Biochemical Clusters as Substitutes of Bone Biopsies in Kidney Transplant Patients.

Bone and mineral metabolism abnormalities are frequent in kidney transplant recipients and have been associated with cardiovascular morbidity. The primary aim of this study was to analyse the association between routine clinically available biochemical evaluation, non-routine histomorphometric bone evaluation, and vascular disease in kidney transplanted patients. A cross-sectional analysis was performed on 69 patients, 1-year after kidney transplantation. Laboratory analysis, radiography of hands and pelvis, bone biopsy, bone densitometry, and coronary CT were performed. One-year post-transplantation, nearly one-third of the patients presented with hypercalcemia, 16% had hypophosphatemia, 39.3% had iPTH levels > 150 pg/mL, 20.3% had BALP levels > 40 U/L, and 26.1% had hypovitaminosis D. Evaluation of extraosseous calcifications revealed low Adragão and Agatston scores. We divided patients into three clusters, according to laboratory results routinely used in clinical practice: hypercalcemia and hyperparathyroidism (Cluster1); hypercalcemia and high BALP levels (Cluster2); hypophosphatemia and vitamin D deficiency (Cluster 3). Patients in clusters 1 and 2 had higher cortical porosity (p = 0.001) and osteoid measurements, although there was no difference in the presence of abnormal mineralization, or low volume. Patients in cluster 2 had a higher BFR/BS (half of the patients in cluster 2 had high bone turnover), and most patients in cluster 1 had low or normal bone turnover. Cluster 3 has no differences in volume, or turnover, but 60% of the patients presented with pre-osteomalacia. All three clusters were associated with high vascular calcifications scores. Vascular calcifications scores were not related to higher bone mineral density. Instead, an association was found between a higher Adragão score and the presence of osteoporosis at the femoral neck (p = 0.008). In conclusion, inferring bone TMV by daily clinical biochemical analysis can be misleading, and bone biopsy is important for assessing both bone turnover and mineralization after kidney transplantation, although hypophosphatemia combined with vitamin D deficiency is associated with abnormal mineralization. The presence of hypercalcemia with high levels of PTH or high levels of BALP, or hypophosphatemia and vitamin D deficiency should remind us to screen vascular calcification status of patients.Clinical Research: ClinicalTrials.gov ID NCT02751099.

The Role of Bone Volume, FGF23 and Sclerostin in Calcifications and Mortality; a Cohort Study in CKD Stage 5 Patients.

Chronic kidney disease-mineral and bone disorder has been associated with increasing morbid-mortality. The aim of this study was to determine the prevalence and phenotype of bone disease before transplantation and to correlate FGF23 and sclerostin levels with bone histomorphometry, and study possible associations between FGF23, sclerostin, and bone histomorphometry with cardiovascular disease and mortality. We performed a cross-sectional cohort study of a sample of 84 patients submitted to renal transplant, which were prospectively followed for 12 months. Demographic, clinical, and echocardiographic data were collected, laboratory evaluation, bone biopsy, and X-ray of the pelvis and hands were performed. Patient and graft survival were recorded. We diagnosed low bone turnover in 16 patients (19.5%); high bone turnover in 22 patients (26.8%); osteomalacia in 1 patient (1.2%), and mixed renal osteodystrophy in 3 patients (3.7%). At the end of 12 months, 5 patients had graft failure (5.9%), 4 had a cardiovascular event (4.8%), and 4 died. Age was associated with low remodeling disease, whereas high BALP and phosphorus and low sclerostin with high turnover disease. Sclerostin was a risk factor for isolated low bone volume. High BALP, low phosphorus, and low FGF23 were risk factors for abnormal mineralization. FGF23 appears as an independent factor for severity of vascular calcifications and for cardiovascular events, whereas the presence of valve calcifications was associated with low volume and with turnover deviations. Sclerostin was associated a higher HR for death. Sclerostin and FGF23 seemed to provide higher cardiovascular risk, as well as low bone volume, which associated with extra-osseous calcifications.

Bone densitometry versus bone histomorphometry in renal transplanted patients: a cross-sectional study.

Bone loss leads to increase risk of fractures in renal transplantation. The aim of this study was to analyse the relationship between bone densitometry (DXA) findings, bone histomorphometry and bone-related molecules 1-year after renal transplantation. We performed a cross-sectional study of de novo renal transplanted patients that agreed to perform a bone biopsy and a DXA examination 1 year after transplantation. All patients underwent a laboratory evaluation, bone biopsy, DXA examination and cardiac CT 1 year after transplantation. 67 patients were included, 16 had a normal examination, and 18 patients were classified as having osteoporosis by DXA. Correlations between bone mineral density and T-scores of total femur and femoral neck were the ones that best correlated with bone volume assessed by a bone biopsy. The sensitivity of DXA for osteoporosis diagnosis was 47.0%, and the specificity was 81.2%. The positive predictive value was 50.0%, and the negative predictive value (NPV) was 80.0%. DXA parameters also correlated with klotho and sclerostin serum levels. In this population, a normal examination excluded the presence of osteoporosis, helping in identifying patients that would not benefit from therapy. Overall, densitometry in total femur and femoral neck correlated well with bone volume measured by bone biopsy.

Renal regeneration after acute kidney injury.

Acute kidney injury is common and associated with negative renal and patient outcomes. The human kidney has a real but limited regeneration capacity. Understanding renal regeneration may allow us to manipulate this process and thus develop therapeutic weapons to improve patients' outcome. In the first part of this paper we discuss the clinical factors associated with renal recovery: baseline patient particularities, acute kidney injury characteristics and the medical approach taken in the short and long-term. In the second part, the cellular and molecular mechanisms underlying renal regeneration are explored. The immune system seems to have an important role, first promoting inflammation and then tissue healing. Other players, such as cellular senescence, mitochondrial dysfunction, renal haemodynamics and metabolic reprogramming also have a role in renal regeneration. We aim to develop a short review of renal regeneration, offering a holistic view of this process.

Improvement of Mineral and Bone Disorders After Renal Transplantation.

BACKGROUND: Posttransplant mineral and bone diseases are causes of fractures, and their association with cardiovascular events is being studied. METHODS: We analyzed the evolution of biochemical, histological, and imaging parameters pre- and 1 y post-renal transplantation in 69 patients and correlated mineral and bone findings with coronary calcifications. At inclusion and after 12 mo, clinical data and echocardiographic findings were recorded, and laboratory evaluations, radiography of the pelvis and hands, and bone biopsy were performed. Noncontrast cardiac computed tomography was performed during the second evaluation. RESULTS: Serum levels of fibroblast growth factor 23 and sclerostin decreased in all patients, parathyroid hormone levels decreased in 89.8% of patients, bone alkaline phosphatase levels decreased in 68.1% of patients, and alpha-Klotho levels increased in 65.2% of patients. More than half of the patients presented with renal osteodystrophy at both biopsies, but histological findings improved: a significant transition from high to normal or low turnover and no significant differences in volume, mineralization defect, or cortical porosity at the 2 evaluations. Alpha-Klotho, sclerostin, and bone alkaline phosphatase shifts affect bone changes. Neither echocardiographic findings nor vascular calcification scores differed between the 2 points. Both the pretransplant period (dialysis vintage, sclerostin, and low bone volume at baseline) and the maintenance of abnormalities in the posttransplant period (high turnover posttransplant) were the most reliable predictors of the severity of the coronary calcification percentile. CONCLUSIONS: Renal transplantation improved bone and mineral abnormalities. The pretransplant period determines the severity of calcification.

Synthesis and evaluation of N-acylamino acids derivatives of triazenes. Activation by tyrosinase in human melanoma cell lines.

In this research work we report the synthesis of a new series of triazene prodrugs designed for Melanocyte-Directed Enzyme Prodrug Therapy (MDEPT). These compounds are derived from the N-acyltyrosine amino acid - a good enzyme substrate for the tyrosinase enzyme, which is significantly overexpressed in melanoma cells. We analysed their chemical stability and plasma enzymatic hydrolysis, and we also evaluated the release of the antitumoral drug in the presence of the tyrosinase. Subsequently, we performed the evaluation of the prodrug cytotoxicity in melanoma cell lines with different levels of tyrosinase activity. Prodrug 5c showed the highest cytotoxicity against melanoma cell lines, and this effect correlated well with the tyrosinase activity suggesting that prodrug cytotoxicity is tyrosinase-dependent.