracy by which proteinuria or estimated glomerular filtration rate can predict these events, exceeds that obtained by the combination of all the other traditional risk factors. These important findings have led to chronic kidney disease being considered as a cardiovascular risk equivalent. Although this needs further investigation, a great effort has been made to reduce the cardiovascular risk in chronic kidney disease patients. Indeed, many clinical trials have been carried-out testing the effect of antihypertensive, proteinuria-lowering, lipid-lowering and hypoglycemic agents on cardiovascular risk protection. All these trials reduced, but did not eliminate, the overall cardiovascular risk. Future studies should be undertaken to identify high cardiovascular risk patients and novel therapeutic targets for cardiovascular protection in chronic kidney disease patients.

Key words: Epidemiology cardiovascular risk blood pressure chronic kidney disease statins proteinuria albuminuria

Submitted: 06 August 2019 Accepted: 16 October 2019 Published: 30 December 2019

^*Corresponding Author(s): Giuseppe Coppolino E-mail: gcoppolino@unicz.it

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Michele Provenzano, Giuseppe Coppolino, Teresa Faga, Carlo Garofalo, Raffaele Serra, Michele Andreucci. Epidemiology of cardiovascular risk in chronic kidney disease patients: the real silent killer. Reviews in Cardiovascular Medicine, 2019, 20(4): 209-220.

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https://rcm.imrpress.com/EN/10.31083/j.rcm.2019.04.548 OR https://rcm.imrpress.com/EN/Y2019/V20/I4/209

Figure 1. Prevalence of common cardiovascular diseases in patients with (Red area) or without (Blue area) chronic kidney disease (CKD) in the United States, in the year 2015.

Figure 2. Prevalence (%) of cardiovascular disease (myocardial infarction, stroke, peripheral vascular disease, chronic heart failure, angina) by primary renal disease categories. HTN, Hypertensive Nephropathy; DN, Diabetic Nephropathy; OTHER/UK, Other or Unknown; ADPKD, Autosomal Dominant Polycystic Kidney Disease; TIN, Tubulo-Interstitial Nephropathies; GN, Glomerulonephritis. Data source: 3.957 patients selected from the Italian multicenter cohort of CKD patients referred to nephrologists (Provenzano et al., 2018).

Table 1 Studies comparing rates of cardiovascular (CV) events among patients with CKD.

Study	Population	Intervention	Outcome	Results
PROGRESS Study (Perkovic et al., 2007)	Cerebrovascular disease and CKD	Perindopril vs. placebo	Total stroke (fatal or non-fatal) and major vascular events.	In patients treated with perindopril, risks of major vascular events and stroke were 30% and 35% lower then placebo. This evidence is found in patients with CKD, where the effect of treatment was greater as compared to patients without CKD.
CV outcomes in the Irbesartan Diabetic Nephropathy Trial (Berl et al., 2003)	Type 2 diabetic nephropathy and hypertension	Irbesartan, amlodipine, or placebo.	Doubling of serum creatinine, end-stage renal disease, death from any cause.	Cardiovascular risk was unchanged with the addition of irbesartan, amlodipine, or placebo to conventional antihypertensive therapy in patients with type 2 diabetes and nephropathy.
Risk of coronary events in people with chronic kidney disease compared with those with diabetes (Tonelli et al., 2012)	CV events in CKD and diabetes		Demonstrating whether chronic kidney disease should be considered as a coronary heart disease risk equivalent.	The rate of incident myocardial infarction was lower in diabetic patients than in patients with CKD defined eGFR < 45 mL/min per 1.73 m² and severe proteinuria
ALLHAT Study (Rahman et al., 2006)	CKD and hypertension	Chlorthalidone vs. Amlodipine vs. Lisinopril.	Rates of coronary heart disease (CHD) and ESRD; Predictors of CHD; Efficacy of a first-step treatment with a Calcium channel Blocker or an Angiotensin Rreceptor Blocker each compared with a diuretic in modifying CVD risk.	Older patients with hypertension and reduced eGFR developed more frequently CHD than ESRD. A low GFR was and independent predictor of increased CHD risk. Neither amlodipine nor lisinopril is superior to chlorthalidone in reducing risks for CHD, stroke or combined CVD. Chlorthalidone was superior to amlodipine and lisinopril for preventing heart failure.
ADVANCE Study (Heerspink et al., 2010)	CKD and type 2 diabetes	Perindopril and Indapamide vs. placebo	Major adverse cardiac event or MACE (cardiovascular death, non-fatal myocardial infarction, unstable angina, heart failure, stroke and other cardiovascular events requiring hospitalization).	The treatment with perindopril-indapamide in patients with type 2 diabetes reuduced the risk of cardiovascular, renal outcomes and death across all stages of CKD. Absolute risk reductions were higher in patients with CKD, thus demonstrating the importance of blood pressure control in this population.
EMPA-REG OUTCOME Study (Wanner et al., 2016)	Type 2 diabetes at increased cardiovascular risk	10 mg Empaglifozin vs. 25 mg of Empagliflozin vs. placebo	Progression of CKD (development of macroalbuminuria, doubling of the serum creatinine, ESRD, or death from renal disease) and incident albuminuria.	Empagliflozin slowed the progression of kidney disease as compared to standard care.
HIJ-CREATE Study (Shiga et al., 2010)	High-risk hypertensive patients with CHD and CKD	Candesartan vs. non-ARB treatment	Major adverse cardiac event (MACE)	There was no difference in MACE between the two treatment groups in patients without CKD. However, there was a lower incidence of MACE in the candesartan-based treatment group than in the non-ARBs treatment group in patients with CKD.
ALTITUDE Study (Parving et al., 2012)	Type 2 diabetes and CKD, CVD, or both	Aliskiren vs. placebo in addition to an ACE inhibitor or an ARB	Major adverse cardiac event (MACE); ESRD, death due to kidney failure, need for renal-replacement therapy with no dialysis or transplantation available or initiated, doubling of serum creatinine.	The addition of aliskiren to standard RAAS therapy with renin-angiotensin system blockade in diabetic patients was not demonstrable and was potentially dangerous.
HOPE Study (Mann et al., 2001)	CKD and non CKD patients	Ramipril vs. Vitamina E vs. Placebo and Vitamina E vs. Placebo	Major adverse cardiac event (MACE); effect of Ramipril on CV risk reduction.	In patients with previous cardiovascular disease and diabetes, mild renal impairment significantly increased the risk for subsequent cardiovascular events. Ramipril showed to be effective in reducing cardiovascular risk.
EUROPA Study (Brugts et al., 2007)	CKD and non CKD patients with stable CHD	Perindopril vs. Placebo	Major adverse cardiac event (MACE).	Treatment benefits of perindopril were present in both patient groups with low or high eGFR ( ≥ 75 or < 75).
PEACE Study (Solomon et al., 2006)	CKD and non-CKD patients with stable CHD	Trandolapril vs. placebo	Major adverse cardiac event (MACE).	Trandolapril determined a reduction in mortality risk in patients with CKD. Conversely, this result was not confirmed in non-CKD patients.
Val-HeFT Study (Anand et al., 2009)	CKD and non CKD patients with Hearth failure (HF)	Valsartan vs. placebo	Death and first morbid event (death, sudden death with resuscitation, hospitalization for HF, or administration of intravenous inotropic or vasodilator drugs for 4 hours or more).	Valsartan reduced the risk of the first morbid event in patients with CKD and HF.
AASK Study (Norris et al., 2006)	African Americans with hypertensive nephrosclerosis	Metoprolol vs. Ramipril vs. Amlodipine	Major adverse cardiac event (MACE).	Neither randomized antihypertensive drugs nor blood pressure level had a significant effect on the occurrence of CV events.
PREVEND IT Study (Asselbergs et al., 2004)	Microalbuminuric subjects	Fosinopril vs. placebo	Major adverse cardiac event (MACE).	In microalbuminuric subjects, fosinopril significantly reduced albuminuria. In addition, fosinopril treatment appeared to reduce the risk for cardiovascular events.

Figure 3. Baseline renal risk in DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME and CREDENCE trials. Horizontal dotted lines and white arrows estimate trials averaged mean eGFRs minus 1 pooled standard deviation; vertical dotted lines and white arrows approximate trials’ quartile 3 of UACR. (Reproduced and adapted from (Kluger et al., 2019))

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