Tubular phosphate transport: a comparison between different methods of urine sample collection in FGF23-dependent hypophosphatemic syndromes.

OBJECTIVES: Tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR) is used to evaluate renal phosphate reabsorption and it is a useful tool for the differential diagnosis of hypophosphatemic syndromes. TmP/GFR is typically calculated from fasting plasma and second morning void urine samples, obtained 2 h after the first void (TmP/GFR 2 h). The purpose of this study was to evaluate if TmP/GFR calculated from 24 h urine collection (TmP/GFR 24 h) can be used as an alternative for TmP/GFR 2 h in patients with urine phosphate wasting. METHODS: We enrolled adult patients with X-linked hypophosphatemia (XLH) or tumor-induced osteomalacia (TIO). All patients underwent blood and urine sample collections, to calculate TmP/GFR 24 h and TmP/GFR 2 h. RESULTS: Twenty patients (17 XLH and 3 TIO), aged 24-78 years, were included. All patients had low TmP/GFR 2 h (0.35 mmol/L, IQR 0.24-0.47 mmol/L) and TmP/GFR 24 h (0.31 mmol/L, IQR 0.22-0.43 mmol/L). The concordance correlation coefficient between TmP/GFR 2 h and TmP/GFR 24 h was 0.86 (95 % CI: 0.69-0.93), with a systematic bias of 0.05 mmol/L (95 % limits of agreement: -0.10 to 0.20). Furthermore, in 70 % (i.e., 14 patients out of 20) and 80 % (i.e., 16 patients out of 20) of cases the difference between TmP/GFR 2 h and TmP/GFR 24 h was within ±30 % and ±35 %, respectively. CONCLUSIONS: Despite TmP/GFR 2 and 24 h show a relatively suboptimal agreement, the difference between the two parameters appears to be small and not clinically significant in the setting of adult patients with FGF23-dependent urine phosphate wasting and secondary hypophosphatemia.

Persistent urinary phosphate wasting in a patient with metastatic breast cancer: What's your diagnosis?

Tumor-induced osteomalacia (TIO) can cause severe, persistent hypo-phosphatemia due to high fibroblast growth factor-23 (FGF-23) levels, which lead to uri-nary phosphate wasting. TIO is frequently encountered in association with mesenchy-mal tumors and responds well to resection of the primary malignancy. Rarely, TIO may be seen as a paraneoplastic phenomenon with solid organ malignancies where correction of biochemical abnormalities requires ongoing phosphorus replacement. We report a case of TIO in a patient with metastatic breast cancer complicated by increased parathyroid hormone release secondary to denosumab-induced hypocalcemia. The patient required intensive intravenous and oral phosphate supplementation in addition to vitamin D repletion. A high index of clinical suspicion can yield the correct diagnosis where TIO arises in the setting of a solid organ tumor and help the clinician appropriately manage these challenging cases.

Oncogenic osteomalacia, a rare paraneoplastic syndrome due to phosphate wasting--a case report and review of the literature.

An appropriate phosphate homeostasis is absolutely required for correct bone mineralization and remodeling, for diverse signaling pathways as well as cell membrane formation. Its disequilibrium results in serious complications like hypophosphatemia and excessively reduced fractional tubule phosphate reabsorption (TRP). A rare cause of such a disturbed phosphate balance is tumor-induced osteomalacia (TIO)--a phosphate wasting disorder sometimes associated with certain mesenchymal tumors. These primitive tumors secrete so-called phosphatonins--recently identified factors involved in the regulation of phosphate homeostasis such as the secreted frizzled related protein 4 (sFRP-4), the fibroblast growth factors 7 and 23 (FGF-7/-23), or the matrix extracellular phosphoglycoprotein (MEPE). Progressive muscular weakness and spontaneous bone fractures caused by inadequate osteoid mineralization are the characteristic clinical symptoms, which completely resolve after tumor resection. Here we report a new case of TIO caused by tumor secreted FGF-23 and review the literature to facilitate the correct diagnosis of this rare disorder.

Renal tubular dysfunction and abnormalities of calcium metabolism in cadmium workers.

Tubular proteinuria is generally accepted as the critical effect following long-term, low-level exposure to cadmium as seen in an industrial environment. This effect may not be of immediate importance to the health of the individual, but the significance, in terms of long-term morbidity and mortality, of the renal tubular defect of which it is an indicator is not fully understood, and certain sequelae may have remained unrecognized due to inadequate follow-up.Follow-up studies have been performed in nine of 12 workers who were initially investigated in 1962. In six of the men exposures ranged from 28 to 45 years to cadmium sulfide dust and for shorter periods in the earlier years to cadmium oxide fume and dust. These six men had tubular proteinuria when first seen, and this has persisted in the five survivors. All six men had hypercalciuria, and two of them became recurrent stone formers. One man whose urinary calcium excretion later fell to a low level more recently developed vitamin D resistant osteomalacia. In addition, each of the six men had exhibited some, but not all, of a variety of biochemical abnormalities related to other proximal renal tubular defects, and the worker who developed osteomalacia had additional evidence of a distal tubular defect. The five survivors also have evidence of slowly progressive deterioration in glomerular function.Follow-up of this small group has shown that renal tubular dysfunction in cadmium workers may continue symptom-free for long intervals, but in a proportion of cases serious clinical effects may develop after a number of years.

Biomarkers and imaging in non-malignant and malignant osteomalacia.

Deoxypyridinium (DPD) cross-links are a specific parameter for collagen type I degradation. We report the longitudinal tracking of DPD in relation to other bone markers and imaging techniques in a patient with osteomalacia and secondary hyperparathyroidism from reduced light exposure due to attire. This patient was first admitted for diffuse skeletal pain. X-rays showed general demineralization and Looser's transformation zones in the neck of the left femur. MRI examinations of the pelvis and the proximal femora demonstrated bilateral signs of acute sacroiliitis, as well as edema-like lesions in the femoral heads and necks bilaterally. The baseline parathyroid hormone level was 8 times higher than the normal upper limit, whereas 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were significantly reduced. A 7-fold increase in free urinary DPD and a 17-fold increase in bone-specific alkaline phosphatase (bone-AP) were also measured. Percutaneous transiliac bone biopsy revealed markedly increased osteoidosis. Osteomalacia was diagnosed due to chronically reduced sun exposure caused by restrictive attire, and cholecalciferol substitution therapy was begun. After a follow-up of 28 weeks, non-specific parameters of bone turnover (parathyroid hormone, total alkaline phosphatase, serum calcium and serum phosphate) had normalized, while DPD, as a specific bone degradation marker, and bone-AP, as a bone formation parameter, both remained elevated. This example underlines the validity of DPD and bone-AP as indicators of increased bone metabolism: not only were they the parameters with the highest baseline deviation, but they were also the last to normalize.

Phosphaturic mesenchymal tumor: a case report.

Osteomalacia induced by tumor is a rare phenomenon in which the resection of tumor is followed by dramatic amelioration of clinical signs and symptoms. We hereby report a case of a 66 years old male who presented with features of osteomalacia in which the characteristic clinical presentation was associated with the phosphaturic mesenchymal tumor, mixed connective tissue variant. The case is reported for its rarity.