Chronic Kidney Disease Identified as Risk Factor for Cardiovascular Complications

Chronic kidney disease (CKD) is common, affecting around 5% to 10% of the population. Most patients with CKD do not develop progressive kidney disease or end-stage renal disease (ESRD), but are at increased risk of cardiovascular disease (CVD). This could reflect the fact that CKD is more common in patients with CVD risk factors, such as diabetes mellitus, preexisting CVD, hypertension, and older age.

However, registry studies have identified the reduction in glomerular filtration rate (GFR) as an independent effect on cardiovascular risk in the general population and in patients with previous CVD, heart failure or stroke.

The magnitude of this effect is difficult to quantify. The independent effect of IFG, reduced in the early stages of CKD, appears to be minimal. Living kidney donors, studied as an ideal and highly selected population of healthy people, who undergo surgery that removes 50% of their kidney mass, recover between 60% and 70% of postoperative GFR.

In a large Norwegian cohort, the increased long-term CVD risk was small, largely driven by the small proportion of these patients who progressed to ESRD, presumably reflecting an unrecognized genetic risk of kidney disease in these individuals. .

These data are consistent with previous observations that cardiovascular risk increases significantly only when GFR falls to <60 ml/minute/1.73 m2.

From this value, the cardiovascular risk increases progressively and is maximum in patients with ESRD who require dialysis, with an age-adjusted cardiovascular risk of at least 20 times higher than in the general population. Cardiovascular risk falls with successful kidney transplantation, but remains 3-5 times higher than in the general population.

In this summary, the authors focus on patients with ESRD, including those requiring dialysis and transplant. However, it is important to appreciate that CKD is a continuum, and that the pattern of CVD in ESRD is very different from that of early CKD, where it is similar to that of the general population.

Untreated ESRD presents with uremic complications such as pericarditis and pericardial effusions, although these are now rare with the development of effective renal replacement therapies.

Although ESRD is a state of accelerated atherosclerosis, acute myocardial infarction is not particularly increased in these patients, and it is unusual to see typical ST elevation in patients with ESRD undergoing dialysis.

Acute myocardial infarction can be difficult to diagnose in this group of patients, who often have no pain, a high prevalence of electrocardiographic abnormalities, and chronically elevated troponin concentrations.

Perhaps as a result of this, registry data and clinical trials show notable differences in the pattern of cardiovascular events in ESRD compared to the general population. Considering that the most common mode of cardiovascular death in the general population is myocardial infarction, sudden cardiac death (presumably due to arrhythmia) and death due to heart failure predominate in ESRD.

In ESRD, significant structural cardiac anomalies develop, with left ventricular hypertrophy (LVH) almost universal at the start of hemodialysis. LVH is the probable substrate for sudden cardiac death, presenting a vulnerable myocardium regularly insulted by the contribution of fluids and electrolytes, as well as microscopic ischemia during dialysis sessions.

Pulmonary edema becomes more common with decreased kidney function, as a result of increased water retention. This is also exacerbated by abnormalities of the left ventricle, either by its hypertrophy and diastolic dysfunction or by its systolic dysfunction.

Edema can occur even in patients with normal systolic function, as a consequence of extreme fluid overload, and in patients with CKD due to bilateral renal artery stenosis.

Conventional cardiovascular risk factors are highly frequent in CKD and ESRD.

However, certain CVD risk factors are specific or have a dominant effect on CKD. These factors include albuminuria and proteinuria, anemia, homeostasis of abnormal calcium/phosphate/vitamin D metabolism (so-called bone mineral disorders), and arterial calcification and inflammation.

> ​ Hypertension

Hypertension is common in non-dialysis CKD and is a major risk factor for CVD as well as CKD progression. The mechanisms involve inappropriate activation of the reninangiotensin system, and alteration of endothelial function in early CKD, but in the advanced and terminal stages it depends more on sodium and water retention.

Vascular calcification is also important, associated with reduced vascular compliance, which contributes to systolic hypertension in particular.

Once the individual is established on dialysis, the relationship with outcomes is less clear: there is a “J”-shaped relationship with mortality, reflecting “reverse causality” and the fact that patients with comorbid conditions They may have low blood pressure, probably reflecting underlying cardiac dysfunction. This makes blood pressure goals in ERT difficult to define.

> ​ Smoking

This is a risk factor for CVD in CKD as well as for CKD progression. The risk persists in patients treated with maintenance dialysis or after transplant.

> ​ Diabetes mellitus

Diabetes mellitus is also a risk factor for CVD in CKD, as well as for progression of CKD. Diabetic nephropathy is one of the main causes of ESRD and represents 35-50% of patients with ESRD. This proportion increases in accordance with the increasing incidence of type 1 diabetes mellitus, but particularly type 2.

After transplant, the prevalence of diabetes also increases; New onset diabetes after treatment appears as a consequence of the action of immunosuppressive agents. Tight glycemic control reduces the progression of microvascular complications such as nephropathy, while meticulous blood pressure control reduces the progression of CKD and cardiovascular events.

> ​ Hypercholesterolemia and dyslipidemia

In the general population, these terms are interchangeable in terms of prevalence and risk implication, but neither the pattern of dyslipidemia nor the relationships with outcome are the same in CVD, particularly ESRD.

Although plasma lipids are abnormal, normal or reduced total cholesterol and low-density lipoproteins, with elevated triglycerides (triacylglycerols) and decreased high-density lipoproteins, can be found as a characteristic picture. This is less evident in ESRD, while low total cholesterol is associated with worse outcomes, the overall relationship has a ’J’ shape that resembles that seen in hypertension.

>​ Ischemic heart disease

Although not the main cause of mortality, ischemic heart disease remains prevalent in ESRD, while significant coronary atherosclerosis is found in almost 30% of potential kidney transplant candidates.

Symptomatic angina can occur even in the absence of coronary artery disease, reflecting subendocardial ischemia caused by myocyte-capillary mismatch in the presence of LVH and microvascular dysfunction.

>​ Cardiac structural abnormalities

Structural abnormalities, such as alterations in the structure of the myocardium and heart valves, are common in CVD and CKD. In ESRD, myocardial abnormalities (uremic cardiomyopathy) are closely associated with adverse outcomes.

Echocardiographic studies have reported 3 patterns of cardiomyopathy affecting up to 85% of patients with ESRD: LVH (with diastolic dysfunction); left ventricular dilation and left ventricular systolic dysfunction, with reported prevalences of 50-80%, 20-40% and 16%, respectively.

LVH develops early in CKD and is associated with left ventricular wall stiffness, a precursor to diastolic heart failure.

The major determinant of LVH is hypertension, but anemia, volume overload, and vascular calcification (strongly influenced by hyperparathyroidism and abnormal phosphocalcium metabolism) may also contribute. In fact, left atrial size (left atrial volume >32 ml/m2), dependent on diastolic dysfunction and intravascular volume, has been identified as a strong predictor of cardiovascular morbidity and mortality across the spectrum of ERC.

Calcified valve anomalies, mainly aortic stenosis, are increasingly recognized. Its development is accelerated in the advanced and late stages of kidney disease (reflecting mineral bone disorders). Calcific aortic stenosis is a therapeutic challenge in patients with ESRD, with substantial comorbidity, and is likely to influence the very high risk of sudden cardiac death in this population.

> ​ Anemia

Anemia is secondary to erythropoietin deficiency and functional iron deficiency; It is almost universal in patients with ESRD.

This coincides with the development and progression of left ventricular abnormalities, particularly LVH, and increased mortality. However, some of the echocardiographic abnormalities reported in relation to the anemia of CKD are, in part, artificial.

Common echocardiographic calculations for determining left ventricular mass are based on chamber volume or diameter. Thus, the large fluctuations in intravascular volume that occur in ESRD, particularly during dialysis gains, result in an overestimation of left ventricular mass.

Therefore, it is important to schedule echocardiographic studies immediately after dialysis, when patients are at their "target" weight and direct measurements such as septal and posterior wall thickness should be obtained rather than derived measurements such as blood pressure index. left ventricular mass.

> ​ Albuminuria and proteinuria

Both predict the progression of CKD and future CVD. Proteinuria is a consequence of kidney damage, although moderate. Increased albuminuria may reflect endothelial injury and vascular dysfunction and is therefore a risk factor for CVD (the kidney acts as a "window" to the vasculature).

> ​ CVD -mineral bone disorder

The name defines the abnormal physiological relationships between the kidney and the skeletal and cardiovascular systems in CKD. The key abnormalities are hyperparathyroidism in the setting of chronic hyperphosphatemia and hypocalcemia associated with functional vitamin D deficiency. Serum parathyroid hormone (PTH) is elevated in CKD.

In experimental models of uremia, it promotes cardiac fibrosis and arteriolar thickening.

Due to impaired excretion, hyperphosphatemia is almost universal in ESRD and is associated with mortality.

Conventional thinking is that phosphate promotes vascular calcification, inducing the transformation of vascular smooth muscle cells into an osteoblast-like phenotype. Recent data also support direct effects of phosphate on vascular function, specifically altered endothelial function. Vascular calcification on plain radiographs is common in ESRD.

Calcification of the coronary arteries, demonstrated by computed tomography, and calcific valvular heart disease are also highly prevalent and act as markers of future CVD and mortality. Other determinants of vascular calcification are age, length of dialysis, and the homocysteine-inflammation relationship.

Fibroblast growth factor-23 (FGF-23) is a phosphaturic hormone, the levels of which are increased in acute kidney injury and CVD. In recent years, FGF-23 has been recognized not only as a biomarker of CKD but also as a key biomarker in CVD associated with ESRD. FGF-23 acts directly on cardiac myocytes to cause LVH and cardiac fibrosis, while its action on the distal convoluted tubule increases sodium reabsorption and circulating volume, also contributing to LVH. Therefore, altered bone physiology in ESRD contributes to increased CVD through two main pathophysiological mechanisms.

The first is vascular calcification and dysfunction, resulting from increased calcium phosphate product and the direct vascular effects of hyperphosphatemia. The second is fibrotic LVH, to which FGF-23 and PTH contribute, leading to an increased risk of heart failure and sudden death due to cardiac arrhythmias.

> ​ Inflammation

ESRD is a state of chronic inflammation and elevated levels of circulatory inflammatory mediators such as C-reactive protein. Interleukin 6 and hypoalbuminemia have also been implicated in an increased cardiovascular risk. Unlike other CVD populations, atheroma is not the main driver of inflammation and C-reactive protein levels, with infection being a more important factor.

>  General measures

To a large extent, the management of CVD in CKD has been based on evidence from the general population, including subanalyses of clinical trials based on estimated GFR; There are few studies on cardiovascular outcomes in renal populations, despite clear differences in CVD in patients with CKD and ESRD, compared to the general population.

For patients with CKD who experience an atherosclerotic cardiac event, it is reasonable to prescribe secondary preventive treatment with antiplatelet agents, adrenergic receptor blockers, angiotensin-converting enzyme inhibitors, and statins. However, there is little evidence to support its use in this setting, and patients with CVD have worse outcomes after myocardial infarction or coronary revascularization. There is a tendency towards undertreatment in CKD, secondary to intolerance, enhanced adverse effects or polypharmacy, making it imperative to avoid “therapeutic nihilism”.

A healthy lifestyle is recommended for all patients with CKD, which involves stopping smoking cigarettes, a low-sodium diet, weight control, avoiding physical inactivity and good diabetes control. In patients with type 2 diabetes and mild to moderate CKD, more intensive glycemic control (glycated hemoglobin <6.5%) has been associated with greater cardiovascular and overall mortality.

In the ESRD population on maintenance hemodialysis, daily nocturnal hemodialysis appears to improve cardiovascular health and survival. This is probably the result of better control and fewer “swings” of intravascular volume and electrolytes. However, except for small cohorts undergoing home hemodialysis, daily treatment is impractical or unaffordable.

>  Dyslipidemia

For lipid-lowering, trials have shown that statins were associated with a reduction in cardiovascular events in patients with mild to moderate CKD. The SHARP study showed that the simvastatin/ezetimibe combination reduced the risk of atherosclerotic vascular events in CKD. However, the benefits of lipid lowering in SHARP were mainly observed in predialysis CKD patients while lipid-lowering agents did not significantly influence non-atherosclerotic cardiac events such as sudden death.

In patients on hemodialysis treated with atorvastatin 20 mg/day, study 4D showed no significant effects on cardiovascular death, nonfatal myocardial infarction, and stroke in patients with type 2 diabetes and ESRD.

In the AURORA study, rosuvastatin did not reduce cardiovascular events compared with placebo in 2,800 patients with ESRD undergoing maintenance hemodialysis. However, in kidney transplant recipients, the ALERT trial showed that fluvastatin reduced cardiac deaths and nonfatal myocardial infarction.

The lack of expected impact of statin therapy on ESRD is consistent with the lack of a clear relationship between lipid concentrations and cardiovascular events in patients with CKD and ESRD.

It is generally accepted that this reflects the decreasing contribution of atheromatous CVD to the total CVD burden as renal function declines. Still, guidelines support the use of statins in early CKD , where the CVD pattern is similar to that of the general population, and to prevent atheromatous CVD across the spectrum of CVD.

The KDIGO (Kidney Disease Improving Global Outcomes) guidelines suggest that statins should be used, but without evidence supporting a cholesterol target, which has supported a controversial "fire and forget" approach to statin treatment.

>  Blood pressure

Good blood pressure control in patients with CKD stages 1-4 is associated with a lower rate of renal function deterioration, delay in the development of ESKD, and possible benefits for CVD. In general, guidelines recommend that blood pressure in patients with CKD should be <140/90 mmHg; in patients with CKD and diabetes, and those with significant proteinuria (protein/creatinine ratio 100 mg/mmol), target values ​​should be <130/80 mmHg.

It is preferable to use renin-angiotensin system inhibitors (angiotensin receptor blockers) when tolerated, particularly in diabetes and/or in the presence of proteinuria. Recent data suggest that moderate dietary sodium restriction (<5 g of salt/day) may enhance the effects of renin-angiotensin system blockers.

Once patients are established on dialysis, strategies for blood pressure control are less clear. Blood pressure varies during dialysis and between dialysis sessions and is closely related to intravascular volume. It has been suggested that blood pressure measurements on days without dialysis are better than measurements made intradialysis, while prospective studies show a linear relationship with mortality.

The choice of agent in patients undergoing dialysis is equally difficult to recommend. There were no great results, although the FOSIDIAL study of fosinopril versus placebo showed a trend towards better survival in the active treatment group. The KDIGO blood pressure guidelines did not include dialysis patients, and while it is reasonable to follow their guidance on individualizing therapy, it is difficult to say more than avoiding extreme blood pressures (systolic pressure >160 or <120 mmHg).

There is no evidence to suggest that aspirin or clopidogrel should be used specifically for primary prevention of CVD in patients with CKD. For secondary prevention of CVD or after coronary intervention, aspirin or clopidogrel should be used following guidelines similar to those in the general population, despite a small increase in the risk of bleeding in CKD.

>  Anemia

Anemia in CKD is secondary to iron deficiency due to decreased absorption and increased blood loss, as well as reduced erythropoietin concentrations. In the recent PIVOTAL trial, higher doses of proactive intravenous iron in patients on maintenance hemodialysis reduced several secondary cardiac outcomes, including myocardial infarction (fatal, nonfatal) and hospitalization for heart failure.

On the other hand, clinical trials that have studied the effects of normalizing hemoglobin concentration with erythropoiesis-stimulating agents have not shown a reduction in the risk of CVD; Normalizing hemoglobin in this context, with erythropoiesis-stimulating agents, could be harmful, with an increased risk of thrombotic complications. This remains controversial, but current guidelines suggest that in patients with CKD requiring such agents, hemoglobin should be maintained between 100 and 120 g/L.

An interesting new development in this area is the investigation of hypoxia-inducible factor prolyl hydroxylase inhibitors, a new class of drugs that activate the hypoxia-inducible factor pathway, leading to the secretion of endogenous erythropoietin and greater availability of iron. Currently, these drugs are in phase III clinical trials, with measurements of cardiovascular outcomes.

>  Diabetes

As diabetes becomes the predominant cause of progressive kidney disease and ESRD, and a consequence of kidney transplantation, it is a critical therapeutic target.

Preventing type 2 diabetes is likely to stop the growing number of patients requiring dialysis. It has been established that, in diabetics, strict control of blood pressure using blockers of the renin-angiotensin system reduces the development of ESRD.

In recent years, a major advance has been the observation in clinical trials that sodium glucose cotransporter-2 (SGLT-2) inhibitors reduce the risk of ESRD and cardiovascular events by about one-third to one-half.

The CREDENCE trial has shown that these benefits persist in patients with established CKD, with an estimated GFR as low as 30 ml/minute/1.73 m2. Although these findings have not yet been supported in guidelines, and the mechanism is unclear, it is difficult not to support their use.

>  CVD-mineral bone disorder

Hyperphosphatemia and elevated PTH are associated with increased mortality in observational studies of patients with ESRD. However, no specific phosphate binder has been shown to reduce cardiovascular mortality.

The EVOLVE study (although in an unbalanced population of dialysis patients) showed no significant effect of cinacalcet on primary composite cardiovascular outcomes (death, myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular disease).

However, there was a suggestion of better survival in patients with calcific valvular disease. Currently, FGF-23 and other molecular targets implicated in CVD-bone mineral disease remain speculative therapeutic targets.

> Cardiovascular evaluation of the potential kidney transplant recipient

CVD is the leading cause of death after kidney transplantation, and death with a functioning graft is the leading cause of graft loss. Therefore, it seems logical to perform CVD screening before transplantation to identify and treat critical coronary artery lesions, and guide the initiation of optimal medical treatment. Controversy remains over how and who to evaluate, and whether there are potential benefits from medical therapy and/or coronary artery revascularization.

For patients >50 years old or with diabetes, preexisting CVD, ischemic ECG, or cerebrovascular or peripheral disease, evaluation by echocardiography and stress testing is suggested. The authors state that, in their experience, even aggressive CVD screening results in a low rate of coronary revascularization (<10% of patients screened). Undue delay in transplant listing is detrimental to asymptomatic or low- to medium-risk stress-tested patients.