Systemic sclerosis complicated with renal thrombotic microangiopathy: a case report and literature review

Background Systemic sclerosis (SSc) may overlap with other connective tissue diseases, which is named overlap syndrome. Scleroderma renal crisis (SRC) is a rare but severe complication of SSc. SSc related thrombotic microangiopathy (SSc-TMA) is an infrequent pathology type of SRC, while SSc-TMA accompanied by overlap syndrome is very rare. Case presentation This study reported a case of acute kidney injury (AKI) accompanied with overlap syndrome of SSc, systemic lupus erythematosus (SLE) and polymyositis (PM). The renal pathology supported the diagnosis of SSc-TMA but not SLE or PM-related renal injury, characterized by renal arteriolar thrombosis, endothelial cells edema, little cast in tubules and mild immune complex deposition. The primary TMA related factors (ADAMTS13 and complement H factor) were normal. Thus, this case was diagnosed as secondary TMA associated with SSc. The patient was treated with renin angiotensin system inhibitors, sildenafil, supportive plasma exchange/dialysis, and rituximab combined with glucocorticoids. After 2 months of peritoneal dialysis treatment, her renal function recovered and dialysis was stopped. Conclusion This study presented a case of SSc-TMA with overlap syndrome. Rituximab can be used as a treatment option in patients with high SRC risk or already manifesting SRC.

Autoantibodies Targeting AT1- and ETA-Receptors Link Endothelial Proliferation and Coagulation via Ets-1 Transcription Factor

Scleroderma renal crisis (SRC) is an acute life-threatening manifestation of systemic sclerosis (SSc) caused by obliterative vasculopathy and thrombotic microangiopathy. Evidence suggests a pathogenic role of immunoglobulin G (IgG) targeting G-protein coupled receptors (GPCR). We therefore dissected SRC-associated vascular obliteration and investigated the specific effects of patient-derived IgG directed against angiotensin II type 1 (AT1R) and endothelin-1 type A receptors (ETAR) on downstream signaling events and endothelial cell proliferation. SRC-IgG triggered endothelial cell proliferation via activation of the mitogen-activated protein kinase (MAPK) pathway and subsequent activation of the E26 transformation-specific-1 transcription factor (Ets-1). Either AT1R or ETAR receptor inhibitors/shRNA abrogated endothelial proliferation, confirming receptor activation and Ets-1 signaling involvement. Binding of Ets-1 to the tissue factor (TF) promoter exclusively induced TF. In addition, TF inhibition prevented endothelial cell proliferation. Thus, our data revealed a thus far unknown link between SRC-IgG-induced intracellular signaling, endothelial cell proliferation and active coagulation in the context of obliterative vasculopathy and SRC. Patients’ autoantibodies and their molecular effectors represent new therapeutic targets to address severe vascular complications in SSc.

Management of Endothelial Dysfunction in Systemic Sclerosis: Current and Developing Strategies

Systemic Sclerosis (SSc) is an autoimmune disease marked by dysregulation of the immune system, tissue fibrosis and dysfunction of the vasculature. Vascular damage, remodeling and inadequate endothelial repair are hallmarks of the disease. Since early stages of SSc, damage and apoptosis of endothelial cells (ECs) can lead to perivascular inflammation, oxidative stress and tissue hypoxia, resulting in multiple clinical manifestations. Raynaud's phenomenon, edematous puffy hands, digital ulcers, pulmonary artery hypertension, erectile dysfunction, scleroderma renal crisis and heart involvement severely affect quality of life and survival. Understanding pathogenic aspects and biomarkers that reflect endothelial damage in SSc is essential to guide therapeutic interventions. Treatment approaches described for SSc-associated vasculopathy include pharmacological options to improve blood flow and tissue perfusion and, more recently, cellular therapy to enhance endothelial repair, promote angiogenesis and heal injuries. This mini-review examines the current knowledge on cellular and molecular aspects of SSc vasculopathy, as well as established and developing therapeutic approaches for improving the vascular compartment.

Scleroderma renal crisis in a patient with paraneoplastic systemic sclerosis

The incidence of malignancy is increased in systemic sclerosis (SS). Nevertheless, only a few cases of paraneoplastic SS (pSS) have been described. Scleroderma renal crisis is an uncommon but severe complication of SS, with acute kidney failure, abrupt onset of hypertension and microangiopathy. We present the case of a previously healthy patient who was diagnosed with ovarian carcinoma and underwent chemotherapy with carboplatin and paclitaxel. In association with the cancer, she developed SS and scleroderma renal crisis. She received initial supportive treatment, but her renal function worsened, and she started on hemodialysis. Furthermore, she received adjuvant surgical treatment for the cancer. Eighty-four days after cytoreductive surgery, her renal function recovered, and her SS manifestations improved.

Autoantibodies from Patients with Scleroderma Renal Crisis Promote PAR-1 Receptor Activation and IL-6 Production in Endothelial Cells

Background. Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc). Autoantibodies (Abs) against endothelial cell antigens have been implicated in SSc and SRC. However, their detailed roles remain poorly defined. Pro-inflammatory cytokine interleukin-6 (IL-6) has been found to be increased in SSc, but its role in SRC is unclear. Here, we aimed to determine how the autoantibodies from patients with SSc and SRC affect IL-6 secretion by micro-vascular endothelial cells (HMECs). Methods. Serum IgG fractions were isolated from either SSc patients with SRC (n = 4) or healthy individuals (n = 4) and then each experiment with HMECs was performed with SSc-IgG from a separate patient or separate healthy control. IL-6 expression and release by HMECs was assessed by quantitative reverse transcription and quantitative PCR (RT-qPCR) and immunoassays, respectively. The mechanisms underlying the production of IL-6 were analyzed by transient HMEC transfections with IL-6 promoter constructs, electrophoretic mobility shift assays, Western blots and flow cytometry. Results. Exposure of HMECs to IgG from SSc patients, but not from healthy controls, resulted in a time- and dose-dependent increase in IL-6 secretion, which was associated with increased AKT, p70S6K, and ERK1/2 signalling, as well as increased c-FOS/AP-1 transcriptional activity. All these effects could be reduced by the blockade of the endothelial PAR-1 receptor and/or c-FOS/AP-1silencing. Conclusions. Autoantibodies against PAR-1 found in patients with SSc and SRC induce IL-6 production by endothelial cells through signalling pathways controlled by the AP-1 transcription factor. These observations offer a greater understanding of adverse endothelial cell responses to autoantibodies present in patients with SRC.

New-Onset and Relapsed Kidney Histopathology Following COVID-19 Vaccination: A Systematic Review

Introduction: The introduction of COVID-19 vaccination programs has become an integral part of the major strategy to reduce COVID-19 numbers worldwide. New-onset and relapsed kidney histopathology have been reported following COVID-19 vaccination, sparking debate on whether there are causal associations. How these vaccines achieve an immune response to COVID-19 and the mechanism that this triggers kidney pathology remains unestablished. We describe the results of a systematic review for new-onset and relapsed kidney histopathology following COVID-19 vaccination. Methods: A systematic literature search of published data up until 31 August 2021 was completed through the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guideline. Research articles reporting new onset or relapsed kidney histopathology in adult patients (>18 years) following COVID-19 vaccination were included for qualitative review. Only full-text articles published in the English language were selected for review. Results: Forty-eight cases from thirty-six articles were included in the qualitative synthesis of this systematic review. Minimal change disease (19 cases) was the most frequent pathology observed, followed by IgA nephropathy (14 cases) and vasculitis (10 cases). Other cases include relapse of membranous nephropathy, acute rejection of kidney transplant, relapse of IgG4 nephritis, new-onset renal thrombotic microangiopathy, and scleroderma renal crisis following COVID-19 vaccination. There was no mortality reported in any of the included cases. Patients in all but one case largely recovered and did not require long-term renal replacement therapy. Conclusion: This systematic review provides insight into the relationship between various kidney pathologies that may have followed COVID-19 vaccination. Despite these reported cases, the protective benefits offered by COVID-19 vaccination far outweigh its risks. It would be recommended to consider early biopsy to identify histopathology amongst patients presenting with symptoms relating to new-onset kidney disease following vaccination and to monitor symptoms for those with potential relapsed disease.

Overview of Scleroderma Renal Crisis - A Review

Scleroderma renal crisis is a life-threatening condition. It usually starts with a sudden onset of severe hypertension, followed by renal failure, hypertensive encephalopathy, congestive heart failure, and/or microangiopathic hemolytic anemia. Renal ischemia, hyperplasia of the juxtaglomerular apparatus, activation of the renin-angiotensin-aldosterone system (RAAS), and an increase in blood pressure are caused by decreased blood flow caused by structural changes in the blood vessels as well as renal vasospasm ("Raynaud's phenomenon"). This overview discusses the evaluation, diagnosis, and treatment of scleroderma renal crisis, emphasizing the importance of early detection of disease, strong correlation of corticosteroids intake and the disease incidence, and best approach of such cases.