Cardiovascular complications in chronic kidney disease: a review from the European Renal and Cardiovascular Medicine Working Group of the European Renal Association

Abstract

Chronic kidney disease (CKD) is classified into five stages with kidney failure being the most severe stage (stage G5). CKD conveys a high risk for coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. Cardiovascular complications are the most common causes of death in patients with kidney failure (stage G5) who are maintained on regular dialysis treatment. Because of the high death rate attributable to cardiovascular (CV) disease, most patients with progressive CKD die before reaching kidney failure. Classical risk factors implicated in CV disease are involved in the early stages of CKD. In intermediate and late stages, non-traditional risk factors, including iso-osmotic and non-osmotic sodium retention, volume expansion, anaemia, inflammation, malnutrition, sympathetic overactivity, mineral bone disorders, accumulation of a class of endogenous compounds called 'uremic toxins', and a variety of hormonal disorders are the main factors that accelerate the progression of CV disease in these patients. Arterial disease in CKD patients is characterized by an almost unique propensity to calcification and vascular stiffness. Left ventricular hypertrophy, a major risk factor for heart failure, occurs early in CKD and reaches a prevalence of 70-80% in patients with kidney failure. Recent clinical trials have shown the potential benefits of hypoxia-inducible factor prolyl hydroxylase inhibitors, especially as an oral agent in CKD patients. Likewise, the value of proactively administered intravenous iron for safely treating anaemia in dialysis patients has been shown. Sodium/glucose cotransporter-2 inhibitors are now fully emerged as a class of drugs that substantially reduces the risk for CV complications in patients who are already being treated with adequate doses of inhibitors of the renin-angiotensin system. Concerted efforts are being made by major scientific societies to advance basic and clinical research on CV disease in patients with CKD, a research area that remains insufficiently explored.

Keywords: Cardiovascular disease; Chronic kidney disease; Clinical aspects; Death; Heart failure; Sudden death.

Figure 1

Cardiovascular prognosis in CKD. CKD is defined as abnormalities for kidney function (eGFR) or damage (albuminuria) lasting >3 months. The figure shows the prognosis for cardiovascular disease and CKD progression according to ACR and eGFR and ACR categories. Green, low risk; yellow, moderate risk; orange, high risk; red, very high risk. Adapted by permission by the KDIGO 2012 Guideline on CKD, Kidney International Supplement 1, volume 3, pages 1–150, 2013.

Figure 2

Relationship between the eGFR and the risk of all-cause and cardiovascular mortality in the CKD Epi consortium meta-analysis.. The Figure has been drawn on the basis of data reported in this study and on Figure 1 data of the same study. The diamond at 95 mL/min/1.73 m² is the reference point (i.e. the eGFR level assumed as normal).

Figure 3

Main pathophysiological alterations leading to hypertension in CKD. High renin and aldosterone levels are common among CKD patients. Angiotensin II, a direct vasoconstrictor, increases vascular resistance and arterial pressure. Angiotensin II also enhances, in a direct manner, sodium reabsorption in the proximal tubule and stimulates via aldosterone hypersecretion sodium reabsorption in the collecting duct. Furthermore, renal function loss per se reduces sodium excretion, which amplifies sodium retention. Non-osmotic sodium accumulation activates pro-hypertensive mechanisms via the inflammatory-immune system (see text). Due to sodium retention and volume expansion secondary to reduced GFR, endogenous cardiotonic steroids (ouabain and other ouabain-like steroids) are increased in CKD patients. High levels of these steroid compounds contribute to raise BP by impairing vasodilatory mechanisms.

Figure 4

Separate and overlapping risk factors for cardiovascular disease in overweight and obesity and in CKD. Risk factors triggered by obesity and Type 2 diabetes are listed in the light green panel and those by CKD in the yellow panel. Overlapping risk factors by obesity/Type 2 diabetes and CKD are listed in the light red panel, at the centre of the figure.

Figure 5

Alterations in lipoprotein metabolism in CKD. The liver generates triglyceride-rich VLDL. Triglycerides are hydrolyzed by lipoprotein lipase (LPL), and the VLDL particles decrease to form IDL particles and finally LDL-cholesterol particles. The LDL particles carry cholesterol to the liver and peripheral tissues. The LDL receptor (LDLR) and scavenger receptors (scavenger receptor B1, SR-B1) are keys to LDL particles clearance. Triglyceride-rich chylomicrons are carriers of lipids from the gut to the liver. Hydrolysis of chylomicrons by LPL produces free fatty acids (FFAs), and chylomicrons in the process become smaller (chylomicron remnants) to be eventually captured by the liver via the LDLR. HDL particles are fundamental for the control of the reverse cholesterol transport (from macrophages and endothelial cells to the liver). Comorbidities like diabetes mellitus and nephrotic syndrome have obvious influences in these alterations. Key alterations in lipoprotein metabolism in CKD patients are clearly identified as increased (+) or decreased (−) or unchanged (≂).

Figure 6

Sequence of CKD-MBD hormones alterations in CKD. Phosphate accumulation and hyperphosphataemia secondary to reduced GFR stimulate FGF23 synthesis in the bone. FGF23 in turn not only augments phosphate excretion but also reduces 1,25 vitamin D levels thereby lowering serum calcium. Reduced renal mass in the course of CKD contributes to lower 1,25 vitamin D, a hormone synthesized in the kidney. Hypocalcaemia stimulates the calcium receptor in the parathyroid glands, which raises circulating PTH. High PTH contributes to increase phosphate excretion.

Figure 7

Multiple inter-relationships between uremic toxins, derangements in endocrine control, inflammation and oxidative stress impinging upon cardiovascular risk in CKD. ‘Progressive renal injury, which facilitates accumulation of uremic toxins, and alterations in the gut microbiota, which increase the synthesis of the same compounds, are main factors for the high levels of uremic toxins in CKD patients and alterations in liver and bone metabolism contribute to this process. Uremic toxins incite inflammation and cardiovascular events and contribute to the chronic kidney disease -metabolic bone disorder (CKD-MBD) and the resulting high risk for fractures of CKD patients. Inflammation, the CKD-MBD disorder and the high risk for cardiovascular events all conjure in causing a high death risk in the CKD population’.

Figure 8

Dialysis-induced systemic stress resulting in a multi-organ injury superimposed on pre-existing comorbidities and affecting outcomes. During haemodialysis, the dialysis apparatus–patient interface triggers a series of risk factors for the cardiovascular system and other organ systems. This may result in myocardial ischaemia and arrhythmia, peripheral vascular disease aggravation, brain ischaemia and damage, and malnutrition.