© Borgis - Postępy Nauk Medycznych 2/2013, s. 164-170
*Tomasz Stompór1, Katarzyna Pankrac2
Czy przewlekła choroba nerek wpływa na występowanie chorób układu sercowo-naczyniowego i zgony z ich powodu u osób w wieku podeszłym?
Does chronic kidney disease impact on cardiovascular complications and mortality in the elderly?
1Department of Nephrology, Hypertension and Internal Medicine, University of Warmia and Mazury, Olsztyn
Head of Department: Tomasz Stompór, MD, PhD, associate prof.
2Department of Nephrology and Dialysis Regional Specialist Hospital, Konin
Head of Department: Dorota Frankiewicz, MD
Przewlekła choroba nerek (PChN) dotyczy znacznego odsetka pacjentów w wieku podeszłym, a ryzyko jej rozwoju rośnie wraz z wiekiem. Obniżona wartość współczynnika przesączania kłębuszkowego jest istotnym czynnikiem ryzyka rozwoju chorób układu sercowo-naczyniowego w tej grupie pacjentów oraz niezależnym czynnikiem predykcyjnym zgonu. Podobną rolę pełni inny wskaźnik uszkodzenia nerek, albuminuria. Ogromne ryzyko powikłań sercowo-naczyniowych i zgonu powoduje, że – pomimo dużej częstości występowania PChN w starszym wieku – zmniejsza się względne ryzyko rozwoju schyłkowej niewydolności nerek (wymagającej leczenia dializami lub przeszczepienia nerki) w tej grupie wiekowej. Większość pacjentów umiera bowiem zanim PChN rozwinie się do najbardziej zaawansowanego, schyłkowego stadium. Wiele spośród uznanych metod leczenia chorób układu krążenia, stosowanych w populacji ogólnej, nie zostało poddanych formalnej ocenie u pacjentów z PChN; niemniej jednak można przyjąć, że wiele z nich cechuje podobna skuteczność także u chorych z upośledzoną czynnością nerek. Dotyczy to zarówno leczenia farmakologicznego (m.in. aspiryny, statyn, inhibitorów enzymu konwertującego angiotensynę), jak i procedur rewaskularyzacyjnych. Pacjenci w podeszłym wieku ze współistniejącą PChN wymagają szczególnej uwagi i opieki medycznej, aby zmniejszyć ryzyko powikłań sercowo-naczyniowych.
Chronic kidney disease (CKD) is highly prevalent among elderly patients and the risk of CKD increases with age. Reduced glomerular filtration rate (GFR) is well-recognized risk factor for development of atherosclerotic cardiovascular (CVS) disease. It is also an independent predictor of increased all-cause and CVS death. Albuminuria, another parameter of kidney damage, is even better prognostic factor for adverse outcome. Excessive risk of CVS complications in patients with CKD translates into relatively lower risk of end-stage renal disease in elderly people as compared to the younger age groups – much more patients in an advanced age with CKD die before reaching the more advanced stages of CKD and need of dialysis or kidney transplantation. Although many therapeutic strategies applied to limit the burden of CVS disease and mortality in the general population were not tested in CKD, it seems appropriate to assume than many of them are also effective in patients with CKD. These include: aspirin, statins, angiotensin-converting enzyme inhibitors, beta- blocking agents and revascularization procedures. Elderly patients with CKD deserve special attention and care to limit their excessive CVS mortality.
Chronic kidney disease (CKD) is recognized as one of the contemporary epidemics – it may affect up to 10-15% of the general population and increases together with increasing age (1, 2). It has been reported that in population aged 65 years and older the prevalence of CKD may reach 40% or even more, especially in particular risk groups, such as diabetics (3-5). The true dimension of this epidemic is not known – the knowledge is estimated based on imprecise criteria. For example, in many epidemiological studies one of the key criteria of diagnosis, i.e. chronicity (duration of at least 3 months) has not been confirmed and CKD was diagnosed based just on single serum creatinine measurement and eGFR calculaction (6, 7). Secondly, applied to diagnose CKD, namely formulas used to calculate glomerular filtration rate were not well validated versus reference methods, especially in some risk groups (including elderly) and patients with borderline GFR abnormalities (i.e. close to 60 mL/min.) (8, 9). These flaws forced the renal community to search for new, more precise tools that might be used for the GFR calculation in certain populations, including elderly; the most important new formula, CKD-EPI has been repeatedly validated recently in older people and appeared to be more precise than MDRD formula, although this notion is not universally confirmed (10, 11).
CKD is traditionally considered a potent risk factor for development and acceleration of cardiovascular (CVS) disease. In this paper we would like to discuss the impact of CKD on several aspects of cardiovascular health in the elderly and the issue of competing risks between development of end-stage renal disease (ESRD) and CVS complications and death.
IMPACT OF CKD ON CARDIOVASCULAR COMPLICATIONS AND DEATH
Review of the literature indicates that almost all possible manifestations of CVS disease are associated with progressing CKD. These include: atherosclerotic peripheral artery disease (PAD), coronary artery disease (CAD), chronic congestive heart failure (CHF), stroke, dysrrhythmias, cognitive function impairment, and others.
In a large observational study assessing the risk factors of stroke that included 23,405 patients in a mean age of 64.9 ± 9.6 years 2,586 subjects with eGFR below 60 mL/min./1.73 m2 were identified. These patients were older (71.1 ± 9.3 vs 64.1 ± 9.4 years) and significantly more frequently suffered from stroke or TIA (18.6 vs 8.3%), CAD (24.9 vs 11.6%), diabetes (33 vs 19%), arterial hypertension (79.7 vs 54.8%) and left ventricular hypertrophy (6.7 vs 6.1%) as compared with subjects with GFR above 60 mL/min./1.73 m2 (all differences with p < 0.001) (12). The Reduction of Atherothrombosis for Continued Health (REACH) registry which included 51,208 patients with high risk for development of atherothrombotic event (patients with CAD, PAD, cerebrovascular disease, diabetes, hypertension, etc.) revealed that CKD significantly increases risk of CVS death, myocardial infarction and limb amputation; the risk increases by factor two or more in subjects with GFR < 30 mL/min./1.73 m2 as compared to those with normal kidney function (13).
Recently the long-term follow-up results of the milestone trial in hypertension (ALLHAT; Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack trial) were published with respect to kidney function. The authors found that during 8.8-year follow-up period the risk of all-cause and cardiovascular mortality, congestive heart failure, stroke or composite cardiovascular end-point was only marginally affected by moderately impaired kidney function (i.e. MDRD-eGFR between 60 to 90 ml/min./1.73 m2), but hazard ratio for all above events was 50 to 100% higher for subjects with eGFR below 60. This was the case for the whole study population and patients with diabetes. In terms of treatment, all three strategies applied in this trial (chlorthalidone, amlodypine and lisinoril) led to similar results and none of them appeared superior to another in terms of prevention of death, CVS events nor development end-stage renal disease (ESRD) (14).
Many data from elderly population come from the US Veteran Affair health system. In the group of 5.787 veterans with PAD falling GFR was associated with increasing prevalence of diabetes, hypertension, coronary artery disease and congestive hear failure (all differences with p value of less than 0.001 between patients with eGFR ≥ 60, 30-60 and < 60 mL/min./1.73 m2). Peripheral artery disease also increased with decrease in GFR and patients with most advanced CKD and PAD manifested in almost 50% with a very severe course (gangrene) as compared to those with eGFR ≥ 60 (35%). Risk of death in patients with PAD and eGFR < 30 mL/min./1.73 m2 was almost three times higher as compared to those with PAD and eGFR exceeding 60 mL/min./1.73 m2 (15).
CKD was an independent predictor of death or unplanned hospital admission in patients with CHF included to the CHARM trial (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity). In the group of patients with a mean age of 65.3 years the hazard ratio of the predefined end-point was not increased in patients with eGFR between 60 and 90 ml/min./1.73 m2 vs. those with eGFR above 90 mL/min./1.73 m2; however fall in GFR into the range of 45 and 60 mL/min./1.73 m2 increased the HR by 50%; it almost doubled (HR 1.86, p < 0.001) in subjects with eGFR below 45 mL/min./1.73 m2 (16). eGFR reduced below 50 mL/min./1.73 m2 was also the most powerful, independent predictor of mortality in the group of 266 patients aged ≥ 70 years with systolic congestive heart failure; interestingly ‘old-fashioned’ formula for GFR calculation (Cockcroft-Gault) predicted the risk better than the modern one (MDRD) (17). These results were confirmed in another study, demonstrating that the Cockcroft-Gault formula best predicts the risk of death associated with decreasing GFR in patients with congestive heart failure as compared to both MDRD and CKD-EPI (18). Since multiple other studies indicated better performance of CKD-EPI formula on cardiovascular risk prediction, it clearly indicates that the optimal formula for GFR estimation is yet to be found (19-21).
CKD impacts also on survival in patients with acute worsening of CHF. Mortality of elderly patients (aged mean 69 ± 13 years) discharged from the hospital after an episode of acute CHF exacerbation was more than doubled if they simultaneously suffered from CKD with eGFR < 60 mL/min./1.73 m2, as compared to those with eGFR above this value. Interestingly, in multivariate analysis low GFR was better prognostic factor than plasma brain natriuretic peptide level, left ventricle ejection fraction below 40% or diabetes mellitus in predicting an adverse outcome (22).
Chronic kidney disease defined as proteinuria and/or eGFR< 60 ml/min./1.73m2 is also a strong pretictor of stroke. In the Japanese stroke registry almost 35% of patients suffered from CKD; survival, neurologic deterioration and functional outcome after stroke were much worse among CKD patients, although the risk was related entirely to the presence of proteinuria, but not to reduced GFR (23). In another registry report CKD almost doubled the risk of stroke independent from other classical risk factors both in people younger and older that 75 years old (24).
Increasing prevalence of CVS morbidity and atherosclerosis advancement with decreasing GFR translates also into the worsening of cognitive function. It has been estimated that cognitive function decreases by 11% for each 10 mL/min./1.73 m2 loss and correlates with cerebrovascular disease. This is important to remember about negative trends in cognition developing with GFR deterioration. Elderly patients with CKD and other comorbidities face several challenges from healthcare system. We prescribe them multiple drugs, recommend troublesome dietary restrictions, expect decisions on future treatment options (such as choice of dialysis mode, transplantation, etc.). This burden may clearly exceed the patient’s potential to cope with and it seems obvious that cognitive impairment may be an important reason of non-compliance and lower-than-expected treatment results (12). According to the latest report cognitive impairment is critically dependent on the level of albuminuria rather than low GFR; decreased GFR leads to increased prevalence of cognitive impairment only in patients with low grade albuminuria (25). Since CKD is mostly associated with vascular (and microvascular) disease, cognitive impairment in the course of this disease is mostly attributable to vascular mechanisms (26).
CKD may also predispose to arrhythmias, including the most prevalent one – atrial fibrillation (AF). In a prospective study of 118 patients in the mean age of 63 years with sinus rhythm at baseline a risk of new-onset AF was assessed over the 4.5 year observation period. Patients were evaluated monthly or bi-monthly using ECG with or without Holter monitoring. There were 57 new cases of AF per year; the risk of new onset AF was doubled in patients with GFR between 30 and 60, tripled in patients with CKD stage 4 (GFR 15 – 50 ml/min./1.73 m2) and was 6 times more frequent in those with GFR below 15, as compared to those with preserved GFR. CKD patients were older, more frequently diabetic, with higher values of systolic and diastolic blood pressure, larger left atrium dimension and left ventricular mass index. Nevertheless, after adjustment to all these variables (as well as tobacco smoking) CKD still remained an independent predictor of AF (27).
COMPETING RISKS BETWEEN CVS COMPLICATIONS AND END-STAGE RENAL DISEASE (ESRD)
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