Rationale and design of the myocardial microinjury and cardiac remodeling extension study in the sodium lowering in dialysate trial (Mac-SoLID study)

The Sodium Lowering in Dialysate (SoLID) trial [1, 2] is an ongoing clinical trial to evaluate the hypothesis that reducing sodium exposure in hemodialysis (HD) patients will result in lower cardiovascular (CV) risk (http://​www.​solid.​org.​nz). This hypothesis is based upon the substantial body of observational and clinical trial evidence that lowering dialysate sodium concentration ([Na+]) improves blood pressure and fluid overload, acceptance of left ventricular (LV) hypertrophy as a strong independent mortality risk [3], and an assumption lower dialysate [Na+] should ameliorate LV hypertrophy. The SoLID trial is a multi-center, prospective, randomised, controlled clinical trial, enrolling 96 patients from 7 centers. The intervention and control groups are dialysed using dialysate [Na+] 135 mM and 140 mM respectively, for 12 months. The primary outcome measure is left ventricular mass index, as measured by cardiac MRI after 12 months of treatment.

Since the design and inception of the SoLID trial, several observational studies have suggested potential harm from lower dialysate [Na+] in at-risk populations. The most robust are from the Dialysis Outcomes and Practice Patterns Study (DOPPS) [4, 5]. The first of these studies reported that lower dialysate [Na+] (<137 mM) was associated with a 35% higher mortality risk compared to higher dialysate [Na+], but only in patients with lower serum [Na+]. The second study reported that lower dialysate [Na+] was also associated with higher hospitalization risk. Similar associations have been found in other studies [6]. Of note, the authors of the DOPPS papers identified those patients with serum sodium < 137 mM as having a discrete “frail” phenotype, with a higher proportion of diabetes mellitus and CV disease.

Due to the observational nature of the studies, any causal association between lower dialysate [Na+] and increased mortality risk is speculative. However, the studies do raise the possibility of harm, especially in frailer patients. One possible causal mechanism involves intra-dialytic hypotension (IDH), as shown in Figure 1. IDH complicates 20-30% of HD sessions, and is more likely to occur with lower dialysate [Na+] [7‐9]. The reduction in myocardial perfusion pressure with IDH is compounded by profound myocardial hypoperfusion that is ubiquitous during HD, even in ostensibly ‘healthy’ dialysis patients without a cardiac history or risk factors for CV disease [10, 11]. Intra-dialytic myocardial stunning is common in the myocardial regions with the greatest hypoperfusion, and manifests as regional LV dysfunction. Repeated episodes of intra-dialytic myocardial stunning lead to regions of fixed systolic dysfunction, probably as a result of underlying myocardial fibrosis [12]. It is therefore unsurprising that IDH is strongly associated with myocardial stunning and micro-injury, and all-cause patient mortality [13‐16]. It is possible that any benefit from lower dialysate [Na+] conferred by reducing inter-dialytic hypertension and LV mass might be offset by increased episodes and severity of IDH and subsequent myocardial stunning and micro-injury. HD patients of the “frail” phenotype are likely to be most at risk of harm from IDH because of their reduced coronary flow reserve, and therefore to have a reduced threshold for developing myocardial ischemia in the setting of reduced coronary perfusion pressure [17‐22].

This causal mechanism linking lower dialysate [Na+] to poorer outcomes is only speculative, however, and several clinical tenets argue against its validity. Firstly, lower dialysate [Na+] is associated with lower inter-dialytic weight gain (IDWG) [23‐35] and consequently less fluid removal during dialysis, factors which are protective against IDH [36] . Secondly, elevation in plasma [Na+] is likely to occur during treatment with a higher dialysate [Na+]. Elevation of plasma sodium by 1-3 mM within the normal range is known to induceand “stiffening” of the vascular endothelium independently of extra-cellular fluid volume [37]. This is thought to be due to down- regulation of vasodilatory nitric oxide formation, in the presence of higher serum [Na+] [38, 39]. Arterial stiffness reduces myocardial perfusion, and reduces the threshold for myocardial ischemia, especially in subendocardial regions for those with LV hypertrophy [40, 41]. Arterial stiffness may also impair pressor responses to sympathetic activation during fluid removal, and reduce capacity for appropriate compensatory mechanisms during fluid removal [42]. Finally, laboratory science has demonstrated that increased sodium concentration can directly induce cellular hypertrophy; hence, higher dialysate sodium itself may be an important determinant of myocardial hypertrophy or LVH [43].

Overall, there is clinical equipoise around the use of lower dialysate [Na+] and uncertainty with respect to CV outcomes. The prime concern, however, is that there could be potential harm from the intervention through exacerbation of IDH and subsequent myocardial micro-injury. Frequency of IDH is a secondary outcome in the SoLID trial and is monitored by the trial’s Data Monitoring Committee. However, these measurements alone are unlikely to be sufficiently sensitive to detect or quantify cardiac micro-injury. The Myocardial Micro-injury and Cardiac Remodeling Extension Study in the Sodium Lowering In Dialysate Trial (Mac-SoLID study) addresses this shortcoming, and aims to determine whether lower dialysate [Na+] results in (i) increased levels of high-sensitivity Troponin T (hsTnT), a well-established marker of intra-dialytic myocardial micro-injury in HD populations [44‐46], and (ii) increased fixed LV segmental wall motion abnormalities, a marker of recurrent myocardial stunning and cumulative micro-injury [12, 13, 46], and (iii) detrimental changes in LV geometry due to maladaptive homeostatic mechanisms [47, 48].

The SoLID trial is the first randomized controlled trial to investigate the effect of lower dialysate [Na+] upon LV structure and function, and is now close to completion. The outcomes of this research will provide definitive evidence about the efficacy of lower dialysate [Na+] to improve CV outcomes in HD populations. The SoLID trial will also provide data on important patient-centered outcomes, such as the effect of lower dialysate [Na+] on thirst, xerostomia, HRQoL and intra-dialytic hypotension. If the benefit of lower dialysate [Na+] is confirmed, other benefits might also flow on from reduced CV morbidity and mortality, including improvements in lower health resource consumption and less societal burden of treatment. Operationally, lower dialysate [Na+] is a simple and cost-free intervention, and for appropriate dialysis populations it can easily be implemented on a large-scale.

The Mac-SoLID trial enhances and complements the SoLID trial. It will provide reassurance that the potential gains in cardiovascular health (reduced LV mass), which lower dialysate [Na+] is expected to deliver, are not off-set by deterioration in cardiovascular health through alternative mechanisms, namely repeated LV stunning and micro-injury. The information forthcoming from the Mac-SoLID trial may also help us to better pinpoint those patients who fit the “frail” phenotype and are inherently unsuitable for dialysis treatment with lower dialysate [Na+].