Phosphorus is a highly required mineral for cell structure, signaling, energy transfer, and other relevant cellular functions. Due to the fact that de novo phosphorus production is not possible, it must be obtained through diet or supplementation [1].

Despite phosphorus being present in all body cells, it is particularly abundant in bones and teeth. Total body phosphorus in adults is estimated to be approximately 700 g (10 g/kg body weight), 85% existing in the form of hydroxyapatite [chemical composition: Ca10 (PO 4) 6 (OH) 2], 14% in soft tissues, and only 1% existing extracellularly [2]. Three major organs tightly participate in phosphorus homeostasis, this being the kidneys, the bones, and the intestine. The mentioned is obtained through filtration and reabsorption in the kidney, shifts into and out of the bones and absorption and secretion in the gastrointestinal tract [1,2]. Phosphorus homeostasis is mainly maintained through renal excretion of ingested phosphate, and nearly all of circulating phosphate is filtered at the glomeruli, as the non-filtrable (around 30%) remaining plasma fraction forms complexes with serum proteins, such as lipoproteins, and other large molecules [3]. About 80-90% of this electrolyte is actively reabsorbed in the proximal tubule, under the influence of the parathyroid hormone (PTH) [3]. This process is done by a sodium dependent phosphorus (NaPi) transport mechanism through the brush-border membrane, specifically two types of NaPi cotransporters [3]: The type II family of cotransporters, which consists of three highly homologous isoforms, two of which are expressed in the brush-border membrane of the renal proximal tubule (Npt2a, Npt2c), and the type III family (PiT2 transporters) [4]. A further 10-12% is passively reabsorbed in the distal nephron [1].

The kidney plays a major role in the control of systemic phosphate levels, and disturbances of its control mechanisms can lead to a variety of diseases [5]. For this balance, the kidney makes use of a bone-parathyroid gland-kidney-based endocrine axis, which involves the participation of FGF-23 (fibroblast growth factor 23), PTH (parathyroid hormone), vitamin D, and Klotho [5]. PTH and FGF-23 can increase urinary phosphate excretion by reducing the activity of type II NaPi cotransporter, in particular the activity of Npt2a and Npt2c [1]. In addition, PTH induces not only these cotransporters inhibition but also their endocytosis [4].

In post-renal transplantation (PRT) patients, hypophosphatemia and renal phosphate wasting are common occurrences. Although these complications have been thought as transient in the early period post-transplantation, they can persist in time under some circumstances. Even though, this topic has not been extensively studied, there are several studies which have analyzed this phenomenon (4). One of the mentioned studies aimed to evaluate the presence of hypophosphatemia in 12 children, aged from 6 to 36 months, who underwent a successful PRT. Other demographic characteristics, such as age, primary kidney disease, duration of hemodialysis before renal transplantation, warm and cold ischemic times of allograft, and histocompatibility between donors and recipients were similar. The studied children and young adults, aged 6-36 months, were evaluated for the presence of hypophosphatemia following transplantation. The study revealed hypophosphatemia in 58% of participants, despite similar demographic characteristics between the two groups (4).

Bhan et al. performed a prospective, longitudinal study of 27 living donor transplant recipients to test the hypotheses that excessive FGF-23 accounts for hypophosphatemia and decreases calcitriol levels following kidney trasplantation. They found that hypophosphahemia <2.5 mg/dl developed in 85% of patients, including one who had previously undergone parathyroidectomy. Moreover, 37% developed serum phosphate levels ≤1,5 mg/dl (6).

Furthermore, studies performed in hypophosphatemic PRT patients have documented that the percentage of phosphorus tubular reabsorption in this group was around 65±6 %, since it should be higher that 80% in a hypophosphatemic setting, this phenomenon demonstrates the renal cause of this syndrome (1,4,6). When normo and hypophosphatemic PTR were compared, the renal phosphorus leak found was an isolated defect, with similar serum bicarbonate concentration in both groups, and without evidence of amino-aciduria or glycosuria. No differences in serum PTH concentrations were detected between the two groups. Such was the case that it could be concluded that this occurrence was possibly independent of prevailing serum PTH concentrations in the hypophosphatemic group. This finding reinforced the concept that even though hyperparathyroidism is known to play a significant role in the development of post-transplant hypophosphatemia, there should be another complementary mechanism to justify the development of a renal phosphorus leak and consequently urinary wastage in this population (5).

In this sense, several clinical studies have determined that the phosphatonin FGF-23 plays a key role in the pathogenesis of inherited and acquired phosphorus wasting disorders, by inhibiting renal 1-hydroxylase and lowering calcitriol synthesis. Serum concentrations of FGF-23 are also known to be elevated in patients with chronic kidney disease (CKD), partially due to its reduced renal clearance, and also stimulated by CKD progression itself (4). Rutkowski et al. documented, using a mice model, that the renoprotective adipokine adiponectin induces bone loss by increasing calcium and phosphorus urinary excretion, as well as FGF23 serum levels, in part through klotho (5).

One study highlighted the relationship between plasma FGF-23 concentrations and renal failure, where FGF-23 levels were significantly elevated in subjects with secondary hyperparathyroidism, and seemed to be directly correlated with serum phosphorus concentrations, implying that this anion plays a regulatory role in FGF release (1). In a separate study, after successful renal transplantation, there was a marked decrease in serum FGF-23 with the associated improvement of renal function, suggesting rapid FGF-23 clearance (4).

Interestingly, FGF-23 concentrations were significantly and inversely correlated with plasma phosphorus but not with creatinine clearance, suggesting that the remaining FGF-23 may have played a role in the development of PRT hypophosphatemia (4). Finally, other phosphatonins other than FGF-23 may hypothetically contribute to PRT phosphorus wasting, but this suggestion has not been documented yet.

In another study, 85% of the 27 living donor transplant recipients developed hypophosphatemia (3). Overall, FGF-23 concentrations remained above normal, despite a significant decrease during the first week after transplantation, and a stronger correlation was shown with FGF-23 and hypophosphatemia than with PTH. Bhan et al., suggested that PRT hypophosphatemia may be in a state of tertiary hyperphosphatoninism. They postulate that tertiary hyperphosphatonemia may be, partially, due to the persistence of PTH secretion in PRT recipients (6). Other phosphatonins role, different from FGF-23, have been suggested but their contribution to Pi wasting in PRT patients has not been revealed.            Another factor that may be relevant in PTR hypophosphatemia is serum 1,25-dihydroxyvitamin D [1,25(OH)2D], considering its inappropriately low levels despite the presence of hypophosphatemia and hyperparathyroidism in this population, which are known to enhance calcitriol synthesis. This could be due to the inhibition of [1,25(OH)2D] production by high FGF-23 concentrations, decreasing its effect on the renal proximal tubule and consequently decreasing phosphorus reabsorption (4).

Immunomodulatory agents may be another contributing factor of PRT. Evidence exists that both high doses of steroids and tacrolimus can be implicated as a cause of renal phosphorus wasting. In contrast, in normal subjects and/or other solid organ transplantations, high doses of steroids seem to lack this effect, where such association seems to be absent. Furthermore, in one study of PRT patients, despite receiving similar immunosuppressive treatments, not all developed hypophosphatemia and, in many instances, such condition disappeared with follow up, although the same immunosuppressive regimen continued (4).

In conclusion, due to its clinical significance, it is necessary to further define the prevalence and natural history of phosphorus wasting and negative balance in post-renal transplantation population. For this purpose, further research into novel therapeutic agents directly targeting FGF-23 production or inhibitory molecules targeting organ receptors, and long-term double blind control studies must be done.

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Conflict of Interest: All the authors declare that they have no conflict of interest.

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2. Chang AR, Anderson C. Dietary Phosphorus Intake and the Kidney. Annual Review of Nutrition. 2017; 37: 321-346. Orias M, Mahnensmith RL, Perazella MA. Extreme hyperphosphatemia and acute renal failure after a phosphorus-containing bowel regimen. American Journal of Nephrology. 1999; 19: 60-63.
3. Sakhaee K. Post-renal transplantation hypophosphatemia Pediatric Nephrology. 2010; 25: 213-220.
4. Rutkowski JM, Pastor J, Sun K, Park SK, Alexandru Bobulescu I, Chen CT, Moe OS, Scherer PE. Adiponectin alters renal calcium and phosphate excretion through regulation of klotho expression. Kidney International. 2017; 91: 324-337.
5. Bhan I, Shah A, Holmes J, Isakova T, Gutierrez O, Burnet SM, Juppner H, Wolf M. Post transplant hypophosphatemua: Tertiary hyper-phosphatoninism? Kidney Int. 2006,70:1486-1494.