Chronic kidney disease (CKD) is defined by structural or functional kidney abnormalities for more than three months with a significant impact on health. The major causes of chronic kidney disease are diabetes and arterial hypertension. Therefore, the increasing incidence of this disease in almost all parts of the world is not surprising. In many countries, about two hundred new cases per one million citizens occur every year, while four hundred such new cases occur in the United States. We estimate that there are about 150,000 patients in Croatia suffering from CKD (1). The general risk factors for CKD in developed countries are overweight, hypertension, diabetes, advanced age, smoking, physical inactivity and a positive family history. CKD is associated with many complications, the most prominent of which is cardiovascular diseases (CVD).

Today, CKD is defined as renal impairment characterized by albuminuria and a glomerular filtration rate less than 60 mL/min lasting for more than three months. Since glomerular filtration can show the impairment very well, kidney disease is accordingly classified in five degrees. However, this classification does not include the factors that are important for the prognosis of the kidney disease, such as proteinuria, so a new classification that simultaneously considers both glomerular filtration and albuminuria has been introduced (Table 1).

This CKD classification has been much discussed in the last ten years. We are trying to find an optimal way to take all disease factors into account (primary disease, glomerular filtration rate and albuminuria as indicators of current renal impairment, other associated diseases and a patient’s condition, individual risk of complications, etc.) and make decisions on a therapy and management of patients accordingly. (2)

Other causes of CKD may be different forms of glomerulonephritis, bacterial infections, stones and parasitic diseases, which are common in underdeveloped countries. Polycystic kidney disease, analgesic nephropathy, tubulointerstitial disease, autoimmune disease, vasculitis, amyloidosis, multiple myeloma, hemolytic uremic syndrome and endemic nephropathy can also lead to chronic renal failure.

Early identification of patients with renal disease is of great importance because timely intervention can reduce the chances of cardiovascular complications or renal function impairment. There are some non-pharmacological measures, such as smoking cessation, a tailored diet accompanied by limited salt intake, moderate exercise, etc., that are also very important. Another key measure is a good control of blood pressure (BP). BP target values for kidney patients are <125-135/75-85 mmHg. Drugs that have an effect on the renin-angiotensin system are the drugs of choice for BP control in CKD because of their renoprotective action and proven effect in reducing complications. In diabetic patients with CKD, glycemic control is also very important. The target values are HbA1c <7% and glycemia 4-7 mmol/L. The correction of dyslipidemia is important. Kidney patients should keep the values prescribed for the general population, while statins also have also have a primary place as a medical therapy. (3) Aspirin is commonly prescribed in CKD because of its proven effect in preventing cardiovascular events, but its administration must be individualized in view of the increased risk of bleeding. (4) The treatment of patients with CKD also requires correction of metabolic complications, the most common of which are anemia and disorders of mineral metabolism.

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the general population and one of the most important factors for ischemic stroke, and it is an independent predictor of death. (5) It is a supraventricular arrhythmia that is initially caused by improper electrical activation originating in the pulmonary veins and results in an incorrect activation and the loss of atrial contraction. Its incidence and prevalence increases with age. The 12-lead ECG shows irregular electrical activity, called the F-waves instead of P-waves. Ventricular action may be correct, but it is commonly irregular. (6)

AF risk factors largely overlap with those for the development of CKD (advanced age, smoking, hypertension, diabetes). AF is a very important public health problem not only because of its prevalence, but because of its potential consequences, such as thromboembolic incidents and heart failure. Some of the symptoms of this arrhythmia that significantly impair the quality of life are palpitations, shortness of breath, dizziness and fatigue. The most common form of AF starts as paroxysmal and patients have symptoms only intermittently. There are several classification of AF. According to the recommendations of the European Society of Cardiology, (7) it is classified into paroxysmal, persistent, longterm persistent and permanent AF. AF recorded for the first time constitutes a special group. Paroxysmal AF is a recurrent form with attacks that last less than seven days, usually up to 48 hours, that cease by themselves. Persistent AF lasts more than 7 days and requires electrical or medicament conversion to sinus rhythm. Long-term persistent AF lasts longer than a year, but still there is an intention of the doctor and patient for conversion to sinus rhythm. The last subgroup, permanent AF, includes patients for whom no decision has been made on cardioversion, or it has been attempted but yielded no results. (8)

Therapeutic options in AF are reduced to symptomatic treatment, followed either by control of frequency or control of heart rate mandatory including anticoagulant therapy. Generally, if the AF lasts longer than 48 hours, conversion of rhythm to sinus rhythm is not permitted without the introduction of oral anticoagulant therapy. Then two other options remain: to rule out the presence of thrombi by transesophageal ultrasound of the heart, and conducting the conversion or conversions without an ultrasound examination one month after the administration of anticoagulant therapy. Another mainstay of AF therapy is frequency control. Studies have not shown which of these two options is better. If drug therapy is not successful, electrocardioversion, catheter ablation of pulmonary venous confluence (in patients with paroxysmal or persistent AF) and implantation of a permanent pacemaker with an AV node ablation is an option to be considered in certain groups of patients. (9)

Patients with CKD are more likely to develop CVD than the rest of the population, and we know that they are the major cause of death in dialysis patients. It has been shown that low glomerular filtration rate and elevated albuminuria are associated with an increased risk of cardiovascular events, regardless of whether they are new or recurring ones. (10) Mortality caused by CVD among patients in end-stage kidney disease is 15-30 times higher than in the general population of the same age. (11) This difference is even more pronounced among the younger age group, from 25-34, in whom the mortality is 500 times higher than among the healthy patients of the same age. (12) Patients in the third and fourth stage of CKD are even more likely to die of CVD than to progress to end-stage kidney disease. (13)

There are many reasons for the increased risk of cardiovascular events in patients with CKD. In addition to traditional risk factors such as obesity, smoking, hypertension, dyslipidemia, etc., patients with CKD also show many non-traditional risk factors such as anemia, disorders of mineral metabolism, malnutrition, oxidative stress, proteinuria or albuminuria. This latter is to be diagnosed and monitored in patients at increased risk for kidney disease not only because of evidencing and classifying the disease, but also because of its predictive value in the therapy. (14)

The aim of this paper is not a detailed explanation of all cardiovascular risk factors in CKD. However, we only wish to warn about three very significant risk factors: anemia, mineral metabolism disorder and proteinuria or albuminuria.

Anemia is almost a normal event in the population of patients with CKD. The most important cause is the lack of erythropoietin. In short, anemia is the cause of reduced tissue oxygenation. It increases sympathicus activity, and consequently, myocardial activity. Reduced viscosity results in an increase in venous return to the heart, which consequently leads to left ventricular hypertrophy.

Mineral metabolism disorder develops in the early stages of CKD. It is reflected in a disorder of the metabolism of calcium and phosphorus, parathyroid hormone, vitamin D and FGF 23 (Fibroblast growth factor 23) hormone, which inter alia regulates phosphorus circulation. The consequence of these disorders is an accelerated calcification of blood vessels and other tissues such as the myocardium.

There is abundant experimental and clinical evidence about the association between proteinuria or albuminuria and cardiovascular events. (15) According to the Canadian study, Hemmelgarn et al, the presence of proteinuria is associated with an increased risk of death, myocardial infarction, and progression of renal disease (increased risk of atherosclerotic events in peripheral vascularization). In the hypertensive population, albuminuria increases the risk of ischemic heart disease by four times. Also, in patients with hypertension and diabetes, albuminuria leads to a thickening of the left ventricle. Patients with type 1 diabetes and albuminuria show cardiovascular mortality that is nine times higher than in normoalbuminuric patients. The World Health Organization (WHO) Multinational Study of Vascular Disease in Diabetics has also proven the association between proteinuria and ischemic heart disease in patients with type 2 diabetes. Albuminuria is associated with chronic heart failure and studies have shown that it is not only a risk factor for heart failure but also provides prognostic information. (15)

There are several ways in which proteinuria and CVD are associated, including inflammation, endothelial dysfunction and thrombogenic factors. "Steno" hypothesis suggests that proteinuria leads to endothelial dysfunction. This hypothesis is reinforced by an increase in adiponectin, CRP, ADMA (Asymmetric dimethylarginine) and vWF (von Willebrand factor). The association via thrombogenic factors has been proven by the correlation of protein excretion and vWF concentration, adhesive molecules, fibrinogen and tissue plasminogen activator, all of which may lead to an increased risk of thrombosis. (16)

The REGARDS study conducted on 26,917 patients in the US demonstrated the increased prevalence of AF in patients with CKD, mostly among the patients in the third and fourth stage of the disease. The prevalence of AF among the subjects without CKD was 1%, among the patients in the first and second stage of CKD it was 2.8%, in the third stage the prevalence was 2.7%, and in the fourth and fifth stage it was 4.2%. Patients in the first two stages of CKD show a 2.67 times greater risk of AF, patients in the third stage show a 1.68 times greater risk, and the risk in the fourth and fifth stage is 3.52 times higher. (17)

AF and CKD share some common risk factors, such as hypertension, diabetes, current CVD, obesity, and metabolic syndrome. (18) Retrospective studies have shown that CKD is an independent risk factor for the occurrence of AF and that the occurrence of AF in CKD is associated with an increased mortality rate. (19)

The investigations suggested that AF could be a factor that accelerates the progression of CKD in the end-stage, and it was later proven that AF is associated with a 67% higher relative rate of progression to the end-stage renal disease. Recent studies confirm that AF may contribute to a faster progression of CKD to the end-stage. AF also stimulates systemic inflammation that contributes to the impairment of renal function. Since AF induces myocardial fibrosis, it is possible that the same process of fibrosis is stimulated in the kidney, perhaps through the systematic profibrotic tendency in the body. AF contributes to systolic and diastolic dysfunction that can impair CKD due to altered hemodynamics, venous congestion and activation RAAS. (20) AF is also known to be associated with long-term impaired clinical outcomes in patients in end-stage CKD. (21)

There are several hypotheses that explain the association between CKD and AF. Neurohormonal activation is involved in the progression of renal impairment and its cardiovascular consequences. The activation of the renin-angiotensinaldosterone system in patients with CKD causes an increase in the proliferation of cardiac fibroblasts and cardiac hypertrophy. This effect could be proven by an increased secretion of profibrotic factor TGF-β1. (22) This is confirmed by the fact that spironolactone proved to be effective in reducing AF due to blocking of the mineralocorticoid receptor and its antifibrotic effect. (23) Arrhythmogenesis is also stimulated by the sympathetic activation that, like the increase in the concentration of adrenergic hormones in serum, is present in patients with CKD. (22) Systemic inflammation present in renal disease also plays a role in the pathogenesis of AF, while the marker CRP is elevated in CKD and AF. This assumption is confirmed by a cardiac biopsy sample analysis in patients with AF where inflammatory changes are found. (24) Hhs-CRP was identified as a good marker for the prognosis of cardiovascular events, including death, due to its association with systemic inflammation, endothelial dysfunction and the risk of thromboembolic incidents. (25) Cardiac structural abnormalities associated with CKD from an earlier date, such as left ventricular and atrial hypertrophy, increase the risk of arrhythmic events in the same way. (24) Metabolic abnormalities that are present in CKD, such as metabolic acidosis, impaired potassium and calcium circulation, can also lead to an increased risk of the development of AF. (26) Oxidative stress plays an important role in the AF pathogenesis, and it increases with the impairment of renal function. For example, the expression of nicotinamide adenine dinucleotide phosphate oxidase is increased in the left atrium. (27)

Patients with a progressing form of CKD and a co-existing AF diagnosis have a significantly higher risk of death. (19) It has been proven that proteinuria is associated with a 50% higher risk of thromboembolic incidents. AF therapy in patients with CKD is indeed a complex therapy primarily because patients suffering from CKD have a significantly higher risk of bleeding during anticoagulant therapy, which also contributes to a higher rate of mortality. Warfarin in patients with CKD leads to an increased risk of bleeding. It has also been proven that it can contribute to calcification of blood vessels and heart valves and increase uremic arteriolopathy. (28) The benefit or the risk of administering warfarin in patients with CKD is still debatable. (29) A 2012 trial shows that more recent oral anticoagulant drugs such as dabigatran, apixaban and rivoroxaban might replace warfarin in the future in patients in the third and fourth stage of renal disease, who are also suffering from AF. (30)

We see a similar situation in dialysis patients. AF prevalence among hemodialysis patients is 11-27%, as opposed to that in the general population, which is 1%. Since we know that the AF is associated with stroke, warfarin is administered in the general population to prevent it, while the bleeding rate is negligible. However, this is not a case in dialysis patients. Some recent trials have shown contradictory results on the reduction of cerebrovascular events when administering warfarin in patients on hemodialysis. However, a higher incidence of bleeding during its administration in patients with CKD has been definitely proven compared to the population without impaired renal function. Thus, it is likely that the risk of administering warfarin in these patients outweighs its positive impact. (31)

The administration of anti-arrhythmic drugs used in the treatment of AF is severely limited in patients with CKD because most of them are eliminated through the kidneys and their administration can easily raise serum creatinine values and have adverse effects. (32) L'Allier et al report a decreased incidence of AF in 10,926 patients with hypertension treated with ACE inhibitors. (33)

Another treatment option is catheter ablation. Patients with CKD are more likely to have recurring AF after one procedure is performed, so the value of this therapeutic procedure is open to question. (34) Some studies suggest a completely unsatisfactory outcome of catheter ablation in patients with CKD and with a lower glomerular filtration rate, (35) while other studies have demonstrated that the successful elimination of arrhythmias by catheter ablation improves renal function in patients with mild to moderate renal impairment. (36) Overall, it is difficult to predict and prevent a relapse of AF after catheter ablation in patients with end-stage CKD and there is a greater likelihood that the procedure will have to be performed again. (32)

Chronic kidney disease is a major public health problem in the developed world, and is becoming an ever greater problem in developing countries. The incidence of cardiovascular complications in patients with CKD is high. There is ample evidence that AF in patients with CKD is more common than in the general population.

Unfortunately, there is a shortage of evidence of the efficacy and side effects of drugs and the efficacy of various procedures in patients with CKD. Recent drugs and new methods have entered into clinical practice after rigorous clinical trials on subjects with preserved renal function without involving patients with impaired renal function and those on dialysis. The importance of involving this group of patients in all clinical trials is commonly emphasized in order to define clear guidelines and for indications and contraindications. (37) There are no clear guidelines for the treatment of AF in patients with CKD, especially for the administration of warfarin to prevent strokes, a common complication of cardiac arrhythmias. Because of more common bleeding with the administration of warfarin in patients with CKD than in the general population, its benefit remains a subject of debate. Further investigations of chronic kidney disease and CVD are required, while close coordination in daily clinical work between nephrologists and cardiologists is necessary. In this way, many potential complications in patients with CKD can be successfully prevented and treated.