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What is nephrocalcinosis?
Linda Shavit1, Philippe Jaeger2 and Robert J. Unwin2
1
Adult Nephrology Unit, Shaare Zedek Medical Center, Jerusalem, Israel and 2UCL Centre for Nephrology, Royal Free Campus and
Hospital, University College London, London, UK
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Kidney International 19
Clinical manifestations
Defect of the proton secretion affecting the -intercalated cells of the collecting
duct. Hypokalemic hyperchloremic acidosis with nephrocalcinosis and nephrolithiasis.
Defect in bicarbonate transport at the basolateral membrane of the intercalated cells of the collecting duct. Hypokalemic hyperchloremic acidosis,
nephrocalcinosis, and nephrolithiasis.
Defect of the proton secretion in the -intercalated cells of the collecting duct.
Hypokalemic hyperchloremic acidosis with nephrocalcinosis and nephrolithiasis,
and neural deafness.
Decreased sodium, potassium, and chloride reabsorption in the ascending limb
of Henle loop leading to hypokalemia, alkalosis, hypercalciuria, secondary
aldosteronism, and in some cases nephrocalcinosis.
Decreased sodium, potassium, and chloride reabsorption in the ascending limb
of Henle loop leading to hypokalemia, alkalosis, hypercalciuria, secondary
aldosteronism, and in some cases nephrocalcinosis.
Inhibition of calcium reabsorption in the ascending limb of Henle loop leading to
hypercalciuria, hypocalcemia, hyperphosphatemia, and hypophosphaturia, and
in some cases hypokalemia. Nephrocalcinosis in some cases.
Urinary losses of magnesium and calcium with nephrocalcinosis, and progressive
kidney failure in homozygotes; heterozygotes may produce kidney stones only.
Renal wasting of magnesium and calcium, nephrocalcinosis, and progressive
kidney failure in homozygotes; macular colobomata, myopia, and nystagmus.
Gene/protein/inheritance mode
ATP6N1B/7q33-q34, autosomal recessive -subunit ATP6N1B of
the H+-pump
Disorder
Table 1 | Clinical manifestations and genetic basis of inherited disorders associated with medullary nephrocalcinosis (NC)
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Abbreviations: dRTA, distal renal tubular acidosis; FGF23, fibroblast growth factor-23; PTH, parathyroid hormone; ROMK, renal outer medullary potassium.
Gene/protein/inheritance mode
Patients with PH type 2 generally have less severe disease than those with PH
type 1. Patients primarily present with recurrent urolithiasis, are less likely to have
nephrocalcinosis, and rarely progress to ESRD.
Patients with PH type 3 generally present early in life (mean age, 2 years) with
nephrolithiasis. In contrast to the other two forms of PH, patients with PH type 3
typically do not have recurrent nephrolithiasis after the age of 6 years, and do
not progress to ESRD.
Elfin face, supravalvular aortic stenosis, hypertension, impaired cognition, short
stature, endocrine, genitourinary, auditory, dental, ophthalmologic, and dermatologic abnormalities. Episodic hypercalcemia and hypercalciuria; nephrocalcinosis in 4510% of patients.
Recurrent calcium nephrolithiasis and nephrocalcinosis, hypercalciuria, hypocitraturia, and incomplete and overt dRTA (2.9% and up to 40% of patients,
respectively), metabolic bone disease. Chronic pain, recurrent episodes of urinary
tract obstruction, and infection; however, normal kidney function in the majority
of patients with rare reports of ESRD.
Disorder
Table 1 | Continued
Clinical manifestations
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excretion. These disorders include X-linked hypophosphatemia (XLH; mutant phosphate-regulating endopeptidase on the
X chromosome (PHEX)), autosomal dominant hypophosphatemic rickets (ADHR; mutant fibroblast growth factor23), and autosomal recessive hypophosphatemic rickets
(ARHR; mutant dentine matrix protein 1 (DMP1), ENPP1,
or FAM20C). Treatment for XLH, ADHR, and ARHR is with
long-term oral phosphate supplements and calcitriol that
is often complicated by nephrocalcinosis (up to 80% of
patients with XLH); this is believed to be the result of
intermittent episodes of hypercalcemia and hypercalciuria
from overtreatment with active vitamin D or poor compliance
with oral phosphate supplementation.2325
Another recently reported genetic association is with
mutations in the insulin receptor that are known to cause
severe insulin resistance, growth retardation, reduced fat and
muscle, and soft tissue overgrowth, and are also associated with
hypercalciuria and nephrocalcinosis, but which have not been
reported in a kidney-specific knockout (KO) mouse model.26
Thus, perhaps apart from hypercalciuria, seeking a common
underlying or unifying mechanism from genetic disorders in
which nephrocalcinosis is a feature has raised more questions
than provided answers. Indeed, recently described mutations in
FAM20A (see FAM20C above) have been reported in enamelrenal syndrome (ERS), a rare autosomal recessive disorder
presenting with nephrocalcinosis and characteristic dental defects
(amelogenesis imperfecta, gingival hyperplasia, impaired tooth
eruption), in which affected patients are hypocalciuric rather
than hypercalciuric.27,28
Although there is still no defined mechanism for the
nephrocalcinosis seen in ERS, we propose that dysregulation
of calcium homeostasis either locally within the renal
interstitium, or perhaps also systemically, may have a key
role. As the protein product of FAM20A is locally secreted
in low abundance in saliva and blood, and is also expressed
in the kidney, we suggest that de novo interstitial calcification,
rather than intratubular crystallization, is biologically
plausible and may be primarily owing to the normally
high calcium transport and flux across the renal tubular
epithelium that must be prevented from depositing
in the renal interstitium; therefore, nephrocalcinosis may
resemble in some way the process of abnormal metastatic
tissue calcification. FAM20A is a secreted kinase related to
FAM20C that can phosphorylate caseins and prevent CaPi
precipitation in milk; FAM20C mutations cause Raine
syndrome, in which there is ectopic calcification.29 Both
FAM20C and FAM20A can phosphorylate the SIBLING
proteins MEPE (or its ASARM products), DMP1 and
osteopontin involved in biomineralization and found in the
kidney.30,31 Given that the SIBLING proteins can promote or
inhibit mineralization, depending on their form and phosphorylation status, such an interaction could underlie the
nephrocalcinosis and enamel defect seen in enamel-renal
syndrome.
Distal renal tubular acidosis, a condition in which tubular
secretion of hydrogen ions in the distal nephron is impaired,
Kidney International
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MacGibbonLubinsky
syndrome (ERS)
Idiopathic hypercalciuria
Hypomagnesemiahypercalciuria
dRTA
MSK
Sarcoidosis
Hypervitaminosis D
Milk-alkali syndrome
Undiscovered cases
Autonomous
hyperparathyroidism
Acetazolamide
Progressive
osteoporosis
Cortical NC
Figure 1 | Frequencies of the main clinical causes of nephrocalcinosis (NC) in a series of 375 patients presenting with radiological NC.
This chart is based on the largest clinical series of Wrong3 and consists of 375 patients with macroscopic NC collected over more than 40 years
of clinical practice in London, Manchester, Newcastle, and Dundee. It shows that autonomous hyperparathyroidism, distal renal tubular acidosis
(dRTA), and medullary sponge kidney (MSK) are the most frequent clinical diagnoses in patients with radiological NC; 7% of patients had no
clear diagnosis. Others refers to WilliamsBeuren syndrome (WBS), Bartters syndrome, idiopathic renal Fanconi syndrome, hypothyroidism,
glucocorticoid-suppressible hyperaldosteronism, and severe acute tubular necrosis (ATN).
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6.
Plasma Ca2+
Interstitium
Cells
2+
Ca
7.
Tubules
Ca2+
Proximal tubule
8.
TAL
9.
Ca2+
RP
TL
10.
Ca2+
Distal tubule
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
DISCLOSURE
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