Cardiovascular Diseases in Chronic Kidney Disease

Abstract

Cardiovascular Disease in Chronic Kidney Disease. Cardiovascular Disease (CVD) is a topical issue of public health concern in Chronic Kidney Disease (CKD) Patients. Worldwide, CVDs are the leading cause of death. The burden of CKD is growing and CKD patients have been observed to develop CVD very early, contributing to the accelerated progression of the underlying kidney disease. CVD has also been found as the usual cause of death in CKD patients rather than the progression of the CKD itself. The risk factors for CKD and CVD are mutual and interwoven, hence CKD has been termed CVD risk equivalent. Early identification and intervention of CVD risk factors in CKD patients is imperative to limit the progression of disease and mitigate its attendant consequences.

1. Introduction

Chronic Kidney Disease (CKD) is defined as the glomerular filtration rate (GFR) <60 ml/min/1.73m² or the presence of other markers of kidney damage including proteinuria or albuminuria for >3 months [1].

The kidneys are essential organs in the body; they function to filter out wastes, toxins and excess fluid. They also function as endocrine organs, producing and activating various hormones such as erythropoietin, 1, 25 dihydroxycholecalciferol, Renin angiotensin aldosterone system.

CKD is one of the non communicable diseases of public health concern. It is a cause of premature mortality, and contributes to significant morbidity and poor quality of life. It is also an independent risk factor for cardiovascular disease which is the global leading cause of premature mortality.

CKD is a progressive disease and it is classified based on how well the kidney is functioning which is usually assessed by the estimated glomerular filteration rate (eGFR) and the level of protein in the urine.

GFR categories in CKD [2].

Stage	Description	eGFR (ml/min/1.73m^2)
Stage 1(G1)	Normal or high	≥90
Stage 2(G2)	Mildly reduced	60–89
Stage 3(G3)	Mildly to moderately reduced	45–59
Stage 3b(G3b)	Moderately to severely reduced	30–44
Stage 4(G4)	Severely reduced	15–29
Stage 5(G5)	Renal failure	<15

Abbreviations: CKD: chronic kidney disease; GFR: glomerular filteration rate.

In the past, CKD staging was only limited to eGFR classification only, however albuminuria level was included to improve the prognostic value of the classification. Albuminuria greatly increases the incidence of end stage renal disease (ESRD) and has been proven to hastens the progression of CKD to ESRD [2, 3].

The essence of staging is for early detection of those with accelerated risk of renal function decline and to promptly institute treatment to halt or delay the progression.

Albuminuria stages	AER (mg/day)	Description.
A1	<30	Normal to mildly increased
A2	30 to 300	Moderately increased
A3	>300	Severely increased.

AER: albumin excretion rate.

2. Etiology of CKD

Diabetes and hypertension are the leading causes of CKD [4]. They are responsible for about 70% of the cases of CKD.

Other causes of CKD include: Glomerulonephritis, Inherited disease conditions like polycystic kidney disease, Congenital renal and urinary tract abnormality, autoimmune disease.

3. Epidemiology

The impact of kidney disease on global health is significant contributing greatly to increasing morbidity, mortality and health care costs both directly, and indirectly as an invaluable cause of cardiovascular disease (CVD).

The world wide estimated prevalence of CKD is 13.4%, 10.1% in Africa and 13.2% in sub Saharan Africa. There has been an increase in the global mortality rate of CKD [5]. The worldwide CKD mortality rate increased by approximately 40% between 1990 and 2017. In year 2017, more than 1 million people died of CKD with sub Saharan Africa recognized as one of the regions with the highest burden of the disease [4].

Early stages of CKD are asymptomatic; hence screening is important for early detection and prompt initiation of management of the disease.

The prevalence of CVD is markedly higher in CKD patients compared to the general population and it is a major contributor to premature mortality and reduced quality of care in CKD patients.

4. Symptoms

Since early stages of CKD are largely asymptomatic, diagnosis relies heavily on blood and urinary investigations. Other pointers to CKD include: hypertension, Diabetes, anemia.

5. Complications of CKD

CKD is a systemic disease and hence has numerous implications. The various complications of CKD directly or indirectly heighten cardiovascular risk hence further contributing to the adverse outcomes in CKD patients.

Increased cardiovascular risk in CKD patients is well recognized. With significant cardiovascular risks found across the various CKD stages, CKD has been termed an independent risk factor for cardiovascular disease [6]. Albuminuria greatly increases the incidence of ESRD and has been proven to hasten the progression of CKD to end stage renal disease [2, 3].

It has been well established that Cardiovascular disease such as Peripheral arterial disease, Ischemic heart disease, heart failure and stroke are unarguably commoner in CKD patients compared to the general population [7].

The various complications of CKD include: Hypertension, anemia, bone disease, heart disease, hyperlipidemia, electrolyte imbalance such hyperkalemia, hyper or hypocalcaemia, salt and water retention.

Hypertension remains one of the commonest complications of CKD [8]. Hypertension is both a cause and consequence of CKD and contributes significantly to the cardiovascular risks in CKD patients.

Anemia is defined as hemoglobin level < 13 g/dl and < 12 g/dl in men and women respectively by the WHO, [9] while the National Kidney Foundation sets a slightly higher target of <13.5 g/dl in men [10].

Anemia is a common complication in CKD patients and it develops majorly as a result of deficiency in erythropoietin synthesis. Erythropoietin is a glycoprotein produced by the kidney and plays a critical role in the formation of red blood cells. This production is significantly compromised when the kidney is damaged. Anemia plays a significant role in cardiovascular disease outcome in CKD patients contributing to IHD, left ventricular hypertrophy, fluid retention hence, worsening heart failure. and accelerating CKD progression [11]. This has formed a therapeutic target in CKD patients.

Another major function of the kidney is the regulation of calcium phosphate homeostasis, a function that is also altered when the kidney is dysfunctional. This results in disruption of this balance resulting in low calcium and excess phosphate level in the blood. Hyperphosphatemia has been established as a risk factor for cardiovascular disease, as high serum phosphate level has been associated with hypertension, vascular and cardiac calcifications, atherosclerosis, left ventricular hypertrophy and myocardial fibrosis [12].

Cardiac Disease: Various forms of cardiac diseases such as left ventricular hypertrophy, cardiac arrhythmias, cardiac valvular calcifications, IHD, heart failure, sudden cardiac death have characterized CKD outlook. Cardiac diseases are present at all CKD stages in higher proportion compared with the general population and the burden is undoubtedly higher at the advanced stages of CKD. It has been well established that cardiovascular disease rather than progression to end stage renal disease is the cause of death in majority of the CKD patients. Although, therapies to target cardiovascular diseases have been recommended, mortality outcome in CKD attributable to cardiac disease remains disproportionately high [13].

Dyslipidemia and CKD outcome: Dyslipidemia is a common complication in CKD patients and is a precursor to atherosclerosis formation. Dyslipidemia is a major modifiable risk factor for CVD in the general population and contributes significantly to the cardiovascular burden in CKD patients. Studies have shown that dyslipidemia contributes to systolic heart failure, ischemic and non ischemic cardiac dysfunction [14].

Electrolyte imbalance: The kidney functions to regulate water and electrolyte balance in the body. When there is insufficient water and electrolytes, the kidney conserves fluid as much as possible; it decreases urine output, produces concentrated urine and water intake is triggered. When there is excess, the body compensates by increasing urinary excretion.

Hyperkalemia is the most common electrolyte imbalance in CKD patients. The kidney normally excretes about 90% of the serum potassium. Hyperkalemia can trigger a life threatening arrhythmia that can result in cardiac arrest [15]. Disordered metabolism of sodium, calcium and magnesium are other important electrolyte derangement of great impact in CKD patients and they worsen outcomes in these patients [16].

Abnormal fluid status is a common finding in CKD patients with fluid overload being a major presentation in advanced CKD patients. Assessment of fluid status in CKD patients remains challenging. Various technologies to objectively evaluate fluid level to support the clinical examination method still prevalently utilized are being recommended for better assessment and improved management [17]. Fluid overload in CKD patients is associated with hypertension, LVH, heart failure, pulmonary edema [18].

The complications of CKD ultimately culminate in worsened cardiovascular outcomes and premature mortality in these patient group [19].

6. Markers in CKD

The high incidence of various cardiovascular complications in CKD patients have been linked with several pathophysiological pathways. Over the years, there have been concerns about the possible utility of markers to improve and enhance the diagnostic, prognostic and therapeutic accuracy of CVD in CKD patients. Although, this has been met with divergent viewpoints, a combination of biochemical and cardiac markers rather than any single one have been suggested as likely useful prognostic tools in these patients [20]. Some of the markers of interest include: Natriuretic peptides, Cardiac troponins, inflammatory cytokines, Fibroblast growth factor 23 (FGF 23), Asymmetric Dimethylarginine (ADMA).

Natriuretic Peptide: Studies have shown that B type natriuretic peptide (BNP) and amino – terminal pro B type natriuretic peptide (NT- proBNP) are useful markers in early identification and risk prediction of cardiac disease. Plasma BNP levels have been shown to increase progressively with declining renal function, and natriuretic peptides have shown significant correlation with heart failure severity, ischemic heart disease prevalence and left ventricular dysfunction in CKD patients [20].

Cardiac Troponins: Coronary artery disease is a frequent finding in CKD patients and is the leading cause of morbidity and mortality in them. The traditional risk factors in CKD patients accelerate atherosclerosis formation thus contributing to the high prevalence of Ischemic heart disease found in these patients [21]. Troponins T (cTnT) and I (cTnI) are useful markers of cardiac injury. They have been found to be elevated in CKD patients and are useful predictor of mortality in them [22].

CKD has been recognized as a chronic inflammatory condition with production of reactive oxygen species and other proinflammatory substances through various pathophysiologic mechanisms. The ongoing persistent inflammatory state in CKD patients has been associated with cardiovascular and all cause mortality. Various factors catalyzing the inflammatory state in CKD patients include: increased generation and reduced clearance of reactive oxygen species and inflammatory cytokines, metabolic acidosis, impaired metabolism of adipose tissue and recurrent infections [23]. Raised Interleukin 6 (IL – 6), C reactive protein (CRP), Tumor Necrosis Factor alpha (TNF) are some of the inflammatory markers that have been reported in CKD patients, they predict CKD severity and have prognostic implications for cardiovascular diseases [24].

Calcium Phosphorus homeostasis is critical in human physiology. This delicate balance is disrupted in CKD. Vitamin D activation is impaired with kidney disease and serum phosphate excretion is disrupted resulting in low blood calcium and elevated serum phosphate. FGF 23 is a phosphorus regulating hormone. Studies have shown that high levels of FGF 23 is an independent predictor of mortality and is associated with worsening of CKD progression and cardiovascular complications [25].

ADMA is an endogenous inhibitor of nitric oxide synthase. Its presence implies reduced production of nitric oxide (NO). Nitric oxide maintains endothelial function via its vasodilatory and anti inflammatory properties. Raised ADMA levels have been found in CKD patients and is associated with endothelial dysfunction, atherosclerosis, and ultimately CVD [26].

7. Treatment

Since CKD is largely asymptomatic at inception, preventive measures and regular screening are necessary strategies to minimize its incidence and prevalence.

Healthy lifestyle is recommended. Exercise has been found to play a critical role in blood pressure and blood glucose control; it keeps body weight in check and prevents obesity. It is a very important tool in cardiovascular risk reduction [27].

Hypertension: The current KDIGO blood pressure recommendation suggests a target systolic blood pressure of <120 mmHg. This is in view of the recent evidence of enormous cardiovascular benefits that is associated with lower blood pressure reduction in high risk groups such as CKD patients [28]. Both lifestyle adjustment and pharmacological approach to blood pressure control are required to achieve optimal blood pressure control.

Blood glucose control should be individualized and tailored to individual need and target HBAic of between 6.5 and 8% has been recommended [29].

Anemia: Treating anemia with erythropoietin to a safe target of between 11 and 12 g/dl has been recommended. Values higher than this has been associated with increase morbidity and mortality [30].

Hyperphosphatemia: Owing to the association of excess phosphate level to adverse cardiovascular outcomes in CKD patients, reducing the blood phosphate levels has been considered a promising therapeutic target that might improve the prognosis of CKD patients [13]. Currently dietary and pharmacological approaches aimed at this reduction are being employed [13].

Cardiac disease: various lifestyles and pharmacologic agents have been established to improve outcome however, studies are still ongoing to ensure better and improved prognoses in CKD patients as current data still shows excess premature mortality in CKD patients attributable to cardiac complications.

Dyslipidemia: There are various means of reducing serum lipid and its effect on cardiovascular outcome especially in CKD patients. While the role of dietary control in dyslipidemia cannot be undermined, statins have been established as pharmacologic agents of choice in the treatment of dyslipidemia in CKD patients [31].

Diuretics are prescribed to eliminate excess fluid and provide symptomatic relief to fluid overload in CKD patients.

8. Conclusion

The burden of CKD is enormously huge and its impact and contributions to premature mortality, morbidity and economic loss is quite concerning. Healthy lifestyle measures should be adopted early as preventive measures and to limit CKD progression when present, prompt screening, diagnosis and early initiation of treatment of the risk factors when required will go a long way to improve outcomes of CKD.