Cardiac manifestations of MIS-C: cardiac magnetic resonance and speckle-tracking data

BackgroundCardiac involvement is central in MIS-C and represents the main cause of morbidity. In this study, we aimed to assess myocardial damage in patients with MIS-C using cardiac magnetic resonance (CMR) during the acute phase, as well as left ventricular and atrial longitudinal strain on admission, at discharge, and after 3 months.MethodsWe performed a single-center prospective cohort study and case–control study. Between September 2020 and February 2022, we enrolled 39 patients hospitalized for MIS-C at our center. We performed left ventricular and atrial longitudinal 2D strain analysis on admission and during follow-up; echocardiographic data were compared to a matched control population. Patients above 4 years old with increased troponin underwent CMR.ResultsOf 24 patients (mean age: 8.2 ± 4.9 years) who underwent CMR, 14 (58%) presented myocardial edema and 6 (25%) late gadolinium enhancement (LGE). LGE was associated with older age (p < 0.01), increased BMI (p = 0.03), increased ferritin levels (p < 0.001), lower left ventricular (LV) ejection fraction (p < 0.001), LV longitudinal strain (p = 0.004), left atrial (LA) strain (p = 0.05), and prolonged hospital stay (p = 0.02). On admission, LV ejection fraction, LV longitudinal strain, and LA strain were impaired, but each improved gradually over time; LVEF was the fastest to recover, while global LV longitudinal strain was still impaired as compared to controls after 3 months (p = 0.01).ConclusionOur study demonstrates that myocardial injury is present in a quarter of MIS-C patients, and impaired LA and LV myocardial deformation persist for at least several weeks after the acute phase. CMR and LV/LA strain could help us to individualize follow-up of MIS-C patients

Peripheral Blood Mononuclear Cells (PBMCs) to Dissect the Underlying Mechanisms of Bone Disease in Chronic Kidney Disease and Rare Renal Diseases

International audiencePurpose of review: To describe the methods that can be used to obtain functional and mature osteoclasts from peripheral blood mononuclear cells (PBMCs) and report the data obtained with this model in two peculiar diseases, namely pediatric chronic kidney disease-associated mineral and bone disorders (CKD-MBD) and nephropathic cystinosis. To discuss future research possibilities in the field.Recent findings: Bone tissue undergoes continuous remodeling throughout life to maintain bone architecture; it involves two processes: bone formation and bone resorption with the coordinated activity of osteoblasts, osteoclasts, and osteocytes. Animal models fail to fully explain human bone pathophysiology during chronic kidney disease, mainly due to interspecies differences. The development of in vitro models has permitted to mimic human bone-related diseases as an alternative to in vivo models. Since 1997, osteoclasts have been generated in cell cultures, notably when culturing PBMCs with specific growth factors and cytokines (i.e., M-CSF and RANK-L), without the need for osteoblasts or stromal cells. These models may improve the global understanding of bone pathophysiology. They can be been used not only to evaluate the direct effects of cytokines, hormones, cells, or drugs on bone remodeling during CKD-MBD, but also in peculiar genetic renal diseases inducing specific bone impairment

Inhibition of Osteoclast Differentiation by 1.25-D and the Calcimimetic KP2326 Reveals 1.25-D Resistance in Advanced CKD

International audienceActive vitamin D analogs and calcimimetics are the main therapies used for treating secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD). Peripheral blood mononuclear cells of 19 pediatric patients with CKD1-5D and 6 healthy donors (HD) were differentiated into mature osteoclasts with receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). The effects of single or combined treatment with active vitamin D (1.25-D) and/or calcimimetic KP2326 were evaluated on osteoclastic differentiation and osteoclastic-mediated bone resorption. Although 1.25-D inhibited osteoclastic differentiation, a significant resistance to 1.25-D was observed when glomerular filtration rate decreased. A significant albeit less important inhibitory effect of KP2326 on osteoclastic differentiation was also found both in cells derived from HD and CKD patients, through a putative activation of the Erk pathway. This inhibitory effect was not modified by CKD stage. Combinatorial treatment with 1.25-D and KP2326 did not result in synergistic effects. Last, KP2326 significantly inhibited osteoclast-mediated bone resorption. Both 1.25-D and KP2326 inhibit osteoclastic differentiation, however, to a different extent. There is a progressive resistance to 1.25-D in advanced CKD that is not found with KP2326. KP2326 also inhibits bone resorption. Given that 1.25-D has no effect on osteoclastic resorption activity and that calcimimetics also have direct anabolic effects on osteoblasts, there is an experimental rationale that could favor the use of decreased doses of 1.25-D with low doses of calcimimetics in SHPT in dialysis to improve the underlying osteodystrophy. However, this last point deserves confirmatory clinical studies. © 2020 American Society for Bone and Mineral Research

Intermittent Bi-Daily Sub-cutaneous Teriparatide Administration in Children With Hypoparathyroidism: A Single-Center Experience

International audienceIntroduction: The use of teriparatide has been reported in children with hypoparathyroidism as an investigational physiologic replacement therapy.Methods: We aimed to retrospectively report our pediatric experience of bi-daily sub-cutaneous teriparatide. Results are presented as median (25th-75th quartile). As part of the routine follow-up of these patients with hypoparathyroidism, total calcium at H0 (i.e., just before injection) and H4 (i.e., 4 h after teriparatide injection) and other biomarker parameters were regularly assessed.Results: At a median age of 10.7 (8.1-12.6) years, an estimated glomerular filtration rate (eGFR) of 110 (95-118) mL/min/1.73 m2, calcium levels of 1.87 (1.81-1.96) mmol/L and an age-standardized phosphate of 3.8 (2.5-4.9) SDS, teriparatide therapy was introduced in 10 patients at the dose of 1.1 (0.7-1.5) μg/kg/day (20 μg twice daily), with further adjustment depending on calcium levels. Six patients already displayed nephrocalcinosis. Severe side effects were reported in one child: two episodes of symptomatic hypocalcemia and one of iatrogenic hypercalcemia; one teenager displayed dysgueusia. Calcium levels at H0 did not significantly increase whilst calcium at H4 and phosphate levels significantly increased and decreased, respectively. After 12 months, eGFR, calcium and age-standardized phosphate levels were 108 (90-122) mL/min/1.73 m2, 2.36 (2.23-2.48) mmol/L, 0.5 (-0.1 to 1.5), and 68 (63-74) nmol/L, respectively, with a significant decrease in phosphate levels (p = 0.01). Urinary calcium and calcium/creatinine ratio remained stable; no nephrolithiasis was observed but two moderate nephrocalcinosis appeared.Conclusion: Intermittent teriparatide therapy significantly improves calcium and phosphate control, without increasing calciuria. It appears to be safe and well-tolerated in children

Off-label use of cinacalcet in pediatric primary hyperparathyroidism: A French multicenter experience

Background Cinacalcet is a calcimimetic approved in adults with primary hyperparathyroidism (PHPT). Few cases reports described its use in pediatric HPT, with challenges related to the risk of hypocalcemia, increased QT interval and drug interactions. In this study, we report the French experience in this setting. Methods We retrospectively analyzed data from 18 pediatric patients from 7 tertiary centers who received cinacalcet for PHPT. The results are presented as median (interquartile range). Results At a median age of 10.8 (2.0–14.4) years, 18 patients received cinacalcet for primary HPT ( N = 13 inactive CASR mutation, N = 1 CDC73 mutation, N = 1 multiple endocrine neoplasia type 1, N=3 unknown etiology). Cinacalcet was introduced at an estimated glomerular filtration rate (eGFR) of 120 (111–130) mL/min/1.73 m 2 , plasma calcium of 3.04 (2.96–3.14) mmol/L, plasma phosphate of 1.1 (1.0–1.3) mmol/L, age-standardized (z score) phosphate of −3.0 (−3.5;−1.9), total ALP of 212 (164–245) UI/L, 25-OHD of 37 (20–46) ng/L, age-standardized (z score) ALP of −2.4 (−3.7;−1.4), PTH of 75 (59–123) ng/L corresponding to 1.2 (1.0–2.3)-time the upper limit for normal (ULN). The starting daily dose of cinacalcet was 0.7 (0.6–1.0) mg/kg, with a maximum dose of 1.0 (0.9–1.4) mg/kg per day. With a follow-up of 2.2 (1.3–4.3) years on cinacalcet therapy, PTH and calcium significantly decreased to 37 (34–54) ng/L, corresponding to 0.8 (0.5–0.8) ULN ( p = 0.01), and 2.66 (2.55–2.90) mmol/L ( p = 0.002), respectively. In contrast, eGFR, 25-OHD, ALP and phosphate and urinary calcium levels remained stable. Nephrocalcinosis was not reported but one patient displayed nephrolithiasis. Cinacalcet was progressively withdrawn in three patients; no side effects were reported. Conclusions Cinacalcet in pediatric HPT can control hypercalcemia and PTH without significant side effects

Inhibition of Osteoclast Differentiation by 1. 25‐D

International audienceActive vitamin D analogs and calcimimetics are the main therapies used for treating secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD). Peripheral blood mononuclear cells of 19 pediatric patients with CKD1-5D and 6 healthy donors (HD) were differentiated into mature osteoclasts with receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). The effects of single or combined treatment with active vitamin D (1.25-D) and/or calcimimetic KP2326 were evaluated on osteoclastic differentiation and osteoclastic-mediated bone resorption. Although 1.25-D inhibited osteoclastic differentiation, a significant resistance to 1.25-D was observed when glomerular filtration rate decreased. A significant albeit less important inhibitory effect of KP2326 on osteoclastic differentiation was also found both in cells derived from HD and CKD patients, through a putative activation of the Erk pathway. This inhibitory effect was not modified by CKD stage. Combinatorial treatment with 1.25-D and KP2326 did not result in synergistic effects. Last, KP2326 significantly inhibited osteoclast-mediated bone resorption. Both 1.25-D and KP2326 inhibit osteoclastic differentiation, however, to a different extent. There is a progressive resistance to 1.25-D in advanced CKD that is not found with KP2326. KP2326 also inhibits bone resorption. Given that 1.25-D has no effect on osteoclastic resorption activity and that calcimimetics also have direct anabolic effects on osteoblasts, there is an experimental rationale that could favor the use of decreased doses of 1.25-D with low doses of calcimimetics in SHPT in dialysis to improve the underlying osteodystrophy. However, this last point deserves confirmatory clinical studies. © 2020 American Society for Bone and Mineral Research

The use of cinacalcet after pediatric renal transplantation: an international CERTAIN Registry analysis

BACKGROUND Secondary hyperparathyroidism (SHPT) may persist after renal transplantation (RTx), inducing hypophosphatemia and hypercalcemia that precludes the use of vitamin D analogs. The calcimimetic cinacalcet improved plasma calcium and parathyroid hormone (PTH) levels in randomized controlled trials in adults after RTx, but pediatric data are scarce. METHODS In this retrospective study, we analyzed 20 pediatric patients from the Cooperative European Paediatric Renal TransplAnt Initiative (CERTAIN) Registry who received cinacalcet after RTx. The results are presented as median and interquartile range (25th-75th percentile). RESULTS At 13.7 (11.0-16.5) years of age, 20 pediatric patients received a renal allograft. Cinacalcet was introduced at 0.4 (0.3-2.7) years post-transplant at an estimated glomerular filtration rate (eGFR) of 50 (34-66) mL/min/1.73 m$^{2}$, plasma calcium of 2.58 (2.39-2.71) mmol/L, age-standardized (z score) phosphate of - 1.7 (- 2.7-- 0.4), and PTH of 136 (95-236) ng/L. The starting dose of cinacalcet was 0.5 (0.3-0.8) mg/kg per day, with a maximum dose of 1.1 (0.5-1.3) mg/kg per day. With a follow-up of 3.0 (1.5-3.6) years on cinacalcet therapy, eGFR remained stable; PTH levels decreased to 66 (56-124) ng/L at the last follow-up (p = 0.015). One patient displayed hypocalcemia (1.8 mmol/L). Cinacalcet was withdrawn in three patients (hypocalcemia, parathyroidectomy, incompliance). Nephrocalcinosis of the graft was not reported. CONCLUSIONS This pilot study suggests that cinacalcet as off-label therapy for SHPT after pediatric RTx is efficacious in controlling post-transplant SHPT with acceptable tolerability. Continuing cinacalcet even with normal PTH can lead to dangerous life-threatening hypocalcemia. Therefore, at each subsequent visit, the need to continue cinacalcet must be assessed