ACTA ENDOCRINOLOGICA (BUC)

Severe hypokalemia is a life threatening event, which triggers a number of therapeutic and diagnostic attitudes. In this paper we present a case of 63 years old man, who presented with progressive lassitude, edema, weight loss. The mild hypertension and hyperglycaemia were treated with spironolactone and diet. Initial evaluation showed severe hypokalemia (1.7 mmol/l), hepatomegalia, hyperplasic/nodular adrenal masses; in addition, he has developed a right middle lobe pneumonia which improved with antibiotics. Referred for the suspicion of hyperaldosteronism, aldosterone values were normal (9.3-9.5 ?g/dl), but ACTH was high (725 pg/ml) and did not suppress (710.8 pg/ml) to high dose DXM, as well as cortisol: basal values 27.78 ug/dl, high dose DXM 35.06 ug/dl, showing an ACTH dependent Cushing syndrome despite lack of suggestive clinical signs. Tumor markers suggested a neuroendocrine neoplasia: carcinoembryonic antigen=101 ng/ml (normal values=0.52-6.3 ng/ml), CA 19-9= 155 ng/ml (N < 33 ng/ml). Further radiological evaluation showed a 3 cm right lobe lung tumour. Despite high potassium supplements and spironolactone, the hypokalemia remained around 3.2 mmol/l, characteristic for an apparent mineralocorticoid excess. Because of aggressive evolution of the lung tumour, he died three months after the initial admission into the hospital. Pathology report showed a lung carcinoma. ACTH immunostaining of the lung tumour was positive and revealed a paraneoplastic secretion.

Secondary hyperparathyroidism, i.e. increased synthesis and secretion of parathyroid hormone and gland hyperplasia, is commonly found in chronic kidney disease. Although it is, at first, an adaptive response to the loss of renal functions in order to maintain the calcium/phosphate homeostasis and normal bone turnover, it is also an important cause of increased morbidity in this clinical setting by leading to renal osteodystrophy and cardiovascular complications. Recent advances in the knowledge on the pathogenesis of parathyroid-related complications in renal failure allowed for new therapeutic approaches. However, many problems remain to be solved in the future. This paper briefly presents the current understanding of pathogenic mechanisms of hyperparathyroidism, bone disease and vascular calcification during chronic kidney disease. In addition, it summarizes the main therapeutic methods available today for controlling secondary hyperparathyroidism and the challenges of practitioners concerning this issue. Finally, the current status of secondary hyperparathyroidism management is analyzed, with emphasis on the Romanian experience.

Background. There are scarce data about prevalence of mineral metabolism (MM) disorders in Romanian predialysis patients, so we assessed their occurrence and relationships in mild to severe chronic kidney disease (CKD). Methods. One hundred fifteen non-dialysis CKD (eGFR 31, 95% CI 29-35mL/min) and 33 matched non-CKD subjects entered this multicentric, cross-sectional study. Serum 25-hydroxyvitamin D (25OHD), intact parathyroid hormone (iPTH), phosphate (PO4), total calcium (tCa) and alkaline phosphatase (AP) were measured, along with demographic and past medical history data. Results. Hypovitaminosis D was equally prevalent in Controls and CKD (91% vs. 96% had 25OHD<30ng/mL). Increasing proportions of hyperparathyroidism (33% - stage 2 to 100% - stage 5; p<0.001) and hyperphosphatemia (2% - stage 3 to 38% - stage 5; p<0.001) were found. Hypocalcemia was more prevalent in stage 5 (25% vs. 6% in stage 4, none in stage 3 and Controls, p<0.001). Mineral metabolism parameters correlated with eGFR. In addition, iPTH was directly associated with PO4, AP, and urinary albumin-tocreatinine ratio (ACR), but inversely with tCa and 25OHD, while negative correlation of 25OHD with age, AP, ACR, and C-reactive protein emerged. In multiple regression, eGFR was the only predictor of iPTH (Beta -0.68, 95%CI -1.35 to -0.90, R2 0.46, p<0.001), whereas age and ACR were the determinants of 25OHD (a model which explained 14% of its variation). Conclusions. Hypovitaminosis D was very common irrespective of CKD presence and severity, and it seems worsened by older age and higher albuminuria. Hyperparathyroidism preceded hyperphosphatemia and hypocalcemia, and it seems mostly dependent on kidney function decline

Oxidative stress is defined as a rupture in the prooxidant-antioxidant balance in favor of\r\nthe former, leading to characteristic changes in biomolecules of all types, and to tissue damage.\r\nIt was implied in ageing-related processes, both by direct actions of various oxidative adducts\r\nand by its cardiovascular consequences. In the latest years, it has become evident that chronic\r\nkidney disease (CKD) is itself a condition characterized by oxidative stress. Although\r\nconflictual results were reported in non-dialysis CKD patients, there is an increasing trend in\r\noxidative stress markers and a decreasing one in antioxidative activity along with progressive\r\nreduction in glomerular filtration rate. A combination of inflammation, abnormal nutrition,\r\ndisturbed metabolism by the uremic milieu and defective renal clearance seems to be the cause.\r\nClearly, longitudinal studies with larger participation are necessary to define the precise\r\ncontribution of each element and the relationships between oxidative stress and CKD\r\nprogression. In dialysis CKD patients, bioincompatibility reactions during HD sessions\r\n(dialyzor membrane, dialysis solution), anemia and its therapy (iv iron) come into play. The\r\nclinical consequences of oxidative stress are difficult to ascertain, because oxidative stress,\r\ninflammation and malnutrition were found to be, in various proportion, strong predictors of\r\noutcome in CKD patients, but the precise contribution of each factor is difficult to elucidate for\r\nthe moment.

Context. Benefits of vitamin D therapies in chronic kidney disease (CKD) are debated. Objective. To compare the effects of medium-term native (VitD) and active (VDRA) vitamin D on parameters of mineral metabolism and arterial function in non-dialysis CKD. Design. Open-label, active comparator, randomized study. Subjects and Methods. Forty-eight adult patients, vitamin D naïve, CKD stage 3 to 5 with increased parathyroid hormone (iPTH) were randomized to receive either oral cholecalciferol 1000UI/day (n=24) or paricalcitol 1mcg/day (n=24) for 6 months. Median changes at end of study vs. baseline in serum calcidiol, iPTH, total alkaline phosphatase (ALP), and cardio-ankle vascular index (CAVI) were the efficacy parameters. Results. Higher increase in calcidiol (15.5 [95%CI 13.3; 17.2] vs. 0.4 [95%CI −6.1; 3.7]ng/mL, p<0.001) were found in VitD group. Conversely, the decline of iPTH (−35.2 [95%CI −83; 9] vs. 13.3 [95%CI −8.1; 35]pg/mL, p=0.008) and ALP (−34 [95%CI −58; −11] vs. −10 [95%CI −23; −2] U/L, p=0.02) were greater after paricalcitol. More subjects experienced iPTH decrease in VDRA group (71% vs. 39%, p=0.03). The variation in CAVI and the incidence of hypercalcemia and hyperphosphatemia were similar. Conclusions. It seems that secondary hyperparathyroidism was more efficiently treated by VDRA, whereas cholecalciferol better corrected the calcidiol deficiency in non-dialysis CKD.

Long lasting hypocalcemia, hyperphosphatemia, low calcitriol and high fibroblast growth factor 23 could result in progressive parathyroid gland hyperplasia with high, uncontrolled, parathormone production, e.g. severe secondary hyperparathyroidism (sHPT), in 10% of dialysis patients. Parathyroidectomy (PTX) could be a solution, but has inherent (low) surgical risks and although dramatically decreases parathormone levels, could induce hypoparathyroidism (50-66%) and low turnover bone disease. Moreover, the rate of recurrences is 15-20% at 10 years. Total and subtotal PTX with autografting are equally safe and effective with similar recurrences rates. Calcimimetics are efficient drugs, but with limited effectiveness in sHPT, as only 25% of patients responded to cinacalcet. In the USA, they are more cost-effective than PTX only in patients with >2 years expected dialysis duration. As there are not randomized studies to compare surgical to medical therapy, the strength of evidence allows only for suggestions in guidelines. In countries like Romania, where dialysis vintage is high because of the low transplantation rate and calcimimetics are costly, PTX seems a better solution when parathyroid glands are large (diameter >1cm or\r\ntotal mass >500mg), parathormone levels >800pg/mL, in patients who are not candidates for renal transplantation or are anticipated to stay >2 years on dialysis.