Hypocitraturia Is an Untoward Side Effect of Synthetic Human Parathyroid Hormone (hPTH) 1-34 Therapy in Hypoparathyroidism That May Increase Renal Morbidity.

Subcutaneous human parathyroid hormone (hPTH) therapy can effectively manage hypocalcemia in hypoparathyroidism, with varying effects on hypercalciuria. However, little is known about its ability to decrease the renal comorbidities of hypoparathyroidism: nephrocalcinosis (NC), nephrolithiasis (NL), and renal insufficiency. Urinary citrate (Ucit) promotes the solubility of urinary calcium (UCa); hypocitraturia is a risk factor for NC/NL. Twenty-four-hour UCa, Ucit, and UCa/Ucit were determined in 31 hypoparathyroid subjects receiving hPTH 1-34 therapy for up to 5 years. Before hPTH 1-34, the geometric least squares mean UCa was 346 mg/day (normal <250) and Ucit was 500 mg/day (normal 250-1190); UCa/Ucit was 0.67 mg/mg. After 6 months of hPTH 1-34, UCa decreased (238, p < 0.001), but with a greater decrease in Ucit (268, p < 0.001), increasing UCa/Ucit, which became significant over time (p < 0.001). After stopping hPTH 1-34 and resuming conventional therapy (follow-up; FU), compared to the last measures on hPTH 1-34, Ucit rose to 626 (p < 0.001), reducing UCa/Ucit to 0.44, (p < 0.05); UCa also rose (273), but was still lower than baseline (p < 0.05). Daily hPTH 1-34 dose did not correlate with UCa, but was inversely related to Ucit, and directly related to UCa/Ucit (p < 0.01). Mean blood bicarbonate decreased significantly on hPTH 1-34 and remained lower than baseline at FU (p < 0.01). Mean eGFR increased on hPTH 1-34 (86 to 96 mL/min/1.73 m2 , p < 0.001) and returned to baseline at FU. On renal imaging, 6 subjects did not have NC/NL, 8 had NC/NL prior to hPTH 1-34 that remained unchanged, and 16 developed new-onset (n = 10) or progressive (n = 6) NC/NL while on hPTH 1-34. Our data demonstrate that treatment with subcutaneous hPTH 1-34 may have an untoward effect of hypocitraturia and high UCa/Ucit ratio that may increase renal morbidity. With increasing use of PTH therapy in hypoparathyroidism, close monitoring and exploration for treatment of hypocitraturia seem warranted. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Transient Increased Calcium and Calcitriol Requirements After Discontinuation of Human Synthetic Parathyroid Hormone 1-34 (hPTH 1-34) Replacement Therapy in Hypoparathyroidism.

Synthetic human PTH 1-34 (hPTH 1-34) replacement therapy in hypoparathyroidism maintains eucalcemia and converts quiescent bone to high-turnover bone. However, the skeletal and metabolic effects of drug discontinuation have not been reported. Nine subjects with hypoparathyroidism received subcutaneous injections of hPTH 1-34 two to three times daily for 19.8 to 61.3 months and then transitioned back to calcium and calcitriol. Biochemistries and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) were assessed at baseline, while on treatment, and at follow-up 3 to 12 months after drug discontinuation. Two subjects developed hypocalcemia when hPTH 1-34 was abruptly discontinued. Thus, to avoid hypocalcemia, subjects were slowly weaned from hPTH 1-34 over several weeks. When hPTH 1-34 was stopped, subjects were requiring two to three times pretreatment doses of calcitriol and calcium to maintain blood calcium levels. Doses were gradually reduced over many weeks until calcium levels were stable on doses similar to baseline. Bone-specific alkaline phosphatase (BSAP), N-telopeptide (NTX), and osteocalcin (OC) increased significantly with hPTH 1-34; at follow-up, BSAP and NTX had returned to baseline while OC was still slightly elevated. During treatment, BMD was unchanged at the hip and lateral spine but declined at the anterior-posterior (AP) spine, radius, and total body. During weaning, BMD increased, with the hip and lateral spine exceeding pre-hPTH 1-34 values and the whole body returning to baseline. AP spine was increased non-significantly compared to baseline at follow-up. hPTH 1-34 must be gradually weaned in hypoparathyroid patients with high doses of oral medications given to avoid hypocalcemia. The transient increased requirements accompanied by increased BMD after long-term hPTH 1-34 therapy suggest a reversal of the expanded remodeling space favoring bone formation as the skeleton returns to a low-turnover state, reminiscent of the hungry bone syndrome. Further study and close monitoring is required to ensure safe transition to conventional therapy and to elucidate the physiological mechanism of this phenomenon.

Pain and other non-neurological adverse events in children with sickle cell anemia and previous stroke who received hydroxyurea and phlebotomy or chronic transfusions and chelation: results from the SWiTCH clinical trial.

To compare the non-neurological events in children with sickle cell anemia (SCA) and previous stroke enrolled in SWiTCH. The NHLBI-sponsored Phase III multicenter randomized clinical trial stroke with transfusions changing to hydroxyurea (SWiTCH) (ClinicalTrials.gov NCT00122980) compared continuation of chronic blood transfusion/iron chelation to switching to hydroxyurea/phlebotomy for secondary stroke prevention and management of iron overload. All randomized children were included in the analysis (intention to treat). The Fisher's Exact test was used to compare the frequency of subjects who experienced at least one SCA-related adverse event (AE) or serious adverse event (SAE) in each arm and to compare event rates. One hundred and thirty three subjects, mean age 13 ± 3.9 years (range 5.2-19.0 years) and mean time of 7 years on chronic transfusion at study entry, were randomized and treated. Numbers of subjects experiencing non-neurological AEs were similar in the two treatment arms, including SCA-related events, SCA pain events, and low rates of acute chest syndrome and infection. However, fewer children continuing transfusion/chelation experienced SAEs (P = 0.012), SCA-related SAEs (P = 0.003), and SCA pain SAEs (P = 0.016) as compared to children on the hydroxyurea/phlebotomy arm. The timing of phlebotomy did not influence SAEs. Older age at baseline predicted having at least 1 SCA pain event. Patients with recurrent neurological events during SWiTCH were not more likely to experience pain. In children with SCA and prior stroke, monthly transfusions and daily iron chelation provided superior protection against acute vaso-occlusive pain SAEs when compared to hydroxyurea and monthly phlebotomy.

Ultrasound is superior to computed tomography for assessment of medullary nephrocalcinosis in hypoparathyroidism.

CONTEXT: Nephrocalcinosis is a complication of hypoparathyroidism and other metabolic disorders. Imaging modalities include ultrasonography (US) and computed tomography (CT). Few studies have compared these modalities, and standard clinical practice is not defined. OBJECTIVE: The objective of the study was to determine the preferred method for assessing nephrocalcinosis. DESIGN: The design of the study was a retrospective, blinded analysis. SETTING: The study was conducted at a clinical research center. PATIENTS: Twenty-two hypoparathyroid subjects and 7 controls participated in the study. INTERVENTIONS: Contemporaneous renal US and CT images were reviewed in triplicate by 4 blinded radiologists. Nephrocalcinosis was classified using a 0-3 scale with 0 meaning no nephrocalcinosis and 3 meaning severe nephrocalcinosis. MAIN OUTCOME MEASURES: Intraobserver, interobserver, and interdevice agreements were measured. RESULTS: Intraobserver agreement was high, with an overall weighted kappa of 0.83 for CT and 0.89 for US. Interobserver agreement was similar between modalities, with kappas of 0.74 for US and 0.70 for CT. Only moderate agreement was found between US and CT scores, with an intermodality kappa of 0.47 and 60% concordance. Of discordant pairs, 81% had higher US scores and only 19% had higher CT scores. Of nephrocalcinosis seen on US and not CT, 45%, 46%, and 9% were grades 1, 2, and 3, respectively. Overall, US scores were higher than CT with a cumulative odds ratio (95% confidence interval) of 5.97 (2.60, 13.75) (P < .01). In controls, 100% of US ratings were 0, and 95% of CT ratings were 0. CONCLUSIONS: US is superior to CT for assessment of mild to moderate nephrocalcinosis in patients with hypoparathyroidism. This finding, in combination with its low cost, lack of radiation, and portability, defines US as the preferred modality for assessment of nephrocalcinosis.

Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity.

In adults with sickle cell disease (SCD), an increased tricuspid regurgitation velocity (TRV) by Doppler echocardiography is associated with increased morbidity and mortality. Although sildenafil has been shown to improve exercise capacity in patients with pulmonary arterial hypertension, it has not been evaluated in SCD. We therefore sought to determine whether sildenafil could improve exercise capacity in SCD patients with increased TRV and a low exercise capacity. A TRV ≥ 2.7 m/s and a 6-minute walk distance (6MWD) between 150 and 500 m were required for enrollment in this 16-week, double-blind, placebo-controlled sildenafil trial. After 74 of the screened subjects were randomized, the study was stopped early due to a higher percentage of subjects experiencing serious adverse events in the sildenafil arm (45% of sildenafil, 22% of placebo, P = .022). Subject hospitalization for pain was the predominant cause for this difference: 35% with sildenafil compared with 14% with placebo (P = .029). There was no evidence of a treatment effect on 6MWD (placebo-corrected effect -9 m; 95% confidence interval [95% CI] -56-38; P = .703), TRV (P = .503), or N-terminal pro-brain natriuretic peptide (P = .410). Sildenafil appeared to increase hospitalization rates for pain in patients with SCD. This study is registered at www.clinicaltrials.gov as NCT00492531.