Increased Risk of Kidney Injury and Early Death from Activating Mutations in the Calcium-Sensing Receptor: A Regional Case Series

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Introduction: Calcium-sensing receptors (CASR), primarily expressed in the parathyroid glands and kidney tubules, play a key role in calcium homeostasis. Heterozygous activating, or gain-of-function, mutation of the CASR gene causes autosomal dominant hypocalcemia type 1 (ADH1) resulting in severe hypocalcemia associated with inappropriately normal to low parathyroid hormone, hyperphosphatemia, and hypercalciuria. We present 8 patient cases from North East England with this rare condition. Case Description: Table 1 describes the clinical characteristics including the genetic mutation, biochemistry, and complications in 8 patients with ADH1. All patients were identified to have hypocalcemia at birth or childhood before a formal diagnosis of ADH1 was considered, at which point caution was taken to avoid overcorrection of serum calcium through reduction or complete avoidance of calcium and vitamin D supplementation. However, despite this, 7 out of 8 patients suffered from nephrocalcinosis and/or nephrolithiasis, increasing the risk of recurrent urinary tract infections and renal impairment. 2 out of 8 patients developed kidney failure and suffered from premature death. Other complications such as short stature, dental issues, hypertension, and/or brain calcifications were also noted across all 8 patients. Discussion: Ectopic calcification, particularly in the kidneys, is a known complication of ADH1. Close monitoring and acceptance of a low serum calcium levels is thought to reduce hypercalciuria and prevent rapid onset of nephrocalcinosis and subsequent renal impairment. However, this case series demonstrates that renal complications in ADH1 is inevitable, despite maintaining ‘optimal’ serum calcium levels for these patients. Therefore, the use of a novel therapeutic agent, such as a CASR antagonist, may prove to be helpful, and is something we will soon look to offer to these patients as part of a clinical trial.

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