Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. Here, we reported a severe uremic calciphylaxis patient with progressive skin ischemia, large areas of painful malodorous ulcers, and mummified legs. Because of the worsening symptoms and signs refractory to conventional therapies, treatment with human amnion-derived mesenchymal stem cells (hAMSCs) was approved. Pre-clinical release inspections of hAMSCs, efficacy, and safety assessment including cytokine secretory ability, immunocompetence, tumorigenicity, and genetics analysis in vitro were introduced. We further performed acute and long-term hAMSC toxicity evaluations in C57BL/6 mice and rats, abnormal immune response tests in C57BL/6 mice, and tumorigenicity tests in neonatal Balbc-nu nude mice. After the pre-clinical research, the patient was treated with hAMSCs by intravenous and local intramuscular injection and external supernatant application to the ulcers. When followed up to 15 months, the blood-based markers of bone and mineral metabolism improved, with skin soft tissue regeneration and a more favorable profile of peripheral blood mononuclear cells. Skin biopsy after 1-month treatment showed vascular regeneration with mature non-calcified vessels within the dermis, and 20 months later, the re-epithelialization restored the integrity of the damaged site. No infusion or local treatment-related adverse events occurred. Thus, this novel long-term intravenous combined with local treatment with hAMSCs warrants further investigation as a potential regenerative treatment for uremic calciphylaxis with effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, anti-inflammatory and immune modulation, multi-differentiation, re-epithelialization, and restoration of integrity.
Introduction Circulating intact parathyroid hormone (iPTH) levels include full-length (1-84) PTH and long C-PTH fragments, but primarily (7-84) PTH, which have been reported to have antagonistic effects on the bones and kidneys. However, their effects on the cardiovascular system remain unclear. In this study, the relationships between the plasma PTH fragments levels and heart rate variability (HRV) in stage 5 chronic kidney disease (CKD5) patients are explored. Furthermore, the effects of parathyroidectomy (PTX) on the above indices are investigated. Methods In this cross-sectional study, 164 healthy controls and 354 CKD5 patients, including 208 secondary hyperparathyroidism (SHPT) subgroup with PTX, were enrolled. Circulating (7-84) PTH levels were calculated by subtracting plasma (1-84) PTH levels from iPTH levels. The HRV parameters were measured using a 24-hour Holter. Results The baseline levels of plasma iPTH, (1-84) PTH, and (7-84) PTH in the CKD5 patients were 930.40 (160.65, 1792.50) pg/mL, 448.60 (99.62, 850.45) pg/mL, and 468.20 (54.22, 922.55) pg/mL, respectively. In the CKD5 patients, plasma (1-84) PTH levels were independently correlated with the standard deviation of the normal-to-normal R-R intervals (SDNN) and the standard deviation of the five-minute average of the normal R-R intervals (SDANN). With a median follow up time of 6.50 months after PTX in the SHPT patients ( n = 30), improved SDNN and SDANN markers were related with decreased (1-84) PTH levels. Furthermore, an improved SDNN was related with decreased (7-84) PTH levels. Conclusions The CKD5 patients’ baseline (1-84) PTH levels were correlated with the SDNN and SDANN. After PTX, an improved SDNN was related with decreased (1-84) PTH and (7-84) PTH levels, while improved SDANN was related with decreased (1-84) PTH levels. No antagonistic effects of (1-84) PTH and (7-84) PTH on HRV were found in the CKD5 patients.
BACKGROUND AND AIMS Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. Here, we reported multidisciplinary regenerative treatment for rescuing a severe uremic calciphylaxis patient with human amnion-derived mesenchymal stem cells (hAMSCs). METHOD A 34-year-old uremic woman presented progressive skin ischaemia, large areas of painful malodorous ulcers and mummified legs. The patient was diagnosed as calciphylaxis based on clinical manifestations, laboratory examinations and skin pathological features. Because of her refractory to conventional therapy, treatment with hAMSCs was approved. HAMSCs were administered intravenously to the patient at a dose of 1.0 × 106 cells per kilogram of body weight, local intramuscular injection along the wound edge (2.0 × 104 cells/cm2) and external application of the cell culture supernatant on wound surfaces. RESULTS Following up 15 months regularly after hAMSCs treatment, the patient's blood biochemical, inflammatory, mineral and bone metabolic indices improved significantly, with immunoregulation effects, regeneration of skin and soft tissue. Besides, wound healing (Figure 1), pain status and quality of life, evaluated by Pain Visual Analog Scale, Bates-Jensen Wound Assessment and the wound-quality of life questionnaire were also improved significantly (Figure 2). CONCLUSION This case represented the new method of hAMSC regeneration therapy for uremic calciphylaxis with safety and effectiveness, which deserved further investigation. Before hAMSC treatment, the patient had irregular ulcers on the buttocks and lower extremities, some of which were crusted on the surface or had purulent fishy discharge. Skin and soft tissue necrosis can be seen at the ulcerated area of the buttocks, localized deep to the fascia, with purulent secretions on the surface and brown pigmentation of the skin at the edge of the ulcer (Figure 1A and B). Because of her worsening symptoms and signs refractory to conventional therapy, the patient was given intravenous and local intramuscular injections of hAMSCs, supplemented by application of hAMSC culture supernatant to the wound. After 4 months of treatment, the sacrococcygeal wound has reduced size and become shallow with less exudate, some new granulation tissue was visible. The infection was controlled with pain significantly reduced (Figure 1C). After 12 months, most of the sacrococcygeal wound had healed with only a few erosions (Figure1D). Fifteen months later, her skin scarring of the wound was healed without pain (Figure 1E). The pain Visual Analogue Scale (Figure 2A) showed that the pain was unbearable before treatment (10 points) and disappeared after 15 months of hAMSC treatment (0 point). BWAT (Figure 2B) showed that all the 13 indexes got 5 points (worst) before hAMSC treatment, with a total score of 65 points. After 15 months of hAMSC treatment, each index got 1 point (best), and the total score was 13 points. The Wound-QoL questionnaire (Figure 2C) showed that the 17 items were quantified as 4 points (very serious) before treatment, with a total score of 68 points. After 15 months of hAMSC treatment, the score was 0 (none at all), and the total score was 0.
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