Chapter 14 Phosphate

14.1 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).

14.1.1 General approach

Usually simplest and therefore preferable to calculate FEPO4 (or TRP) rather than TmP/GFR.

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)

14.1.2 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 UCr and UPO4 (and often also calcium)
  • interpret results by calculating TRP or TmP/GFR

\[\begin{equation} \text{fractional excretion of phosphate, }FE_{PO_{4}} = \frac{U_{PO_{4}}}{P_{PO_{4}}} \times \frac{P_{Creat}}{U_{Creat}} \tag{14.1} \end{equation}\]

\[\begin{equation} \text{tubular re-absorption of phosphate, }TRP = 1 - FE_{PO_{4}} \tag{14.2} \end{equation}\]

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 PPO4 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…

\[\begin{equation} \text{TmP/GFR} = TRP \times P_{PO_{4}} \tag{14.3} \end{equation}\]

If TRP > 0.86 then values lie on splay and…

\[\begin{equation} \text{TmP/GFR} = \alpha \times P_{PO_{4}} \tag{14.4} \end{equation}\]

…where,

\[\begin{equation} \alpha = \frac{0.3 \times TRP}{1 - (0.8 \times TRP)} \tag{14.5} \end{equation}\]

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

14.1.3 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 PPO4 < 0.8 mM).

Age-specific reference ranges for TmP/GFR have been reported (Payne, 1998). These are approximately the same as reference ranges for PPO4. In other words, TmP/GFR < 0.8 mM indicates renal phosphate wasting in hypophosphataemia.

14.2 Hypophosphataemia

14.2.1 Consequences

Largely due to lack of ATP:

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

14.2.2 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 re-feeding syndrome
hungry bones
LOW GI ABSORPTION vit D-indep poor dietary intake
malabsorption (usually EtOH XS)
phosphate binders (including antacids)
liver disease
vitamin D deficient / impaired signalling
RENAL LOSSES FGF23-dep inherited (e.g. XLH, fibrous dysplasia…)
acquired (e.g. tumour-induced osteomalacia, post-transplant…)
without Fanconi (hyperPTH, diuretics, HHRH)
with Fanconi syndrome (inherited or acquired)
MISCELLANEOUS FGF23-dep IV iron (inhibits FGF-23 clearance)
sepsis / burns

14.2.3 Notes on specific causes

Renal phosphate wasting:

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

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

Hereditary hypophosphataemic rickets: Almost always X-linked (PHEX mutations - leading to increased FGF-23).


TIO

  • benign mesenchymal tumours secreting FGF-23 (or sometimes other phosphatonins)
  • isolated hypoPO4
  • usually profound and symptomatic (multiple pathological fractures)
  • differentiated from genetic causes by historically normal phosphate level
  • usually very hard to find the tumour; can use MRI, PET but Ix of choice is dotadate scan (used for NET tumours)