Primary hyperparathyroidism (pHPT), characterized by elevated serum levels of calcium and parathyroid hormone (PTH), is associated with a number of metabolic derangements causing secondary manifestations. These include osteoporosis and increased risk of fractures, but also risk factors for cardiovascular morbidity and mortality. These risk factors include impaired glucose tolerance (IGT), dyslipidemia, increased body mass index and hypertension. While the skeletal abnormalities are mainly due to elevated PTH, the latter disturbances are still unexplained. Non-insulin dependent diabetes mellitus (NIDDM), IGT, dyslipidemia and hypertension are all included in the metabolic syndrome, also associated with morbidity and mortality in cardiovascular diseases. In this thesis, decreased bone mineral density (BMD) and variables of the metabolic syndrome are explored in patients with mild and normocalcemic pHPT before and after parathyroidectomy. To further investigate the relationship between insulin sensitivity and calcium, a community-based cohort was investigated. In two different patient cohorts of pHPT, lipoprotein alterations with decreased levels of HDL-cholesterol and elevated triglycerides were found in association with a high frequency of IGT, NIDDM and decreased insulin sensitivity. Parathyroidectomy had effects on the dyslipidemia and in part on the glucose metabolism. The disturbed glucose metabolism in pHPT was substantiated by results from the general population by a negative association between insulin sensitivity, measured by hyperinsulinemic clamp, and serum calcium. In conclusion, normocalcemic, mild and overt pHPT are associated with a range of risk factors for cardiovascular diseases, development of NIDDM and decreased BMD in cortical as well as trabecular bone. These findings explain, at least in part, the elevated morbidity and mortality from cardiovascular disease as well as fractures, reported in pHPT patients. Moreover, in the general population, serum calcium is associated with decreased insulin sensitivity. Parathyroidectomy has positive effects on several, but not all, of the investigated metabolic parameters.

Primary hyperparathyroidism (pHPT) due to parathyroid tumours with hypersecretion of parathyroid hormone and hypercalcaemia is a common disease with incompletely understood etiology affecting more than 1 % of the population, primarily postmenopausal women. In secondary hyperparathyroidism (sHPT), parathyroid tumours develop in response to calcium and vitamin D deficiency generally in patients with uraemia. HPT is usually treated by surgical removal of enlarged parathyroid glands. The aim of this thesis was to examine the Wnt/β-catenin signalling pathway in parathyroid tumours. Aberrantly accumulated β-catenin was found in all analysed pHPT and sHPT tumours, with a stabilising homozygous mutation (Ser37Ala) in 7.3% of the pHPT tumours. Truncation of the APC protein was not found. MYC, a β-catenin target gene was overexpressed in a substantial fraction of pHPT and sHPT parathyroid tumours. A parathyroid tumour cell line (sHPT-1) was established from a hyperplastic gland removed at operation of a patient with sHPT. The cells produced parathyroid hormone and grew with a doubling time of approximately 72 hours. Stabilised nonphosphorylated transcriptionally active β-catenin was expressed. Efficient transfection of siRNA against β-catenin decreased expression of cyclin D1 and MYC, and inhibited cell growth with ensuring cell death. The Wnt coreceptor LRP5 was found expressed with an internal deletion of 142 amino acids (LRP5Δ) in 86% and 100% of pHPT and sHPT tumours, respectively. Stabilising mutation of β-catenin and expression of LRP5Δ was mutually exclusive. Expression of LRP5Δ was required to maintain the nonphosphorylated transcriptionally active ß-catenin level, MYC expression, parathyroid cell growth in vitro, and tumour growth in transplanted SCID mice. Wnt3 ligand and LRP5Δ strongly activated transcription, and LRP5Δ was insensitive to inhibition by DKK1. Aberrant accumulation of β-catenin by stabilising mutation or expression of LRP5Δ appears as a common pathogenic pathway for hyperparathyroid disease. LRP5Δ in particular presents a potential target for therapeutic intervention.

Primary hyperparathyroidism (PHPT) is a common endocrine disease, existing in both genders and in all age groups. Postmenopausal women are at particular risk of developing the disease and estrogen decline after menopause is suggested to affect the progress. Although PHPT is mild in its presentation with subtle or no subjective symptoms, it is associated with an increased risk of associated morbidity and also mortality i.e cardiovascular complications, psychiatric instability, concomitant metabolic abnormalities, obesity and decrease in bone mineral density. The current cure is surgical removal of the diseased gland/s, but other medical alternatives have been investigated. The disease is thoroughly explored in postmenopausal women but less is known about other populations groups. Since progression of the disease generally is slow, the underlying disturbance of the calcium homeostasis can be suspected to have been established a long time prior to diagnose with potential to affect associated morbidity. The general aim of this thesis is to clarify the expression of PHPT in premenopausal women and in elderly men and to explore how frequent the disease in these populations occurs. The women and men were investigated through population-based studies. Baseline data and prevalence of PHPT in premenopausal women age 40-50 years were studied (Paper I), the prevalence was 5.1% in this population and was associated with decreased bone mineral density and associated obesity. In a three years follow up of the female cohort, the effects of menopausal transition and associated morbidity was investigated (Paper II). The prevalence and expression of PHPT in men between 69 and 81 years and impact on bone mineral density, physical performance, fall and fracture prevalence was explored through data from Mr Os Sweden (Papers III and IV). In this population prevalence of PHPT was 0.73% and associated with lower bone mineral density and inferior physical performance.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 7 uppsatser.

Cette thèse de mathématiques appliquées en physiologie rénale a pour thème principal l'étude de l'homéostasie du calcium à travers le développement d'un modèle mathématique à l'échelle de l'organisme. Nous cherchons à répondre à certaines questions soulevées par les néphrologues dans le cas de pathologies impliquant la formation de calculs rénaux ou de calcifications. Nous examinons notamment les cas de l'hypercalciurie observée durant l'hyperparathyroïdie primaire dont les causes ne sont pas élucidées ainsi que les mécanismes de complexation du calcium et phosphate et notamment les conséquences d'une infusion intraveineuse de phosphate sur l'homéostasie du calcium. Notre modèle est composé d'équations différentielles décrivant la dynamique du calcium dans les compartiments impliqué dans son métabolisme (intestin, os, reins) ainsi que les mécanismes de régulation par l'hormone parathyroïdienne (PTH), la vitamine D3 et le récepteur sensible au calcium (CaSR). Ce modèle est par ailleurs couplé à un modèle de l'homéostasie du phosphate. Les résultats de ce modèle suggèrent que la présence ou non d'une hypercalciurie lors de l'hyperparathyroïdie primaire peut être expliquée par des mécanismes antagonistes dans la branche ascendante large de Henle, avec d'un côté le CaSR inhibant la réabsorption de calcium et de l'autre la PTH diminuant l'excrétion de calcium. Nous concluons que l'infusion intraveineuse de phosphate induit une hypocalcémie majeure, due principalement à la précipitation du calcium et du phosphate dans le plasma et dans l'os. En outre, cette étude suggère un retard dans l'activation de la synthèse de PTH par le phosphate. / This thesis of applied mathematics in renal physiology focuses on the study of calcium homeostasis, through the development of a mathematical model at the organism scale. This model is built based upon recent experimental studies as well as previous models in the field. We aim to answer several questions raised by nephrologists regarding diseases involving calcium stone formation or calcifications. In particular, we are interested in the origins of the hypercalciuria observed during primary hyperparathyroidism, the causes of which remain to be elucidated, the effects of bone resorption inhibition by bisphosphonates on calcium metabolism, as well as the consequences of an intravenous infusion of phosphate on calcium homeostasis. Our model is composed of differential equations describing the dynamics of calcium in the compartments involved in its metabolism (intestine, bone and kidneys), as well as complex feedback mechanisms by parathyroid hormone (PTH), vitamin D3 and the calcium sensing receptor (CaSR). Besides, this model is coupled to a phosphate homeostasis model. This model suggests that the variable presence of hypercalciuria during primary hyperparathyroidism can be explained by counteracting mechanisms in the thick ascending limb of Henle, involving on one hand the calcium sensing receptor, which inhibits calcium reabsorption, and on the other hand PTH which decreases calcium excretion. We conclude that the intravenous infusion of phosphate triggers a major hypocalcemia, mainly due to the precipitation of calcium and phosphate in both bone and plasma. Moreover, this study suggests a delay in the activation of PTH synthesis by phosphate

A hiperfosfatemia está relacionada com o hiperparatireoidismo secundário renal (HPTSR) e com a progressão da doença renal crônica (DRC). A retenção de fósforo estimula a síntese do fator de crescimento de fibroblastos 23 (FGF-23), o qual promove fosfatúria, com o objetivo de evitar o aparecimento de hiperfosfatemia. Atualmente, o tratamento disponível para DRC é de manutenção e, portanto, novas estratégias para evitar a progressão da DRC seriam de grande relevância. Recentemente têm sido demonstrado o papel da célula-tronco mesenquimal (CTM) em minimizar os mecanismos inflamatórios e imunológicos envolvidos na progressão da DRC. Portanto, o estudo teve como hipótese de que a CTM possa evitar ou controlar a progressão para o HPTSR, investigada por meio da avaliação de biomarcadores do metabolismo de fósforo, ou seja, as concentrações sérica de fósforo (sP), FGF-23, cálcio total e cálcio ionizado, bem como a excreção fracionada de fósforo urinária (uFEP) em cães com DRC nos estágios 2 (Grupo A) e 3 (Grupo B), submetidos ou não a terapia com CTM, bem como investigar se os valores elevados de FGF-23 estariam relacionados com o menor tempo de sobrevida. Trata-se de um estudo prospectivo, longitudinal, duplo-cego e randomizado em que foram avaliados 22 cães com DRC, tratados com solução fisiológica (SF) ou CTM, avaliados a cada 30 a 45 dias em 12 momentos (T0 a T12). No Grupo A (n= 9; SF: n= 6, CTM: n= 3) todos os cães eram normofosfatêmicos no momento inicial do acompanhamento (T0) e foi observado níveis elevados de FGF-23 em 33,3% dos cães (3 de 9), assim como o aumento de uFEP foi detectado em 33,3% dos casos (3 de 9). A média ± EPM dos valores de FGF-23 sérico do Grupo A foi de 481,5 ± 75,23pg/mL. Já no Grupo B (n = 13; SF: n = 6, CTM: n = 7), todos os cães apresentaram altas concentrações séricas de FGF-23 desde T0 (média ± EPM de 12744 ± 6879pg/mL), sendo que 53,8% dos cães eram normofosfatêmicos. A média ± EPM de fósforo sérico em T0, T6 e T12 ou momento do óbito no Grupo A e B foi de 3,74 ± 0,13mg/dL e 6,40 ± 0,54mg/dL. Ao longo do curso da doença, o desenvolvimento de hiperfosfatemia foi observada em apenas 11,1% dos cães do Grupo A e em 84,6% dos cães do Grupo B. O Grupo B (SF e CTM) apresentou valores mais elevados de FGF-23 do que o Grupo A (SF e CTM), e foi detectada diferença estatística entre os dois grupos. A uFEP nos cães dos Grupos A e B em T0, T6 e T12 ou óbito obteve média ± EPM de 20,93 ± 3,92% e 24,05 ± 2,22%, respectivamente. Além disso, a sobrevida foi menor no Grupo B, a qual estava associada com hiperfosfatemia intensa, altas concentrações de FGF-23 e diminuição da uFEP. Dessa forma, em cães DRC normofosfatêmicos, a presença de aumentos de uFEP e de FGF-23 parece terem atuado como marcador precoce do HPTSR. Em contrapartida, nos estágios tardios da DRC, o aumento de FGF-23 associado a diminuição da uFEP pode indicar mau prognóstico. Em relação à terapia com CTM nos cães com DRC, de acordo com o número de cães avaliados e os resultados obtidos, não foi possível concluir de forma contundente sobre o efeito da terapia com CTM na doença renal crônica de curso natural em cães, entretanto, os resultados obtidos foram relevantes, pois suscitaram questões quanto ao momento ou o estágio da DRC que seria o mais adequado para a indicação da terapia celular para que os efeitos benéficos possam ser obtidos. Assim, ainda se faz necessária a condução de mais pesquisas com um número maior de cães com DRC para avaliar efeito da CTM em evitar o distúrbio no metabolismo mineral, bem como a progressão da DRC em cães / Hyperphosphatemia is associated with renal secondary hyperparathyroidism (SRHP) and chronic kidney disease (CKD) progression. Phosphorus retention stimulates the synthesis of fibroblast growth factor 23 (FGF-23), which promotes phosphaturia in order to avoid the onset of hyperphosphatemia. Conservative treatment of CKD is currently avaliable and new strategies are needed and welcome to avoid the progression of renal injury. Recent studies have shown the role of mesenchymal stem cell (MSC) in minimizing inflammatory and immunological mechanisms known as mediators of CKD progression. Therefore, it was hypothesized that MSCs could avoid or control the progression to SRHP, assessed by serum phosphorus (sP), FGF-23, total and ionized calcium and fractional excretion of phosphorus (uFEP) in CKD dogs in Stages 2 (Group A) and 3 (Group B), also was investigated whether high values of FGF-23 could be associatted with shorter survival time. Prospective, double-blind, randomized and longitudinal study was conducted enrolling 22 dogs with CKD treated with saline solution (SS) or MSC, which were evaluated every 30 to 45 days in 12 moments (T0 to T12). In Group A (n = 9; SF: n = 6, CTM: n = 3) all dogs were normophosphatemic at the beginning of the follow-up (T0) and high levels of FGF-23 were already detected in 33.3% of dogs (3 of 9), as well as increased in uFEP (33.3%; 3 of 9). The mean ± SEM of serum FGF-23 in Group A was 481.50 ± 75.23pg/mL. In Group B (n = 13; SS: n = 6, MSC: n = 7), all dogs showed high concentrations of serum FGF-23 since T0 (mean ± SEM of 12744 ± 6979pg/mL), and normophosphatemia detected in 53.8% of them. The mean ± SEM of serum phosphorus at T0, T6 and T12 or death in Group A and B was 3.74 ± 0.13mg/dL and 6.40 ± 0.54mg/dL. Hyperphosphatemia developed during the follow-up in only 11.1% of the dogs of Group A and 84.6% of the dogs of Group B. Group B (SS and MSC) had higher levels of FGF-23 than Group A (SS and MSC), and difference bewteen those groups detected. The uFEP in dogs of Groups A and B at T0, T6 and T12 or death obtained mean ± SEM of 20.93 ± 3.92% and 24.05 ± 2.22%, respectively. Furthermore, the survival rate was lower in Group B, which was associated with severe hyperphosphatemia, high values of serum FGF-23 and decreased uFEP. Therefore in normophophatemic CKD dogs, the increased in uFEP and high levels of FGF-23 may act as an early marker of SRHP. However, in later stages of CKD, increased levels of serum FGF-23 associated with decreased uFEP and hyperphosphatemia may indicate poor prognosis. Regarding to the MSC therapy in dogs with CKD, the number of dogs involved and also according to the results, it still has not allowed to conclude the effect of therapy with mesenchymal stem cell in spontaneous chronic kidney disease; however, the results obtained raised important questions such as the time or the stage of CKD that could be more suitable for the use of stem cell therapy in order to get its beneficial effects. Therefore, futher studies are needed, including greater number of dogs with CKD and then to evaluate the effect or action of MSC to avoid disturbances in mineral metabolism as well as the progression of CKD in dogs

O hiperparatireoidismo (HPT) secundário é uma complicação da doença renal crônica. A paratireoidectomia total com autoimplante proporciona bons resultados no seu tratamento, mas alguns doentes não desenvolvem níveis adequados de hormônio da paratireóide (PTH) após a operação. Os objetivos, do presente estudo, foram analisar fatores que poderiam interferir no funcionamento do autoimplante de glândula paratireóide e quantificar a taxa de hipofunção segundo alguns critérios. Casuística e Métodos: em um estudo prospectivo e observacional, foram analisados a idade, sexo, peso, altura e a etnia. A causa da doença renal crônica (DRC), tempo de DRC antes da paratireoidectomia, tempo de diálise, antecedente de intoxicação por alumínio e tempo de diagnóstico do HPT. Os dados bioquímicos estudados foram os níveis pré-operatórios de fósforo, cálcio total, cálcio iônico, PTH e fosfatase alcalina e aos 6 meses e 1 ano de pós-operatório. Registrada a quantidade de cálcio (gluconato e carbonato) e calcitriol ofertada no pós-operatório sendo realizada durante a primeira semana, no primeiro, terceiro sexto mês de pós-operatório. A histologia da glândula implantada foi analisada. Os pacientes foram divididos, segundo os níveis preconizados de PTH para indivíduos normais e segundo as recomendações da Fundação Nacional do Rim dos Estados Unidos da América (K/DOQI), em grupos hipofuncionante (grupo 1) e funcionante ( grupo 2). Resultados: Entre julho de 2007 e dezembro de 2008, 48 pacientes (18 homens e 30 mulheres) foram submetidos à paratireoidectomia total com autoimplante imediato. A média de idade dos indivíduos foi 44,7 anos (EP: 12,6), a do tempo de diálise foi 9,6 anos (EP: 5,1), a média do tempo de diagnóstico do hiperparatireoidismo de 2,6 anos (EP: 2). A principal causa da doença renal crônica foi a hipertensão arterial em 16 indivíduos (33,3%) seguida de causa indefinida em 12 (25%), GESF em 5 (10,4%), diabetes mellitus em 4 (8,3%). Com relação ao número de fragmentos implantados, houve tendência a uma diferença entre os grupos 1 e 2 (p= 0,14). Houve tendência a uma diferença entre os grupos 1 e 2 (p= 0,1) no que diz respeito a histologia da glândula implantada. O índice de hipofunção do auto implante, em 1 ano, foi de 21,27% no critério do nível de PTH para indivíduos normais e de 72,9% segundo as recomendações do KDOIQ. As complicações e óbitos por causa cardiovascular não diferiram entre os grupos. CONCLUSÃO: a frequência de hipofunção do implante imediato de paratireóide foi de 21,27% e de 72,9% segundo as recomendações do KDOQ e não houve a identificação de fatores preditivos para sua hipofunção. / The secondary hyperparathyroidism (HPT) is a complication of chronic kidney disease. A total parathyroidectomy with autograft provides good results in treatment, but some patients do not develop adequate levels of parathyroid hormone (PTH) after operation. The objectives of study were to analyze factors that could interfere with the function of the parathyroid gland autograft and measure the rate of hypofunction according several criteria. Patients and Methods: a prospective observational study were analyzed age, sex, weight, height and ethnicity. The cause of chronic kidney disease (CKD), duration of CKD prior to parathyroidectomy, duration of dialysis, previous aluminum intoxication and time of diagnosis of HPT. The biochemical data studied : preoperative levels of phosphorus, total calcium, ionized calcium, PTH and alkaline phosphatase and 6 months and 1 year postoperatively. Recorded the amount of calcium (gluconate and carbonate) and calcitriol offered postoperative being held during the first week, the first, third, sixth month postoperatively. Histology of the implanted gland was analyzed. Patients were divided according to the recommended levels of PTH for normal individuals and in accordance with the recommendations of the National Foundation Kidney the United States of America (K / DOQI) in hypofunction groups (group 1) and functional (group 2). Results: Between July 2007 and December 2008, 48 patients (18 men and 30 women) underwent total parathyroidectomy with immediate autograft. The mean age was 44.7 years (SE: 12.6), the duration of dialysis was 9.6 years (SE: 5.1), the average time of diagnosis of hyperparathyroidism 2.6 years (EP: 2). The main cause of chronic renal disease was hypertension in 16 patients (33.3%) followed by unknown cause in 12 (25%), FSGS in 5 (10.4%), diabetes mellitus in 4 (8.3%.). The number of implanted fragments, there was a trend to a difference between groups 1 and 2 (p = 0.14). There was a trend to a difference between groups 1 and 2 (p = 0.1) as regards the histology of the gland implanted. The rate of self hypofunction implant at 1 year was 21.27% at the discretion of the PTH level in normal individuals and 72.9% according to the recommendations of KDOIQ. Complications and deaths from cardiovascular causes did not differ between groups. CONCLUSION: The rate of hypofunction of the parathyroid immediate implant was 21.27% and 72.9% according to the recommendations of KDOIQ and there was no identification of predictive factors for its hypofunction.

Abstract Multiple endocrine neoplasia type 1 (MEN1) is an inherited syndrome characterized by parathyroid, gastroenteropancreatic and pituitary neuroendocrine tumours. In Northern Finland, two founder mutations of the MEN1 gene (1466del12, 1657insC) accounting for the majority of the MEN1 cases, have common ancestors born in the 18th and 19th centuries, respectively. Three small clusters of familial pituitary adenoma have also been detected, two of which could be linked by genealogy to a common ancestral couple born in the 18th century. Clinical evaluation of 82 MEN1 mutation carriers showed that age was a risk factor for most of the MEN1-related manifestations. In the whole group, nonfunctional pancreatic tumour (NFPT) was more common in the frameshift/nonsense mutation carriers (odds ratio 3.26; 95% confidence interval 1.27–8.33, P = 0.014), whereas gastrinoma was more common in the in-frame/missense mutation carriers (OR 6.77, CI 1.31–35.0, P = 0.022). In the founder mutation carriers, the 1657insC mutation predicted the risk for NFPT (OR 3.56, CI 1.29–9.83, P = 0.015), while the 1466del12 mutation was associated with the risk for gastrinoma (OR 15.1, CI 1.73–131.9, P = 0.014). The mean ages at death of the 32 obligatory MEN1 founder mutation carriers born between 1728 and 1929 were compared to those of the 29 spouses and sex-matched life expectancy estimates derived from Finnish national statistics. The ages at death of the mutation carrier males (61.1 ± 12.0 years) and females (67.2 ± 10.7 years) did not differ from the control groups. PAP (pituitary adenoma predisposition) locus was mapped in the chromosome region 11q12–11q13 by whole-genome single-nucleotide polymorphism genotyping. Combining the linkage and the gene expression array data, AIP (aryl hydrocarbon receptor interacting protein) was chosen for sequencing. The nonsense mutation Q14X was identified in the affected (acromegaly, gigantism, prolactinoma) family members and in four other patients. Loss of heterozygosity was detected in pituitary adenomas of AIP mutation carriers. Mutation analysis of MEN1, HRPT2 (hyperparathyroidism 2), CASR (calcium-sensing receptor), CDKN1B (cyclin-dependent kinase inhibitor 1B) and AIP genes was performed in primary hyperparathyroidism patients with features of inherited predisposition. One out of 29 patients was found to have the 1466del12 mutation, while no mutations were detected in other genes.

A hiperfosfatemia está relacionada com o hiperparatireoidismo secundário renal (HPTSR) e com a progressão da doença renal crônica (DRC). A retenção de fósforo estimula a síntese do fator de crescimento de fibroblastos 23 (FGF-23), o qual promove fosfatúria, com o objetivo de evitar o aparecimento de hiperfosfatemia. Atualmente, o tratamento disponível para DRC é de manutenção e, portanto, novas estratégias para evitar a progressão da DRC seriam de grande relevância. Recentemente têm sido demonstrado o papel da célula-tronco mesenquimal (CTM) em minimizar os mecanismos inflamatórios e imunológicos envolvidos na progressão da DRC. Portanto, o estudo teve como hipótese de que a CTM possa evitar ou controlar a progressão para o HPTSR, investigada por meio da avaliação de biomarcadores do metabolismo de fósforo, ou seja, as concentrações sérica de fósforo (sP), FGF-23, cálcio total e cálcio ionizado, bem como a excreção fracionada de fósforo urinária (uFEP) em cães com DRC nos estágios 2 (Grupo A) e 3 (Grupo B), submetidos ou não a terapia com CTM, bem como investigar se os valores elevados de FGF-23 estariam relacionados com o menor tempo de sobrevida. Trata-se de um estudo prospectivo, longitudinal, duplo-cego e randomizado em que foram avaliados 22 cães com DRC, tratados com solução fisiológica (SF) ou CTM, avaliados a cada 30 a 45 dias em 12 momentos (T0 a T12). No Grupo A (n= 9; SF: n= 6, CTM: n= 3) todos os cães eram normofosfatêmicos no momento inicial do acompanhamento (T0) e foi observado níveis elevados de FGF-23 em 33,3% dos cães (3 de 9), assim como o aumento de uFEP foi detectado em 33,3% dos casos (3 de 9). A média ± EPM dos valores de FGF-23 sérico do Grupo A foi de 481,5 ± 75,23pg/mL. Já no Grupo B (n = 13; SF: n = 6, CTM: n = 7), todos os cães apresentaram altas concentrações séricas de FGF-23 desde T0 (média ± EPM de 12744 ± 6879pg/mL), sendo que 53,8% dos cães eram normofosfatêmicos. A média ± EPM de fósforo sérico em T0, T6 e T12 ou momento do óbito no Grupo A e B foi de 3,74 ± 0,13mg/dL e 6,40 ± 0,54mg/dL. Ao longo do curso da doença, o desenvolvimento de hiperfosfatemia foi observada em apenas 11,1% dos cães do Grupo A e em 84,6% dos cães do Grupo B. O Grupo B (SF e CTM) apresentou valores mais elevados de FGF-23 do que o Grupo A (SF e CTM), e foi detectada diferença estatística entre os dois grupos. A uFEP nos cães dos Grupos A e B em T0, T6 e T12 ou óbito obteve média ± EPM de 20,93 ± 3,92% e 24,05 ± 2,22%, respectivamente. Além disso, a sobrevida foi menor no Grupo B, a qual estava associada com hiperfosfatemia intensa, altas concentrações de FGF-23 e diminuição da uFEP. Dessa forma, em cães DRC normofosfatêmicos, a presença de aumentos de uFEP e de FGF-23 parece terem atuado como marcador precoce do HPTSR. Em contrapartida, nos estágios tardios da DRC, o aumento de FGF-23 associado a diminuição da uFEP pode indicar mau prognóstico. Em relação à terapia com CTM nos cães com DRC, de acordo com o número de cães avaliados e os resultados obtidos, não foi possível concluir de forma contundente sobre o efeito da terapia com CTM na doença renal crônica de curso natural em cães, entretanto, os resultados obtidos foram relevantes, pois suscitaram questões quanto ao momento ou o estágio da DRC que seria o mais adequado para a indicação da terapia celular para que os efeitos benéficos possam ser obtidos. Assim, ainda se faz necessária a condução de mais pesquisas com um número maior de cães com DRC para avaliar efeito da CTM em evitar o distúrbio no metabolismo mineral, bem como a progressão da DRC em cães / Hyperphosphatemia is associated with renal secondary hyperparathyroidism (SRHP) and chronic kidney disease (CKD) progression. Phosphorus retention stimulates the synthesis of fibroblast growth factor 23 (FGF-23), which promotes phosphaturia in order to avoid the onset of hyperphosphatemia. Conservative treatment of CKD is currently avaliable and new strategies are needed and welcome to avoid the progression of renal injury. Recent studies have shown the role of mesenchymal stem cell (MSC) in minimizing inflammatory and immunological mechanisms known as mediators of CKD progression. Therefore, it was hypothesized that MSCs could avoid or control the progression to SRHP, assessed by serum phosphorus (sP), FGF-23, total and ionized calcium and fractional excretion of phosphorus (uFEP) in CKD dogs in Stages 2 (Group A) and 3 (Group B), also was investigated whether high values of FGF-23 could be associatted with shorter survival time. Prospective, double-blind, randomized and longitudinal study was conducted enrolling 22 dogs with CKD treated with saline solution (SS) or MSC, which were evaluated every 30 to 45 days in 12 moments (T0 to T12). In Group A (n = 9; SF: n = 6, CTM: n = 3) all dogs were normophosphatemic at the beginning of the follow-up (T0) and high levels of FGF-23 were already detected in 33.3% of dogs (3 of 9), as well as increased in uFEP (33.3%; 3 of 9). The mean ± SEM of serum FGF-23 in Group A was 481.50 ± 75.23pg/mL. In Group B (n = 13; SS: n = 6, MSC: n = 7), all dogs showed high concentrations of serum FGF-23 since T0 (mean ± SEM of 12744 ± 6979pg/mL), and normophosphatemia detected in 53.8% of them. The mean ± SEM of serum phosphorus at T0, T6 and T12 or death in Group A and B was 3.74 ± 0.13mg/dL and 6.40 ± 0.54mg/dL. Hyperphosphatemia developed during the follow-up in only 11.1% of the dogs of Group A and 84.6% of the dogs of Group B. Group B (SS and MSC) had higher levels of FGF-23 than Group A (SS and MSC), and difference bewteen those groups detected. The uFEP in dogs of Groups A and B at T0, T6 and T12 or death obtained mean ± SEM of 20.93 ± 3.92% and 24.05 ± 2.22%, respectively. Furthermore, the survival rate was lower in Group B, which was associated with severe hyperphosphatemia, high values of serum FGF-23 and decreased uFEP. Therefore in normophophatemic CKD dogs, the increased in uFEP and high levels of FGF-23 may act as an early marker of SRHP. However, in later stages of CKD, increased levels of serum FGF-23 associated with decreased uFEP and hyperphosphatemia may indicate poor prognosis. Regarding to the MSC therapy in dogs with CKD, the number of dogs involved and also according to the results, it still has not allowed to conclude the effect of therapy with mesenchymal stem cell in spontaneous chronic kidney disease; however, the results obtained raised important questions such as the time or the stage of CKD that could be more suitable for the use of stem cell therapy in order to get its beneficial effects. Therefore, futher studies are needed, including greater number of dogs with CKD and then to evaluate the effect or action of MSC to avoid disturbances in mineral metabolism as well as the progression of CKD in dogs