Control of Hyperphosphataemia
serum calcium levels (RR per 1 mg/dL (0.255 mmol/L) increase, 1.08 [95% CI, 1.00–1.16]). Overall in CKD, the evidence for an increased risk of death associated with increased PTH or calcium was weak in this analysis, but there appears to be a stronger association between raised phosphate and mortality.16,17
Since morbidity and mortality in CKD generally worsen in the majority of observational studies as serum phosphate levels increase, controlling serum phosphate is undoubtedly desirable in all patients. In stage 5D patients, however, guideline 4.1.1 suggests that treatment should aim towards achieving normal serum phosphate limits, but may not necessarily reach them. So far it is not clear whether phosphate levels are a passive marker for adverse events or are a cause of them. The consequences of high serum phosphate have not been studied in an interventional study and no causal link has been established between lower levels and improved patient-centred outcomes or a reduced mortality risk. For this reason the guideline on lowering serum phosphate toward the normal range is currently level 2C. Randomised controlled studies are urgently required to confirm or refute this observed association.
KDIGO guideline 4.1.4 suggests that patients at CKD stages 3–5 and 5D are treated with a phosphate binder that takes account of the stage of the disease, other manifestations of CKD-MBD, concomitant therapies and the likely side effects of the treatment. The application of the guideline requires a number of considerations in clinical practice and will be discussed in detail below.
However, many patients around the world continue to use aluminium salts where these alternatives are unaffordable.
KDIGO guideline 4.1.5 recommends that in patients with CKD stages 3–5D, the dose of calcium-based phosphate binders and/or calcitriol or vitamin D analogue should be restricted if the patient has persistent or recurrent hypercalcaemia (level 1B). In patients with CKD stages 3–5D and hyperphosphataemia, it is suggested that the dose of calcium-based phosphate binders might be restricted in the presence of arterial calcification (level 2C) and/or adynamic bone (level 2C) and/or if serum PTH levels are persistently low (level 2C).1 In patients with stage 3–5, CKD guideline 4.1.6 recommends that long-term use of aluminium-based phosphate binders is
avoided.This is a response to the known harmful effects of extended aluminium exposure, principally neurotoxicity and impaired bone mineralisation. Historically, aluminium binders were widely used in CKD and were effective and cheap, but today the potentially toxic effects can be avoided using alternatives that have become available in developed countries.1
KDIGO guideline 4.1.7 advises that in patients with CKD stages 3–5D, dietary phosphate intake might be controlled as a single measure or in combination with other treatments (level 2D).1
There is, however,
only a limited amount of clinical evidence supporting this guideline. Foods such as liver, kidney, most fish, hard cheeses and milk are high in phosphate whereas white meats, some cereals, bread, soft cheese, most fruits and the majority of plain or boiled vegetables have a lower phosphate content.18
One of the few randomised controlled trials that
investigated the effects of restricted dietary phosphate included 90 patients (84 completed) with CKD stage 3–5.19
Those receiving
a phosphate-restricted diet for a two-year period and those receiving this diet with calcium carbonate both showed increases in total calcium score (TCS) and in coronary artery calcification (CAC). Those receiving this diet with the polymeric non-calcium phosphate
EUROPEAN NEPHROLOGY
Figure 1: The Effects of Diminished Phosphate Excretion in Chronic Kidney Disease on Factors Associated with Mineral Bone Disease
Dietry phosphorus absorption 1
+
Hyperphosphataemia 3
+ FGF23 + 5 + 4 +
PTH – +
– 9 – 6
1,25 Dihydroxy- vitamin D
2 +
8
Phosphate excretion
7 Normal serum phosphate
Dietary phosphate intake (1) stimulates fibroblast growth factor 23 (FGF23) secretion by osteocytes. FGF23 secretion is also augmented in the presence of calcitriol (2) and possibly by increased serum phosphate (3). In the proximal tubule, FGF23 increases urinary phosphate excretion (4) by down-regulating luminal sodium-phosphate co-transporters via internalisation and endocytosis. As a consequence, phosphate reabsorption declines and more phosphate is excreted in the urine. In the parathyroid gland, FGF23 inhibits synthesis and secretion of parathyroid hormone (PTH). (5) Moreover, FGF23 decreases the availability of active calcitriol (6) in order to decrease phosphate levels. (7). Decreased vitamin D levels lower intestinal phosphate absorption (8) and increase the circulating PTH levels (9). As a result, urinary phosphate excretion is further augmented.8,10
Source: Isakova et al., 2009.85
binder, sevelamer, however, showed no change in either TCS or CAC. It was notable that the diet alone did not reduce urinary phosphate excretion, but it is also obvious to all clinicians that uncontrolled phosphate intake can easily exceed the ability of oral binders to reduce absorption. Therefore, dietary review and advice remains one of the cornerstones of management.
KDIGO guideline 4.1.8 indicates that patients at stage 5D with persistent hyperphosphataemia may have their dialytic removal of serum phosphate increased.1
The comment to the guideline suggests frequent
nocturnal HD as a possible means of achieving this higher removal, but this will only be a possibility for a relatively small subset of the dialysis population. Culleton et al. compared high frequency nocturnal HD given six times weekly (dialysis time of at least six hours per session, a blood flow up to 250 ml/min and a dialysate flow rate of 300 ml/min) with the standard three-times weekly HD regimen. The nocturnal HD produced significantly reduced serum phosphate and iPTH levels compared with patients receiving the standard HD regimen.20
The higher frequency
treatment did not affect serum calcium levels but did reduce the requirement for phosphate binders. Standard HD of four hours three times weekly alone, however, is usually insufficient and fails to control serum phosphate in the majority of patients.21 to address this deficiency are quotidian HD21
Alternative strategies and haemodiafiltration.22
Nephrological and financial expertise are therefore required to apply the available technical possibilities in order to increase dialytic phosphate removal.
In clinical studies, haemodiafiltration improved pre-dialysis serum phosphate levels and beta-2 microglobulin compared with standard HD.22
Translating the KDIGO guidelines for lowering serum phosphate into clinical practice and aiming at lowering serum phosphate towards
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