Calculation of age and/or sex-dependent z-scores for TmP/GFR and other key parameters of the phosphate homeostasis including calcium and phosphate to creatinine ratios
Measurement of TmP/GFR and other key parameters of the phosphate homeostasis
Introduction
Disturbances in phosphate homeostasis can result in hypophosphatemia and consecutive metabolic bone disease, e.g. rickets and osteomalacia [1]. The ratio of tubular maximum reabsorption of phosphate (TmP) to glomerular filtration rate (GFR) is used to evaluate renal phosphate transport. Renal tubular phosphate reabsorption is mainly controlled by nutritional phosphate and hormones, e.g. PTH, FGF23, and insulin-like growth factor 1. Important to note, the below given formula for TmP/GFR calculation is valid in the fasting and non-fasting state which is a great advantage when using in clinical practice in children [1].
TmP/GFR
This essentially corresponds to the theoretical lower limit of serum phosphate (Pi), below which all filtered phosphate would be reabsorbed. Calculation of TmP/GFR assumes that serum Pi concentration is equal to its concentration in the glomerular filtrate, and that creatinine clearance is a close approximation to GFR. Of note, in the era of isotope-dilution mass spectrometry-standardized (IDMS) creatinine assays, only IDMS-standardized creatinine value-based TmP/GFR reference values as given by Pott et al. and Dubourg et al. are reliable [2, 3]. The latter includes TmP/GFR reference values for adults and children.
Fractional Tubular Reabsorption of Phosphate (TRP)
The fraction of Pi in the glomerular filtrate that is reabsorbed in the renal tubules. If TRP is low in hypophosphatemia this usually points to a renal tubule defect.
Phosphate/creatinine ratio in urine
Phosphate/creatinine ratio in urine can be helpful in settings where patients may have an impaired phosphate absorption from the intestine or reduced phosphate intake which may cause hypophosphatemia. Unfortunately, TmP/GFR is not a reliable parameter in these settings. The key is to demonstrate low urinary phosphate/creatinine ratio in these patients, which supports the presumed diagnosis of impaired intestinal phosphate absorption based on patient history [1]. In contrast, phosphate/creatinine ratio will be elevated in case of renal phosphate wasting, although TmP/GFR remains the main parameter [1].
Calcium/creatinine ratio in urine
The calcium/creatinine ratio in spot urine is widely used to assess hypercalciuria in children as well as in adults. Low urinary calcium/creatinine ratio suggests a low calcium intake. The latter may promote inadequate bone mineralization especially in subjects at risk such as patients with metabolic bone disease due to X-linked hypophosphatemia [4].
z-scores
We present all parameters in absolute values as well as age- and sex adjusted z-scores (standard deviation scores) allowing comparisons across all ages. The underlying reference values are derived from the HARP-cohort [2].
Indications
Assessment of renal phosphate handling may be indicated in a variety of pathological conditions associated with hypophosphatemia. Impaired renal phosphate reabsorption may be due to elevated levels of phosphaturic hormones, i.e. FGF23 and PTH, or due to primary or acquired renal tubular phosphate wasting. It is also recommended to monitor the response to burosumab in X-linked hypophosphatemia [4].
Procedure
TmP/GFR can be calculated, using a second morning spot urine and serum sample taken at the same time point [5-8]. Similarly, serum Pi, TmP/GFR are highest in early childhood and constantly decrease with age, reaching adult values after completion of pubertal growth. A commonly used formula to calculate TmP/GFR, which is applicable in both the fasting and non-fasting child, age-dependent reference values and an online calculator, are given below.
Although calculation of the percentage of tubular reabsorption of phosphate (TRP) can easily be done, this method is not reliable in order to exclude renal phosphate wasting. Indeed, TRP may be falsely normal, despite renal phosphate wasting, as, in contrast to TmP/GFR, it does not correct for the amount of filtered phosphate. Thus, in cases of low serum Pi levels, the remaining phosphate reabsorption capacity may still be enough to maintain a normal TRP, whereas TmP/GFR, which corrects for GFR and thus for the amount of filtered phosphate, is already clearly reduced.
CALCULATOR
The calculator provided below allows to assess absolute and standardized (z-scores) values for key parameters of phosphate homeostasis including serum phosphate, TRP, TmP/GFR, and urinary calcium/creatinine and phosphate/creatinine ratios. Therefore, please enter the required urine and serum concentrations below. Please make sure, that you indicate and select the correct unit for each parameter.
| Parameter | Value | Unit |
| Serum creatinine1 | µmol/L | mg/dL | |
| Serum phosphate1 | mmol/L | mg/dL | |
| Urine creatinine2 | µmol/L | mg/dL | |
| Urine phosphate2 | mmol/L | mg/dL | |
| Urine calcium2 | mmol/L | mg/dL | |
| Age | Years | |
| Sex | Male | Female | |
| | Calculate | Reset | | ||
| Serum phosphate | z-score | |
| TmP/GFR | mmol/L | |
| TmP/GFR | mg/dL | |
| TmP/GFR | z-score | |
| TRP | % | |
| TRP | z-score | |
| Pi/creatinine ratio in urine | mol/mol | |
| Pi/creatinine ratio in urine | z-score | |
| Calcium/creatinine ratio in urine | mol/mol | |
| Calcium/creatinine ratio in urine | z-score | |
TmP: tubular maximum reabsorption of phosphate; GFR: glomerular filtration rate; TRP: Fractional Tubular Reabsorption of Phosphate; Pi: inorganic phosphate.
1 The underlying reference values are based on measurements for phosphate and creatinine from serum samples. Nevertheless, there should be no problems when using values from plasma measurements.
2 The required urine values were measured in spontaneous urine and given as concentration per volume (e.g. mmol/L), not in a 24-hour urine test given as concentration per time (e.g. mmol/d).
Detailed reference values can be found here:
Pott V, Tietze H, Kanzelmeyer N, von der Born J, Baumann U, Mindermann C, et al. LMS-based pediatric reference values for parameters of phosphate homeostasis in the HARP cohort. J Clin Endocrinol Metab. 2023 Oct 18. PMID: 37850343
FORMULA
TRP = (1- ((Up/Sp) x (Scr/Ucr))) x 100;
TmP/GFR = Sp – (Up/ Ucr) x Scr;
Calcium/creatinine ratio = Uc/Ucr;
Phosphate/creatinine ratio = Up/Ucr; [5, 6]
S: Serum; p: phosphate; U: urine; cr: creatinine; c: calcium.
Interpretation
- Reduced serum phosphate z-score indicates hypophosphatemia.
- Low levels of TmP/GFR and TRP indicate renal phosphate wasting in the setting of hypophosphatemia.
- Low urinary phosphate/creatinine ratio suggests impaired phosphate absorption or reduced nutritional phosphate intake in the setting of hypophosphatemia.
- High urinary calcium/creatinine ratio indicates hypercalciuria.
- Low urinary calcium/creatinine ratio suggest low calcium intake.
© for this presentation:
Prof. Dr. Dieter Haffner, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany, and Cand. med. Johannes Lahring, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany, and Dr. Dirk Schnabel, Center for Chronic Sick Children, Pediatric Endocrinology, Charité, University Medicine Berlin, Berlin, Germany, 2024.
References
| 1. | Haffner D, Leifheit-Nestler M, Grund A, Schnabel D. Rickets guidance: part I-diagnostic workup. Pediatr Nephrol. 2022 Sep;37(9):2013-36. |
| 2. | Pott V, Tietze H, Kanzelmeyer N, von der Born J, Baumann U, Mindermann C, et al. LMS-based pediatric reference values for parameters of phosphate homeostasis in the HARP cohort. J Clin Endocrinol Metab. 2023 Oct 18. |
| 3. | Derain Dubourg L, Aurelle M, Chardon L, Flammier S, Lemoine S, Bacchetta J. Tubular phosphate handling: references from child to adulthood in the era of standardized serum creatinine. Nephrol Dial Transplant. 2022 Oct 19;37(11):2150-2156. |
| 4. | Haffner D, Emma F, Seefried L, Högler W, Javaid KM, Bockenhauer D, Bacchetta J, Eastwood D, Duplan MB, Schnabel D, Wicart P, Ariceta G, Levtchenko E, Harvengt P, Kirchhoff M, Gardiner O, Di Rocco F, Chaussain C, Brandi ML, Savendahl L, Briot K, Kamenický P, Rejnmark L, Linglart A. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2025 Jan 15. doi: 10.1038/s41581-024-00926-x. Epub ahead of print. PMID: 39814982. |
| 5. | Derain Dubourg L, Aurelle M, Chardon L, Flammier S, Lemoine S, Bacchetta J. Tubular phosphate handling: references from child to adulthood in the era of standardized serum creatinine. Nephrol Dial Transplant. 2022 Oct 19;37(11):2150-2156. |
| 6. | Brodehl J, Gellissen K, Weber HP. Postnatal development of tubular phosphate reabsorption. Clin Nephrol. 1982 Apr;17(4):163-71. |
| 7. | Brodehl J, Krause A, Hoyer PF. Assessment of maximal tubular phosphate reabsorption: comparison of direct measurement with the nomogram of Bijvoet. Pediatr Nephrol. 1988 Apr;2(2):183-9. |
| 8. | Alon U, Hellerstein S. Assessment and interpretation of the tubular threshold for phosphate in infants and children. Pediatr Nephrol. 1994 Apr;8(2):250-1. |
| 9. | Brodehl J. Assessment and interpretation of the tubular threshold for phosphate in infants and children. Pediatr Nephrol. 1994 Oct;8(5):645.
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