The PARADIGHM (physicians advancing disease knowledge in hypoparathyroidism) registry for patients with chronic hypoparathyroidism: study protocol and interim baseline patient characteristics

Background The PARADIGHM registry of adult and pediatric patients with chronic hypoparathyroidism evaluates the long-term safety and effectiveness of treatment with recombinant human parathyroid hormone, rhPTH(1-84), and describes the clinical disease course under conditions of routine clinical practice. In this first report, we detail the registry protocol and describe the baseline characteristics of two adult patient cohorts from an interim database analysis. One cohort after study entry were prescribed rhPTH(1-84), and the other cohort received conventional therapy of calcium and active vitamin D. Methods An observational study of patients with chronic hypoparathyroidism in North America and Europe, collecting data for ≥10 years per patient. Main outcome measures were baseline patient demographics, clinical characteristics, medications, and disease outcome variables of symptoms, biochemical parameters, and health assessments. Baseline is the enrollment assessment for all variables except biochemical measurements in patients treated with rhPTH(1-84); those measurements were the most recent value before the first rhPTH(1-84) dose. Exclusion criteria applied to the analysis of specified outcomes included pediatric patients, patients who initiated rhPTH(1-84) prior to enrollment, and those who received rhPTH(1-34). Clinically implausible biochemical outlier data were excluded. Results As of 30 June 2019, data of 737 patients were analyzed from 64 centers; 587 (80%) were women, mean ± SD age 49.1±16.45 years. At enrollment, symptoms reported for patients later prescribed rhPTH(1-84) (n=60) and those who received conventional therapy (n=571), respectively, included fatigue (51.7%, 40.1%), paresthesia (51.7%, 29.6%), muscle twitching (48.3%, 21.9%), and muscle cramping (41.7%, 33.8%). Mean serum total calcium, serum phosphate, creatinine, and estimated glomerular filtration rate were similar between cohorts. Health-related quality of life (HRQoL) 36-item Short Form Health Survey questionnaire scores for those later prescribed rhPTH(1-84) were generally lower than those for patients in the conventional therapy cohort. Conclusions At enrollment, based on symptoms and HRQoL, a greater percentage of patients subsequently prescribed rhPTH(1-84) appeared to have an increased burden of disease than those who received conventional therapy despite having normal biochemistry measurements. PARADIGHM will provide valuable real-world insights on the clinical course of hypoparathyroidism in patients treated with rhPTH(1-84) or conventional therapy in routine clinical practice. Trial registration EUPAS16927, NCT01922440

Comparative Analysis of Whole Blood Ionised Calcium, Lactate and Chloride Concentrations by Gem Premier 3000 and Edan I15 Vet and the Effect of Parity and Postpartum Blood Collection Time on Blood Calcium Status in Holstein With and Without Subclinical Hypocalcemia - Part 1

Lactating Holstein (n=125) were enrolled randomly for the coccygeal whole blood analysis by blood gas devices GEM Premier 3000 (GEM) and Edan i15 Vet (EDAN) between calving to postpartum day 3 (G1) and postpartum day 4 to 27 (G2). Blood pH, ionised calcium (ICA7.4) and lactate analysis were significantly correlated between GEM and EDAN (r=0.86, 0.94, 0.87 respectively). The bias for ICA7.4, lactate and pH analysis was -0.054, -0.344 mmol/L and +0.009 respectively. ICA7.4 was correlated negatively with parity and chloride, but positively with lactate. The averages of ICA7.4 and serum total calcium (TC) was significantly lower in G1 than G2. Chloride and lactate were significantly higher in G1 than G2. Subclinical hypocalcemia prevalence (SCH) (serum TC<2.15 mmol/L, as reference) was 52.9% in G1 and 21.1% in G2. Cows with SCH had frequently over 50% ICA7.4/TC ratio. Sensitivity analysis provided a sensitivity of 57.4% for ICA7.4 cut-points of 1.02 (GEM) and 1.05 (EDAN) mmol/L to detect SCH based on reference serum TC. Primiparous (PRP) with and without SCH in G1 had significantly higher ICA7.4 than multiparous (MUL). Cows with SCH had significantly higher chloride in G1 than G2. MUL had significantly higher lactate and chloride in G1 than G2. Conclusively, ICA7.4 and pH analysis between GEM and EDAN were correlated well with acceptable biases, but high differences occurred in lactate analysis. MUL was at risk in G1 due to lower ICA7.4 and TC over PRP. Higher ICA7.4 of PRP can reduce the risk and frequency of clinical hypocalcemia. SCH correlated negatively with Cl concentration in G1, but not lactate.

Calcium-phosphorus relationships in the combined course of stable ischemic heart disease in patients with obesity

The purpose of the study was to optimize the diagnosis and prediction of the development of structural and functional disorders of bone tissue in patients with SCHD and obesity. Thus, lipid profile analysis showed a clinically significant increase in total cholesterol and triglycerides in patients with SCHD. Serum bone mineral status did not exceed normal values, but serum total calcium levels were significantly higher in patients with SCHD and obesity compared to other groups. The indicators of calcium-phosphorus metabolism in the daily urine of patients with SCHD were significantly higher. When conducting densitometric studies in patients with SCHD with normal weight, osteopenic conditions were diagnosed more often than in patients with overweight and obesity. That is, the comorbid course of SCHD and obesity is a high risk of osteodeficiency, which is confirmed by early changes in calcium-phosphorus metabolism.

Analysis of the Prevalence and Severity of Dysregulated Bone Mineral Homeostasis in Nondialyzed Chronic Kidney Disease Patients

Background Progressive loss of kidney function in chronic kidney disease (CKD) leads to altered mineral homeostasis, reflected by the imbalance in calcium and phosphorus, and has been associated with progression of renal failure. Aims The aim of this study was to investigate CKD-mineral bone disorder (CKD-MBD)-associated candidate variables and its relationship with parathyroid hormone (PTH), as well as to quantify the prevalence of CKD-associated mineral disturbances in nondialyzed CKD patients. Study Design, Materials, and Methods This cross-sectional analytical study included 124 CKD patients and 157 control participants. Blood samples were analyzed for serum total calcium, phosphorus, PTH, electrolytes, and other hematological/hemodynamic parameters by standard methods. Suitable descriptive statistics was used for different variables. Results The 124 patients had a mean age of 50.2 ± 7.8 years with male to female ratio of 1.58; majority of patients had stage 3 CKD (40.32%), and the most common comorbid conditions were diabetes mellitus ( n = 78 [62.9%]) and hypertension ( n = 63 [50.8%]). A high prevalence of mineral metabolite abnormalities was observed in a patient cohort; overall prevalence of hyperparathyroidism was found in 57.25% patients, hypocalcemia in 61.29%, and hyperphosphatemia in 82.25% patients. Prevalence of abnormal homeostasis (with regard to total calcium, phosphate, and PTH) increased progressively with the severity of disease (analysis of variance; p < 0.05). Significant differences in the mean values of total calcium, phosphorus, alkaline phosphatase, and PTH were seen compared with healthy participants ( p < 0.0001). Furthermore, there was a significant positive correlation between serum PTH with serum phosphorous ( R 2: 0.33; p < 0.0001), serum creatinine ( R 2: 0.084; p < 0.0259), serum potassium ( R 2: 0.068; p < 0.0467), and a significant negative correlation with serum total calcium ( R 2: 0.37; p < 0.0001). Conclusions CKD patients are at risk of or may already have developed secondary hyperparathyroidism apparent from PTH-linked derangements in mineral metabolism in predialysis CKD patients. These abnormalities start in early stages of CKD and worsen with disease progression. This accentuates the significance of early recognition of mineral bone disorder, understanding its pathophysiological consequences and scheduling necessary interventions/management strategies to protect the CKD patients from a plethora of complications.

MO411ACUTE KIDNEY INJURY AFTER PARATHYROIDECTOMY FOR PRIMARY HYPERPARATHYROIDISM: PREVALENCE, PREDICTORS AND RISK ASSESSEMENT

Background and Aims Surgery is the most effective and the only definitive treatment of primary hyperparathyroidism (PHPT). We aimed to assess the prevalence of acute kidney injury (AKI) among patients underwent surgery for PHPT, to determine the possible risk factors. Method A retrospective cohort study included 290 patients who underwent successful selective parathyroidectomy (PTx) for PHPT. We did not include patients who underwent re-operative surgeries. AKI was defined according to KDIGO-2012 criteria. Results In our cohort, 106 patients (36,6%) met AKI criteria after PTx. Most of the patients developed AKI stage 1. In univariate analysis preoperative serum PTH level (р=0,0004) aa well as degree of its decrease before/after PTx (р&lt;0,0001), preoperative serum total calcium level (р=0,0158), size of the parathyroid adenoma (р=0,0184), presence of proteinuria (RR=1,9 [95%CI: 1,19; 3,54], р=0,0061), hypertension (р=0,019) and anemia (р=0,0313), older age (RR=1,32 [95%CI: 1,03; 1,72], р=0,0265) were significant risk factors of AKI development. In multivariate analysis age (OR 1,05 [95%CI: 1,02; 1,08] per a year, р=0,002), body-mass index (OR 1,07 [95%CI: 1,02; 1,13] per each kg/m2, р=0,005), anemia (yes/no OR 3,38 [95%CI: 1,38; 8,2], р=0,008), preoperative PTH (OR 1,03 [95%CI: 1,01; 1,05] per each pmol/l, р=0,002), proteinuria (yes/no OR 3,45 [95%CI: 1,34; 8,93], р=0,011), use of ACE inhibitors/ARBs (yes/no OR 2,84 [95%CI: 1,58; 5,12], р=0,001) were discovered as independent predictors of AKI. Considering the most significant risk factors we developed two regression models for AKI risk assessment: the model 1 for patients with preserved kidney function (estimated glomerular filtration rate (eGFR ≥60 ml/min/1,73 m2) and the model 2 for those with decreased kidney function (eGFR less than 60 ml/min/1,73 m2) – tab. 1 and 2. Both models were statistically significant: χ2=25,39, df=5, р&lt;0,001, RN2=0,341 for the model 1, χ2=19,355, df=3, р&lt;0,001, RN2=0,428 for the model 2. The proposed models had good discrimination to predict AKI with area under the receiver operating characteristic curves (AUC-ROC) of 0,792 [95%CI: 0,691; 0,894], р&lt;0,001 for the model 1 (normal kidney function) and 0,84 [95%CI: 0,73; 0,951], р&lt;0,001 for the model 2 (decreased kidney function). Optimal cut-off values for predicted probability of AKI to define high-risk individuals were &gt; 0,57 (Youden’s index 0,525) for the model 1 and &gt; 0,439 (Youden’s index 0,589) for the model 2. Conclusion We observed high prevalence of AKI in patients after PTx for primary HPT. Developed risk models predict AKI with adequate accuracy. Risk factors of AKI should be considered when planning PTx, special attention should be paid to modifiable ones.

Serum Calcium Level as a Useful Surrogate for Risk of Elevated Intraocular Pressure

Background: Uncontrolled intraocular pressure (IOP) plays a principal role in the deterioration of glaucoma, and the intraocular pressure is also accepted as the most important modifiable factor. Calcium ion has been found to play a vital role in regulating the resistance of the trabecular meshwork in humans. However, the relationship between serum total calcium and IOP has not been well-established. Methods: We investigated the association between serum total calcium and the IOP in a large population (14,037 eligible participants, consisting of 7712 men and 6325 women, were included) at the Tri-Service General Hospital from 2010 to 2016. Several models of covariate adjustments associated with IOP were designed. Univariate and multivariate regression analysis was performed for gender differences in the association between the serum total calcium level and IOP. Results: There was a significant relationship between serum total calcium levels and IOP in women and men with a β coefficient of 0.050 (95% confidence interval (CI), 0.030–0.069) and 0.025 (95%CI, 0.007–0.043). Notably, participants in the highest tertiles of serum total calcium levels had significantly higher IOP, in both the male and female participants. Conclusions: Our study shows that IOP is significantly associated with serum total calcium levels in a large Asian population. This study supports the notion that serum total calcium may play an important role in groups at high risk for elevated IOP.

OPTIMIZATION OF DIAGNOSIS OF EARLY STAGES OF LEGG-CALVE-PERTHES DISEASE IN CHILDREN

Aim. Optimization of the diagnosis of the initial stages of Legg-Calve-Perthes disease in children of 4-7 years old using biochemical and ultrasound methods. Materials and Methods. Patients aged 4-9 years (15 boys, 10 girls) complaining of morning pain in walking, contracture in the hip joint, lameness, were examined. The duration of the disease ranged from several days to 2-3 months. The control was a group of healthy children aged 4-9 years (n=22, 12 boys, 10 girls). Ultrasound of the hip joints was performed on Hitachi scanner (Japan) using a linear sensor with 7.5 MHz frequency. In the blood serum of patients, the follow-ing markers of resorption of the organic matrix of bone tissue were determined: the amount of sulfate sulfur, hexuronic acids (HAC), hexoses, hexosamines, sialic acids with calculation of their ratios: hexoses/hexuronic acids, hexoses/sulfate, sulfate/hexuronic acids, hexuronic ac-ids/hexosamines. Besides, concentration of electrolytes was determined in serum: total calcium and chloride ions and inorganic phosphate. On the basis of these fata, the system index of elec-trolytes SIE=ССа.CCl/CPO4 was calculated. The concentrations of parameters obtained in the ex-amination of 25 healthy children of 4 to 7 years of age were taken for norm. Results. In children with duration of the disease from several days to several weeks, an ultra-sound scan along the neck of the femur revealed thickening of the joint capsule to 0.73 (0.7:0.77) mm. With the progression of the pathological process, separate lumpy formations were visualized in the region of the subchondral plate of the femoral head in the position of abduction of the limb and internal/external rotation, which indicated the appearance of initial destructive changes in the region of the subchondral plate of the femoral head. Using biochemical methods, besides increase in the concentration of organic matrix degradation markers, there were also determined increase in the extent of sulphatation of the organic matrix and insignificant alterations of the content of separate electrolytes. Conclusions. The use of biochemical and ultrasound research methods allows optimization of the diagnosis of the initial stages of Legg-Calve-Perthes disease.