Left ventricular function and chronic kidney disease: how soon does it start?

Patients with chronic kidney disease (CKD) manifest an increased prevalence of cardiovascular morbidity and mortality compared with age-matched persons, and this relationship is directly proportional to the severity of CKD [1, 2]. After age, left ventricular hypertrophy (LVH) is considered to be the strongest independent predictor of cardiovascular disease and events, cardiovascular death and total mortality. In CKD patients, LVH contributes to diastolic dysfunction, congestive heart failure, arrhythmia and sudden death [3]. The prevalence of LVH in the general population is 15–21% [4], but it affects 50–70% of patients during intermediate stages of CKD and up to 90% of patients with end-stage kidney disease [5–7]. In a cross-sectional study of 3487 participants of the Chronic Renal Insufficiency Cohort Study, the prevalence of LVH assessed by echocardiography was 32, 48, 57 and 75% for estimated glomerular filtration rate (eGFR) categories ≥60, 45–59, 30–44 and <30 mL/min per 1.73 m2, respectively. In fully adjusted multivariable analyses, subjects with eGFR levels of <30 mL/min per 1.73 m2 had 2-fold higher odds of LVH (OR = 2.20, 95% CI = 1.40–3.40; P < 0.001) relative to subjects with eGFR levels of ≥60 mL/min per 1.73 m2 [8]. In a Spanish general practice multicentre study of 13,687 hypertensive patients, the relationship between electrocardiographic (EKG)-LVH and CKD stage was present in women but absent in men [9]. How soon in the course of CKD cardiac dysfunction occurs has been a matter of debate. It is reasonable to assume that in patients with CKD and hypertension or diabetes mellitus this may occur relatively early in the course of the disease, particularly if these conditions remain inadequately treated. Whether cardiac dysfunction can occur early in the course of CKD independent of co-morbidity remains to be established. Two previous studies failed to demonstrate an association between CKD stage 2–4 and LVEF [10, 11]. In contrast, one study demonstrated an association between LV function and circulating cystatin C levels in 818 patients with coronary heart disease [12]. In this issue of NDT, Nerpin et al. [13] described the association between glomerular filtration rate and left ventricular function in two independent community-based cohorts with no clinical evidence of heart failure, left ventricular ejection fraction >40% and with eGFR >60 mL/min per 1.73 m2. The first study was the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) and included 911 participants (50% women) with a mean age of 70 years. The second study was the Uppsala Longitudinal Study of Adult Men (ULSAM) and included 538 men with a mean age of 71 years. In both studies, the investigators observed a significant correlation between eGFR and systolic, diastolic, and global left ventricular function. These observations are of interest because they suggest that even with levels of eGFR above 60, there is a relationship between kidney function and cardiac function. The study has several limitations besides those addressed by the investigators: the cross-sectional design, the age of the patients and the use of cystatin C to estimate GFR. The investigators provide no clear evidence for superiority of cystatin C versus eGRFCKD-EPI in a population aged more than 70 years. When eGFRCKD–EPI formula were used, the correlation between these parameters was not statistically significant. It is intriguing that the difference in eGFR between the two studies was approximately 31 mL/min per 1.73 m2 when eGFR was calculated using cystatin C and only 7 mL/min per 1.73 m2 when eGFR was estimated using the eGRFCKD-EPI formula. The study provides no information on myocardial structure and no clue on what is driving this interrelation. Is reduced eGFR responsible for the decrease in LVEF or is a primary decrease in LVEF responsible for the reduction in eGFR? The authors do not address the discrepancy between findings in ULSAM and previous studies that failed to show an association in male patients. Finally, the study provides no information on the pathogenesis of this association. This is needed to identify future strategies to prevent and treat cardiac dysfunction in early phases of CKD. The relationship between reduced kidney function and increased prevalence of LVH and left ventricular dysfunction in CKD patients is complex and difficult to address therapeutically. LVH, reduced LVEF and congestive heart failure have been attributed in part to the co-existence of traditional risk factors such as hypertension, hypercholesterolemia, obesity, diabetes mellitus and in part to non-traditional risk factors such as inflammation, oxidative stress, [14] anaemia [15], endothelial dysfunction, activation of the renin–angiotensin aldosterone system [16, 17], activation of the sympathetic nervous system [18, 19], abnormalities in bone and mineral metabolism (including serum phosphorus, magnesium and calcium) [20, 21], hormones that regulate mineral metabolism, such as parathyroid hormone and vitamin D metabolites [22], circulating soluble receptor for advanced glycation end product (sRAGE) [23], e-selectin [24], asymmetric dimethylarginine (ADMA) [25], cytokines, such as interleukin-6, homocysteine, urine albumin/creatinine ratio [26], increased arterial stiffness [27], hyperuricemia [28] and glucose load during peritoneal dialysis [29] (Table 1). More recently, a great deal of interest has been given to fibroblast growth factor 23 (FGF23), a hormone secreted by osteoblasts/osteocytes in bone that acts on the kidney to regulate phosphate and active 1,25-dihydroxyvitamin D [1,25(OH)2D] through activation of FGF receptor/α-Klotho co-receptor complexes [30]. FGF23 blood levels are elevated in CKD and higher FGF23 concentrations have been associated with increased risk of cardiovascular events and death in CKD patients [31]. In a previous study of a large cohort of older community-dwelling adults, higher FGF23 concentrations were associated with greater LVM and LVH with stronger relationships in participants with CKD [32], which would support the finding of the study by Nerpin et al. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signalling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed [33]. Traditional and non-traditional factors implicated in the pathogenesis of left ventricular hypertrophy in patients with CKD Traditional and non-traditional factors implicated in the pathogenesis of left ventricular hypertrophy in patients with CKD Vitamin D deficiency is quite prevalent among CKD patients, and it is associated with prevalent myocardial dysfunction, heart failure and sudden cardiac death [34]. Experimental studies have shown that vitamin D deficiency induced myocardial hypertrophy (increased heart weight/body weight ratio) and extracellular matrix production via increased c-myc protein levels [35]. Unfortunately, the study by Dr Nerpin et al. provides no measurements of vitamin D and FGF23 levels. Future efforts should concentrate on evaluating these known contributing factors and develop strategies to prevent cardiovascular complications in CKD patients. None declared. (See related article by Nerpin et al. The association between glomerular filtration rate and left ventricular function in two independent community-based cohorts of elderly. Nephrol Dial Transplant 2014; 29: 2069–2074.)