Management and mechanism of calciphylaxis in a patient treated with the FGFR inhibitor pemigatinib-a case report.

Background: Small molecule fibroblast growth factor receptor (FGFR) inhibitors, such as pemigatinib, have been developed for the treatment of cholangiocarcinoma (CCA) with rearrangements or fusions in the FGFR2. FGFR inhibitors (FGFRis) have dermatologic side effects such as dry skin or nail bed damage. However, in very rare instances, a life-threatening vascular calcification disease known as calciphylaxis has been linked to these therapies. Case Description: We report a patient with metastatic CCA, who developed calciphylaxis following the start of their pemigatinib treatment. Calciphylaxis is associated with skin lesions and affects the dermal microvasculature in addition to the vascular calcification. This case focuses on the management strategy used for this rare adverse event (AE) as well as the pathology and complicated mechanism of calciphylaxis. We highlight the unclear pathophysiology behind this disease by identifying key players in the signaling and molecular pathways in the microenvironment that are needed to trigger this pathology. Conclusions: Calciphylaxis is normally associated with advanced renal failure in the setting of high phosphate and calcium. However, the patient we present here did not have advanced renal failure or high calcium levels and calcium dysregulation. As FGFRi use becomes more widespread, the more important it becomes to identify and have a treatment strategy for this rare AE.

Human and murine kidneys show gender- and species-specific gene expression differences in response to injury.

The incidence of End Stage Renal Disease (ESRD) is approximately 50% higher in men than women. In order to understand the molecular basis of this gender disparity, we examined sex specific gene expression patterns in control and diseased, human and murine kidney samples. Using the Affymetrix platform we performed comprehensive gene expression analysis on 42 microdissected human kidney samples (glomeruli and tubules). We identified 67 genes with gender biased expression in healthy human kidneys and 24 transcripts in diseased male and female human kidneys. Similar analysis performed in mice using male and female control and doxorubicin induced nephrotic syndrome kidneys identified significantly larger number of differentially expressed transcripts. The majority of genes showing gender biased expression either in diseased human and murine kidneys were different from those differentially expressed in healthy kidneys. Only 9 sexually dimorphic transcripts were common to healthy human and murine kidneys and five showed differential regulation in both human and murine diseased kidneys. In humans, sex biased genes showed statistical enrichment only to sex chromosomes while in mice they were enriched to sex chromosomes and various autosomes. Thus we present a comprehensive analysis of gender biased genes in the kidney. We show that sexually dimorphic genes in the kidney show species specific regulation. Our results also indicate that male and female kidneys respond differently to injury. These studies could provide the basis for the development of new treatment strategies for men and women with kidney disease.