Chapter 16 Phosphate

16.1 Urinary phosphate

The usual reason to measure urinary phosphate excretion is to distinguish renal from extra-renal phosphate wasting in chronic hypophosphataemia. Renal phosphate wasting may occur in isolation or as part of a Fanconi syndrome (Imel & Econs, 2012).

16.1.1 General approach

Usually simplest and therefore preferable to calculate FEPO₄ (or TRP) rather than TmP/GFR. (Ideally on a fasted sample though.)

Other investigations in hypophosphataemia:

• repeat plasma phosphate (often transient and may have self-corrected)
  
• Ca, PTH (+/- vitD)
  
• Fanconi screen (LMWH proteinuria, uricosuria, glycosuria)
  
• DEXA (low BMD vs. osteomalacia)

16.1.2 Measuring urinary phosphate and calculating TmP/GFR

A fasted, morning sample is preferred to minimise the effects of circadian and post-prandial changes in phosphate and creatinine (Imel & Econs, 2012).

Spot urine sample to measure phosphate excretion:

• fast overnight; discard the first urine void of the day
  
• collect second voided urine of the day and a paired blood sample
  
• send blood for U&Es, phosphate (and often also HCO₃, calcium, alkaline phosphatase, PTH, vitamin D…)
  
• send urine for U_Cr and U_PO4 (and often also calcium)
  
• interpret results by calculating TRP or TmP/GFR
  

\[\begin{equation} \text{fractional excretion of phosphate, }FE_{PO_{4}} = \frac{U_{PO_{4}}}{P_{PO_{4}}} \times \frac{P_{Creat}}{U_{Creat}} \tag{16.1} \end{equation}\]

\[\begin{equation} \text{tubular re-absorption of phosphate, }TRP = 1 - FE_{PO_{4}} \tag{16.2} \end{equation}\]

It may be preferable to express results in terms of the maximum reabsorption rate of phosphate, TmP. Because net phosphate transport will be largely determined by filtered load, this is usually expressed per unit volume of glomerular filtrate: as TmP/GFR. TmP is a rate of transport (mg per min); GFR is a rate of flow (ml per min); therefore TmP/GFR is a concentration (mg/ml or mM). This concentration is the P_PO4 threshold above which phosphate will appear in the urine (Bijvoet et al., 1969).

This measure is conceptually complex, but offers a number of potential advantages:

1. it represents a relevant physiological paramater (the capacity of the renal tubule to re-absorb phosphate)

2. there are well-defined, age-specific reference ranges (see below)

Strictly speaking, TmP/GFR can only be determined by subjecting individuals to continuous intravenous phosphate infusions. However, it can be estimated from the TRP using one of two methods.

The first is to consult a Walton-Bijvoet nomogram (Imel & Econs, 2012).

The second is to use an equation derived by Kenny & Glen (Payne, 1998):

If TRP \(\leq\) 0.86 then values lie on linear portion of curve and…

\[\begin{equation} \text{TmP/GFR} = TRP \times P_{PO_{4}} \tag{16.3} \end{equation}\]

If TRP > 0.86 then values lie on splay and…

\[\begin{equation} \text{TmP/GFR} = \alpha \times P_{PO_{4}} \tag{16.4} \end{equation}\]

…where,

\[\begin{equation} \alpha = \frac{0.3 \times TRP}{1 - (0.8 \times TRP)} \tag{16.5} \end{equation}\]

There is some evidence that using the equation is less likely result in errors (Barth et al., 2000).

16.1.3 Reference ranges

The normal renal response to hypophosphateaemia is to drop FEPO₄ to 5% (i.e. TRP > 0.95).

Therefore, FEPO₄ > 20% (TRP < 0.8) is abnormal; or 10% and 0.9 if P_PO4 < 0.8 mM).

Age-specific reference ranges for TmP/GFR have been reported (Payne, 1998). These are approximately the same as reference ranges for P_PO4. In other words, TmP/GFR < 0.8 mM indicates renal phosphate wasting in hypophosphataemia.

There is diurnal variation plus variation with age and sex, driven by changes in TmP/GFR.

16.2 Hypophosphataemia

16.2.1 Consequences

Largely due to lack of ATP:

• osteomalacia
  
• muscle weakness / respiratory failure
  
• arrhythmia
  
• rhabdo
  
• metabolic acidosis
  
• haemolytic anaemia

16.2.2 Causes of hypophosphataemia

The differential diagnosis and diagnostic approach is reviewed by Imel & Econs (2012).

Broadly, hypophosphataemia may be due to:

CELLULAR SHIFTS	respiratory	respiratory alkalosis
	metabolic	insulin
		re-feeding syndrome
		hungry bones
		post liver surgery
LOW GI ABSORPTION	vit D-indep	poor dietary intake
		malabsorption (EtOH XS, bariatric surgery)
		phosphate binders (including antacids)
		liver disease
		vitamin D deficient / impaired signalling
RENAL LOSSES	FGF23-dep	inherited (XLH, fibrous dysplasia…)
		acquired (TIO, post-transplant…)
		without Fanconi (hyperPTH, diuretics, HHRH)
		with Fanconi syndrome (inherited or acquired)
MISCELLANEOUS	FGF23-dep	IV iron (inhibits FGF-23 clearance)
		sepsis / burns

16.2.3 Notes on specific causes

Renal isolated phosphate wasting:

Outside of the post-transplant setting, the only three possible causes are:

1. Fanconi syndrome
   
2. hereditary hypophosphataemic rickets
   
3. TIO

IV iron: Apparently restricted to ferric carboxymaltose (e.g. Ferinject). Inhibits FGF23 degradation. Can persist for weeks - months.

Inherited renal phosphate wasting: XLH: X-linked hypophosphataemic rickets. Presents in young boys. PHEX loss of function mutations > elevated intact FGF23 > phosphate-wasting and low vitD; tooth mineralisation defects. Treat with neutralising Ab (Burosumab).

AR mutations in NaPi-IIa (SLC34A1) = Fanconi, nephrocalcinosis, stones
AR mutations in NaPi-IIc (SLC34A3) = HHRH: heretidary hypophosphataemic rickets with hypercalciuria

Less aggressive forms may present in adulthood:

• late-onset hereditary hypophosphataemic rickets with hypercalciuria (NaPi-IIc; SLC34A3)
  
• kidney stones (SLC34A3 or SLC34A1 heterozygotes - 3 – 4% allele frequency in general population)
  
• female HLX carriers

TIO

• benign, small, slow-growing mesenchymal tumours secreting FGF-23 (or sometimes other phosphatonins not measured with standard assays)
  
• isolated hypoPO4
• renal PO4 wasting with high / inappropriately normal FGF-23 (unless other phosphatonin) and low 1-25 vitD
  
• usually profound and symptomatic bone demineralisation (bone pain > multiple pathological fractures)
  
• differentiated from genetic causes by historically normal phosphate level
  
• usually very hard to find the tumour; can use MRI but…
• …Ix of choice is whole body 68Ga-DOTATATE PET CT scan for NET tumours; need to emphasise top-to-toe scan in the request as may be in extremities (e.g. heels)
• in theory could treat with Burosumab if tumur resection not possible

TIO mimics

Sometimes high FGF-23 but no detectable tumour. A proportion of these cases likely to be autoimmune acquired osteomalacia (e.g. autoAbs against PHEX).

Can also get autoAbs against PHEX > acquired osteomalacia. Look for this if TIO but not tumour!