Suppression Of Secondary Hyperparathyroidism Research Articles

The induction of C/EBPβ contributes to vitamin D inhibition of ADAM17 expression and parathyroid hyperplasia in kidney disease.

In secondary hyperparathyroidism (SHPT), enhanced parathyroid levels of transforming growth factor-α (TGFα) increase EGF receptor (EGFR) activation causing parathyroid hyperplasia, high parathyroid hormone (PTH) and also reductions in vitamin D receptor (VDR) that limit vitamin D suppression of SHPT. Since anti-EGFR therapy is not an option in human SHPT, we evaluated ADAM17 as a therapeutic target to suppress parathyroid hyperplasia because ADAM17 is required to release mature TGFα, the most potent EGFR-activating ligand. Computer analysis of the ADAM17 promoter identified TGFα and C/EBPβ as potential regulators of the ADAM17 gene. Their regulation of ADAM17 expression, TGFα/EGFR-driven growth and parathyroid gland (PTG) enlargement were assessed in promoter-reporter assays in A431 cells and corroborated in rat and human SHPT, using erlotinib as anti-EGFR therapy to suppress TGFα signals, active vitamin D to induce C/EBPβ or the combination. While TGFα induced ADAM17-promoter activity by 2.2-fold exacerbating TGFα/EGFR-driven growth, ectopic C/EBPβ expression completely prevented this vicious synergy. Accordingly, in advanced human SHPT, parathyroid ADAM17 levels correlated directly with TGFα and inversely with C/EBPβ. Furthermore, combined erlotinib + calcitriol treatment suppressed TGFα/EGFR-cell growth and PTG enlargement more potently than erlotinib in part through calcitriol induction of C/EBPβ to inhibit ADAM17-promoter activity, mRNA and protein. Importantly, in rat SHPT, the correction of vitamin D deficiency effectively reversed the resistance to paricalcitol induction of C/EBPβ to suppress ADAM17 expression and PTG enlargement, reducing PTH by 50%. In SHPT, correction of vitamin D and calcitriol deficiency induces parathyroid C/EBPβ to efficaciously attenuate the severe ADAM17/TGFα synergy, which drives PTG enlargement and high PTH.

Carbamazepin antagonizes the vitamin D-mediated suppression of secondary hyperparathyroidism: Pathogenesis and therapeutical options

This commentary updates: 1) the patophisiology responsible for carbamazepine-induced resistance to paricalcitol suppression of PTH in CKD; 2) the contribution of vitamin D deficiency to the adverse effects of carbamazepine; 3) the benefits of cholecalciferol supplementation either alone or in combination with paricalcitol in preventing/attenuating the onset of resistance to vitamin D suppression of secondary hyperparathyroidism (SHPT); 4) the successful correction of vitamin D deficiency in chronic kidney disease (CKD) patients receiving anti-epileptic medication other than carbamazepine, with the goal of providing nephrologists with a practical, safe and efficacious therapeutic approach to improve outcomes in SHPT.

The serum 24,25-dihydroxyvitamin D concentration, a marker of vitamin D catabolism, is reduced in chronic kidney disease

Chronic kidney disease is characterized, in part, as a state of decreased production of 1,25-dihydroxyvitamin D (1,25(OH)2D); however, this paradigm overlooks the role of vitamin D catabolism. We developed a mass spectrometric assay to quantify serum concentration of 24,25-dihydroxyvitamin D (24,25(OH)2D), the first metabolic product of 25-hydroxyvitamin D (25(OH)D) by CYP24A1, and determined its clinical correlates and associated outcomes among 278 participants with chronic kidney disease in the Seattle Kidney Study. For eGFRs of 60 or more, 45–59, 30–44, 15–29, and under 15 ml/min/1.73m2, the mean serum 24,25(OH)2D concentrations significantly trended lower from 3.6, 3.2, 2.6, 2.6, to 1.7 ng/ml, respectively. Non-Hispanic Black race, diabetes, albuminuria, and lower serum bicarbonate were also independently and significantly associated with lower 24,25(OH)2D concentrations. The 24,25(OH)2D concentration was more strongly correlated with that of parathyroid hormone than was 25(OH)D or 1,25(OH)2D. A 24,25(OH)2D concentration below the median was associated with increased risk of mortality in unadjusted analysis, but this was attenuated with adjustment for potential confounding variables. Thus, chronic kidney disease is a state of stagnant vitamin D metabolism characterized by decreases in both 1,25(OH)2D production and vitamin D catabolism.

No difference between alfacalcidol and paricalcitol in the treatment of secondary hyperparathyroidism in hemodialysis patients: a randomized crossover trial

Alfacalcidol and paricalcitol are vitamin D analogs used for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease, but have known dose-dependent side effects that cause hypercalcemia and hyperphosphatemia. In this investigator-initiated multicenter randomized clinical trial, we originally intended two crossover study periods with a washout interval in 86 chronic hemodialysis patients. These patients received increasing intravenous doses of either alfacalcidol or paricalcitol for 16 weeks, until parathyroid hormone was adequately suppressed or calcium or phosphate levels reached an upper threshold. Unfortunately, due to a period effect, only the initial 16-week intervention period for 80 patients was statistically analyzed. The proportion of patients achieving a 30% decrease in parathyroid hormone levels over the last four weeks of study was statistically indistinguishable between the two groups. Paricalcitol was more efficient at correcting low than high baseline parathyroid hormone levels, whereas alfacalcidol was equally effective at all levels. There were no differences in the incidence of hypercalcemia and hyperphosphatemia. Thus, alfacalcidol and paricalcitol were equally effective in the suppression of secondary hyperparathyroidism in hemodialysis patients while calcium and phosphorus were kept in the desired range.

Effect of pharmacological suppression of secondary hyperparathyroidism on cardiovascular hemodynamics in predialysis CKD patients: A preliminary observation

Cardiovascular events are the principal cause of mortality in patients with chronic kidney disease (CKD). Secondary hyperparathyroidism (SHPT), a common complication of CKD, contributes to cardiac dysfunction. This study is an attempt to demonstrate the effects of parathyroid hormone suppression with oral calcitriol on cardiovascular hemodynamics. Twenty predialysis CKD patients with SHPT were given calcitriol therapy for 12 weeks. Ten similar patients received placebo. Echocardiographic assessment of cardiac function was performed at baseline and after 12 weeks of treatment. Calcitriol therapy effectively suppressed SHPT. Baseline left ventricular (LV) end diastolic diameter and LV end systolic diameter were 4.86+/-0.48 and 2.86+/-0.33 cm, and the mean FS was 41.02+/-4.79%. Left ventricular end systolic and end diastolic volumes were normal (42.30+/-9.07 and 91.40+/-19.68 mL). The ejection fraction was slightly reduced (53.54+/-3.57%). Pretreatment Doppler indices including E velocity (0.816+/-0.087 m/s), A velocity (0.696+/-0.089 m/s), and E/A ratio (1.193+/-0.210) were significantly impaired. After 12 weeks of calcitriol therapy, there was no significant change in the LV dimensions or ejection fraction, but there was a significant improvement in the diastolic parameters, namely the A velocity (0.680+/-0.084) and E/A ratio (1.238+/-0.180). Secondary hyperparathyroidism is an important factor in the pathogenesis of cardiovascular complications in CKD. There is evidence to support that correction of hyperparathyroidism can improve the systolic dysfunction seen in advanced kidney disease. This study shows that diastolic dysfunction seen in predialysis CKD patients may also be possibly improved with calcitriol therapy.

Overview of clinical studies in hemodiafiltration: What do we need now ?

Despite several technical advances in dialysis treatment modalities and a better patient care management including correction of anemia, suppression of secondary hyperparathyroidism, lipid and oxidative stress profiles improvement, the morbidity and the mortality of dialysis patients still remain still elevated. Recent prospective interventional trials in hemodialysis (HEMO study and 4D study) were not very conclusive in showing any significant improvement in dialysis patient outcomes. High-efficiency convective therapies, such as online hemodiafiltration (HDF), are claimed to be superior to conventional diffusive hemodialysis (HD) in improving the dialysis efficacy and in reducing intradialytic morbidity and all-cause and cardiovascular mortality in dialysis patients. The aim of this report was, first, to review the evidence-based facts tending to prove the superiority of HDF vs. HD in terms of efficacy and tolerance, and, second, to analyze the needs to prove the clinical superiority of HDF in terms of reducing morbidity and all-cause mortality of dialysis patients. A systematic review of studies comparing HDF and HD has been performed in the microbiological safety of online production, the solute removal capacity of small and medium-size uremic toxins, and its implication in the reduction of the bioactive dialysis system vs. patient interaction. Major planned randomized international studies comparing HDF and HD in terms of morbidity and mortality have been reviewed. To conclude, it is thought that these long-term prospective randomized trials will clarify on a scientific evidence-based level the putative beneficial role of high-efficiency HDF modalities on dialysis patient outcomes.

The treatment of renal osteodystrophy.

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Serum phosphate, parathyroid hormone and vitamin D metabolites in patients with chronic renal failure: effect of aluminum hydroxide administration.

Patients with chronic renal failure showed the existence of phosphate retention, secondary hyperparathyroidism, and reduced production of 1,25-(OH)2D. In order to determine the effect of correction of hyperphosphatemia on secondary hyperparathyroidism and vitamin D metabolism in those patients, 7 nondialyzed patients with chronic renal failure were treated with large doses of A1(OH)3 (15-18 g/day) to correct their high levels of serum phosphate. After treatment with A1(OH)3, serum phosphate fell significantly (p less than 0.005) from 6.3 +/- 1.3 (mean +/- SD) to 3.7 +/- 0.5 mg/dl. Serum parathyroid hormone decreased significantly (p less than 0.02) from 2.87 +/- 1.64 to 1.85 +/- 1.26 ngEq/ml. Serum 1,25-(OH)2D was low compared to the normal mean level before A1(OH)3 administration and decreased significantly (p greater than 0.02) from 19.4 +/- 6.1 to 11.4 +/- 4.3 pg/ml after the treatment. Aluminum levels increased significantly (p greater than 0.02) from 1.7 +/- 1.0 to 3.6 +/- 1.5 micrograms/dl. Serum calcium, calcitonin, and 25-(OH)D showed no significant change. Our data suggested that the suppression of secondary hyperparathyroidism by A1(OH)3 treatment results in a decrease of the 1,25-(OH)2D level in patients with chronic renal failure, even though their hyperphosphatemia has been corrected. We speculate that aluminum loading might play a role in diminishing the secretion of parathyroid hormone and the production of 1,25-(OH)2D in humans.

Suppression of secondary hyperparathyroidism in uraemia: acute and chronic studies.

A study was conducted evaluating the response of serum parathyroid hormone to acute hypercalcaemia and long term administration of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in patients receiving maintenance haemodialysis. During infusion of elemental calcium 4 mg/kg/h over four hours in 12 patients not receiving vitamin D the concentration of serum amino terminal parathyroid hormone fell by 31-96% (mean 74.8 (SD 17.6)%) while that of carboxy terminal parathyroid hormone changed little. There was a strong inverse correlation between baseline serum calcium concentration and percentage fall in amino terminal parathyroid hormone during infusion (r = 0.88; p less than 0.001). In seven patients who received prolonged treatment with 1,25(OH)2D3 after calcium infusion there was a positive correlation between maximum percentage fall in amino terminal parathyroid hormone during infusion and the percentage fall in amino terminal parathyroid hormone after 1,25(OH)2D3 treatment (r = 0.79; p less than 0.05). The responsiveness of the parathyroid glands to changes in calcium in acute studies may be used to predict the efficacy of long term treatment with 1,25(OH)2D3. Patients in whom calcium infusion does not suppress parathyroid hormone may have true parathyroid autonomy and require early parathyroidectomy.

Suppression of secondary hyperparathyroidism by propranolol in renal failure patients.

Renal osteodystrophy in part due to secondary hyperparathyroidism, is one of the major unresolved problems affecting patients on chronic hemodialysis. In addition, evidence has shown that parathyroid hormone (PTH) is toxic to other organ systems besides bone. The results of a prospective study on the effect of propranolol in reducing PTH levels in chronic renal failure patients on hemodialysis are reported. Propranolol administration reduced PTH levels by over 50-75%. The levels of calcium, phosphorus, alkaline phosphatase and hematocrit were variable, but patients with severe derangements in these measurements also seemed to benefit from propranolol. It should now be determined by larger and longer studies whether these biochemical improvements can be translated into clinical benefits.