New insights into the mechanism of abnormal calcification in nephrogenic systemic fibrosis - gadolinium promotes calcium deposition of mesenchymal stem cells and dermal fibroblasts

Background

Recent studies have suggested that there is a close association between the administration of gadolinium (Gd)-based contrast agents and the development of nephrogenic systemic fibrosis (NSF), an acquired disorder characterized by systemic fibrosis and abnormal calcification in patients with severe renal dysfunction. However, the causative roles of Gd remain unknown.

Objective

The aim of this in vitro study was to investigate the effect of Gd on the development of fibrosis and calcification in cultured cells.

Methods

MC3T3-E1 cells (pre-osteoblastic cells), human adipose tissue-derived mesenchymal stem cells (HAMSCs), human subcutaneous preadipocytes, and human dermal fibroblasts (HDFs) were each cultured in differentiation medium with or without gadolinium chloride. Calcium deposition of MC3T3-E1 cells, HAMSCs, and HDFs was determined by alzarin red S staining. Adipogenic differentiation of human subcutaneous preadipocytes and HAMSCs was determined by oil red O staining. Fibrogenesis of HDFs was determined by real-time PCR to measure the mRNA expression of type I collagen. Cell proliferation was determined by MTS assay.

Results

Gd induced calcium deposition in MC3T3-E1 cells, HAMSCs and HDFs in osteogenic differentiation media. Gd did not induce adipogenic differentiation in human subcutaneous preadipocytes and HAMSCs. Gd did not increase the mRNA expression of type I collagen in HDFs, but did promote cell proliferation.

Conclusions

We have demonstrated a direct effect of Gd on calcium deposition in cultured cells. The result will help us to understand the mechanism of abnormal calcification in NSF.     

Sclerotic bodies in nephrogenic systemic fibrosis: a new histopathologic finding

Nephrogenic systemic fibrosis (NSF – known previously as nephrogenic fibrosing dermopathy) is a systemic disorder observed exclusively in patients with a history of kidney disease associated with renal failure. Reported histopathologic findings of NSF include spindle-shaped fibroblast-like cells with fibrosis, thickened collagen bundles with surrounding spindled and epithelioid cells, increased number of elastic fibers, sparse inflammatory infiltrate and increased stromal mucin. Two populations of multinucleated giant cells (Factor XIIIa and CD68 positive) have also been observed. We observed the presence of sclerotic bodies with entrapped elastic fibers in two cases of NSF, which we interpreted to be collagenous in nature, a finding not previously reported. These bodies should not be confused with osseous metaplasia previously seen in association with NSF, which show lacunae and cells within the osseous bodies that may or may not be calcified. We did not observe lacunae or cells within the sclerotic bodies in our cases. Furthermore, the sclerotic bodies in our cases stained blue on Masson trichrome, whereas previous investigators observed the osseous metaplasia to be red. We suggest that sclerotic bodies may be an additional clue to the diagnosis of NSF.     

Cavernosal smooth muscle biopsy is a useful tool in the diagnosis of erectile dysfunction

Needle biopsy of the corpus cavernosum with the Biopty gun system has been performed in impotent patients for obtaining erectile tissue to identify the presence of intracavernous structures (smooth muscle cells, collagen, arteries, and nerves). This technique is cost effective, rapid, safe, relatively harmless, and effective. It can replace the open surgical method, but we have to determine its place in the assessment of impotent patients.     

The role of the hospital dermatologist in the diagnosis and treatment of calciphylaxis and nephrogenic systemic fibrosis

Calciphylaxis and nephrogenic systemic fibrosis are rapidly progressive diseases associated with renal impairment with high rates of mortality and morbidity. In this review, we highlight the role of the dermatologist in the multispecialty team approach to the diagnosis, treatment, and management of these patients. We present sample cases from our hospital practice to emphasize the importance of diagnosis, clinicopathologic correlation, rapid intervention, and treatment of these challenging skin disorders.     

Gadolinium-induced nephrogenic systemic fibrosis in a patient with an acute and transient kidney injury

Nephrogenic systemic fibrosis (NSF) describes a characteristic fibrosing disorder which typically presents with indurated plaques on the trunk and extremities of patients with advanced renal disease. We present a case of biopsy-confirmed NSF in a patient with severe acute kidney injury with no prior history of renal disease. A 64-year-old man with an acute and severe decrease in glomerular filtration rate underwent magnetic resonance imaging studies with gadolinium contrast (Omniscan) and subsequently developed NSF. His renal disease had normalized at the time his skin disease developed. Skin biopsies revealed findings of NSF and scanning electron microscopy with energy-dispersive X-ray spectroscopy confirmed insoluble gadolinium within lesional tissue.     

The clinical and histopathologic spectrum of "dermal hypersensitivity reactions," a nonspecific histologic diagnosis that is not very useful in clinical practice,and the concept of a "dermal hypersensitivity reaction pattern"

BACKGROUND: "Dermal hypersensitivity reaction" (DHR) is diagnosed by dermatopathologists but is not an accepted clinical disease entity. There are no clear guidelines for its diagnosis, differential diagnosis, or management. OBJECTIVES: The objectives were to define the histologic criteria for cases histologically diagnosed as DHR and identify corresponding clinical disorders. METHODS: Skin biopsy specimens from 130 patients diagnosed as "consistent with DHR" were reviewed. Additional information was obtained from patients, their dermatologists, and medical records. RESULTS: Follow-up in 74 of 110 patients (median, 26.6 mo) revealed, most commonly, diagnoses of urticaria, drug reactions, and spongiotic (eczematous) dermatitis. Among the remaining cases, 37 of 59 reported persistence of disease, some exhibiting a uniform phenotype characterized by excoriated, edematous papules on the trunk. Histopathologic features present in more than 90% of 143 biopsy specimens included superficial and mid-perivascular lymphocytic infiltrates with eosinophils. CONCLUSION: DHR is a perivascular lymphocytic dermatitis with eosinophils involving the papillary and upper reticular dermis and minimal, if any, primary epidermal alteration. The term DHR does not represent any known clinical disorder; rather, it corresponds to many clinical disorders. The use of the phrase "dermal hypersensitivity reaction pattern" may be helpful in conveying the idea that a particular histologic pattern may be seen in a number of clinical disorders.     

Role of endothelin‐1/endothelin receptor signaling in fibrosis and calcification in nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis (NSF) is characterized by systemic fibrosis and abnormal calcification in patients with severe renal dysfunction. It is considered that gadolinium (Gd)‐containing contrast agents used for magnetic resonance imaging trigger the development of NSF. However, the causative role of Gd and the mechanism of Gd‐induced fibrosis and calcification in NSF are unknown. Recently, it has been known that endothelin‐1 (ET‐1)/ET receptor (ETR) signalling regulates fibrosis and calcification. The objective was to elucidate the role of ET‐1/ETR signalling in Gd‐induced fibrosis and calcification in NSF. First, we demonstrated that Gd enhanced proliferation and calcification of human adipose tissue‐derived mesenchymal stem cells (hMSC) in vitro. Next, we examined the expression of ET‐1 and ETR‐A in hMSC using proliferation or calcification assay. ET‐1 and ETR‐A expression in hMSC treated with Gd were elevated. ET‐1/ETR signalling inhibitor, bosentan, inhibited Gd‐induced proliferation and calcification of hMSC. In addition, bosentan inhibited Gd‐induced phosphorylation of ERK and Akt in hMSC. Plasma ET‐1 levels of the patients were significantly higher than these of normal individuals and systemic sclerosis patients. In immunofluorescence staining, the expression of ETR‐A in fibroblasts in dermal fibrosis lesion of NSF was increased. We conclude that Gd induces proliferation and calcification of hMSC via enhancement of ET‐1/ETR signalling. Our results contribute to understand the pathogenesis of NSF.     

Findings of osseous sclerotic bodies: a unique sequence of cutaneous bone formation in nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis (NSF) is a progressive and potentially fatal fibrosing skin disorder found mainly in patients with renal insufficiency. NSF is characterized by thickened and hyperpigmented skin lesions with or without systemic involvement. In essentially all patients, this disease entity has been associated with the administration of gadolinium contrast agents for imaging purposes. Microscopic recognition of this entity remains challenging, as the diagnosis is based on various clinical and histopathologic features that overlap with other fibrosing disorders. No single feature is absolutely specific for NSF. We report a finding of osseous sclerotic bodies with elastin trapping appearing on histopathology in the clinical setting of NSF with hemodialysis‐dependent renal failure. Our report of an additional attribute indicative of NSF may aid in making the diagnosis. Kartono F, Basile A, Roshdieh B, Schwimer C, Shitabata PK. Findings of osseous sclerotic bodies: a unique sequence of cutaneous bone formation in nephrogenic systemic fibrosis.