Nephrocalcinosis: A Review of Monogenic Causes and Insights They Provide into This Heterogeneous Condition

Abstract

The abnormal deposition of calcium within renal parenchyma, termed nephrocalcinosis, frequently occurs as a result of impaired renal calcium handling. It is closely associated with renal stone formation (nephrolithiasis) as elevated urinary calcium levels (hypercalciuria) are a key common pathological feature underlying these clinical presentations. Although monogenic causes of nephrocalcinosis and nephrolithiasis are rare, they account for a significant disease burden with many patients developing chronic or end-stage renal disease. Identifying underlying genetic mutations in hereditary cases of nephrocalcinosis has provided valuable insights into renal tubulopathies that include hypercalciuria within their varied phenotypes. Genotypes affecting other enzyme pathways, including vitamin D metabolism and hepatic glyoxylate metabolism, are also associated with nephrocalcinosis. As the availability of genetic testing becomes widespread, we cannot be imprecise in our approach to nephrocalcinosis. Monogenic causes of nephrocalcinosis account for a broad range of phenotypes. In cases such as Dent disease, supportive therapies are limited, and early renal replacement therapies are necessitated. In cases such as renal tubular acidosis, a good renal prognosis can be expected providing effective treatment is implemented. It is imperative we adopt a precision-medicine approach to ensure patients and their families receive prompt diagnosis, effective, tailored treatment and accurate prognostic information.

Incidental chronic kidney disease in an obese child with high myopia: Answers

“…It is the defect in reabsorption of calcium due to monogenic causes that leads to hypercalciuria in the majority of cases. In FHHNC, the defective claudins in the TAL of the loop of Henle are responsible for disease manifestations [2].…”

“…a. Dent's disease types 1 and 2/Fanconi syndrome/ cystinosis, b. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), c. Primary hyperoxaluria (PH), d. Cystinuria [1,2] There are many other disorders that may present with nephrocalcinosis, like Bartter syndromes, disorders of calcium sensing receptors (CaSR), and idiopathic calcium and kidney stone diseases. Then, there are disorders of vitamin D metabolism due to CYP24A1 mutations presenting as idiopathic infantile hypercalcemia type 1 (HCINF1) or type 2 due to mutations of sodium phosphate co-transporter (NaPi 2a) (SLC34A1), hypervitaminosis D, and primary distal renal tubular acidosis.…”

Calcium oxalate crystal deposition in the kidney: identification, causes and consequences

“…The presence of CaOx crystal deposition within a renal biopsy may indicate serious underlying pathology and indicate an underlying diagnosis that may not have previously been considered [7,8]. Of particular relevance are the primary hyperoxalurias (PH), which may cause end stage kidney disease and may recur following kidney transplantation.…”

Editorial of Special Issue “Rare Kidney Diseases: New Translational Research Approach to Improve Diagnosis and Therapy”

“…Fay J. Dickson and John A. Sayer [ 17 ] elegantly reviewed recent literature evidences regarding the employment of a novel precision-medicine approach to ensure patients affected by nephrocalcinosis and their families receive prompt diagnosis (that may slow down the progression to CKD), tailored treatment and accurate prognostic information (it is also useful to screen other family members).…”

“…Schena FP group [16], describing recent research findings on C3 glomerulopathy, emphasized the importance of a multidisciplinary approach (that involves nephrologists, renal pathologists, molecular biologists and geneticists) to optimize the diagnosis and the treatment of this rare and neglected disease. Fay J. Dickson and John A. Sayer [17] elegantly reviewed recent literature evidences regarding the employment of a novel precision-medicine approach to ensure patients affected by nephrocalcinosis and their families receive prompt diagnosis (that may slow down the progression to CKD), tailored treatment and accurate prognostic information (it is also useful to screen other family members).…”