Nonuremiccalciphylaxis-A Systematic Review

Background: Calciphylaxis, also known as calcific uremic arteriolopathy, is a welldescribed condition in renal transplant and end-stage kidney disease (ESKD) patients; however, little is known about calciphylaxis induced by nonuremic causes. This systematic study aimed to determine the causes, prognosis of nonuremic calciphylaxis, clinical features and laboratory abnormalities. Systematic Article Albalawi et al.; JPRI, 33(39B): 158-170, 2021; Article no.JPRI.72237 159 Patients and methods:A comprehensive review of the literature for nonuremic calciphylaxis case reports and case series published between 2016 and 2021 was performed. Cases included satisfied the criteria for a histological diagnosis of nonuremic calciphylaxis in the absence of ESKD, renal transplantation, or acute kidney injury requiring renal replacement therapy. Results: The authors identified 53 cases of nonuremic calciphylaxis (83.14 % women, Caucasian 13.33 %, aged 25 to 83 years). The most prevalent documented associations were of patients having multiple conditions 18 (33.33 %), warfarin-induced (7.4 %), calcium and Vitamin D supplementation (3.7 %), primary hyperparathyroidism (3.7 %), liver disease (3.7 %), Acenocumarol use (3.7 %), Systematic lupus erythematosus (3.7 %), alcoholic cirrhosis (3.7 %), respectively. Conclusion:When investigating skin lesions in patients with sensitive conditions, calciphylaxis must often be addressed in the absence of ESKD or renal transplantation. Obese women with various underlying illnesses such as alcohol intake, smoking, diabetes, liver disease, and so on are more likely to develop nonuremic calciphylaxis (NUC).Calciphylaxis is linked with high mortality; however, sodium thiosulfate (ST) has made clear progress in terms of treatment, yet there are still areas that need to be addressed to describe the effectiveness of ST.


INTRODUCTION
Calciphylaxis, also known as calcific uremic arteriopathy (CUA), is a disease that has a 60-80% one-year mortality rate [1,2]. It's more common in those with end-stage renal illness (ESRD). Calciphylaxis is a condition that causes painful skin lesions that eventually turn into ulcers [3][4][5][6][7][8]. The calcification of small and medium-sized dermal and subcutaneous veins, intimal hyperplasia, and thrombosis distinguishes this rare disease histologically. The prevalence of calciphylaxis in ESRD patients is increasing [1]. There are now registries and clinical studies underway to investigate the etiology of calciphylaxis in ESRD patients and to discover new treatments. The cause of the increase in occurrence is unknown. Patients with ESRD, a challenging group, are the ones who are most impacted by this disease. Calciphylaxis affects 35 out of every 10,000 hemodialysis patients in the United States, 4 out of 10,000 in Germany, and less than 1 out of 10,000 in Japan [2]. Given the high morbidity and death rates associated with calciphylaxis, as well as the lack of FDA-approved treatments, identifying and removing the risk factors associated with the disease is critical.
While abnormal bone and mineral metabolism, hyperparathyroidism, and vitamin D supplementation are commonly suspected as causes of CUA, the disease procedures are seldom acknowledged; as a result, therapeutic attempts remain untested, and mortality continues to grow [3]. Despite this, nonuremic calciphylaxis (NUC) can occur in people who have normal kidney function; the risk factors, etiology, consequences, and therapies for NUC remain unknown. [4]. The causes, clinical characteristics, laboratory abnormalities, and prognosis of calciphylaxis from NUC were all investigated thoroughly. A thorough examination of the clinical features of NUC might aid our understanding of CUA.

Research Questions
The research questions posed in this systematic review concern:  What are the conditions associated with nonuremic causes of calciphylaxis?  What are the clinical features, laboratory abnormalities and prognosis of calciphylaxis from NUC?  What are the treatment options for NUC patients?
To answer these above questions, the following procedure/methodology was followed in the research.The study was conducted using the standard reporting requirements for systematic reviews and meta-analyses (PRISMA). Methodology for doing a literature search: PubMed, Embase, Ovid, Google Scholar, and Science Direct were used to perform a thorough review of the literature. The search was conducted between June 2 and June 10, 2021. The keywords used for retrieval of articles were "calciphylaxis," "nonuremic calciphylaxis," cause and aetiology." To enhance the quality of search, the keywords were combined with "laboratory abnormalities, treatment options, and clinical features of calciphylaxis".The titles and abstracts of the produced results were used to filter the findings. Articles that were duplicated were deleted.

Inclusion and Exclusion Criteria
Studies depicting any association of a risk factor with the development of NUC were included in the review. Case studies and case series were the types of articles that were included. Cases that met the objective measure of NUChistopathologic finding of calciphylaxis in the nonappearance of (ESKD), severe chronic kidney illness delineated as serum creatinine 3 mg/dl or creatinine clearance 15 ml/min, acute kidney injury permitting renal substitution therapy, and renal transplantation-were all included. There were no language prerequisites.

Data Extraction
The papers were chosen separately by different investigators based on the aforementioned inclusion and exclusion criteria. If the number of articles chosen by the investigators differed, an agreement was established after discussion. Next, both investigators separately studied the complete contents of the publications and extracted the pertinent data into excel sheets. Finally, a third investigator evaluated the findings. The following data linked to the studies were obtained; authors, race, histopathologic findings, lesion location, treatment strategy, death or alive, and reasons (if available).

DISCUSSION
Calciphylaxis was initially characterized as a systemic hypersensitivity response by Selye et al. [58] in 1961. They used animal studies to cause calcification in a variety of areas after exposing the animals to a variety of reactive chemicals known as "calcifiers" (e.g., vitamin D2, vitamin D3, dihydrotachysterol, parathyroid hormone), followed by exposure to a "challenger" (e.g., metallic salts such as egg albumin, aluminum, iron, and trauma). Calciphylaxis, on the other hand, was originally reported in humans some years ago by Selye et al. as a condition characterised by small mural calcification, uremic kidney thrombosis ischemia, extravascular calcification, skin and soft tissue necrosis, and a high mortality rate. [4].
In this systematic review, we reported 53 reported cases of NUC during the last five years. Thus, reporting of NUC has increased significantly, implying an increasing frequency of the syndrome; conversely, increased knowledge that the illness might arise beyond the ESKD and in renal transplant patients, on the other hand, may have resulted in a more significant number of cases getting detected and finally discussed in the literature. As a consequence, while some have speculated that the rise in CUA is due to more rigorous mineral metabolism management and secondary hyperparathyroidism among dialysis patients, the growth in CUA appears to be in lockstep with the rise in NUC.It might be because of greater understanding and relatively early skin surgery.
Secondary hypercalcemia, hyperparathyroidism, hyperphosphatemia, calcium-based phosphate binders, and vitamin D supplements, among other uremia-related metabolic diseases and medicines, are thought to worsen CUA risks. [59]. That idea appears to be supported by the histopathologic picture, which revealed substantial soft tissue calcification. As a consequence, it's worth mentioning that the majority of study participants had normal calcium, phosphate, and parathyroid hormone levels, while just five were vitamin D deficient. Because calcium and phosphorous "intake" during the precipitation method may represent part of the normal or low blood levels of these minerals. Anomalies in bone and mineral metabolism, as well as associated therapies, may have a role in calciphylaxis in certain individuals; the pathogenesis is likely far more complex than we now comprehend. It might reflect a similar histopathologic characteristic of tissue damage in retort to several diverse stimuli. Inadequacies in vascular calcification antagonists e.g., fetuin-A and matrix Gla protein [60][61][62] are now thought to have a role in CUA, adding to our approach to the analysis of vascular calcification. Because this system is implicated in the etiology of CUA, irrationalities of receptor activator of NF-K B (RANK), RANK ligand, and osteoprotegerin could be implicated [63]. Many of the factors associated for NUC (corticosteroid, liver disease, parathyroid hormone) have been shown to enhance the synthesis of RANK ligand while decreasing the manifestation of osteoprotegerin, activating NF-K B or damaging the regulatory protein of NF-K B (or a blend of these) [64].
As with every systematic review, there is a lack of comprehensive information, potential selection, publishing biases, and a controlled method to reporting in this one. Though NUC has become more widely recognized in recent years, a lack of understanding of the disease, as evidenced by patients' lack of awareness of the disease, may have resulted in under-recognition and, [60][61][62][63][64][65][66][67][68] as a result, confidential reporting of the disease, limiting the representativeness of this systematic review. In addition, we did not disclose attempting to contact the authors of original reports to collect missing data (e.g., time to death, laboratory parameters, histopathologic confirmation, or bone scans), which may lead to some of the stated words being "associated" with the NUC. While our method may have overlooked some real NUC instances, many more are likely to have gone unreported, a shortcoming that continues to hinder efforts to precisely estimate the syndrome's prevalence and thoroughly evaluate its health consequences.

CONCLUSION
NUC is a rare disorder that is becoming more prevalent. The four Ws (woman, white race, overweight, and warfarin) are the most common ethnic and concomitant features in NNC. The majority of cases in our review were caused by warfarin usage, calcium and vitamin D supplements, Acenocoumarol, and alcoholic cirrhosis, emphasising the importance of maintaining a consistent ratio of concern while assessing skin abnormalities in NUC patients. While sodium thiosulfate is the therapy of choice among nephrologists, there is still more work to be done to effectively treat NUC.

CONSENT
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ETHICAL APPROVAL
It is not applicable.