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review

2015 International Society of Nephrology

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

The available publications on nephrocalcinosis are

wide-ranging and have documented multiple causes and
associations of macroscopic or radiological nephrocalcinosis,
most often located in the renal medulla, with various
metabolic and genetic disorders; in fact, so many and various
are these that it is difficult to define a common underlying
mechanism. We have reviewed nephrocalcinosis in relation
to its definition, genetic associations, animal models, and
putative mechanisms. We have concluded, and hypothesized,
that nephrocalcinosis is primarily a renal interstitial process,
resembling metastatic calcification, and that it may have
some features in common with, and pathogenic links to,
vascular calcification.
Kidney International advance online publication, 25 March 2015;
doi:10.1038/ki.2015.76
KEYWORDS: bone; calcium; hypercalciuria; hyperoxaluria; mineral metabolism;
urology

Correspondence: Robert J. Unwin, UCL Centre for Nephrology, Royal Free

Hospital and Campus, University College London, Rowland Hill Street, London
NW3 2PF, UK. E-mail: robert.unwin@ucl.ac.uk
Received 29 November 2014; revised 18 January 2015; accepted 22
January 2015
Kidney International 19

Strictly, the term nephrocalcinosis refers to the generalized

deposition of calcium oxalate (CaOx) or calcium phosphate
(CaPi) in the kidney. However, in most cases, deposition
seems to be interstitial, and this is what nephrocalcinosis is
now generally taken to mean. Although some authorities
may limit the definition of nephrocalcinosis to the deposition
of mainly interstitial CaPi crystals, this is not universally
acknowledged, and thus for the purposes of this review we have
retained the broader definition of nephrocalcinosis to include
both CaPi and CaOx deposition. When high-resolution Fourier
transform infrared microspectroscopy and electron diffraction
have been used to investigate the composition of Randalls
plaque (areas in the renal papillae containing interstitial apatite
deposits that can serve as a nidus for urothelial surface CaOx
deposition), CaPi crystals are detected as their major
component.1 However, CaOx calculi overlie and adhere to
Randalls plaque in up to 50% of stone formers.2 Therefore,
concurrent deposition of both hydroxyapatite and CaOx
crystals may occur in the same patient with nephrocalcinosis.
CaPi is present as crystalline apatite, but it is not known
whether amorphous deposits of CaPi also occur.
A variety of inherited and acquired diseases have been
associated with nephrocalcinosis and recognized as potential
causes. Nephrocalcinosis can be classified in three ways that
represent increasing degrees of severity of renal involvement:1
molecular or chemical, often observed in patients with overt
hypercalcemia and which is usually reversible when hypercalcemia is corrected;2 microscopic, which in most cases is a precursor
to macroscopic nephrocalcinosis and is diagnosed by identification of mineral deposits on light microscopy of renal tissue;3 and
macroscopic, in which calcification is visible on either a plain
abdominal X-ray or ultrasound scan and/or confirmed by a
computed tomography scan, is the well-known clinical and
diagnostic feature of nephrocalcinosis. Although the clinical
presentation and outcomes of these forms of nephrocalcinosis
can be different, in clinical practice there is often some overlap.
Nephrocalcinosis usually involves the renal medulla (in
97% of patients) or, less often, the cortex. Cortical
nephrocalcinosis has been described in patients with renal
cortical necrosis (typically, and originally described, following
postpartum hemorrhage), chronic glomerulonephritis or
pyelonephritis, primary and secondary oxalosis (which are
more often causes of medullary nephrocalcinosis), autosomal
recessive polycystic disease, chronic renal allograft rejection,
and benign nodular cortical nephrocalcinosis.3
1

review

In this review, we try to summarize the extensive literature

on multiple causes of macroscopic medullary nephrocalcinosis, and their implication in promoting clinically significant
renal injury. We review the recent studies that have
investigated some novel pathogenic mechanisms and the
genetic background to progressive renal calcification. A
review of molecular nephrocalcinosis due to overt hypercalcemia and its consequences is beyond the scope of this review.
ETIOLOGY OF NEPHROCALCINOSIS

Several novel genetic disorders have been described in

association with metabolic abnormalities that predispose to
the development and progression of nephrocalcinosis.
Epithelial cell and paracellular disturbances in calcium
transport resulting in hypercalciuria seem to be the most
important, along with an increase in phosphate or oxalate,
and decrease in urinary citrate excretion. In addition, in some
cases specific anatomical abnormalities predispose to the
development of nephrocalcinosis, for example, in medullary
sponge kidney (MSK).
Recent advances in genetics have helped identify a number
of transporters, channels, and receptors that are involved
in regulating renal tubular reabsorption of calcium and
phosphate (Table 1). Several genes involved in rare monogenic disorders have been associated with hypercalciuric
nephrolithiasis with nephrocalcinosis (that is, CLCN5, CASR,
CLDN16, CLDN19, ADCY10, SLC34A1, SLC9A3R1, GLUT2,
HSPG2, and FN1), whereas variants of uromodulin and fetuin
seem to be protective.412 For example, mutations with loss of
function of the calcium-sensing receptor (CaSR) have been
reported in the hypercalcemic disorders of familial benign
hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated hyperparathyroidism,
whereas gain-of-function CaSR mutations result in autosomal
dominant hypocalcemia with hypercalciuria and Bartter
syndrome type V.4,1316 However, modest hypercalcemia
per se, when not accompanied by hypercalciuria, seems to be
insufficient to trigger nephrocalcinosis, for example, in
patients with familial benign hypocalciuric hypercalcemia;
only those patients with significant hypercalciuria appear to
be at risk of developing renal calcium deposition.
Several additional mutations have been identified in
Bartter syndrome, which usually presents with hypokalemic
alkalosis, renal salt wasting, hyperreninemic hyperaldosteronism, hypercalciuria, and hypocitraturia (presumed to be
secondary to hypokalemia and potassium depletion): mutations in genes encoding the loop diuretic-sensitive NaK2Cl
(NKCC2) cotransporter, the renal outer medullary potassium
(ROMK) channel, the voltage-gated chloride channel, CLCKb, and the CLC-Kb -regulatory subunit, barttin.12,17,18
Nephrocalcinosis has been described as a clinical feature in
Bartter syndrome types I, II, and V (mutations in NKCC2,
ROMK, and CaSR) (Table 1).
Another hereditary disorder associated with nephrocalcinosis, which is X-linked and characterized by low-molecularweight proteinuria, hypercalciuria, and nephrolithiasis, is
2

L Shavit et al.: Nephrocalcinosis

Dents disease (now known as Dent-1) that is caused by a

mutation in the gene for the chloride/proton antiporter 5,
CLC5, that regulates proximal tubular cell endocytosis.5
In addition, the X-linked recessive disease known as the
oculocerebrorenal syndrome of Lowe, or just Lowe syndrome,
which is due to a mutation in the OCRL gene, a
phosphatidylinositol 4,5-bisphosphate-5- phosphatase involved in actin polymerization, and that presents typically
with congenital glaucoma, cataracts, mental retardation, as
well as multiple reabsorption defects in the proximal tubule,
is also associated with nephrocalcinosis and renal stones;
similar to Dent-1, it can lead to renal failure. There is also a
clinical variant of Lowe syndrome known as Dent-2 that
presents predominantly with a renal phenotype and is similar
to Dent-1.5
Familial hypomagnesemia with hypercalciuria and
nephrocalcinosis is an autosomal recessive renal tubular
disorder that is frequently associated with progressive kidney
failure and recurrent urinary tract infections: it was originally
linked to mutations of the claudin-16 gene (also known as
paracellin-1), a member of the claudin family of membrane
proteins that form the intercellular tight junction barrier in a
variety of epithelia, including the thick ascending limb of the
loop of Henle, the site of the defect in this disorder; although
other claudin mutations (claudin-19) have also been
described.8,9
Several disorders have been associated with homozygous
and compound heterozygous inactivating mutations of
the solute carrier family 34, member 3 SLC34A3, the gene
encoding the sodium (Na+)-dependent phosphate cotransporter 2c (NPT2c). Hereditary hypophosphatemic rickets
with hypercalciuria is an autosomal recessive renal phosphatewasting disorder leading to hypophosphatemic rickets,
bowing of the legs, short stature, as well as appropriately
elevated 1,25(OH)2 vitamin D levels, often with hypercalciuria, renal calcification, and kidney stones.1921 Recent studies
have revealed that individuals with mutations affecting both
SLC34A3 alleles have a significantly increased risk of kidney
stone formation or medullary nephrocalcinosis (46% compared with 6% observed in healthy family members carrying
only the wild-type SLC34A3 allele).22 Renal calcification was
also more frequent in heterozygous carriers compared with
the general population, and it was more likely to occur in
homozygous and compound heterozygous and heterozygous
individuals with decreased serum phosphate, decreased
tubular reabsorption of phosphate, and increased serum
1,25(OH)2 vitamin D levels;22 however, there was no
correlation between genotype and urinary calcium excretion.
Various genetic causes have been identified in patients with
fibroblast growth factor-23dependent hypophosphatemic
disorders that usually present with significant hypophosphatemia, a decreased tubular reabsorptive threshold for
phosphate, growth retardation, rickets or osteomalacia,
inappropriately normal or suppressed 1,25(OH)2 vitamin D
levels, normal serum levels of calcium, normal-to-high
parathyroid hormone levels, and normal urinary calcium
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NKCC2/15q15-q21.1, autosomal recessive NKCC2 sodiumpotassiumchloride transporter

KCNJ1/11q24, autosomal recessive ROMK1 potassium channel

CASR/3q13.3-q21, autosomal dominant calcium-sensing receptor

(activating mutations)
CLDN16/3q27, autosomal dominant claudin 16

dRTA With neural deafness at birth or late

onset

Bartters syndrome type 1

Bartters syndrome type 2

Autosomal dominant hypoparathyroidism Bartters syndrome type 5

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis with ocular
impairment
Autosomal dominant hypocalcemia with
hypercalciuria (ADHH)

FGF23, autosomal dominant

Autosomal dominant hypophosphatemic

rickets (ADHR)
Autosomal recessive hypophosphatemic
rickets (ARHR)
MacGibbonLubinsky syndrome
(ERS, enamel-renal syndrome)
Primary hyperoxaluria (PH) type 1

AGXT/ 2q36-37, alanine glyoxylate aminotransferase (AGT)

FAM20A/17q24, autosomal recessive

Dentine matrix protein 1 (DMP1), ENPP1, or FAM20C

PHEX, X-linked phosphate-regulating endopeptidase

SLC34A3/ 2c (NPT2c), autosomal recessive sodium-dependent

phosphate cotransporter
CLCN5/Xp11.22, X-linked recessive chloride channel 5 on the
endosome membrane
OCRL1/Xq26.1, X-linked recessive phosphatidylinositol 4,5bisphosphate 5-phosphatase

CASR activating mutation, autosomal dominant

X-linked hypophosphatemia (XLH)

Lowes syndrome (also known as Dent-2)

Hereditary hypophosphatemic rickets

with hypercalciuria (HHRH)
Dents disease (also known as Dent-1)

ATP6B1/2cen-q13, autosomal recessive subunit ATP6B1 of the H+pump

dRTA Autosomal dominant

Characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia,

impaired tooth eruption) and nephrocalcinosis.
Nephrocalcinosis nephrolithiasis, renal impairment, and ESRD in 50% of
patients by early adulthood. Nonrenal manifestations of systemic oxalosis
include cardiac conduction defects, bone pain, increased risk of fractures, and
diminished visual acuity.

Hypocalcemia, hypercalciuria, normal PTH, recurrent nephrolithiasis, and

nephrocalcinosis, particularly during treatment with vitamin D and calcium
supplementation. Children may present with seizures and neuromuscular
irritability during periods of stress; low serum magnesium in some cases.
Renal phosphate wasting, hypophosphatemic rickets, leg bowing, short stature,
elevated 1,25(OH)2D levels, hypercalciuria, nephrocalcinosis, and kidney stones.
Multiple reabsorption defects in the proximal tubule associated with nephrolithaisis, nephrocalcinosis, and in many cases end-stage renal disease (ESRD).
Multiple reabsorption defects in the proximal tubule (cf. Dents) nephrolithaisis,
nephrocalcinosis, and many cases end-stage renal failure. Hydrophthalmia,
cataract, mental retardation (less common in Dent-2 variant).
Treatment for XLH, ADHR, and ARHR consists of the long-term oral administration of phosphate and calcitriol, and can be complicated by nephrocalcinosis (in
up to 80% of patients with XLH) attributable to intermittent episodes of
hypercalcemia and hypercalciuria.

SLC4A1/17q21-q22, autosomal dominant anion exchanger (AE1)

dRTA Autosomal recessive

CLDN19/1p34.2, autosomal dominant claudin 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)

L Shavit et al.: Nephrocalcinosis

review

GRHPR/9p11, decreased or absent activity of glyoxylate reductase/

hydroxypyruvate reductase (GRHPR)

HOGA1, mitochondrial 4-hydroxy-2-oxoglutarate aldolase enzyme

7q11.23 28 genes including the elastin gene, ELN, and LIMK1

Glial cell linederived neurotrophic factor (GDNF) and receptor

tyrosine kinase (RET) genes Sporadic (nongenetic forms)

Primary hyperoxaluria type 2

Primary hyperoxaluria type 3

WilliamsBeuren Syndrome (WBS)

Medullary sponge kidney (MSK)

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.

L Shavit et al.: Nephrocalcinosis

Disorder

Table 1 | Continued

Clinical manifestations

review

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,
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L Shavit et al.: Nephrocalcinosis

resulting in metabolic acidosis, an alkaline urine pH,

hypocitraturia and hypercalciuria with nephrocalcinosis, and
metabolic bone disease, can be due to mutations of the
erythrocyte anion exchanger (band 3, AE1) in its autosomal
dominant form and mutations of subunits of the H+-ATPase
(proton) pump in its autosomal recessive forms.3234 As with
Bartter syndrome, hypokalemia in distal renal tubular acidosis
may contribute to hypocitraturia and tendency to renal
calcification and stones.
Another multisystem genetic disorder, WilliamsBeuren
syndrome, is caused by hemizygous deletion of 1.51.8 Mb
on chromosome 7q11.23, encompassing 28 genes, including the elastin gene. Affected patients have a variety of
phenotypes that include narrow facial features, supravalvular
aortic stenosis or other vascular disorders, hypertension,
impaired cognition, short stature, and endocrine, genitourinary, auditory, dental, ophthalmologic, and dermatologic
abnormalities. It has been reported that 550% of patients
with WilliamsBeuren syndrome experience one or more
episodes of hypercalcemia that are generally mild and
asymptomatic. Hypercalciuria can accompany the hypercalcemia, but isolated hypercalciuria can also occur, especially in
adults. Nephrocalcinosis is relatively rare, found in o510%
of patients undergoing renal ultrasonography.35 However,
although the optimal imaging test for detecting nephrocalcinosis reliably is yet to be determined, the available evidence
suggests that a combination of computed tomography scan
with either ultrasonography or kidneysuretersbladder X-ray
yields the most accurate results.36
In MSK, which was originally considered to be a sporadic
disorder that can occur rarely in families with developmental
and growth-related defects such as hemihypertrophy, a recent
study has shown that 50% of MSK stone-forming patients
have relatives with milder forms of MSK.37 Mutations or
polymorphisms in genes that are primarily involved in
nephrogenesis, such as those encoding a glial cell linederived
neurotrophic factor and receptor tyrosine kinase, have been

found in a cohort of 55 apparently sporadic MSK patients,

supporting the hypothesis of a possible disruption of the
initial events involved in nephrogenesis at the ureteric bud
metanephric mesenchyme interface. Although not all MSK
patients have glial cell linederived neurotrophic factor
variants, and some do not have a family history of the
disease, both genetic heterogeneity and nongenetic forms of
MSK are likely to exist.38
Finally, several genetic forms of primary hyperoxaluria
have been described and associated with a different incidence
and severity of nephrocalcinosis and renal impairment
(Table 1). A recent study of over 100 patients with confirmed
primary hyperoxaluria looked at the prevalence of nephrocalcinosis and the relationship between stone burden and
stone recurrence, and nephrocalcinosis and renal function.
The findings of this study suggested that the prevalence of
nephrocalcinosis was 34% and its presence was associated
with more severe renal impairment.39
The contribution of monogenic disorders to the overall
prevalence of kidney stone disease and nephrocalcinosis has
been studied recently in a cohort of 272 genetically unresolved
individuals (106 children and 166 adults) from 268 families
with nephrolithiasis (n = 256) or isolated nephrocalcinosis
(n = 16).40 A total of 50 likely causative mutations in 14 of 30
analyzed genes was detected, leading to a molecular diagnosis
in 14.9% of all cases. The percentage of monogenic cases was
notably high in both the adult (11.4%) and pediatric cohorts
(20.8%). The cystinuria gene SLC7A9 (n = 19) was most
frequently mutated in this series.
Many other diseases have been described in association
with nephrocalcinosis. The largest clinical series is that of
Wrong3 in the United Kingdom that consists of 375 patients
with macroscopic (radiological) nephrocalcinosis collected
over more than 40 years of clinical practice in London,
Manchester, Newcastle, and Dundee. Figure 1 shows that
autonomous hyperparathyroidism (all patients had primary
hyperparathyroidism), distal renal tubular acidosis, and MSK
Oxalosis
Dent's disease
Renal papillary necrosis
Others

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).
Kidney International 19

review

are the most frequently associated clinical diagnoses in this

series.
Nephrocalcinosis has also been described in kidneys after
transplantation. Rebound hyperparathyroidism and associated hypercalcemia are common after successful renal
transplantation and have been reported to adversely affect
graft function either acutely, by inducing vasoconstriction,
or chronically, by leading to calcification in the tubulointerstitium of the transplanted kidney.41 In a recent prospective
observational cohort study of 303 incident renal transplant
recipients, with 21 on cinacalcet treatment at the time of
transplantation, CaPi deposits in the renal transplant were
observed in 33.3% and 25.7% of posttransplant protocol
biopsies at months 3 and 12, respectively.42 Interestingly, both
pretransplant parathyroid hormone and fibroblast growth
factor-23 were found to be independent predictors of
nephrocalcinosis that might be related to their phosphaturic
effect. However, pretransplant treatment with cinacalcet did
not seem to affect either the need for posttransplant parathyroidectomy or the incidence of posttransplant nephrocalcinosis in this study.42 Although a disturbance of mineral
metabolism after transplantation is likely to explain the
propensity to crystal formation, exposure to potentially
nephrotoxic immunosuppressive drugs with associated epithelial cell injury may aggravate crystal adhesion and deposition.
ANIMAL MODELS OF NEPHROCALCINOSIS

A variety of animals, including mice, rabbits, rats, and pigs,

have been used to create experimental models of nephrocalcinosis in an attempt to reveal the mechanisms governing
this common yet complex condition. In rats, hyperoxaluria
induced by vitamin B6 depletion or administration of glycolic
acid, glyoxylate, sodium oxalate, ammonium oxalate, ethylene
glycol, or hydroxy-L-proline has been shown to lead to CaOx
deposition in the kidneys, and additional administration of
vitamin D or calcium chloride aggravates this process.43,44
In most rat studies, ethylene glycol was used to induce
hyperoxaluria, and it resulted in increased urinary excretion
of oxalate within 2 days, established hyperoxaluria within
3 days, CaOx crystalluria within 2 weeks, and CaOx
nephrolithiasis within 46 weeks.45 Crystals appear first in
the tubular lumen and are associated with damage to the
epithelial cells lining the crystal-containing renal tubules.
Thereafter, many of the crystals move to intercellular and
intracellular locations and eventually into the interstitium.46
Translocation into the interstitium is associated with
inflammationthat is, attraction of leukocytes, monocytes,
and macrophages that have been proposed to remove the
crystalline material.47 Following the loss of surface epithelium, which results in loosening of tight junctions, the
deposits become exposed to pelvic urine and continue to
grow as large papillary stones.48
In the rat, hyperoxaluria has been shown to increase urinary
levels of alkaline phosphatase, -glutamyl transpeptidase, and
N-acetyl--glucoseaminidase, probably reflecting proximal
tubular injury.49 The role of TammHorsfall protein (THP)
6

L Shavit et al.: Nephrocalcinosis

in the rat CaOx nephrocalcinosis model is less well understood.

In humans, THP (uromodulin), a potent inhibitor of CaOx
crystal aggregation, is consistently present in the stone matrix;
decreased urinary excretion of THP has been demonstrated in
patients with CaOx or CaPi nephrolithiasis.50 However, in rats
with CaOx stones, studies have shown a decrease or an increase
in THP expression and production.51,52
Additional molecules are involved in crystallization and the
inflammatory cascade of experimentally induced nephrocalcinosis: osteopontin, various inter- inhibitorrelated macromolecules, bikunin, prothrombin, and heparan sulfate are
substantially increased in rats with nephrocalcinosis, as
determined by the expression of their respective mRNAs.44
Even though most rats with experimentally induced
hyperoxaluria develop CaOx renal deposits, reliable mouse
models of nephrocalcinosis seem to be more difficult to
generate. Mice with hyperoxaluria alone either do not
produce or maintain any CaOx crystals deposits or form
only a few crystals in their kidneys.53,54 Manipulations of the
gene for alanine glyoxylate aminotransferase or anion
transporter Slc26a6 have produced hyperoxaluric mice. The
alanine glyoxylate aminotransferasenull mice present with
severe hyperoxaluria, but develop only a few CaOx crystal
deposits in their kidneys.55 Mice lacking anion transporter
Slc26a6 (the chlorideoxalate exchanger in the proximal
tubule) also develop severe hyperoxaluria, but only those with
increased urinary calcium excretion develop CaOx crystal
deposits and bladder calculi.44 Thus, it seems that experimental induction of hyperoxaluria alone is not sufficient to
produce nephrocalcinosis in mice, and additional factors such
as concomitant hypercalciuria and male gender appear to be
critical factors for crystal deposition. Mouse models with a
disrupted sodium phosphate cotransporter gene (Npt2a/)
exhibit increased urinary excretion of phosphorus and
hypophosphatemia that leads to increased serum 1,25(OH)2
vitamin D levels, increased expression of intestinal calcium
channels, intestinal calcium hyperabsorption, hypercalcemia,
and hypercalciuria.56 Using this model, CaOx crystal deposits
were successfully produced in male Npt2a-null mice.44
Unlike CaOx stone mouse models, deposition of CaPi
crystals in mouse kidneys seems to occur more easily;
crucially, this depends on THP and osteopontin. THP KO
mice exhibit microcrystal formation in their renal papillae,
consisting mainly of CaPi (apatite) and located interstitially
or in the basement membrane zone.57,58 Hypercalciuria and
hyperoxaluria induced by the administration of vitamin D3
and ethylene glycol, respectively, lead to significant CaOx
crystal deposition in the kidneys in 76% of the THP KO mice,
whereas no crystal deposition can be detected in the kidneys
of wild-type mice.
Spontaneous interstitial deposits of CaPi within the renal
papillae were detected in a small proportion of osteopontin
KO mice.53 Lack of both osteopontin and THP proteins
caused interstitial renal crystallization in 39% of the doublenull mice, associated with elevated concentrations of urinary
phosphate and CaPi supersaturation.53
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L Shavit et al.: Nephrocalcinosis

Manipulations of the gene for Npt2a have been shown to

produce both tubular and interstitial CaPi crystal deposition
in male and female Npt2a KO mice of different ages.59
Moreover, sodiumhydrogen exchanger regulator factor-1
NHERF-1null mice, which also have very low expression of
Npt2a, develop hypercalciuria, hyperphosphaturia, hypermagnesuria, and uricosuria; however, they show only a few
interstitial CaPi deposits in their renal papillae at 4854 weeks
of age. By 72 months of age a significant increase in interstitial
CaPi deposits is observed in these mice.45
Cortical and medullary nephrocalcinosis is often detected
in critically ill and low-birth-weight preterm infants who were
treated especially (though not only) with furosemide or
vitamin D, and in children with inherited renal tubulopathies
with hypercalciuria, such as Bartter syndrome. The mechanism by which furosemide can cause nephrocalcinosis has been
attributed to hypercalciuria; however, a recent rat model of
CaPi (rather than the more usual CaOx) nephrocalcinosis has
been described in which animals on a chloride-only or
sodium- and chloride-depleted diet, and given furosemide,
develop nephrocalcinosis. Furosemide given alone on a
control diet had no effect, but rats on a sodium chloride
depleted diet without furosemide also developed significant
nephrocalcinosis.60 However, it is not clear whether CaPi
deposition in this model is mainly cortical or medullary or
both. An earlier rat model of presumed CaPi nephrocalcinosis
described by Buck et al.61 involved regular intraperitoneal
injection of calcium gluconate, but the calcium deposition
was typically more cortical than medullary. Thus, up to now,
there are no good animal models of medullary nephrocalcinosis due to CaPi deposition.
In conclusion, development of animal models of nephrocalcinosis is a difficult undertaking, and the models reproduce
poorly the features and associations seen in humans,
confirming the complex interplay of genetic and metabolic
risk factors leading to increased urinary excretion of calcium,
phosphate, or oxalate, as well as abnormalities in molecular
epithelial transport of crystallization inhibitors required to
trigger a process that can be considered as nephrocalcinosis.
A PROPOSED MECHANISTIC EXPLANATION OF RENAL
CALCIFICATION IN NEPHROCALCINOSIS

Although genetic studies have provided valuable insights into

the renal tubular pathways that regulate calcium, phosphate,
and oxalate handling, and that predispose to metabolic
disturbances that may result in nephrocalcinosis, such as
increased urinary excretion of calcium, oxalate, phosphate, or
decreased excretion of citrate, they do not provide a complete
explanation of the complexity of the mechanisms leading to
renal calcification that can be interstitial, intratubular, or
both. Indeed, additional intratubular factors are required to
explain crystal retention and adhesion to the tubular
epithelium: decreased urine volume, urinary supersaturation,
the presence of insufficient concentrations of crystal inhibitors such as citrate, magnesium, and various proteins (such as
THP, osteopontin, bikunin, urinary prothrombin fragment 1),
Kidney International 19

review

and the integrity of tubular epithelial cells. A number of

experimental and clinical observations strongly suggest that
crystals do not adhere to the normally differentiated tubular
epithelium, but rather attach to dedifferentiated/regenerating
epithelial cells that express multiple crystal-binding molecules
such as sialic acidcontaining proteins and/or phospholipids,
phosphatidyl serine, nucleolin-related protein, annexin II,
osteopontin, and hyaluronan on the luminal surface of the
tubular epithelium.6265 The causal role of aberrant epithelial
tissue crystal adhesion has been demonstrated in renal cell
lines in vitro, in animal models, in kidney transplant patients,
and in neonates in whom osteopontin and hyaluronan
expression are closely associated with nephrocalcinosis.6668
Although these factors may account for intratubular crystal
formation and retention, the specific pathogenic mechanisms
leading to interstitial crystal formation and deposition,
including the development of Randalls plaque, are still
unclear.1 However, translocation of intratubular crystals and/
or de novo interstitial calcification have been proposed.
Many factors have been put forward to account for
intratubular crystal formation and retention, but the specific
pathogenic mechanisms resulting in interstitial crystal formation, which must underlie nephrocalcinosis in patients,
have been elusive, despite the many clinical and genetic
associations, and they are still the subject of ongoing debate.
Dysregulation of calcium homeostasis locally within the
renal interstitium, and probably also systemically, may have a
key role in the pathogenesis of nephrocalcinosis. Indeed,
studying a rare genetic disorder, the enamelrenal syndrome
mentioned earlier that presents with abnormal enamel
formation, impaired tooth eruption, and nephrocalcinosis,
has recently delineated some of these processes. The causative
gene FAM20A was implicated in this systemic disorder of
calcium homeostasis, and its protein product FAM20A is
locally secreted in low abundance in saliva and blood. This
association raises the possibility that de novo interstitial
calcification, rather than intratubular crystallization, is
biologically plausible in nephrocalcinosis and that it may be
primarily owing to increased calcium transport and flux
across the renal tubular epithelium (Figure 2) that is normally
prevented from depositing in the interstitium, and thus may
resemble in some way the process of abnormal metastatic
tissue calcification as the initiating event. Indeed, a recent
study of nephrocalcinosis in mice has shown the importance
of genes known to be associated with ectopic mineralization,69 and the FAM20 family of secreted protein kinases have
as substrates the phosphatonin-like peptides MEPE and
DMP1 that can inhibit both bone and tooth mineralization,70,71 and that have also been detected in the kidney72
along with FAM20A28 (see earlier). Thus, we suggest that a
complex dysregulation between calcification inhibitors and
promoters, with similarities to the process of vascular
calcification, may have a pivotal role in the development of
nephrocalcinosis. In this context, it is currently thought that
fetuin-A, matrix Gla protein, osteoprotegerin, and pyrophosphates all act in a local or systemic manner to prevent
7

review

L Shavit et al.: Nephrocalcinosis

6.

Plasma Ca2+

Interstitium

Cells
2+

Ca

7.

Tubules
Ca2+

Proximal tubule

8.
TAL

9.

Ca2+
RP

TL

10.
Ca2+

Distal tubule

Fetuin-A, matrix Gla

protein, osteoprotegerin,
pyrophosphates

Figure 2 | Simplified scheme of a proposed mechanism for

interstitial calcification in nephrocalcinosis. RP, Randalls plaque;
TAL, thick ascending limb of loop of Henle; TL, thin (descending and
ascending) limbs of loop of Henle.

11.

12.
13.

14.

15.

calcification of the vasculature,31 and that nephrocalcinosis

could represent another process of unwanted calcification in
which the same or similar calcification inhibitors can have a
role locally in the renal interstitium.
Over the past decade, a number of large-scale epidemiological studies have provided evidence for an association
between kidney stones and systemic conditions such as the
metabolic syndrome, hypertension, chronic kidney disease,
and cardiovascular disease. Our own recent study found that
the abdominal aorta is significantly more calcified in calcium
stone formers when compared with healthy adults,72
suggesting that vascular calcification may be an underlying
mechanism explaining reported associations between nephrolithiasis and cardiovascular disease. However, there is
no study to date addressing this issue in patients with
nephrocalcinosis, although renal interstitial calcification is
frequently associated with disorders of extrarenal organs and
systems, perhaps pointing the way to a common underlying
process of abnormal calcium balance.

16.

17.

18.

19.

20.

21.

22.

23.
24.

DISCLOSURE

All the authors declared no competing interests.

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