Vitamina D y su efecto positivo sobre el eje PTH/vitamina D/calcio-FGF23/klotho/fósforo en pacientes con trasplante renal / Vitamin D and its positive effect on the PTH/vitamin D/calcium-FGF23/klotho/phosphorus axis in kidney transplant recipients

Introducción: la hipovitaminosis D es frecuente en los receptores de trasplante renal (RTR) y se asocia con efectos deletéreos tanto a nivel óseo como extraóseo. El tratamiento con colecalciferol es eficaz para la normalización de la 25(OH)D, demostrándose un efecto benéfico sobre el eje calciotrópico; sin embargo, su efecto sobre el eje fosfotrópico no se ha reportado. El objetivo de este estudio fue evaluar el efecto de la normalización de las concentraciones séricas de 25(OH)D sobre el eje PTH/vitamina D/calcio-FGF23/klotho/fósforo en RTR tratados con colecalciferol, así como la asociación entre sus componentes. Métodos: estudio prospectivo en 23 RTR con hipovitaminosis D y antecedente de nefropatía primaria tratados con colecalciferol, en quienes se evaluó el eje PTH/vitamina D/calcio y FGF23/klotho/fósforo durante el estado de hipovitaminosis D y a la normalización de la 25(OH)D. Resultados: a la normalización de la 25(OH)D se evidenció una reducción de la PTH [103 (58,5-123,9) vs. 45,6 (30,1-65,1) pg/mL; p = 0,002] y un aumento del fósforo sérico [3,1 (2,3-3,5) vs. 3,3 (3-3,6) mg/dL; p = 0,01], sin diferencias en las concentraciones de calcio, klotho y FGF23. El tiempo para lograr la normalización de la 25(OH)D fue de 12 semanas (4-12), con una dosis de 5000 UI/día (4000-6000). Se corroboró una asociación positiva entre klotho y PTH (r = 0,54; p = 0,008; regresión lineal, β = 0,421; IC 95 %: 0,003-0,007; p = 0,045). (AU)

Background: hypovitaminosis D is frequent in kidney transplant recipient (KTR) patients and is associated with deleterious effects both at the bone and extraosseous levels. Treatment with cholecalciferol is effective for the normalization of 25(OH)D, demonstrating a beneficial effect on the calcium-tropic axis in other populations; however, its effect on the PTH/vitamin D/calcium and FGF23/klotho/phosphorus axis in RTR has not been reported. The aim of this study was to evaluate the effect of normalization of serum 25(OH)D concentrations on the PTH/vitamin D/calcium-FGF23/klotho/phosphorus axis in KTR treated with cholecalciferol, as well as the association between the components of this axis. Methods: a prospective study in 23 KTR with hypovitaminosis D, with evolution from 1 to 12 months post-transplantation, an estimated glomerular filtration rate > 60 mL/min/1.73 m2 and a history of primary nephropathy treated with cholecalciferol, in whom the PTH/vitamin D/calcium and FGF23/klotho/phosphorus axis was evaluated during the state of hypovitaminosis D and at normalization of 25(OH)D. Results: at the normalization of 25(OH)D, a reduction in PTH [103 (58.5-123.9) vs 45.6 (30.1-65.1) pg/mL; p = 0.002] and an increase in serum phosphorus [3.1 (2.3-3.5) vs 3.3 (3-3.6) mg/dL; p = 0.01] were evident, with no differences in calcium, klotho and FGF23 concentrations. The time to achieve normalization of 25(OH)D was 12 weeks (RIC, 4-12), with a dose of 5000 IU/day (RIC, 4000-6000). A positive association between klotho and PTH was corroborated (r = 0.54; p = 0.008; linear regression, β = 0.421; B = 0.004; 95 % CI, 0.003-0.007; p = 0.045). (AU)

[Vitamin D and its positive effect on the PTH/vitamin D/calcium-FGF23/klotho/phosphorus axis in kidney transplant recipients]. / Vitamina D y su efecto positivo sobre el eje PTH/vitamina D/calcio-FGF23/klotho/fósforo en pacientes con trasplante renal.

Introduction: Background: hypovitaminosis D is frequent in kidney transplant recipient (KTR) patients and is associated with deleterious effects both at the bone and extraosseous levels. Treatment with cholecalciferol is effective for the normalization of 25(OH)D, demonstrating a beneficial effect on the calcium-tropic axis in other populations; however, its effect on the PTH/vitamin D/calcium and FGF23/klotho/phosphorus axis in RTR has not been reported. The aim of this study was to evaluate the effect of normalization of serum 25(OH)D concentrations on the PTH/vitamin D/calcium-FGF23/klotho/phosphorus axis in KTR treated with cholecalciferol, as well as the association between the components of this axis. Methods: a prospective study in 23 KTR with hypovitaminosis D, with evolution from 1 to 12 months post-transplantation, an estimated glomerular filtration rate > 60 mL/min/1.73 m2 and a history of primary nephropathy treated with cholecalciferol, in whom the PTH/vitamin D/calcium and FGF23/klotho/phosphorus axis was evaluated during the state of hypovitaminosis D and at normalization of 25(OH)D. Results: at the normalization of 25(OH)D, a reduction in PTH [103 (58.5-123.9) vs 45.6 (30.1-65.1) pg/mL; p = 0.002] and an increase in serum phosphorus [3.1 (2.3-3.5) vs 3.3 (3-3.6) mg/dL; p = 0.01] were evident, with no differences in calcium, klotho and FGF23 concentrations. The time to achieve normalization of 25(OH)D was 12 weeks (RIC, 4-12), with a dose of 5000 IU/day (RIC, 4000-6000). A positive association between klotho and PTH was corroborated (r = 0.54; p = 0.008; linear regression, ß = 0.421; B = 0.004; 95 % CI, 0.003-0.007; p = 0.045). Conclusions: treatment with cholecalciferol is effective for the normalization of 25(OH)D, with a beneficial effect on calcium-phosphotropic metabolism characterized by a reduction in PTH concentration, without significant changes in calcemia or calciuria, as well as an increase in phosphatemia, without modifications in FGF23 or klotho concentrations.

Introducción: Introducción: la hipovitaminosis D es frecuente en los receptores de trasplante renal (RTR) y se asocia con efectos deletéreos tanto a nivel óseo como extraóseo. El tratamiento con colecalciferol es eficaz para la normalización de la 25(OH)D, demostrándose un efecto benéfico sobre el eje calciotrópico; sin embargo, su efecto sobre el eje fosfotrópico no se ha reportado. El objetivo de este estudio fue evaluar el efecto de la normalización de las concentraciones séricas de 25(OH)D sobre el eje PTH/vitamina D/calcio-FGF23/klotho/fósforo en RTR tratados con colecalciferol, así como la asociación entre sus componentes. Métodos: estudio prospectivo en 23 RTR con hipovitaminosis D y antecedente de nefropatía primaria tratados con colecalciferol, en quienes se evaluó el eje PTH/vitamina D/calcio y FGF23/klotho/fósforo durante el estado de hipovitaminosis D y a la normalización de la 25(OH)D. Resultados: a la normalización de la 25(OH)D se evidenció una reducción de la PTH [103 (58,5-123,9) vs. 45,6 (30,1-65,1) pg/mL; p = 0,002] y un aumento del fósforo sérico [3,1 (2,3-3,5) vs. 3,3 (3-3,6) mg/dL; p = 0,01], sin diferencias en las concentraciones de calcio, klotho y FGF23. El tiempo para lograr la normalización de la 25(OH)D fue de 12 semanas (4-12), con una dosis de 5000 UI/día (4000-6000). Se corroboró una asociación positiva entre klotho y PTH (r = 0,54; p = 0,008; regresión lineal, ß = 0,421; IC 95 %: 0,003-0,007; p = 0,045). Conclusiones: el tratamiento con colecalciferol es eficaz para la normalización de la 25(OH)D con un efecto benéfico sobre el metabolismo calcio-fosfotrópico caracterizado por una reducción de la PTH y un incremento de la fosfatemia, sin modificaciones de calcemia, calciuria, FGF23 o klotho.

FGF23 in hemodialysis patients is associated with left ventricular hypertrophy and reduced ejection fraction.

BACKGROUND: Fibroblast growth factor 23 (FGF23) is known to cause left ventricular hypertrophy (LVH), but controversy exists concerning its effect in dialysis. This study evaluated associations between FGF23 levels, echocardiography and prognosis in patients on hemodialysis (HD). METHODS: Patients >18 years on chronic HD were included in this cross-sectional study. Plasma C-terminal FGF23 concentration was measured with ELISA and transthoracic echocardiography was performed, both before and after HD treatment. RESULTS: 239 haemodialysis (HD) patients were included in the study. The FGF23 was median 3560RU/ml (IQR 1447-9952). The mean left ventricular mass index (LVMI) was 110.2±26.7g/m2 and the left ventricular ejection fraction (LVEF) was 52.7±9.9%. Defined by LVMI, LVH was found in 110 patients (46%), of which 92 (84%) had hypertension (p<0.01). Patients with LVH had FGF23 levels of 5319 RU/ml (IQR 1858-12,859) and those without 2496 RU/ml (IQR 1141-7028) (p<0.01). FGF23 was significant positive correlated with LVMI (p<0.01), and negatively to LVEF (p<0.01). In a multivariate analysis, FGF23 was correlated with LVEF (p<0.01), but only marginally to LVMI (p<0.01). Cardiovascular events in the follow up period was not correlated with FGF23. Furthermore, FGF23 was independently correlated with overall mortality (p<0.001). CONCLUSION: FGF23 was positively correlated with LVH and negatively to LVEF. FGF23 was an independent predictor for overall mortality.

Tumour-induced osteomalacia: An emergent paraneoplastic syndrome.

Endocrine paraneoplastic syndromes are distant manifestations of some tumours. An uncommon but increasingly reported form is tumour-induced osteomalacia, a hypophosphatemic disorder associated to fibroblast growth factor 23 (FGF-23) secretion by tumours. The main biochemical manifestations of this disorder include hypophosphatemia, inappropriately low or normal tubular reabsorption of phosphate, low serum calcitriol levels, increased serum alkaline phosphatase levels, and elevated or normal serum FGF-23 levels. These tumours, usually small, benign, slow growing and difficult to discover, are mainly localized in soft tissues of the limbs. Histologically, phosphaturic mesenchymal tumours of the mixed connective tissue type are most common. Various imaging techniques have been suggested with variable results. Treatment of choice is total surgical resection of the tumour. Medical treatment includes oral phosphorus and calcitriol supplements, octreotide, cinacalcet, and monoclonal antibodies.

Fibroblast growth factor is associated to left ventricular mass index, anemia and low values of transferrin saturation.

BACKGROUND: Fibroblast growth factor 23 (FGF-23) is a phosphorus-regulating hormone. In chronic kidney disease (CKD), circulating FGF-23 levels are markedly elevated and independently associated with mortality. Left ventricular hypertrophy (LVH) is a potent risk factor for mortality in CKD, and FGFs have been implicated in the pathogenesis of myocardial hypertrophy. In addition, the effect of anemia on CV disease and LVH is well known in CKD. A relation between iron and FGF-23 metabolism is mentioned in a few studies. The aim of this study was to test the association of FGF-23 levels with echocardiographic (ECHO) and iron parameters in peritoneal dialysis patients (PD). METHODS: In this cross-sectional study, 61 subjects with PD (29 women and 32 men, mean age: 46.9±13.3 years, mean PD vintage: 69.5±39 months) underwent echocardiograms to assess left ventricular mass index (LVMI). Medical treatments and average values of the basic laboratory results of the last 6 months for all patients were recorded. Serum FGF-23 concentrations were measured using intact FGF-23 (iFGF-23) human enzyme-linked immunosorbent assay (ELISA) kit. According to the median levels of serum FGF-23 the patients were grouped into two (FGF-23 high and low groups). RESULTS: Significant positive correlation was recorded between serum FGF-23 levels and LVMI (P=0.023). There was also significant difference in terms of hemoglobin (12.1±2 versus 11.0±2, P=0.017), transferrin saturation (TSAT) (24.9±16.8 versus 19.5±10.8, P=0.042) between low and high FGF-23 group. Also in linear regression analysis the negative relation between FGF-23 and hemoglobin is persisted (r=0.199, P=0.045). CONCLUSIONS: FGF-23 is associated with LVMI, anemia and low TSAT in patients with PD. Whether increased FGF-23 is a marker or a potential mechanism of myocardial hypertrophy and anemia in patients with end-stage renal disease (ESRD) requires further study.

Osteomalacia oncogénica: Presentación de dos casos

La osteomalacia oncogénica es una enfermedad rara. Existen descriptos alrededor de 337 casos. Es ocasionada por un tumor productor del factor de crecimiento fibroblástico 23 (FGF-23), hormona que disminuye la reabsorción tubular de fosfatos y altera la hidroxilación renal de la vitamina D, con hipofosfatemia, hiperfosfaturia y niveles bajos de calcitriol. Se presentan dos pacientes de 44 y 70 años, que consultaron por dolores óseos generalizados de aproximadamente un año de evolución en los que se hallaron alteraciones bioquímicas compatibles con osteomalacia hipofosfatémica. En el primer caso se realizó la resección de una tumoración en tejido celular subcutáneo del pie derecho, un año después del diagnóstico clínico. Luego de la exéresis, se disminuyó el aporte de fosfatos que recibía el paciente, pero reaparecieron los dolores al intentar suspenderlos. Ocho años más tarde, hubo recidiva local de la tumoración por lo que se efectuó resección completa. Después de la misma, se logró suspender el aporte de fosfatos. En el segundo caso, el paciente se estudió con tomografía por emisión de positrones con 18F-fluorodesoxiglucosa, hallando formación nodular hipermetabólica en partes blandas de antepie derecho, de 2.26 cm de diámetro. Luego de su escisión se pudo suspender el aporte de fosfatos. Ambos pacientes se encuentran asintomáticos con indicadores de metabolismo fosfocálcico normales. El diagnóstico anatomopatológico en ambos fue un tumor mesenquimático fosfatúrico, variante mixta del tejido conectivo, la entidad más frecuentemente asociada a la osteomalacia oncogénica.

Oncogenic osteomalacia is a rare disease. It is caused by a tumor that produces fibroblast growth factor 23, a hormone that decreases the tubular phosphate reabsorption and impairs renal hydroxylation of vitamin D. This leads to hyperphosphaturia with hypophosphatemia and low calcitriol levels. About 337 cases have been reported and we studied two cases; 44 and 70 year-old men who sought medical attention complaining of suffering diffuse bone pain over a period of approximately one year. In both cases, a laboratory test showed biochemical alterations compatible with a hypophosphatemic osteomalacia. In the first case, a soft tissue tumor of the right foot was removed, one year after the diagnosis. The patient was allowed to diminish the phosphate intake, but symptoms reappeared at this time. Eight years later, a local recurrence of the tumor was noted. A complete excision was now performed. The patient was able to finally interrupt the phosphate intake. In the second case, an F-18 fluorodeoxyglucose positron emission tomography, with computed tomography revealed a 2.26 cm diameter hypermetabolic nodule in the soft tissue of the right forefoot. After its removal, the patient discontinued the phosphate intake. Both patients are asymptomatic and show a regular phosphocalcic laboratory evaluation. The histopathological diagnosis was, in both cases, a phosphaturic mesenchymal tumor, a mixed connective tissue variant. This is the prototypical variant of these tumors.

Osteomalacia oncogénica: Presentación de dos casos

La osteomalacia oncogénica es una enfermedad rara. Existen descriptos alrededor de 337 casos. Es ocasionada por un tumor productor del factor de crecimiento fibroblástico 23 (FGF-23), hormona que disminuye la reabsorción tubular de fosfatos y altera la hidroxilación renal de la vitamina D, con hipofosfatemia, hiperfosfaturia y niveles bajos de calcitriol. Se presentan dos pacientes de 44 y 70 años, que consultaron por dolores óseos generalizados de aproximadamente un año de evolución en los que se hallaron alteraciones bioquímicas compatibles con osteomalacia hipofosfatémica. En el primer caso se realizó la resección de una tumoración en tejido celular subcutáneo del pie derecho, un año después del diagnóstico clínico. Luego de la exéresis, se disminuyó el aporte de fosfatos que recibía el paciente, pero reaparecieron los dolores al intentar suspenderlos. Ocho años más tarde, hubo recidiva local de la tumoración por lo que se efectuó resección completa. Después de la misma, se logró suspender el aporte de fosfatos. En el segundo caso, el paciente se estudió con tomografía por emisión de positrones con 18F-fluorodesoxiglucosa, hallando formación nodular hipermetabólica en partes blandas de antepie derecho, de 2.26 cm de diámetro. Luego de su escisión se pudo suspender el aporte de fosfatos. Ambos pacientes se encuentran asintomáticos con indicadores de metabolismo fosfocálcico normales. El diagnóstico anatomopatológico en ambos fue un tumor mesenquimático fosfatúrico, variante mixta del tejido conectivo, la entidad más frecuentemente asociada a la osteomalacia oncogénica.(AU)

Oncogenic osteomalacia is a rare disease. It is caused by a tumor that produces fibroblast growth factor 23, a hormone that decreases the tubular phosphate reabsorption and impairs renal hydroxylation of vitamin D. This leads to hyperphosphaturia with hypophosphatemia and low calcitriol levels. About 337 cases have been reported and we studied two cases; 44 and 70 year-old men who sought medical attention complaining of suffering diffuse bone pain over a period of approximately one year. In both cases, a laboratory test showed biochemical alterations compatible with a hypophosphatemic osteomalacia. In the first case, a soft tissue tumor of the right foot was removed, one year after the diagnosis. The patient was allowed to diminish the phosphate intake, but symptoms reappeared at this time. Eight years later, a local recurrence of the tumor was noted. A complete excision was now performed. The patient was able to finally interrupt the phosphate intake. In the second case, an F-18 fluorodeoxyglucose positron emission tomography, with computed tomography revealed a 2.26 cm diameter hypermetabolic nodule in the soft tissue of the right forefoot. After its removal, the patient discontinued the phosphate intake. Both patients are asymptomatic and show a regular phosphocalcic laboratory evaluation. The histopathological diagnosis was, in both cases, a phosphaturic mesenchymal tumor, a mixed connective tissue variant. This is the prototypical variant of these tumors.(AU)

Tumor mesenquimatoso fosfatúrico de fosa nasal con compromiso intracraneano: reporte de un caso y revisión de la literatura / Nasal fossa phosphaturic mesenchymal tumor with intracraneal compromise: case report and review of the literature

El tumor mesenquimatoso fosfatúrico (TMF) es una enfermedad extremadamente rara. Según evidencia reciente es causado por la sobreexpresión del factor de crecimiento fibroblástico 23 (FGF23), el cual genera hipofosfemia y osteomalacia. A continuación presentamos el caso de un paciente de 42 años con un tumor mesenquimatoso fosfatúrico de fosa nasal izquierda con extenso compromiso intracraneano. Cabe destacar que hasta la fecha hay 142 casos reportados de TMF en la literatura de los cuales solo 11 se ubican en fosa nasaly cavidades sinusales, y sólo dos de ellos ubicados en fosa nasal¹. El paciente tuvo una exitosa resolución quirúrgica con la consecuente normalización de parámetros analíticos (incluido el FGF23), mejoría sintomática y ausenia de recidiva hasta la fecha.

The phosphaturic mesenchymal tumor (PMT) is an extremely rare disease. According to recent evidence is caused by overexpression of fibroblast growth factor 23 (FGF23) which generates hypophosphatemia and osteomalacia. We report the case of a 42 year old patient with a left nasal fossa phosphaturic mesenchymal tumor with intracranial involvement. Should be noted that to date there are 142 reported cases of PMT in the literature of which only 11 are located in nasal fossa and sinus cavities, two of them located in nasal fossa¹. The patient had a successful surgical resolution with consequent normalization of analytical parameters (including FGF23), absence of symptoms and no recurrence to date.