Background and objectives The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older ($65 years, n=1005) and younger (,65 years, n=2878) patients.Design, setting, participants, & measurements Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.Results Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were .3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. ConclusionsIn the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.

Objective Primary hyperparathyroidism (PHPT) is diagnosed by the presence of hypercalcemia and elevated or nonsuppressed parathyroid hormone (PTH) levels. Although surgery is usually curative, some individuals fail or are unable or unwilling to undergo parathyroidectomy. In such individuals, targeted medical therapy may be of value. Cinacalcet normalized calcium level and lowered PTH in patients with PHPT in several phase 2 and open-label studies. We compared cinacalcet and placebo in subjects with PHPT unable to undergo parathyroidectomy. Design Phase 3, double-blind, multi centere, randomized, placebo-controlled study. Methods Sixty-seven subjects (78% women) with moderate PHPT were randomized (1:1) to cinacalcet or placebo for ≤ 28 weeks. Main outcome measure Achievement of a normal mean corrected total serum calcium concentration of ≤ 10.3 mg/dl (2.575 mmol/l). Results Baseline median (quartile 1 (Q1), Q3) serum PTH was 164.0 (131.0, 211.0) pg/ml and mean (s.d.) serum Ca was 11.77 (0.46) mg/dl. Serum Ca normalized (≤ 10.3 mg/dl) in 75.8% of cinacalcet- vs 0% of placebo-treated subjects (P<0.001). Corrected serum Ca decreased by ≥ 1.0 mg/dl from baseline in 84.8% of cinacalcet- vs 5.9% of placebo-treated subjects (P<0.001). Least squares mean (s.e.m.) plasma PTH change from baseline was −23.80% (4.18%) (cinacalcet) vs −1.01% (4.05%) (placebo) (P<0.001). Similar numbers of subjects in the cinacalcet and placebo groups reported adverse events (AEs) (27 vs 20) and serious AEs (three vs four). Most commonly reported AEs were nausea and muscle spasms. Conclusions These results demonstrate that cinacalcet normalizes serum calcium in this PHPT population and appears to be well tolerated.

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Purpose: To determine the impact of initiating enzyme replacement therapy (ERT) with agalsidase alfa early in the course of Fabry disease, we evaluated renal and cardiac outcomes for ≤10 years after ERT initiation in males from the Fabry Outcome Survey (FOS). Patients and Methods: Male patients from FOS were stratified into three cohorts by age at ERT initiation: ≤18 years (cohort 1), >18 and ≤30 years (cohort 2), and >30 years (cohort 3). Analysis included age at symptom onset, diagnosis, and ERT initiation; ERT duration; FOS-Mainz Severity Score Index (FOS-MSSI); estimated glomerular filtration rate (eGFR); proteinuria level; and left ventricular mass indexed to height (LVMI). Mixed-effect models estimated renal and cardiac outcomes during follow-up between and within cohorts. Findings: The analysis included 560 male patients: 151 (27.0%) in cohort 1, 155 (27.7%) in cohort 2, and 254 (45.4%) in cohort 3. Mean±SD duration of ERT for cohorts 1, 2, and 3 was 6.3 ±4.3, 8.6±4.9, and 7.9±4.9 years, respectively. Mean±SD baseline FOS-MSSI scores increased with age from 9.8±7.2 in cohort 1 to 24.7±11.4 in cohort 3. Cohort 3 showed the lowest baseline mean±SD value for eGFR (87.1±29.0 mL/min/1.73m 2 ) and highest baseline mean±SD values for proteinuria (801.9±952.6 mg/day) and LVMI (56.7±16.0 g/m 2.7 ) among the three cohorts. Evaluation of mean annual rates of change in eGFR, proteinuria, and LVMI revealed no significant differences in any parameter for cohort 1. For cohort 2, proteinuria and LVMI remained stable, whereas eGFR significantly deteriorated annually (-1.12 mL/min/1.73m 2 ; P<0.001). Cohort 3 demonstrated significant annual deteriorations in eGFR (-2.60 mL/min/ 1.73m 2 ; P<0.001), proteinuria (+34.10 mg/day; P<0.001), and LVMI (+0.59 g/m 2.7 ; P=0.001). Implications: Renal and/or cardiac disease progression appears attenuated in patients starting ERT in childhood or early adulthood versus patients starting ERT in later adulthood. These findings support early ERT initiation in Fabry disease. ClinicalTrials.gov identifier: NCT03289065.

Abstract. Hypothyroidism is associated with impaired urinary concentrating ability in humans and animals. The purpose of this study was to examine protein expression of renal sodium chloride and urea transporters and aquaporins in hypothyroid rats (HT) with diminished urinary concentration as compared with euthyroid controls (CTL) and hypothyroid rats replaced with L-thyroxine (HTϩT). Hypothyroidism was induced by aminotriazole administration. Body weight, water intake, urine output, solute and urea excretion, serum and urine osmolality, serum creatinine, 24-h creatinine clearance, and fractional excretion of sodium were comparable among the three groups. However, with 36 h of water deprivation, HT rats demonstrated significantly greater urine flow rates and decreased urine and medullary osmolality as compared with CTL and HTϩT rats at comparable plasma vasopressin concentrations. Western blot analyses revealed decreased renal protein abundance of transporters, including Na-K-2Cl, Na-K-ATPase, and NHE3, in HT rats as compared with CTL and HTϩT rats. Protein abundance of renal AQP1 and urea transporters UTA 1 and UTA 2 did not differ significantly among study groups. There was however a significant decrease in protein abundance of AQP2, AQP3, and AQP4 in HT rats as compared with CTL and HTϩT rats. These findings demonstrate a decrease in the medullary osmotic gradient secondary to impaired countercurrent multiplication and downregulation of aquaporins 2, 3, and 4 as contributors to the urinary concentrating defect in the hypothyroid rat.Hypothyroidism is a very common clinical disorder that is associated with abnormalities in many organs, including the kidney. The ability to conserve water during periods of fluid deprivation is an important function of the kidney. Hypothyroidism has been associated with an impaired urinary concentrating capacity (1,2). However, the mechanisms of this defect at the cellular and molecular level have not been defined.In the present study, the effect of hypothyroidism in rats on the pivotal components of the urinary concentrating mechanism have been examined and compared with euthyroid animals. These components during fluid deprivation include release of the antidiuretic hormone, arginine vasopressin (AVP), and upregulation of the abundance of aquaporin-2 (AQP2) water channels in the principal cells of the collecting duct. Activation of the countercurrent concentrating mechanism, which is initiated by increased sodium-potassium-2 chloride (Na-K-2Cl) co-transporter in the water impermeable ascending limb, creates the osmotic driving force for passive water reabsorption across the collecting duct. There are also roles for other water channels, including aquaporins 1, 3, and 4, and for urea transporters in urinary concentration. The present study was undertaken to define the effect of hypothyroidism on these various molecular events during fluid deprivation in the rat. Materials and Methods Animal ModelThe study protocol was approved by the University of Colorado Institutional Animal Ca...