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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.
Highlights
Nephrocalcinosis can broadly be defined as the deposition of calcium, either as calcium phosphate or calcium oxalate, within the interstitium of the kidney [1]
A further ~7–10% of calcium is reabsorbed within the distal convoluted tubule, no monogenic causes of nephrocalcinosis have been identified which affect this section of the renal tubule [2]
Used medications may inadvertently worsen the condition of patients with other inherited tubulopathies: loop diuretic use can potentiate hypercalciuria and worsen nephrolithiasis/nephrocalcinosis burden, whereas use of potassium-sparing diuretics should be avoided in patients with distal renal tubular acidosis [10]
Summary
Nephrocalcinosis can broadly be defined as the deposition of calcium, either as calcium phosphate or calcium oxalate, within the interstitium of the kidney [1]. Nephrocalcinosis in itself is a rare disorder, and monogenic forms affect even smaller numbers of the population For those individuals affected by nephrocalcinosis, a tailored, individualised approach to their initial diagnostic work-up is imperative. Used medications may inadvertently worsen the condition of patients with other inherited tubulopathies: loop diuretic use can potentiate hypercalciuria and worsen nephrolithiasis/nephrocalcinosis burden, whereas use of potassium-sparing diuretics should be avoided in patients with distal renal tubular acidosis [10]. In cases where a proactive approach to personalised genetic medicine has been taken, generation sequencing has identified CLCN5 mutations (Dent disease 1) in patients for whom only low-molecular weight proteinuria was present at diagnosis, i.e., before the full phenotype had emerged [11]. Given the current paucity of treatment options for nephrocalcinosis, it is potentially from the study of these rare monogenic causes that key future therapeutic targets may emerge which could revolutionise our management of the condition (Table A1)
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