Genetic, pathophysiological, and clinical aspects of nephrocalcinosis Ben Oliveira, X Robert Kleta, Detlef Bockenhauer, and Stephen B. Walsh University College London, Centre for Nephrology, London, United Kingdom Submitted 7 April 2016; accepted in final form 6 September 2016 Oliveira B, Kleta R, Bockenhauer D, Walsh SB. Genetic, pathophysiological, and clinical aspects of nephrocalcinosis. Am J Physiol Renal Physiol 311: F1243–F1252, 2016. First published September 7, 2016; doi:10.1152/ajprenal.00211.2016.—Nephro- calcinosis describes the ectopic deposition of calcium salts in the kidney paren- chyma. Nephrocalcinosis can result from a number of acquired causes but also an even greater number of genetic diseases, predominantly renal but also extrarenal. Here we provide a review of the genetic causes of nephrocalcinosis, along with putative mechanisms, illustrated by human and animal data. nephrocalcinosis; tubular physiology; genetics THE TERM NEPHROCALCINOSIS was first coined in 1934 by Fuller Albright, who was at that time a physician’s assistant (2). Albright was referring to calcium deposition into the kidney of patients with primary hyperparathyroidism usually associated with im- paired kidney function. Presently the term is often used to describe calcium deposition that is seen in the kidneys radiologically, which, as we will discover later, does not necessarily constitute nephrocalcinosis as Albright originally meant it. The calcium is in the form of either calcium phosphate or calcium oxalate; some have termed the latter oxalosis, but here we will use the term nephrocalcinosis to cover both. In the majority of cases, the underlying event leading to nephrocalcinosis is hypercalciuria. This may be the result of extrarenal conditions leading to an increased calcium load with subsequent hypercalciuria, for exam- ple, enhanced absorption of calcium in the gut. Alternatively, hypercalciuria may be caused by impaired renal handing of calcium. Here, we explore the genetic, pathophysiological, and clinical aspects of both renal and extrarenal diseases leading to nephrocalcinosis. Types of Nephrocalcinosis Oliver Wrong proposed dividing nephrocalcinosis into three different types (114a). The first was molecular nephrocalcino- sis, in which there is an increase in renal intracellular calcium but no crystal formation, in essence reflecting the renal dys- function of hypercalcemia. The second was microscopic nephrocalcinosis, in which calcium phosphate or oxalate crys- tals could be identified on light microscopy but not radiologi- cally (as often happens in biopsies of renal tissue with acute tubular necrosis). The third was macroscopic nephrocalcinosis, in which the calcium salt is visible radiologically. It is this third type that is typically referred to by the term nephrocalcinosis and is also the type that we will mainly consider here. Sites of Nephrocalcinosis Cortical nephrocalcinosis is rare [2.4% of the largest pub- lished series (116)] and usually results from severe destructive disease of the cortex. This has been described in chronic glomerulonephritis (although this is often in the presence of another factor, e.g., increased calcium ingestion) (4), acute cortical necrosis (22), chronic pyelonephritis (which may be focal and therefore asymmetric) (31), and trauma (16). Medullary nephrocalcinosis is the usual distribution seen, perhaps unsurprising considering the location of the major homeostatic pathway of Ca 2 reabsorption [the thick ascend- ing limb (TAL) of the loop of Henle] and the segment involved with acid base regulation (the collecting duct). Genetic aspects of nephrocalcinosis. A number of monoge- netic conditions lead to nephrocalcinosis. Over the last few decades we have been able to classify the genetic basis of a number of conditions causing nephrocalcinosis, and these will form the focus of this review. Renal Genetic Disease Causing Nephrocalcinosis Proximal tubule. DENT DISEASE AND LOWE SYNDROME. The term Dent disease was first coined by Wrong and colleagues in 1994 based on the phenotype first described by Dent in the 1960s (26, 117). It is an X-linked recessive disorder charac- terized by the renal Fanconi syndrome (low-molecular-weight proteinuria, aminoaciduria, phosphaturia, uricosuria, and gly- cosuria), hypercalciuria, nephrocalcinosis, and nephrolithiasis. It also causes progressive renal impairment with end-stage renal failure (ESRF) out of keeping with the degree of nephro- calcinosis, often in the fourth to fifth decade. Dent disease (Dent-1) is caused by mutations of the CLCN5 gene that encodes the chloride transporter ClC-5. ClC-5 is found in endosomes involved in the endocytic reabsorption of low- molecular-weight proteins. Forty percent of patients with Dent disease do not have CLCN5 mutations; of these, about a third have a mutation in OCRL, and this condition is referred to as Dent-2 (45). Lowe syndrome, which is caused by OCRL mutations, has the same renal phenotype as Dent disease in addition to congenital cataracts and mental impairment (10). There is some overlap between Dent-2 and Lowe syndrome, but pa- tients with Dent-2 tend to have mild or absent oculocerebral symptoms (11). Address for reprint requests and other correspondence: R. Kleta, Centre for Nephrology, Univ. College London, Royal Free Hospital/Medical School, 1. Floor, Rm. 1.7007, Rowland Hill St., London NW3 2PF, United Kingdom (email: [email protected]). Am J Physiol Renal Physiol 311: F1243–F1252, 2016. First published September 7, 2016; doi:10.1152/ajprenal.00211.2016. Review 1931-857X/16 Copyright © 2016 the American Physiological Society http://www.ajprenal.org F1243 Downloaded from journals.physiology.org/journal/ajprenal (171.243.067.090) on May 28, 2023.
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