The following sections have been prepared to ensure that the state of the art and science related to CVD includes novel concepts, therapeutic strategies, and emerging areas of pathophysiological and practical importance to the care of dialysis patients.
The reader will notice that the format of this section is different, reflecting its different perspective: namely, the relative lack of evidence on which to base plausible guideline statements. The evidence that does exist, and is cited in this section, is either completely in nondialysis populations, or is purely associative information, with no intervention in any population yet tested. Thus, it would be a problem to include guideline statements or recommendations.
Nonetheless, this section describes the current status of knowledge with respect to risk factors and biomarkers, and represents an overview of key areas for future clinical trials. The reader is encouraged to review this section, and examine his or her current understanding and practice within the context of these highlights.
The literature review has been conducted using the same systematic strategy as for the previous guidelines in this document. The reviews presented here have been thoughtfully constructed so that clinicians can adopt different practices based on them. However, for reasons cited above, the ability to truly recommend or suggest changes in practice would be premature at this time.
The mean age of women with CKD Stage 5 suggests that the majority of these women are postmenopausal.17 Different patterns of abnormalities may be seen in women with CKD before and after menopause. The primary hormonal defect observed in premenopausal women with CKD is due to hypothalamic dysfunction. In women of reproductive age and normal renal function, a sustained midcycle increase in estradiol causes an increase in hypothalamic secretion of gonadotropin-releasing hormone (GnRH). This hormone then stimulates the pituitary gland to increase leutinizing hormone (LH) secretion and, with an increase in progesterone and estradiol, follicle-stimulating hormone (FSH) levels increase. This hormonal pattern leads to normal ovulation and menstruation. In the majority of premenopausal uremic women, the positive feedback mechanism of estradiol on the hypothalamus is blunted. The midcycle increase of progesterone, LH, and FSH is impaired, and anovulatory menstrual patterns predominate.712–714 Estradiol levels in uremic women are comparable to normal in the follicular phase, but a reduced midcycle peak has been documented.713 Hyperprolactinemia is present in approximately 70% of women with CKD due to reduced renal clearance, increased secretion by the anterior pituitary, and anterior pituitary resistance due to the downregulatory effects of dopamine.715 Menopause occurs at a younger age among women with CKD; the median age of menopause is 50–51 years in normal women and 47 years among women with CKD.716
Menopause and cardiovascular risk
In the general population, the risk of CVD increases after menopause. This is thought to be due to loss of the protective effect of estrogen on lipids and vascular function. The role menopause plays in the accelerated CVD that is characteristic of CKD is not known.
Prevalence
Although appropriate indications for estrogen replacement therapy are controversial, 5%-11% of women with CKD over 45 years of age are treated with hormone-replacement therapy (HRT).716,717 Younger, better-educated Caucasians are more likely to receive HRT.717 It is not known whether reports from the Women’s Health Initiative (WHI), indicating a lack of cardioprotective effect associated with HRT in healthy women, has impacted the use of HRT.
Cardioprotection
There are few reports that have assessed the impact of HRT on cardiovascular outcomes among CKD patients. In the general population, HRT is known to lower LDL cholesterol and Lp(a), and increase HDL and triglycerides. The most common lipoprotein abnormalities in CKD include reduced HDL and elevated LDL, triglycerides, and Lp(a). Since the only lipoprotein abnormality that has been associated with CVD in dialysis patients is Lp(a), it is possible that HRT has positive cardiovascular effects in CKD patients.610
One small study in women with CKD demonstrated an increase in HDL and ApoA-I with no change in total cholesterol, LDL, Lp(a), or triglycerides after 8 weeks of treatment.718 Estrogen also modifies vascular function and atherosclerosis among women without CKD. In the general population, estrogen increases stroke volume, heart rate and contractility, and reduces peripheral vascular resistance in postmenopausal women.719–721 Regression of atherosclerotic plaques has been shown to occur among women following institution of HRT.722 Although this may, in part, be due to alterations in lipid metabolism, estrogen also inhibits vascular smooth muscle cell proliferation in vitro, a process that contributes to atherogenesis.723
The use of HRT in the general population has become increasingly controversial. Reports from the WHI have documented significant reductions in hip fracture and colorectal cancer rates among postmenopausal women treated with HRT.724 Although estrogens have been reported to improve the lipid profile by increasing high-density lipoprotein and decreasing low density lipoprotein,725 the WHI did not find an overall benefit among those receiving both estrogen and progesterone.724 In addition, studies have demonstrated an increased risk of venous thrombosis among women who use estrogen.724,725 Patients with CKD have an increased risk for pulmonary embolus and are at risk for vascular access thrombosis. The association between HRT and venous thrombosis, particularly vascular access thrombosis, among women with CKD remains unstudied.
Dosing
Previous reports have suggested that renal failure may alter the pharmacokinetics of estrogen, and that dose adjustments are necessary in patients with CKD. One study reported that, after a single dose of estradiol, serum concentrations of estradiol and estrone were 2–3 times that of the controls,726 while another reported that urinary excretion of estradiol in men with normal renal function was 78%-83% over 4 days compared to 1.4% in men with CKD.727 Other potential risks of estrogen, such as breast cancer, coagulopathy, or CAD, may be dose-dependent. A recent study found that estradiol serum concentrations among post-menopausal women with CKD requiring maintenance HD were over 20% greater than those among women with normal renal function, in spite of reducing the dose of β-estradiol by 50%. These data suggest that women with CKD should receive a 50%-70% lower dose of β-estradiol to achieve equivalent concentrations. Measurement of estradiol levels (and possibly FSH levels) may be of value in selected postmenopausal women with CKD receiving HRT. It is likely that any benefit would be relative to the blood concentration and not the actual dose, and there may be potential harm in having excessively high blood concentrations.
Little is known regarding cardiovascular outcomes associated with menopause. Observational studies should assess the impact of menopause on CVD risk. Given that there are over 30,000 women with CKD treated with HRT, studies should assess if the use of HRT is associated with improved CVD outcomes.
Given the lack of data from the CKD population, it may be prudent to follow the recently published guidelines from North American Menopause Society, which state that the treatment of menopause symptoms remains the primary indication for HRT, and that HRT not be used solely for primary or secondary prevention of CHD.728 For those women with CKD on HRT, doses of estrogen replacement that are 50%-70% lower than those among women with normal renal function would have an equivalent effect.