Cardiovascular disease and its associated risk factors in South African chronic kidney disease patients

Abstract

The markedly increased mortality in chronic kidney disease (CKD) patients is mostly due to an enhanced risk of cardiovascular disease (CVD). The most documented CKD induced cardiovascular abnormalities include impaired diastolic function that underlies heart failure with preserved ejection fraction and arteriosclerosis leading to impaired aortic function. CKD is highly prevalent in South Africa. The extent to which CKD enhances CVD risk among black Africans remains largely unknown.

This thesis comprises a series of investigations that evaluated CVD and its risk factors in black compared to other Africans (first study), examined potential determinants of diastolic function in predialysis and dialysis patients (second study) as well as stable kidney transplant recipients (third study), and tested the hypothesis that the optimal haemoglobin target in dialysis patients may be determined by its contrasting effects on arterial stiffness and pressure pulsatility (fourth study).

In the first study, we evaluated cardiovascular risk factors, aortic function by applanation tonometry using SphygmoCor software, cardiac function by echocardiography, atherosclerosis extent by carotid ultrasound and cardiovascular event rates in 115 consecutive predialysis (n=67) and dialysis patients (n=48) including 46 black and 69 other (32 Asian, 28 white and 9 mixed race) participants. Data were analysed in multivariable regression models. Overall, black compared to other African CKD patients had less frequent carotid artery plaque (30.4% versus 58.8%; OR (95% CI)=0.38 (0.16-0.91) despite an increased cardiovascular risk factor burden. In receiver operator characteristic curve analysis, the Framingham score performed well in identifying nonblack but not black CKD patients with carotid plaque (area under the curve (AUC) (95% CI)=0.818(0.714-0.921) and AUC (95% CI)=0.556 (0.375-0.921), respectively). Black compared to other African predialysis patients experienced larger Framingham scores and more adverse non-traditional cardiovascular risk factors, impaired arterial and diastolic function but similar cardiovascular event rates (OR (95% CI)=0.93 (0.22 to 3.87)). Among dialysis patients, black compared to other Africans had an overall similar traditional and non-traditional cardiovascular risk factor burden, similar arterial and diastolic function and reduced cardiovascular event rates (OR (95% CI)=0.22 (0.05 to 0.88)).

For the second study, we assessed cardiovascular risk factors, arterial function, N-terminal natriuretic peptide (NT-proBNP) levels as a marker of volume overload, and diastolic function in 103 (62 non-dialysis and 41 dialysis) patients. In established confounder adjusted analysis, dialysis status impacted the pulse wave velocity-E/e’ relationship (interaction p=0.01) but not the NTproBNP level-E/e’ association (interaction p=0.1). Upon entering arterial function measures and NT-proBNP levels simultaneously in regression models, arterial function measures were associated with E/e’ (p=0.008 to 0.04) in non-dialysis patients whereas NT-proBNP levels were related to E/e’ in dialysis patients (p=0.009 to 0.04). Bivariate associations were found between diabetes (p<0.0001) and E/e’ in non-dialysis patients, and haemoglobin concentrations and E/e’ (p=0.02) in those on dialysis. Upon adjustment for diabetes in non-dialysis patients, only central pulse pressure remained associated with E/e’ (p=0.02); when haemoglobin concentrations were adjusted for in dialysis patients, NT proBNP levels were no longer associated with E/e’ (p=0.2). In separate models, haemoglobin levels were associated with E/e’ independent of left ventricular mass index and preload and afterload measures (p=0.02 to 0.03).

For the third study, we evaluated traditional and non-traditional cardiovascular risk factors, carotid artery atherosclerosis, arterial function and diastolic function in 43 kidney transplant recipients with a transplant duration of >6 months, no acute rejection and a glomerular filtration rate of >15 ml/min/1.73m2. The mean (SD; range) transplant duration was 12.3 (8.0; 0.5-33.8) years. Post transplantation anaemia and persistent secondary hyperparathyroidism were identified in 27.9% and 30.8% of the patients, respectively; 67.5% of participants were overweight or obese. In established confounder adjusted analysis, haemoglobin (partial R=-0.394, p=0.01) and parathyroid hormone concentrations (partial R=0.382, p=0.02) were associated with E/e’. In multivariable analysis, haemoglobin (partial R=-0.278, p=0.01) and parathyroid levels (partial R=0.324, p=0.04) were independently associated with E/e’. Waist-height ratio (partial R=-0.526, p=0.001 and partial R=-0.355, p=0.03), waist circumference (partial R=-0.433, p=0.008 and partial R=-0.393, p=0.02) and body mass index (partial R=-0.332, p=0.04 and partial R=-0.489, p=0.002) were associated with both e’ and E/A, respectively, in established confounder adjusted analysis. The haemoglobin-E/e’ (partial R=-0.422, p=0.02), parathyroid hormone-E/e’ (partial R=0.434, p=0.03), waistheight ratio-e’ (partial R=-0.497, p=0.007) and body mass index-E/A (partial R=-0.386, p=0.04) relationships remained consistent after additional adjustment for left ventricular mass index and cardiac preload and afterload measures.

For the fourth study, cardiovascular risk factors and arterial function was assessed in 48 dialysis patients. In established confounder and diabetes adjusted linear regression models, haemoglobin levels were directly associated with arterial stiffness (partial R=0.366, p=0.03) and inversely with central systolic pressure (partial R=-0.344, p=0.04), central pulse pressure (partial R=-0.403, p=0.01), peripheral pulse pressure (partial R=-0.521, p=0.001) and forward wave pressure (partial R=-0.544, p=0.001). The presence of heart failure and use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers and erythropoietin stimulating agents did not materially alter these relationships upon further adjustment for the respective characteristics in the models, and in sensitivity analyses. In receiver operator characteristic curve analysis, the optimal haemoglobin concentration cut-off values in predicting arterial stiffness and increased central pulse pressure were remarkably similar at 10.95 g/dl and 10.85 g/dl respectively, and with clinically useful sensitivities, specificities and positive and egative predictive values. In logistic regression models, a haemoglobin value of >10.9 mg/dl was associated with both arterial stiffness (>10 m/sec; OR (95% CI) = 10.48 (1.57 – 70.08), p=0.02) and normal central pulse pressure (>50 mmHg; OR (95% CI) = 7.55 (1.58 – 36.03), p=0.01).

In conclusion, black compared to other African predialysis patients experience an increased traditional and non-traditional cardiovascular risk factor burden and more impaired arterial and diastolic function. Once on dialysis, black African patients sustain less frequent cardiovascular event rates, which may represent a survival bias. The atherosclerotic burden is smaller in black compared to other African CKD patients but the Framingham score is unreliable in identifying those with very high risk atherosclerosis, which is nevertheless present in ~30% of them. Cardiovascular risk factors that are independently associated with markers of diastolic function include impaired arterial function and diabetes in predialyis patients, volume overload and low haemoglobin concentrations in dialysis patients, and post transplantation anaemia and persistent secondary hyperparathyroidism in kidney disease transplant recipients. The optimal haemoglobin target in dialysis patients may be determined by its contrasting effects on aortic stiffness and pressure pulsatility. These findings have implications in our understanding of CVD risk and its management among CKD patients.