Background
Abnormalities of mineral and bone metabolism are common in patients with chronic kidney disease (CKD) and contribute significantly to higher rates of mortality and morbidity including cardiovascular disease and fracture [
1‐
5]. Reduced renal function is associated with impaired phosphate excretion and diminished conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D resulting in hypersecretion of parathyroid hormone (PTH) and the osteocyte-derived phosphatonin, fibroblast growth factor-23 (FGF-23). These changes lead to dysregulation of bone turnover and gastrointestinal absorption of calcium and phosphate, and tissue inhibition of calcification with consequences for bone integrity, mineral metabolism and vascular calcification [
6]. In recognition of these intimate associations, the term ‘Chronic Kidney Disease-Mineral and Bone Disorder’ (CKD-MBD) was defined to encompass the disturbances of mineral metabolism, renal bone disease and vascular calcification, together with patient-level outcomes of fracture, cardiovascular disease and mortality in patients with CKD [
7].
Standard treatment for CKD-MBD, including phosphate binders, vitamin D analogues and parathyroidectomy, is complex and not only lacks a firm evidenced-based foundation for efficacy, but also has the potential for harm [
8,
9]. Hyperphosphataemia is the focus of considerable clinical attention, managed by dietary restriction, phosphate binders and dialysis manipulation. Phosphate is predominantly intracellular and moves slowly between the intracellular and extracellular spaces. As such, conventional thrice-weekly haemodialysis is frequently insufficient to attain negative phosphate balance and fewer than half of dialysis patients achieve values recommended by several clinical practice guidelines [
10]. Aggressive adherence to a low-phosphate diet can potentially lead to low dietary protein intake and malnutrition [
11] and the large number of phosphate binder tablets needed to control hyperphosphataemia in end-stage kidney disease (ESKD) can result in pill burden, increased disease intrusion, abdominal symptoms and potentially impact the absorption of other medications [
12]. Frequent haemodialysis (5–6 times per week) has been shown to reduce serum phosphate in a number of small randomised trials [
13‐
15]. Comparisons of 4 h vs. 8 h dialysis sessions confirm greater phosphate removal [
16,
17] and observational research has associated each increase of 30 min of dialysis session time with a decrease of 0.013–0.05 mmol/L phosphate [
18]. Yet, the longer term effects of extended dialysis hours achieved predominantly via longer sessions on key markers of CKD-MBD remains less well understood.
The ACTIVE Dialysis trial randomised 200 participants to extended hours dialysis (≥ 24 h per week) or conventional hours dialysis (≤ 18 h per week) and found no impact on the primary outcome of change in quality of life as measured by EuroQOL-5 Dimensions (EQ-5D) [
19]. Extended hours dialysis was, however, associated with a reduction in serum phosphate, a small increase in serum calcium, no change in PTH and a decrease in phosphate binder tablet burden. These results imply a response by the treating physician to the study intervention, thus raising the possibility that the true impact of the intervention on individual markers of CKD-MBD may have been obscured by secondary changes in associated therapies. Furthermore, no study has examined the potential impact of more intensive dialysis on CKD-MBD markers among patient subgroups. The present analyses were undertaken to assess the impact of extended hours dialysis on CKD-MBD markers in pre-specified patient subgroups and accounting for concurrent changes in non-dialytic CKD-MBD therapies.
Discussion
These results demonstrate that the effect of extended hours dialysis on key markers of CKD-MBD (lower phosphate, higher calcium and no change in PTH) is independent of changes to associated therapies. With few exceptions, these effects were consistent across a range of important patient subgroups. Moreover, patients on extended hours dialysis were more likely to achieve strict therapeutic targets and to experience a reduction in the need for oral phosphate binders.
Elevated serum phosphate is a risk factor for cardiovascular death in patients on dialysis, leading to the hypothesis that phosphate-lowering therapy may improve survival, although RCT (randomised controlled trial) evidence is lacking [
21,
22]. Our study confirms that extended hours haemodialysis can reduce serum phosphate levels, leading to a significant difference compared to conventional dialysis as early as 3 months. The results of our study are consistent with data from the three randomised trials of frequent dialysis. The Frequent Hemodialysis Network (FHN) trials demonstrated that intensive dialysis, delivered as short daily [
13] or long nocturnal schedules [
15] (each 5-6x per week), reduced serum phosphate levels by 0.19 mmol/L and 0.52 mmol/L respectively, relative to standard dialysis of 3 sessions per week (< 5 h each). In the FHN Daily trial, intensive haemodialysis significantly lowered the daily dose of phosphate binders, while in the FHN Nocturnal trial it led to binder discontinuation in 75% of patients [
23]. An earlier study of frequent nocturnal dialysis demonstrated similar results [
14]. With the exception of the latter study, in which median PTH in the frequent dialysis group was lower than the standard dialysis group by 10.5 pmol/L (
P = 0.05) at study end, intensive dialysis appeared to have no meaningful effects on serum calcium and PTH concentrations. This is consistent with the present study, in which no meaningful change in either parameter was noted.
Phosphate clearance on haemodialysis is complex. It is a predominantly intracellular solute and movement between the intravascular space and the main reservoir of body phosphate stores is relatively slow. Phosphate clearance is highest at the start of dialysis and falls steadily over the first 1–2 h of a session before reaching a plateau as the rate of mobilisation of intracellular phosphate equals the ongoing dialytic clearance [
24]. While frequent dialysis maximises the time spent in the early part of a dialysis session when phosphate clearance is highest, the present study confirms that the continued clearance (albeit at a lower rate) that occurs with extending dialysis time is also an effective means of controlling serum phosphate.
Although the optimal serum phosphate levels in patients on dialysis are unknown, both extremes of high or low serum phosphate levels are associated with an increased risk of mortality in dialysis patients [
25]. The Kidney Disease Improving Global Outcomes (KDIGO) CKD-MBD guidelines suggest lowering serum phosphate towards the normal range [
10]. In the present study, extended hours haemodialysis increased the proportion of patients achieving a normal serum phosphate compared with patients on conventional dialysis. Moreover, those patients may have liberalised their dietary phosphate intake, which may in turn ensure adequate protein intake and help to avoid malnutrition. Low body weight and poor nutrition are also strong predictors of adverse outcome in dialysis patients and the ability to avoid dietary restrictions is hypothesised to contribute to the increased survival seen in prospective cohort studies of more frequent or extended hours dialysis [
26]. Beyond this, a reduction in dietary restrictions could avoid the stress and anxiety that commonly accompany diet in patients on dialysis [
27]. Similarly, a reduction in phosphate binder requirement may minimise the high pill burden and common gastrointestinal side effects of these medications, known to contribute to poor patient compliance and lower quality of life [
12]. Finally, we found that the proportion of non-calcium phosphate binders was reduced, although with no difference in calcium-containing binders. One potential hypothesis for this finding is that clinicians may preferentially cease the more expensive non-calcium phosphate binders initially when serum phosphate has improved, especially in countries where more costly phosphate binders are not financially reimbursed.
In subgroup analyses, the statistical interaction between the effect of extended hours dialysis on serum phosphate and dialysis site indicates that those dialysing at an institution (as opposed to at home) may derive greater benefit on their phosphate from longer dialysis hours. This may reflect differences in age, comorbidities and adherence to medication and dietary prescriptions. However, it is also possible that home patients over-reported the actual amount of dialysis that they performed, resulting in a relatively higher delivered dose of dialysis in the institution patients. There was also an interaction between the effect on serum phosphate and baseline PTH, with those having a high baseline PTH experiencing a greater reduction in serum phosphate with extended hours dialysis. The cause of this is unclear. High PTH states result in an expanded pool of exchangeable bone calcium [
28], whether this is accompanied by an increase in exchangeable phosphate such that equilibration between bone and serum phosphate is more rapid and thus facilitating greater phosphate clearance is not known. There was also an interaction between effect on PTH and baseline phosphate, raising the hypothesis that extended hours dialysis is associated with an increase in PTH in those with low baseline phosphate. RCT with larger subject numbers are needed to verify this speculation. We also found a significant increase in serum calcium by 0.05 mmol/L in those on extended hours haemodialysis, although the clinical relevance of this is uncertain. This change remained after adjustment for changes in phosphate, PTH, dialysate calcium, use of active vitamin D and cinacalcet and there were no between-group differences in use of calcium-based phosphate-binding agents. Previous frequent haemodialysis trials have not seen this effect [
13‐
15]. Future studies of extended hours dialysis should report this outcome.
The strengths of this study include a clear separation in dialysis times between the two groups that was maintained over the duration of the study [
19]. The inclusion of a broad patient population also provides greater generalisability. However, despite being the largest randomised trial of extended hours dialysis, the cohort is still relatively small. This limits the power of the study to detect subgroup differences and the results of this present secondary analysis remain exploratory. Along with the short duration of the study, this also prohibited any investigation of clinical endpoints (such as fracture or cardiovascular disease). A further limitation was the lack of serum levels of calcidiol (25-hydroxyvitamin D). While unlikely to be greatly affected by increased dialysis hours (it is predominantly protein-bound and has a high volume of distribution) [
29], we cannot determine if unobserved changes in calcidiol levels influenced the behaviour of other markers of CKD-MBD. Other limitations include the lack of comprehensive data on changes in dietary and dialysis phosphate, dialysate magnesium and bicarbonate, and the absence of more specific serum markers of bone turnover or radiographic investigation of vascular calcification.
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