Treatment effects of human amnion-derived mesenchymal stem cells for skin lesions and metastatic pulmonary calcification in calciphylaxis patients – case series and literature review

Abstract

Background

Calciphylaxis, also termed calcific uremic arteriolopathy (CUA) in patients with end-stage kidney disease (ESKD), is a rare and fatal condition characterized by cutaneous ischemic necrosis.

Methods

Three patients with calciphylaxis and metastatic pulmonary calcification (MPC) were treated with human amnion-derived mesenchymal stem cells (hAMSCs). Effects were evaluated using the Visual Analogue Scale (VAS), modified Bates-Jensen Wound Assessment Tool for CUA (BWAT-CUA), wound quality of life questionnaire (Wound-QoL), and histological analysis. MPC was assessed by high-resolution CT (HRCT) and ⁹⁹ᵐTc-methylene diphosphonate (⁹⁹ᵐTc-MDP) bone scans.⁹⁹ᵐTc-labeled macroaggregated albumin (⁹⁹ᵐTc-MAA) pulmonary perfusion imaging was conducted for the first time in patients with MPC.

Results

Three patients exhibited wound healing and improvement in skin symptoms. Two months before CUA, asymptomatic MPC was detected in Patient 1, who was treated with hAMSCs for 15 months. The condition progressed to chest pain and dyspnea. HRCT and ⁹⁹ᵐTc-MDP bone scans showed worsening calcification, particularly in the upper and mid-thoracic lobes.⁹⁹ᵐTc-MAA pulmonary perfusion imaging revealed impaired or absent blood perfusion in the areas of metastatic calcification. Patient 1 died from respiratory failure. Patients 2 and 3 had asymptomatic MPC at calciphylaxis diagnosis. After 2 months of treatment, Patient 2, showed no significant imaging improvement and passed away 6 months after discontinuing hAMSC treatment. Patient 3 has shown no significant progression of pulmonary lesions and continues hAMSC therapy.

Conclusion

We reported personalized early, noninvasive diagnosis and regenerative treatments for calciphylaxis patients with MPC. Although the current hAMSC treatment regimen is effective for skin lesions, its impact on MPC requires further investigation.

Introduction

Calciphylaxis is a rare, fatal disease characterized by microvascular calcification, intimal fibroplasia, and thrombosis, resulting in progressive cutaneous ischemic necrosis and severe pain, especially in areas of greatest adipose tissue density [1–3]. Enchondral ossification in calciphylaxis of various origins from human subcutaneous tissues has been suggested [4]. It is defined as calcific uremic arteriolopathy (CUA) as most cases are described in patients with end-stage kidney disease (ESKD) [5–8]. Brandenburg et al. recorded an annual incidence of ∼0.04% [9] from a large nationwide registry. The 1-year mortality of calciphylaxis ranges between 45% and 80% [10,11] and the leading cause of mortality is sepsis due to wound infection [5]. Because of the uncleared mechanisms, there is currently no approved therapy for calciphylaxis [12–14], which is a challenging clinical problem [15].

As a metabolic lung disease, metastatic pulmonary calcification (MPC) is characterized by deposition of calcium in bilaterally pulmonary parenchyma [16]. It has been reported to be observed in 60–80% of long-term hemodialysis patients in autopsy studies [17], while its antemortem diagnosis is rare [18]. MPC is usually asymptomatic in the early stages, developed silently over years and progressed to irreversible lung damage and respiratory failure [19–21]. Recognizing early imaging features is essential for diagnosis and treatment [22]. High-resolution CT (HRCT) and ^99mTc-methylene diphosphonate (^99mTc-MDP) bone scan are sensitive and specific for the diagnosis of pulmonary calcification [23], and thus decreasing the need for lung biopsy [17,24]. Though the optimal treatment for MPC remains unknown, new diagnostic and treatment modalities will enhance its clinical management abilities [21].

Mesenchymal stem cells (MSCs) have been reported to reduce inflammatory response and improve wound healing [25]. Compared with other sources of MSCs, human amnion-derived MSCs (hAMSCs) are abundant and have enhanced immunomodulatory properties [26]. We have innovatively treated the severe CUA patient by long-term intravenous combined with local treatment with hAMSCs and achieved favorable clinical outcomes [27,28].

Here we report three male patients with CUA unresponsive to conventional treatments who demonstrated improvement following hAMSC therapy. All patients were diagnosed with calciphylaxis combined with MPC, a condition that is extremely rare [29,30]. To better understand this rare disease, we conducted a comprehensive review of case reports involving calciphylaxis combined with MPC.

Methods

The inclusion and exclusion criteria for CUA patients receiving hAMSC treatment

The inclusion criteria for patients with calciphylaxis are as follows: (1) age 18–70 years; (2) patients with Stage 5 chronic kidney disease (CKD), either not on dialysis or undergoing regular dialysis (glomerular filtration rate <15 mL/min); (3) clinically diagnosed with calciphylaxis, characterized by early manifestations such as localized erythema, purpura, or livedo reticularis. As the disease progresses, ischemic changes worsen, leading to purple plaques or indurations with intractable pain, which gradually develop into skin ulcers with black eschar formation [31]. Skin biopsy is the gold standard for diagnosing calciphylaxis, with typical pathological features including intravascular calcification in the dermis and subcutaneous fat, fibrin thrombi, epidermal ischemic necrosis, and fat necrosis [2]. (4) Ineffective conventional treatment for clinical calciphylaxis and (5) all patients have signed an informed consent form.

The exclusion criteria include: (1) patients with severe cardiovascular disease, liver disease, psychiatric disorders, shock, or malignancies; (2) nursing or pregnant women; (3) participants in other clinical studies; and (4) patients deemed otherwise ineligible for this study.

Patient information

Patient 1 is a 49-year-old male who began maintenance hemodialysis in 2001 and underwent kidney transplantation in 2009. Since February 2020, he developed progressive pain and hyposthenia of both lower extremities. Within 3 months he displayed indurated, ulcerated plaques and nodules which progressed to ulcerations with thick, adherent, necrotic eschar in lower limbs. Hemodialysis was resumed due to his renal allograft failure in May 2020. He was diagnosed as CUA and treated with cinacalcet, sevelamer, sodium thiosulfate (STS, intravenous injection, 4 g in 100 mL of saline, once every other day), roxadustat, vacuum sealing drainage (VSD), hyperbaric oxygen therapy, anti-infective treatment, and nutritional support, etc. However, his lower extremity ulcers continued to progress with severe pain.

Patient 2 is a 42-year-old male who has been undergoing hemodialysis for over 15 years. In 2017, he received a pacemaker implantation, and in 2018, he underwent a parathyroidectomy. In early January 2024, a black spot accompanied by skin cracking appeared on his right heel, which was initially neglected. The wound subsequently progressed to ulceration, peeling, and expansion. One month later, similar symptoms appeared on his left heel, accompanied by severe pain in both heels. Despite two debridement treatments at an external hospital, his condition showed no significant improvement. After receiving symptomatic and nutritional support treatments, including cinacalcet, lanthanum carbonate, roxadustat, STS (intravenous injection, 8 g in 100 mL of saline, once every other day), pain management, and anti-infection therapy, his symptoms remained largely unchanged.

Patient 3 is a 41-year-old male who has been undergoing regular peritoneal dialysis for over 10 years. He underwent a parathyroidectomy in 2018 and received a kidney transplant in February 2023. In September 2023, he developed dark discoloration, pain, and numbness in the distal extremities of his limbs, with symptoms progressively worsening. In November 2023, X-ray results from an external hospital revealed multiple calcification foci in the blood vessels of both hands. He received conventional treatment with STS (intravenous injection, 8 g in 100 mL of saline, every other day), but his symptoms did not significantly improve. In December of the same year, partial black discoloration and gangrene developed in the distal extremities.

The baseline serum albumin levels of the three patients were decreased, whereas their serum calcium levels were normal. Patients 1 and 2 exhibited significantly elevated levels of serum phosphate and intact parathyroid hormone (iPTH), whereas Patient 3 had serum phosphate levels within the reference range and decreased iPTH levels. Additionally, Patients 1 and 3 demonstrated elevated serum C-reactive protein (CRP) levels. Detailed baseline hematological indicators are presented in Table S1.

The acquisition and quality control of hAMSCs

After approval by the Ethics Committee of the First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital (2012-SR-128), human amniotic membranes were donated by healthy pregnant women who had provided informed consent, with no ethical concerns or harm to the donors. The isolation, passaging, and preparation of hAMSCs were conducted using the methods previously described by our team [32]. Considering the potential safety issues associated with hAMSC treatment, including infectious, genetic risks, and tumorigenicity, stringent screening was conducted for both the donors and the extracted hAMSCs, in accordance with national standards [33]. As in our previous study, specific safety evaluation components including microbiology, virology, tumorigenicity, acute toxicity reactions, long-term toxicity reactions, immunotoxicity, and genetic analysis of karyotype and short tandem repeat (STR) were performed [27]. Additionally, evaluations of effectiveness, encompassing cell viability and growth characteristics, pluripotency, cytokine secretion capacity, and immune function, were also conducted [27].

hAMSC treatment for the CUA patients

Based on previous literature and preclinical studies on maximum tolerated doses in mice and rats [27,34,35], we employed the Meeh formula to calculate the body surface area and subsequently converted the equivalent doses between humans and mice/rats to determine the optimal therapeutic dose [36]. Studies have shown that intravenous injection of hAMSCs can exert immunomodulatory effects by reducing the number of macrophages and promoting their polarization toward the M2 phenotype [37,38]. Furthermore, local injection of hAMSCs into the wound area can promote the healing of skin injuries by inhibiting cell apoptosis, promoting proliferation, and enhancing epithelialization [39,40]. Based on the results of these animal experiments, we adopted a combined protocol of intravenous and local injections.

All patients who meet the inclusion criteria for the study are eligible to receive hAMSC treatment. Due to the rapid progression of calciphylaxis and its refractory nature to conventional therapies [5], the three patients initiated hAMSC treatment in September 2020, April 2024, and December 2023, respectively. The treatment regimen of hAMSCs for the three CUA patients is illustrated in Figure S1. The treatment included intravenous infusion (1.0 × 10⁶ cells/kg) and local intramuscular injection along the wound edge (2.0 × 10⁴ cells/kg).

Due to the impact of COVID-19 pandemic, Patient 1 suspended hAMSC treatment for 6 months, from December 2020 to June 2021, and subsequently resumed treatment. For Patient 2, he discontinued the hAMSC treatment after 2 months. Patient 3 is currently continuing with the hAMSC therapy. No adverse events were reported during the course of hAMSC treatment.

Wound healing and quality of life assessment

The wound healing progress, skin pathological characteristics, and quality of life (QoL) of the patients were dynamically monitored. Hematoxylin and eosin (H-E) staining was used to illustrate the skin pathological conditions of the patients. The modified Bates-Jensen Wound Assessment Tool for CUA (BWAT-CUA), comprising 8 items each scored from 1 to 5, was employed [41]. The total score ranges from 8 (best) to 40 (worst), and it was utilized to assess the wound condition before and after treatment. The Visual Analog Scale (VAS) for pain and the Wound QoL (Wound-QoL) questionnaire were used to evaluate improvements in pain and QoL [42,43].

Radiological examination

Angiography was conducted to evaluate the vascular occlusion in Patient 1’s extremities. Following local anesthesia, a 4-Fr sheath (Terumo Medical Corp., Tokyo, Japan) was inserted by antegrade brachial approach. Baseline angiography was performed using the inserted sheath. Optimal imaging of the vessel tree was obtained using Iohexol and digital subtraction angiography. A 0.014’ wire (Boston Scientific, Marlborough, MA) was used to cross the lesions with the assistance of a 3-Fr multipurpose support-catheter (Cook Medical, Bloomington, Indiana). In addition, we used chest CT, single-photon emission CT (SPECT), ^99mTc-MDP bone scanning, and ^99mTc-MAA pulmonary perfusion imaging to observe the calcification and blood perfusion of the patient’s lungs.

In terms of CT scanning, an advanced iterative reconstruction with a medium smooth reconstruction kernel (Bv37) was applied, with a reconstruction slice thickness and interval of 0.75 mm. Electrocardiogram-gated multislice spiral CT was utilized to detect coronary artery calcification (CAC), with the quantitative assessment calculated using the Agatston CAC score (CACS). All sections were evaluated to determine the presence and extent of coronary calcifications. The threshold for calcification was set at a CT density of 130 Hounsfield units (HU) with an area ≥1 mm². The total CACS was determined by summing the scores of all sections.

In ⁹⁹ᵐTc-MDP bone scans, the slice thickness is 3.75 mm, and reconstruction is performed using a standard algorithm. All imaging results were independently interpreted by two radiologists with more than five years of experience, achieving good consistency.

Search strategy

A systematic exploration was conducted in the PubMed online database for case reports published from 2009 to the present, using the keywords ‘calciphylaxis,’ ‘calcific uremic arteriolopathy,’ ‘pulmonary calcification,’ and ‘pulmonary metastatic calcification.’ Cases diagnosed with calciphylaxis and associated with MPC were included, excluding those outside the specified time range. A meticulous review of all articles was conducted to eliminate duplicates, ensuring the inclusion of comprehensive information in the review.

Ethics approve

The participant provided written informed consent, in accordance with the guidelines outlined in the Declaration of Helsinki. This study was approved by the ethics committee of the First Affiliated Hospital with Nanjing Medical University in China (2020-QT-09, 2020-SCR-03, 2025-SR-141).

Results

Skin wound regeneration and symptom improvement in CUA patients undergoing hAMSC treatment

Patient 1 presented with multiple necrotic, round ulcers on the left lower limb, covered with eschar. The areas of ulceration expanded over time, with secretions on the surface (Figure 1(A,B)). Following intravenous and local intramuscular hAMSC injection, the skin lesions on the lower limbs gradually healed (Figure 1(C–F)). After 2 weeks of hAMSC treatment, the eschar decreased, and the ulcer area began to shrink (Figure 1C). After 1 month, the ulcer area continued to shrink, with only a small amount of eschar remaining (Figure 1(D)). After 2 months, regenerative tissue was observed in the lesions (Figure 1(E)). The skin lesions on the left lower limb were fully healed after 1 year (Figure 1(F)). One year after hAMSC treatment, the patient experienced a reduction in wound pain, with the VAS score for pain decreasing from 9 to 5. Additionally, the BWAT-CUA score for the wound area decreased from 34 to 19, and the patient’s QoL improved compared to pretreatment levels (Figure 1(G,H)).

Figure 1.

Healing of lower limb skin lesions and improvement in quality of life in CUA Patient 1 during hAMSC treatment. (A,B). The rapid progression of thigh skin lesions before hAMSC treatment. (A) Multiple ulcers were seen on the posterior side of the left lower extremity, surrounded by redness and swelling, purulent secretions and scabs on the surface (2020.7.21). (B) A 5 cm × 15 cm cord-shaped ulcer with irregular shape was seen on posterior side of the left thigh, with scab on the surface, local erosion and a small amount of purulent secretion (2020.9.21). (C–E) The healing process of skin lesions on the left posterior thigh after hAMSC treatment. (C) A 3 cm × 12 cm cord-shaped irregular shallow ulcer with central scab, mild erosion on both sides and a small amount of purulent secretion. A 1.5 cm × 1.5 cm round erosion with scab on the surface and a small amount of exudation (after hAMSC treatment for 2 weeks). (D) The ulcer area was reduced to 3 cm × 11 cm, with scabs on the edge and a small amount of purulent secretion in the center (after hAMSC treatment for 1 month). (E) The shallow ulcer continued to shrink to 2 cm × 10 cm, with reddish in the center and scar healing above it (after hAMSC treatment for 2 months). (F) The skin lesions were healed in large areas, leaving only a small amount of brownish skin pigmentation and no scar or ulcer (after hAMSC treatment for 1 year). (G,H) Comparison of wound BWAT-CUA scores (G) and Wound Quality of Life scores (H) before and 1 year after treatment. hAMSC: human amnion-derived mesenchymal stem cell; CUA: calcific uremic arteriolopathy; BWAT: Bates-Jensen Wound Assessment.

Patient 2 presented with an ulcer on the left heel, characterized by black eschar and dark red surrounding tissue, accompanied by severe pain prior to hAMSC treatment (Figure 2(A)). After 1 month of hAMSC treatment, some of the eschar on the left heel ulcer had sloughed off (Figure 2(B)). The VAS score decreased from 10 to 6 over 2 months of treatment, reflecting a significant reduction in pain. Due to the relatively short treatment duration, there was a modest improvement in the BWAT-CUA score and QoL score for the wound (Figures 2(C,D)).

Figure 2.

Dynamic changes in foot skin lesions of CUA Patients 2 and 3 during hAMSC treatment. (A–D) Patient 2 experienced healing of skin wounds, improvement in wound scores, and enhanced quality of life. (A,B) Dynamic changes in the left heel wound of Patient 2. (A) Before treatment, there was a large area ulcer on the heel accompanied by the formation of black eschar, with the surrounding skin tissue appearing dark red (2024.3.28). (B) One month post-treatment, some of the eschar on his heel wounds had fallen off (2024.5.2). (C,D) Comparison of wound BWAT-CUA scores (C) and Wound Quality of Life scores (D) before and 1 month after treatment. (E–H) Patient 3 demonstrated healing of skin wounds, improved wound scores, and enhanced living conditions. (E,F) The dynamic changes in the left foot wounds of Patient 3 are illustrated. (E) Before treatment, the patient exhibited ulcers with black eschar formation on the left foot (December 2023). (F) After 8 months of treatment, the foot wounds had healed (December 2024). (G,H) Comparison of wound BWAT-CUA scores (G) and Wound Quality of Life scores (H) before and 8 months after treatment. hAMSC: human amnion-derived mesenchymal stem cell; BWAT-CUA: Bates-Jensen Wound Assessment for calcific uremic arteriolopathy.

Before the hAMSC treatment, Patient 3 had an ulcer on the left side of the foot, covered with black eschar and surrounded by dry, cracked tissue (Figure 2(E)). Eight months post-treatment, the wound on the left foot had fully healed (Figure 2(F)), with a significant reduction in pain, and the VAS score decreasing from 8 to 2. Compared to pretreatment, the patient’s wound BWAT-CUA score and QoL score demonstrated marked improvement (Figure 2(G,H)). The total BWAT-CUA scores and subscores of the three patients at corresponding time points before and after hAMSC treatment are shown in Figure S2.

Dynamic histopathological changes in skin tissue

Before treatment, histopathological examination of Patient 1’s skin tissue revealed calcium salt deposition (Figure 3(A)). One month post-treatment, multiple areas of neovascularization with no signs of calcification, and the lumens remained patent (Figure 3(B)). Skin tissue HE staining revealed that before treatment, Patient 2 had microvascular necrosis and luminal occlusion (Figure 3(C)). One month later, multiple areas exhibited the presence of newly formed microvessels (Figure 3(D)). Patient 3 exhibited calcification and luminal occlusion of microvessel prior to hAMSC treatment (Figure 3(E)).

Figure 3.

Pretreatment and 1 month post hAMSC treatment, skin HE staining was conducted in patients with calciphylaxis. (A,B) Skin pathology of Patient 1 before and 1 month after treatment. (A) Before treatment, calcium salt deposition (↑) was evident in the skin microvessels. (B) One month later, no calcified neovascularization was observed in the skin tissue. (C,D) Skin pathology of Patient 2 before and 1 month after treatment. (C) Prior to treatment, the skin tissue exhibited microvascular necrosis (*), and luminal occlusion (★). (D) One month post-treatment, rich neovascularization was observed, along with a reduction in inflammatory cell infiltration. (E) Before treatment, Patient 3 demonstrated calcium deposition (↑) within the microvessels and luminal occlusion (★).

Patient 1 experienced worsening of gangrene in the fingers during hAMSC treatment

The digital gangrene of Patient 1 continued to be worsen (Figure 4(A–C)). We further performed angioplasty. Despite attempts with guide wire and support catheter combination, the radial artery could not be negotiated antegradely, either intraluminally or subintimally. Besides subcutaneous injection, we had tried to deliver hAMSCs to distal hypoperfused fingers via bilateral brachial artery injection antegradely. However, the cell suspension failed to reach the distal tissues due to high intra-arterial pressure. After hAMSC treatment for 14 months, his digital gangrene was not improved (Figure 4(D,E)). We removed the necrotic tissue by debridement, and there was still necrotic scab at the left little finger (Figure 4(F)).

Figure 4.

Progression of his digits gangrene during hAMSC treatment and the imaging of right brachial artery angiography [76]. (A)Twenty days after the initial hAMSC treatment, dry gangrene involving the tip of index and ring fingers, a tiny ulceration on the middle finger. (B) Nine months after the initial hAMSC treatment, digital gangrene with clear demarcation of the right index, middle and ring fingers, enlarged significantly. (C) Dry Gangrene with clear demarcation of the index, middle and ring fingertips in the right hand (yellow arrows). (D) Fluoroscopic image revealed ‘pipe-stemming’ calcifications in the abandoned fistula radial, interosseous, ulnar artery, and DPA (yellow arrow indicated). The distal radial artery occlusion could not be crossed by guide wire and balloon. (E) Right upper extremity angiography indicated interruption of blood flow in the radial artery with distal opacification resumed by the collateral runoff. The angiography also revealed incomplete palmar artery arch opacification, reduced metacarpophalangeal artery blood flow with no visualization of the second and third proper digital artery. (F) Fourteen months after the initial hAMSC treatment, the necrotic tissue was completely removed by debridement and the phalangeal was exposed. A round ulceration on the left little finger formed a scab. hAMSC: human amnion-derived mesenchymal stem cell; RA: radial artery; UA: ulnar artery; IA: interosseous artery; PPA: princeps pollicis artery; DPA: deep palmar arch; CDA: common palmar digital artery; PDA: proper digital artery.

Radiographic characteristics of the coronary artery calcification and lungs in three CUA patients during hAMSC treatment

CAC was present in all three patients. Before hAMSC treatment, Patient 1 had a calcification volume of 521.3 mm³ and a CACS of 668.3; Patient 2 had a calcification volume of 780.3 mm³ and a CACS of 959.9; Patient 3 had a calcification volume of 5446.7 mm³ and a CACS of 7044.7. All three patients were found to have MPC prior to undergoing hAMSC treatment.

Patient 1

Chest CT scans showed that pulmonary calcification was developed from scratch with diffuse infiltrate, ground-glass opacities, consolidation, and calcified nodules (Figure 5(A–C)). In May 2019, his lung fields were clear with no calcified nodules (Figure 5(A)). Chest CT in March 2020 revealed multiple pulmonary nodules with calcification in the lungs, which presented earlier than CUA (Figure 5(B)). At this time, he had no typical respiratory symptoms. He suspended hAMSC treatment for half a year due to the COVID-19 epidemic and restart hAMSC treatment until June 2021. His shortness of breath was initially intermittent, then progressed to constant shortness of breath over the few weeks. He had no fever, hemoptysis, or chest pain. Based on imaging findings and excluding bacterial infection, tumor and tuberculosis, etc., his lung damage was diagnosed as MPC. Chest CT before restarting treatment with hAMSCs indicated that pulmonary calcification progressed significantly (2021.06, Figure not shown) and the patient had progressive chest tightness, chest pain, and dyspnea. After retreatment with hAMSCs for 3 months, the parenchymal metastatic calcifications of his lungs continued to progress with more calcified nodules (Figure 5(C)). His ^99mTc-MDP bone scan revealed abnormal diffuse uptake in bilateral lungs especially the apices at the initial stage of CUA (2020.5, Figure 5(D)). When restarting hAMSC treatment (2021.6), his bone scan examination revealed higher diffuse radioactive concentration in lungs (Figure 5(E)). ^99mTc-MAA pulmonary perfusion was performed on September 2021, planar imaging showed impaired perfusion of blood flow in both lungs (Figure 6(A)). Chest SPECT/CT tomography fusion imaging displayed multiple calcifications in both lungs, with decreased or no blood perfusion in the calcified area (Figure 6(B)). Unfortunately, the patient passed away with dyspnea and chest pain in a local hospital in December 2021. No pulmonary edema was found in the emergency chest CT, but MPC was severe.

Figure 5.

Chest CT and ^99mTc-MDP bone scan imaging revealed the progression of MPC in CUA Patient 1. (A–C) The CT results during the hAMSC treatment period of CUA Patient 1 demonstrated a worsening of MPC. (A) Lung fields are clear, with no small vessel calcification of the chest wall in the mediastinum window (2019.05). (B) Bilateral, diffuse, ground-glass opacities and heterogeneous, high-density areas were distributed throughout the lungs, predominantly in the upper and middle lobes. Multiple vascular calcifications of chest wall were displayed in the mediastinum window (2020.03). (C) After retreatment with hAMSCs for 3 months, more calcified nodules were observed in the lungs, preferentially located in the apices. The parenchymal metastatic calcifications further progressed (2021.09). (D,E) ^99mTc-MDP bone scan imaging. (D) Diffuse radioactive uptake in both lungs, particularly in the upper lobes, before hAMSC treatment (2020.05); (E) After 3 months of hAMSC treatment and a 6-month suspension, increased diffuse radioactive concentration in bilateral lungs, predominantly in the upper and midthoracic regions (2021.06). hAMSC: human amnion-derived mesenchymal stem cell; CUA: calcific uremic arteriolopathy; ^99mTc-MDP: 99mTc-methylene diphosphonate.

Figure 6.

^99mTc-MAA pulmonary perfusion SPECT/CT imaging revealed MPC and blood flow defects in CUA Patient 1. (A,B) ^99mTc-MAA pulmonary perfusion SPECT/CT imaging (2021.9). (A) The radioactivity in bilateral lungs was unevenly distributed and scattered in the sparse area of flaky radioactivity. (B) SPECT/CT tomographic fusion image. SPECT images (upper row) showed uneven distribution of radioactivity in both lungs, and multiple divergences in irregular clumps of flaky radioactive sparseness and defect areas can be seen; CT images (middle row) displayed nodular high-density shadows with different sizes in both lungs; fusion images (lower row) indicated that the high-density shadows seen in CT were coincide with the location of the radioactive sparse/defect areas revealed by SPECT. ^99mTc-MAA: ^99mTc-labelled macroaggregated albumin; CUA: calcific uremic arteriolopathy; MPC: metastatic pulmonary calcification; ANT: anterior; RAO: right anterior oblique; RL: right lateral; RPO: right posterior oblique; POST: posterior; LPO: left posterior oblique; LL: left lateral; LAO: left anterior oblique.

Patient 2

Patient 2 underwent 2 months of hAMSC treatment, during which there was no significant progression of MPC. In March 2024, a non-contrast multi-slice CT scan of the chest in Patient 2 revealed multiple high-density lesions in both lungs with small cavitations (Figure 7(A)). Two months later, his chest CT results at the end of May 2024 showed multiple high-density shadows with small cavitations in both lungs, which were similar to those before treatment (Figure 7(B)), and he did not experience significant respiratory discomfort. Before treatment, his ^99mTc-MDP bone scan showed diffuse radiotracer uptake in both lungs (2024.4, Figure 7(C)). Simultaneously, a pulmonary perfusion scan showed no obvious abnormal pulmonary (sub)segmental radiotracer distribution with sparse or defective areas (2024.4, Figure 7(D)). Due to the discontinuation of treatment, he passed away in November 2024 at a local hospital from complications related to amputation and severe infection.

Figure 7.

Chest CT, ^99mTc-MDP bone scan, and ^99mTc-MAA pulmonary perfusion SPECT/CT imaging revealed multiple MPC in Patient 2 with CUA. (A,B) CT scan results during the hAMSC treatment period for CUA Patient 2. (A) Before treatment, multiple high-density lesions in both lungs were observed, accompanied by the formation of small cavities (2024.3.28). (B) Two months after treatment, multiple high-density lesions in both lungs with small cavities persisted, indicating a condition similar to that before treatment (2024.5.29). (C,D) ^99mTc-MDP bone scan and ^99mTc-MAA pulmonary perfusion SPECT/CT imaging showed multiple metastatic pulmonary calcifications in CUA Patient 2. (C) ^99mTc-MDP bone scan showed diffuse increased radiotracer uptake in both lungs of the patient before treatment (2024.4.1). (D) The results of ^99mTc-MAA pulmonary perfusion imaging showed no obvious abnormal pulmonary (sub)segmental areas of sparse or absent radiotracer uptake. hAMSC: human amnion-derived mesenchymal stem cell; ^99mTc-MDP: ^99mTc-methylene diphosphonate; ^99mTc-MAA: ^99mTc-labelled macroaggregated albumin; CUA: calcific uremic arteriolopathy; ANT: anterior; RAO: right anterior oblique; RL: right lateral; RPO: right posterior oblique; POST: posterior; LPO: left posterior oblique; LL: left lateral; LAO: left anterior oblique.

Patient 3

Before treatment, Patient 3’s chest CT scan showed multiple patchy, nodular ground-glass opacities in both lungs, with a more pronounced presence in the left lower lung (2023.12, Figure 8(A)). By 1 year after treatment, the CT scan depicted multiple patchy, nodular ground-glass opacities in both lungs (2024.12, Figure 8(B)). A ^99mTc-MDP bone scan before treatment showed increased radioactive uptake in the lower lobe of the left lung (2023.12, Figure 8(C)). At 8 months of treatment, bone scan also showed a localized increase in radioactive uptake in the left lung (2024.8, Figure 8(D)). Despite these findings, the ^99 mTc-MAA lung perfusion scans conducted before treatment and 8 months after treatment showed no defects in blood flow within both lungs (Figure 8(E,F)). Throughout the follow-up period, Patient 3 remained stable, exhibiting no respiratory symptoms, and was considered to be in the early stage of MPC.

Figure 8.

Chest CT, ^99mTc-MDP bone scan, and ^99mTc-MAA pulmonary perfusion SPECT/CT imaging revealed multiple MPC in CUA Patient 3. (A–F) Radiological imaging results of Patient 3 demonstrated relatively stable MPC. (A,B) Pretreatment and 1-year post-treatment chest CT of Patient 3. (A) Pretreatment chest CT of Patient 3 showed multiple high-density shadows in both lungs, predominantly in the left lower lobe. (B) One year after treatment, chest CT revealed multiple patchy and nodular ground-glass opacities in both lungs, with the largest diameter of approximately 11 mm, predominantly in the left lower lobe. (C,D) ⁹⁹ᵐTc-MDP bone scans of Patient 3 before and 8 months after treatment. (C) Pretreatment, the bone scan revealed increased radiotracer uptake in a localized area of the left lung. (D) Eight months post-treatment, the scan demonstrated slightly increased radiotracer uptake in the same localized area of the left lung. (E,F) ^99mTc-MAA pulmonary perfusion imaging, conducted before treatment (E) and 8 months after treatment (F), showed no significant blood flow defects. hAMSC: human amnion-derived mesenchymal stem cell; ^99mTc-MDP: ^99mTc-methylene diphosphonate; ^99mTc-MAA: ^99mTc-labelled macroaggregated albumin; CUA: calcific uremic arteriolopathy; ANT: anterior; RAO: right anterior oblique; RL: right lateral; RPO: right posterior oblique; POST: posterior; LPO: left posterior oblique; LL: left lateral; LAO: left anterior oblique.

Discussion

Patients 1 and 2 are ESKD patients on long-term hemodialysis, with elevated calcium-phosphorus product levels. Patients 1 and 3 had been receiving long-term oral corticosteroids and immunosuppressants following kidney transplantation. These factors have been reported as risk factors for CUA [11,13,44]. Skin lesions with intense pain principally affect proximal and truncal areas of the body. It has been reported that, in addition to areas of adipose-rich tissue such as the thighs, calciphylaxis also affects distal parts such as the fingers [45,46]. The lesions manifest as subcutaneous indurated plaques, and nodules with a pattern of livedo racemosa indicating a vascular event. Progression of the induration to the surface of the skin causes initial skin blisters followed by large ulcerations characterized by a thick black adherent eschar [5,47]. Skin histopathological criteria include microvascular media calcification, intimal hyperplasia, microthrombi, epidermal ulceration or extravascular soft tissue calcification [11]. Based on clinicopathologic correlation [11], these three patients were diagnosed with CUA. Treatment of calciphylaxis requires a multi-disciplinary approach involving nephrology, dermatology, plastic surgery, wound care, pain management, and palliative care. STS is currently the most widely used first-line drug [12,48], with functions including antioxidation and promotion of vasodilation. Its effects on calcium chelation and induction of acidosis remain controversial. It has been reported that STS can improve calcified lesions in 70% of patients [49]. However, a meta-analysis of a retrospective cohort study showed that STS did not reduce mortality [50]. SNF472, named hexasodium fytate, a novel inhibitor of vascular calcification, is currently in Phase 3 clinical trials for the treatment of calciphylaxis. However, recent research suggests that the improvements in BWAT-CUA and VAS are comparable between SNF472 and placebo [51].

MPC is an asymptomatic condition at early stage, which may remain undiagnosed and untreated, progressing to mild shortness of breath and a nonproductive cough, eventually develop restrictive lung disease and acute respiratory failure [21]. Some of the ‘benign’ causes include CKD, excess administration of calcium and vitamin D and hyperparathyroidism, etc. Malignant etiologies include multiple myeloma, parathyroid carcinoma, leukemia and lymphoma, etc. [21]. The decrease of vital capacity, diffusion capacity, and hypoxemia are closely related to the degree of calcifications [16]. With above high-risk factors, CUA Patient 1 we reported has progressive MPC and ultimately resulted in life-threatening acute respiratory.

Liang Z et al. [19] reported a post-kidney transplantation patient whom was misdiagnosed as fungal infection and eventually proved MPC by lung biopsy. Lung calcification can affect the alveoli, alveolar capillaries, bronchi and pulmonary vessels [20]. However, lung biopsy is rarely clinically adopted because of increased bleeding risks. There are three features on CT imaging: (1) multiple diffuse calcified nodules, (2) diffuse or patchy areas of ground-glass opacification, and (3) confluent high-attenuation parenchymal consolidation with lobar distribution [20]. The relative stability of pulmonary consolidations revealed by ^99mTc-MDP bone scintillation imaging with no reaction to the antibiotics was helpful to differentiate MPC from infectious pneumonia [16].

Pulmonary calciphylaxis is a rare vascular calcification disease characterized by intimal calcification of the pulmonary small arteries, which leads to thrombosis, ischemia, and tissue necrosis [52,53]. Accurate differential diagnosis relies on histology and imaging. In a case of calciphylaxis, the high radiotracer uptake on a bone scan may reflect MPC rather than pulmonary calciphylaxis, particularly in the absence of calcium deposition in the walls of the pulmonary small arteries [29]. A case of pulmonary calciphylaxis combined with MPC, indicating that calciphylaxis is associated with medial and intimal calcification of small and medium-sized arteries, leading to ischemic necrosis of the involved tissues. In contrast, metastatic calcification manifests as tissue calcification without ischemic or necrotic changes [54]. As a rare disease condition, we have summarized nine case reports of calciphylaxis with MPC that met the criteria (Table 1), including cases with ESKD and normal kidney function [55,58,60]. Skin and lung tissue pathology are crucial for diagnosis, while chest radiographs, CT scans, and ⁹⁹ᵐTc-MDP bone scans provide imaging references for diagnosis. Imaging results reveal a variety of calcification patterns, including diffuse calcified nodules, ground-glass opacities, consolidation, ring-shaped shadows, and increased radioactive uptake [5–58]. Lung biopsy may show fine, diffuse granular calcification deposits in the alveolar septa, small blood vessel walls, and bronchial walls, accompanied by inflammatory cell infiltration and fibrous tissue proliferation. The differences and connections between pulmonary calciphylaxis and MPC require further investigation.

Table 1.

A Case summary of calciphylaxis associated with metastatic pulmonary calcification.

Author (year)	Age/gender	Diagnosis	Skin Wound Condition	Dialysis modality	Risk factor	Pulmonary imaging and pathology.
[55]	60/Female	Pulmonary calciphylaxis and metastatic calcification.	Without skin manifestation.	Unknown.	Multiple myeloma, hypercalcemia, and corticosteroids.	Chest X-ray demonstrated increased interstitial and alveolar densities, along with parenchymal consolidations in both lungs. Histopathological examination of the lung tissue revealed fine, diffuse granular calcium deposits in the alveolar septa, as well as thin layers of calcification in the walls of small vessels and bronchi.
[56]	37/Male	Pulmonary metastatic calcification and cutaneous calciphylaxis.	Painful necrotic ulcer on the right lower leg.	Hemodialysis.	ESKD, severe secondary hyperparathyroidism, and warfarin.	CT scans of the chest reveal dense alveolar infiltrates predominantly in the upper lobes, and consistent with metastatic pulmonary calcification.
[57]	41/Female	Cutaneous calciphylaxis and pulmonary calcification.	A progressive, burning rash with a reticular, violaceous appearance and exquisite tenderness on both legs.	Hemodialysis.	ESKD, Crohn’s disease, severe vitamin D deficiency and hyperparathyroidism.	A high-resolution CT thorax revealed diffuse, ring-shaped opacities and small, solid nodules in the mid and lower zones, uniformly distributed around the bronchovascular tree, with no evidence of fibrosis.
[53]	40/Male	Cutaneous calciphylaxis and pulmonary calciphylaxis.	Multiple scattered, violaceous, ulcerative, cutaneous lesions on both limbs.	Hemodialysis.	Hypercalcemia.	High resolution chest CT revealed diffuse ground-glass attenuation and calcified consolidation in both lungs, along with diffuse thickening of bronchovascular bundles and pleural effusion. Histologically, near -complete destruction of the pulmonary architecture was evident, primarily due to calcification observed in the alveolar septa, bronchi, bronchioles, and blood vessels.
[58]	19/Female	Pulmonary calciphylaxis.	Palpable breast nodules with a history of lower limb ulcers, which have healed.	No renal impairment.	Severe malnourishment.	Three hours post-injection of ⁹⁹ᵐTc-MDP, the bone scan demonstrated diffuse and intense uptake in the thoracic region. Subsequent chest CT revealed extensive calcification in the breast and alveoli. Histopathological examination of the right lung showed widened alveolar septa, with multiple small foci of alkaline calcifications and reactive fibrous tissue hyperplasia in the alveolar epithelium. The left breast biopsy exhibited calcification, hyaline degeneration, and fibrous hyperplasia within the lesions.
[60]	4/Male	Cutaneous and visceral calciphylaxis.	Irritability, extremely painful, hard, purple subcutaneous nodules located at the level of the nasal pyramid, thorax, and abdomen.	Peritoneal dialysis.	ESKD and secondary hyperparathyroidism.	The chest radiograph revealed bilateral interstitial and alveolar infiltrates with peripheral disposition and a cotton-wool-like appearance. Histopathological examination demonstrated diffuse calcification in the lung tissue.
[59]	55/Male	Cutaneous calciphylaxis and metastatic pulmonary calcification.	A history of recurrent calciphylaxis in the subcutaneous tissue.	Hemodialysis.	ESKD, secondary hyperparathyroidism, hypercalcemia, and hyperphosphatemia.	CT imaging revealed fluffy, poorly defined nodules scattered throughout the right lung field, predominantly in the upper to middle lobes. Bone scintigraphy and gallium scintigraphy both demonstrated a focus of radiotracer uptake in the right middle and lower lung regions. HE staining of the biopsy specimen from the left B4a segment revealed thickening of the alveolar walls, interstitial spaces, and bronchial walls, accompanied by calcium deposition.
[29]	52/Female	Cutaneous calciphylaxis and metastatic pulmonary calcification.	Extensive painful purpura, and necrotic ulcers with black eschars on the lower limbs.	Hemodialysis.	ESKD, secondary hyperparathyroidism, and hyperphosphatemia.	The bone scan with ⁹⁹ᵐTc-MDP demonstrated diffuse abnormal radiotracer uptake in the lungs. High-density, snowflake-like lesions observed on the CT scan suggested the presence of pulmonary calcification. Lung biopsy confirmed calcium deposition in the alveolar walls.
[52]	49/Female	Cutaneous and pulmonary calciphylaxis.	Multiple ulcerative skin lesions on the lower limbs.	Hemodialysis.	ESKD, and warfarin.	Chest radiography revealed bilateral pulmonary infiltrates, predominantly micronodules, predominantly in the upper lung zones. Thoracic CT scan demonstrated tree-in-bud opacities in the upper lobes, accompanied by confluent alveolar opacities. Bronchial biopsies exhibited epithelial changes, calcification of elastic fibers, and calcium deposits in the capillary walls of the alveolar septa, with moderate inflammatory cell infiltration.

ESKD: end-stage kidney disease; CT: computed tomography; HE: hematoxylin and eosin; ^99mTc-MDP: ^99mTc-methylene diphosphonate

To our knowledge, this is the first report of calciphylaxis or MPC patients undergoing ^99mTc-MAA pulmonary perfusion imaging, which demonstrated impaired blood perfusion in the calcified areas of bilateral lungs. Patient 1 displayed upper and middle lobe-predominant calcified nodules in bilateral lungs, probably due to the high ventilation/perfusion (V/Q) ratio in this region which created low carbon dioxide and high oxygen levels. This could result in a higher pH environment in the upper lungs compared to the base and provide an alkaline environment conducive to calcium deposition [19].

The optimal therapy for MPC remains unknown. Current treatment focused on correcting the underlying etiology, adjusted the calcium-phosphate product including the use of bisphosphonates and phosphate binders, and increased frequency of dialysis [5,20]. Kidney transplantation may be considered for eligible patients. Some authors have reported reduction in calcification, but there are also reports of dramatic worsening after kidney transplantation [20].

MSCs are proved to effectively enhance the repairment of cutaneous wound through differentiation and angiogenesis [25]. hAMSCs can promote angiogenesis and wound epithelialization by secreting high levels of cytokines, extracellular vesicles (exosomes, EVs) and chemokines, and thus promote the regeneration of damaged tissues [27]. Both in vivo and in vitro studies have demonstrated the contribution of MSCs in inhibiting vascular calcification. Yokote et al. found that adipose-derived MSCs mitigate renal injury and slow vascular calcification in a rat model of CKD [61]. Bone marrow MSC-derived exosomes inhibit high phosphate-induced aortic calcification and improve renal function via the SIRT6-HMGB1 deacetylation pathway [62]. Conditioned media from MSCs suppress vascular smooth muscle cell (VSMC) calcification by secreting cytokines that reduce inflammation and apoptosis [63]. Given their roles in wound healing, inhibition of vascular calcification, immune regulation, and suppression of hypercoagulability, MSC therapy is a potential treatment for calciphylaxis [64]. Currently, there are no direct clinical studies on using MSCs to treat vascular calcification.

In an acute myeloid leukemia mouse model, the vitamin D receptor (VDR) agonist calcitriol effectively enhanced the pro-differentiation capacity of MSCs, thereby reducing the malignant burden [65]. VDR agonist-assisted therapy can enhance the immunosuppressive properties of MSCs in the context of pathogenic Th17-type immune responses and associated inflammatory reactions [66]. Coppin et al. found that the combination of MSCs and anticoagulants is safe and limits thrombosis associated with MSC infusion to subclinical symptoms [67]. MSCs possess potent immunomodulatory capabilities, their combined application with immunosuppressive agents can exert synergistic effects in diseases such as autoimmune diseases and graft-versus-host disease (GVHD) [68–70]. The use of immunosuppressive agents can enhance the immune response in the brain parenchyma of mice following MSC transplantation, thereby prolonging the persistence of transplanted MSCs [69]. In the context of calciphylaxis, the potential interactions between hAMSCs and VDR, anticoagulants, and immunosuppressive agents warrant further investigation.

Hemodialysis access-induced distal ischemia (HAIDI), earlier referred to as steal syndrome, is a severe complication of hemodialysis vascular access [71,72]. Hand ischemia manifested with pain, paresthesia or gangrene is reported in 1–2% of radio-cephalic arteriovenous fistula (AVF) and 5-10% of brachial artery fistulae [73]. Patient 1 is diagnosed with stage 4 HAIDI which featured by ulcers, necrosis and gangrene pain [74]. In HAIDI with low or normal fistula blood flow, arterial stenosis and distal arteriopathy resulting from generalized vascular calcification and diabetes may be the culprit [75,76]. Our original intervention strategy is to restore his blood flow to the palm arch via right radial or/and ulnar artery to reestablish digital perfusion. However, diagnostic angiography revealed diffuse calcification in the wrist of failed fistula, radial, interosseous, ulnar artery, and palm arch. Further digital subtraction angiography demonstrated occlusions in the distal radial artery, above factors limited the opening surgical procedure for improper landing zone or inadequate distal run-off. Percutaneous transluminal angioplasty is a minimally invasive procedure that may be effective and long-lasting, but data regarding below-the-elbow arteries are scarce [76]. Despite our attempts with guidewire and support catheter combination, antegrade negotiation of the balloon catheter crossing his involved arteries lesions failed. We consider that the aggravation of dry gangrene in the patient’s fingers is attributable to HAIDI, resulting from fistula calcification and occlusion, in conjunction with calciphylaxis. Despite the application of stem cell therapy, reversing the localized lesions remains a challenging endeavor.

During the treatment period, the skin wounds of the three CUA patients showed improvement, with decreased pain symptoms and enhanced QoL. For patients with calciphylaxis, while focusing on skin lesions, it is also necessary to be vigilant for the possibility of MPC. Since MPC can be asymptomatic in its early stages, attention should be paid to relevant examinations, such as HRCT and 99ᵐTc-MDP bone scans. Currently, there is no report on stem-cell therapies for MPC. hAMSC treatment is not effective for the lung lesions of the three patients, which may be related to the insufficient dose and course of treatment. For patients with MPC, under the premise of ensuring safety, whether increasing the frequency of hAMSC treatment can improve treatment effectiveness requires further exploration and verification through multicenter, long-term follow-up studies. Exploring disease models of calciphylaxis with skin lesions and MPC will provide a novel platform for in-depth research into the mechanisms of this rare disease and the development of cell therapy strategies.

Despite the promising aspect of this study, there are some limitations. First, the COVID-19 pandemic has, to a certain extent, affected established treatment protocols. The rarity, aggressiveness, and rapid progression of calciphylaxis, especially when combined with MPC, necessitate further analysis of their pathogenesis and interrelationships. Individualized treatment plans, the potential for more frequent and intensive hAMSC interventions in severe cases, and exploration of new treatment methods or engineered stem cells warrant further study. Second, this study is a descriptive exploratory study owing to the limited sample size. Given the potential impact of variations in disease severity, diversity of treatment protocols, and the small sample size on the comparability of quantitative data, we concentrated on assessing symptomatic improvements in patients. Third, in our pilot study, inconsistent timeline results occurred because three patients with CUA combined with MPC, all from other regions, were unable to undergo regular treatment and follow-up as scheduled. Forth, MPC, which was prior to the skin lesions of calciphylaxis should be diagnosed timely. Fifth, neither of these CUA patients had undergone a pulmonary tissue biopsy, although clinical feasibility is challenging due to ethical and safety concerns. Sixth, the gangrene in the fingers of the Patient 1 was not confirmed histologically, which inherently limited clinical-radiological-pathological correlation.

Conclusion

We report on three cases of calciphylaxis treated with hAMSCs, accompanied by MPC, an extremely rare occurrence. MPC is asymptomatic in the early stages and can progress to life-threatening respiratory failure. HRCT and ⁹⁹ᵐTc-MDP are valuable for the diagnosis and treatment evaluation of MCP. The initial use of ⁹⁹ᵐTc-MAA pulmonary perfusion imaging to analyze the relationship between metastatic calcification and blood flow in MPC patients is conducted. We propose hAMSC strategies tailored individually are promising regenerative treatment for calciphylaxis skin lesions [77]. However, the relationship between MCP and pulmonary calciphylaxis warrants further clarification. The effects of hAMSCs on MPC necessitate further investigation.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Funding Statement

This study was funded by the National Natural Science Foundation of China (81270408, 81570666, 81730041, and 81671447), the International Society of Nephrology (ISN) Clinical Research Program (18-01-0247), Jiangsu Province Key Medical Personnel Project (ZDRCA2016002), CKD Anemia Research Foundation from China International Medical Foundation (Z-2017-24-2037), Outstanding Young and Middle-Aged Talents Support Program of the First Affiliated Hospital with Nanjing Medical University, the National Key Research and Development Program of China (2017YFC1001303), the Program of Jiangsu Province Clinical Medical Center (YXZXB2016001, BL2012009), the State Key Laboratory of Reproductive Medicine Program (SKLRM-GC201803), Jiangsu Province Hospital Clinical Capacity Enhancement Project (JSPH-MA-2023-7), Specialized Diseases Clinical Research Fund of Jiangsu Province Hospital (XB202403), Key Projects of Medical Scientific Research Funded by the Health Commission of Jiangsu Province (K2024005), and the Program of Jiangsu Provincial Medical Key Discipline(Laboratory) Cultivation Unit (JSDW202206).

Authors’ contributions

Project conceived and directed, hAMSC clinical treatment design, and research funding support by Ningning Wang, Lianju Qin and Jiayin Liu. Research ethical issues and administrative guidance by Xiuqin Wang and Ningxia Liang. hAMSC research platform management, quality control and preparation of hAMSCs for clinical use by Jiayin Liu, Lianju Qin, Chunyan Jiang, Yugui Cui, Xiang Ma, Song Ning. Clinical management for the patient by Ningning Wang, Lianju Qin, Ming Zeng, Jingjing Wu, Chun Ouyang, Yanggang Yuan, Hongqing Cui, and Changying Xing. Patient referrals and teleconsultations were conducted by Ling Zhang. The clinical analysis of skin lesions was performed by Yan Lu and Zhonglan Su. Data acquisition and analysis by Shijiu Lu, Fan Li, Ming Zeng, Chun Ouyang, Jiaying Hu, Cui Li, Ningning Wang, Xiaoxue Ye and Anning Bian. Radiological imaging analysis by Wei Liu and Yi Xu. Xiaolin Lv, Ling Wang and Jiahui Yang were responsible for the patient’s care. The data was analyzed and interpreted by Ningning Wang, Ming Zeng, Shijiu Lu, Fan Li, Chun Ouyang, Jingjing Wu, Jiaying Hu, Lianju Qin, Jiayin Liu. Additionally, they participated in the writing and submission of the manuscript. Ningning Wang, Lianju Qin, and Jiayin Liu should take responsibility for the integrity of the work as a whole from inception to published article.

Disclosure statement

The authors declare that they have no other competing interests. Parts of our manuscript were communicated in a poster session at the World Congress of Nephrology (WCN) 2023 [78].

Data availability statement

The data underlying this article will be shared on reasonable request to the corresponding author.