Poster Presentation 29th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2019

A 49-year-old Chinese man was referred for osteoporosis post renal transplant. His past medical history included end stage renal failure of unclear aetiology, hemodialysis from 2005 – 2013, cadaveric renal transplant in 2013 complicated by calcineurin inhibitor toxicity, and Hepatitis B.

Medications at the time included prednisolone 5mg daily, mycophenolate, tacrolimus, pantoprazole, lercanidipine, metoprolol, magnesium and vitamin D 3 daily. Baseline DEXA scan in 2013 revealed a T-score at the lumbar spine of -2.2, neck of femur -2.7. There was no known family history of osteoporosis or past history of fragility fractures, and a thoracolumbar spine X-ray did not reveal morphometric fractures. A secondary osteoporosis screen was performed, with negative coeliac serology and normal testosterone and vitamin D was replete (101 nmol/L). There was mild secondary hyperparathyroidism with a calcium of 2.44 mmol/L, PTH of 13.4 pmol/L (1.6 – 6.0) and eGFR 34 ml/min. He was noted to be persistently hypophosphatemic with a phosphate of 0.7 mmol/L (0.87 – 1.45), which was unexpected in the context of CKD-3bT. His urinary fractional excretion of phosphate was elevated at 43.5% (normal < 10%) confirming renal phosphate wasting and raised the possibility of underlying osteomalacia contributing to his reduced bone density. He was subsequently commenced on oral phosphate replacement Sandoz phosphate 2 daily from February 2015. By July 2015, his lumbar spine aBMD had increased by 18%, total hip aBMD increased by 4%. He was commenced on risedronate 35mg fortnightly. Notably, his bone-specific alkaline phosphatase was normal at 20.3 mcg/L (5 – 24) on treatment. By 2018, the net aBMD increase from baseline was 22% and 9% at the lumbar spine and total hip respectively.

His urinary fractional excretion of phosphate remained high on repeat at 73% in spite of recovery of renal graft function from the initial calcineurin toxicity (eGFR of 45ml/min and PTH of 9.5 pmol/L). Therefore the ongoing renal phosphate wasting could not be attributed to hyperparathyroidism alone. Serum phosphate was maintained in the low normal range with supplementation, plasma FGF-23 result is pending.

Discussion

This case raises the issues of persistent renal phosphate wasting post renal transplant, and the effect this has on bone matrix mineralization and osteoporosis.

Approximately 70% of filtered phosphate is reabsorbed in the proximal renal tubule. Parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) are important regulators of renal phosphate handling (1). FGF-23 induces phosphaturia and inhibits renal 1 alpha hydroxylase. Disorders of FGF-23 are characterized by hypophosphatemia with inappropriate renal phosphate wasting and low calcitriol (10).

Hypophosphatemia and renal phosphate wasting are common occurrences following kidney transplant (2). The major factors implicated are increased PTH, relative deficiency of calcitriol, immunosuppressive drugs and increased levels of FGF-23 (2, 9). Hypophosphatemia is generally perceived to be short term, with most studies suggesting normalization of phosphate levels 12 months post transplantation (4). Persistent phosphate wasting may contribute to a decline in bone mineral density and increased fracture risk (4). Evenepoel et.al. showed that PTH and FGF-23 levels decreased dramatically within the first 3 months post renal transplant, accompanied by an increase in serum calcium and decrease in serum phosphate levels (5).

Accumulated FGF-23 and PTH in CKD contribute to renal phosphate wasting early post- transplant, and phosphate should normalize as these decline (6). Causes of hypophosphatemia persisting long-term post- transplant are less well characterized. Sirilak et.al. found that high levels of FGF-23 were an independent predictor of renal phosphate wasting and hypophosphatemia (6). Whereas Kawarazaki et.al. concluded that persistence of hyperparathyroidism might be more contributory to hypophosphatemia at 12 months (7, 8).  Evenepol et.al. found that pre-transplant FGF-23 levels were the most important predictor of FGF-23 levels at month 3 post-transplant, with elevated levels leading to tertiary hyperphosphatonism- the phenomenon that ongoing high levels of FGF-23 contributes to ongoing renal phosphate wasting despite low levels of serum phosphate (9).  Bhan et.al. similarly found that early post-transplant FGF-23 but not PTH was independently associated with decreased serum phosphate (10).

Causes for low bone mineral density in this patient are multifactorial. At time of transplantation most patients already suffer from renal osteodystrophy, and post- transplant immunosuppressive regimens, as well as deranged hormonal handling contribute to ongoing bone deficits. Following renal transplantation patients have worsening bone density and increased risk of fractures, compared to other solid organ transplants (11,12,15). Studies on bone histomorphometric data post renal transplant suggest presence of defective mineralization (13, 14). Another issue is that areal BMD measurement is unable to differentiate between osteomalacia and osteoporosis, or differentiate between high and low bone turn-over in renal osteodystrophy (11, 12). Hypophosphatemia has been associated with alterations in bone turnover, however the long-term outcomes are still not well studied (16).

There remains limited data regarding anti-fracture efficacy of anti-resorptive therapy post renal transplant. Toth-Manikoswki et.al. and Palmer et al. demonstrated improvements in BMD at the femoral neck and lumbar spine in renal transplant recipients, however the relationship between BMD and fractures is not clearly established in renal transplantation (17, 18). Miller et.al. demonstrated that risedronate was safe and reduced vertebral fracture in a post hoc analysis in subjects with GFR < 30ml/min (18).

As can be highlighted from this case, while renal phosphate wasting is common early post-transplant, longer term renal phosphate wasting is less common and likely due to both persistent secondary hyperparathyroidism and inappropriately elevated FGF-23. In the above patient, given his PTH levels had almost normalized, we would conclude that his persistent phosphate wasting was likely due to inappropriately elevated FGF-23. With replacement of phosphate and treatment with bisphosphonates there was marked improvement in bone density.

Learning points

• Persistent hypophosphatemia and renal phosphate wasting post- transplant can occur, as a consequence of elevated FGF-23 and hyperparathyroidism.
• In the setting of improvement in PTH levels post- transplant, consider inappropriately elevated FGF-23 as a factor.
• Hypophosphataemia may compound low BMD by contributing to defects in bone mineralization and osteomalacia and treatment should be considered.
• The management of CKD-MBD pre and post renal transplantation remains challenging with a paucity of data regarding anti-fracture efficacy of anti-resorptive agents.