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Martin Konrad has documented that he has no relevant financial relationships to disclose or conflict of interest to resolve.
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Nephrocalcinosis
Clinical / Genetic Work-up and Outcome
Martin Konrad
University Children‘s Hospital
Münster, Germany
48th ESPN Meeting, Brussels 2015
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Nephrocalcinosis in Children
• Introduction
• Diagnostic / genetic work-up
• Outcome
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Extracellular calcium balance in adults
300 mg
100 mg
9000 mg
8800 mg
Serum Ca2+ KidneyIntestine
Bone
Intake
1000 mg
Feces
800 mg200 mg200 mg 200 mg
Urine
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55 – 70%
5 – 7 %
20 –
25 %
2 %
Renal tubular calcium reabsorption
free Calcium
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Introduction – Nephrocalcinosis
Is the differentiation between nephrocalcinosis and
kidney stones disease always helpful?
This question certainly is a question
of the right perspective.
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Introduction – Nephrocalcinosis
From the kidney stone perspective?
Many stone-forming conditions carry no or little additional risk for
the development of nephrocalcinosis.
Examples: cystinuria
Lesch-Nyhan syndrome
xanthinuria...
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Introduction – Nephrocalcinosis
From the nephrocalcinosis perspective?
At least in some of the underlying disease entities,
there is considerable overlap (within disease entities, in families,
even within the same individuals.
Examples: Primary hyperoxaluria
CYP24A1 defects
dRTA...
Are younger children more susceptible for NC
rather than stones?
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Introduction – Nephrocalcinosis
• Etiology of pediatric nephrocalcinosis (nephrolithiasis)
higher rate of underlying metabolic abnormalities,
as a consequence,
higher risk of progression of nephrocalcinosis or
stone recurrence (20 – 46 %).
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• Main risk factors in infants and children
hypercalciuria
hyperoxaluria
hypocitraturia
prematurity (steroids, hypocitraturia, diuretics)
medication and intoxication
tumor treatment
strong genetic background
monogenic disorders
Introduction – Nephrocalcinosis
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Underlying disorders in pediatric NC
• Idiopathic Hypercalciuria
• Hypercalcemic disease states
• Fanconi syndrome
• Antenatal Bartter syndrome
• Familial hypomagnesemia / hypercalciuria
• Distal renal tubular acidosis
• CASR – related (FHH)
• Metabolic diseases, e.g. primary hyperoxaluria
• ........
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Dent‘s diseaseClC5, OCRL
Lowe syndromeOCRL
HHRHSLC34A3
Fanconi syndromeHNF4A, EHHADH
Fanconi BickelGLUT2
Metabolic diseases
PH1-3
Infantile Hypercalc
CYP24A1
SLC34A1
Antenatal Bartter syndromeNKCC2
ROMK
BSND
Familial Hypomagnesemia
with hyercalciuriaCLDN16
CLDN19
CASR -relatedCASR
Kidney stonesCLDN14
Gitelman syndromeSLC12A3
EAST syndromeKCNJ10
PHA type IIWNK1, WNK4, Cul3?
dRTAAE1, ATP6B1, ATP6N1B
Human genetic diseases and renal calcium reabsorption
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• Introduction
• Diagnostic / genetic work-up
• Outcome
Nephrocalcinosis in Children
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Pediatric nephrocalcinosis: work-up
• Past Medical History
failure to thrive, growth retardation
polyuria, polydipsia
urinary tract infections
(colicky) pain, hematuria
medication, vitamin D/A supplementation
family history
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• Ultrasound
kidney morphology
size, echogenicity
nephrocalcinosis, concrements
• Radiography / CT scan
rarely necessary (e.g. ureteral stones)
Pediatric nephrocalcinosis: work-up
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U. Vester, Essen
Pediatric NC: cortical nephrocalcinosis
Preterm infant,
CLDN16 mutation
Hypomagnesemia
Hypercalciuria
High risk of CRF
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16 mo, ♀, Williams Beuren syndrome, serume Ca > 3 mmol/l, hypercalciuria
medullary nephrocalcinosis, grade IIa
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♂, proximal tubular
dysfunction after
polychemotherapy
medullary nephrocalcinosis, grade IIa
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10 y, ♂,
Idiopathic
hypercalciuria
medullary nephrocalcinosis, grade IIb
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♀, CLDN16 mutation
medullary nephrocalcinosis, grade III
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Nephrocalcinosis - Imaging
The morphologic appearance rarely allows a clue
towards the etiology.
Repeated analysis serves the assessment of progression and the
occurrence of stones during the course of the disease.
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9 weeks, advanced renal failure, primary hyperoxaluria type I
diffuse nephrocalcinosis
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ESRD, primary hyperoxaluria type I
diffuse nephrocalcinosis
U. Vester, Essen
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• Lab examination
Pediatric Nephrocalcinosis: work-up
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Dent‘s diseaseClC5, OCRL
Lowe syndromeOCRL
HHRHSLC34A3
Fanconi syndromeHNF4A, EHHADH
Fanconi BickelGLUT2
Metabolic diseases
PH1-3
Infantile Hypercalc
CYP24A1
SLC34A1
Antenatal Bartter syndromeNKCC2
ROMK
BSND
Familial Hypomagnesemia
with hyercalciuriaCLDN16
CLDN19
CASR -relatedCASR
Kidney stonesCLDN14
Gitelman syndromeSLC12A3
EAST syndromeKCNJ10
PHA type IIWNK1, WNK4, Cul3?
dRTAAE1, ATP6B1, ATP6N1B
Human genetic diseases and renal calcium reabsorption
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glucose
amino acids
uric acid
Ca++
PO4-,
Na+,
K+
salt
water,
Mg++
Ca++
Salt
Mg++
Ca++
Pediatric Nephrocalcinosis: work-up
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• Lab examination
blood: BGA, Na, Cl, K, Ca, Mg, PO4, gluc, crea
uric acid, AP, (PTH, Vit D/A, oxalate)
urine: osmolality, pH, gluc, prot, sediment, culture
Ca, oxalate, uric acid, citrate, Mg, PO4, crea,
cystine, amino acids
genetic testing upon results might be helpful
Pediatric Nephrocalcinosis: work-up
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• directed testing (conventional) if clinical diagnosis is clear
examples: dRTA, Bartter sy, FHHNC
• what to do if the clinical diagnosis is less clear?
choose candidates one by one?
NGS screening using gene panels?
Within the next years, daily practise will tend to NGS panels
(even exomes?) also for diagnostic purposes
Pediatric Nephrocalcinosis: genetic work-up
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• 1st study published in March 2015
Study cohort: 272 individuals with nephrolithiasis/nephrocalcinosis,
including 106 children (16 with nephrocalcinosis).
Consecutive recruitment from „typical kidney stone clinics“.
NGS panel of 30 genes revealed a monogenic underlying cause in
40 patients (14.5 % overall, 20% of the pediatric cohort).
The majority of mutations cause cystinuria.
Pediatric Nephrocalcinosis: genetic work-up
Halbritter et al, JASN 2015
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• further experience, at this meeting:
P-316, Bockenhauer et al.
NGS (37 genes) for tubular disorders (salt-wasting/dRTA),
mutations found in 64/75 (85%).
P-321, Schlingmann et al., collaboration with Neuber/Bergmann
NGS (137 genes) targeting all tubular disorders including stones/NC,
Pilot study: works well, all previously known mutations detected.
Pediatric Nephrocalcinosis: genetic work-up
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Nephrocalcinosis / Kidney Stones in Children
• Introduction
• Diagnostic / genetic work-up
• Outcome
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Pediatric NC / NL – Outcome (in Adult Life)
• main risk factors:
hypercalciuria
hyperoxaluria
hypocitraturia
strong genetic background
monogenic disorders
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♀, antenatal Bartter syndr
ROMK mutation
low risk for CRF
♀, hypomagnesemia/hypercalciuria
CLDN16 mutation
high risk for CRF
Is Nephrocalcinosis per se a risk for CRF ?
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Calcium reabsorption in the TAL
ROMK
CLDN16
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Pediatric NC / NL – Outcome (in Adult Life)
prematurity little morbidity in late adolescence ?
NC may disappear over time
tumor treatment NC alone has a good prognosis
hypercalcemic disease states
mostly easy to treat, stable NC
stones may occur later in life
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Underlying disorders in pediatric NC/NL – Outcome ?
• Idiopathic Hypercalciuria unknown good?
• Antenatal Bartter syndrome good, except BSND defects
• FHHNC (claudin defects) poor, ESRF frequent
• Primary hyperoxaluria I poor, often progressive
• Fanconi syndrome variable, CRF possible
• Dent /Lowe syndrome often progressive CRF
• Primary metabolic disorders in general rather poor
• Distal renal tubular acidosis little risk of CRF
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• Idiopathic Hypercalciuria unknown good?
• Antenatal Bartter syndrome good, except BSND defects
• FHHNC (claudin defects) poor, ESRF frequent
• Primary hyperoxaluria I poor, often progressive
• Fanconi syndrome variable, CRF possible
• Dent /Lowe syndrome often progressive CRF
• Primary metabolic disorders in general rather poor
• Distal renal tubular acidosis little risk of CRF
Underlying disorders in pediatric NC/NL – Outcome ?
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• Idiopathic Hypercalciuria unknown good?
• Antenatal Bartter syndrome good, except BSND defects
• FHHNC (claudin defects) poor, ESRF frequent
• Primary hyperoxaluria I poor, often progressive
• Fanconi syndrome variable, CRF possible
• Dent /Lowe syndrome often progressive CRF
• Primary metabolic disorders in general rather poor
• Distal renal tubular acidosis little risk of CRF
Underlying disorders in pediatric NC/NL – Outcome ?
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• Idiopathic Hypercalciuria unknown good?
• Antenatal Bartter syndrome good, except BSND defects
• FHHNC (claudin defects) poor, ESRF frequent
• Primary hyperoxaluria I poor, often progressive
• Fanconi syndrome variable, CRF possible
• Dent /Lowe syndrome often progressive CRF
• Primary metabolic disorders in general rather poor
• Distal renal tubular acidosis little risk of CRF
Underlying disorders in pediatric NC/NL – Outcome ?
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• Idiopathic Hypercalciuria unknown good?
• Antenatal Bartter syndrome good, except BSND defects
• FHHNC (claudin defects) poor, ESRF frequent
• Primary hyperoxaluria I poor, often progressive
• Fanconi syndrome variable, CRF possible
• Dent /Lowe syndrome often progressive CRF
• Primary metabolic disorders in general rather poor
• Distal renal tubular acidosis little risk of CRF
Underlying disorders in pediatric NC/NL – Outcome ?
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• Idiopathic Hypercalciuria unknown good?
• Antenatal Bartter syndrome good, except BSND defects
• FHHNC (claudin defects) poor, ESRF frequent
• Primary hyperoxaluria I poor, often progressive
• Fanconi syndrome variable, CRF possible
• Dent /Lowe syndrome often progressive CRF
• Primary metabolic disorders in general rather poor
• Distal renal tubular acidosis little risk of CRF
Underlying disorders in pediatric NC/NL – Outcome ?
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• Idiopathic Hypercalciuria unknown good?
• Antenatal Bartter syndrome good, except BSND defects
• FHHNC (claudin defects) poor, ESRF frequent
• Primary hyperoxaluria I poor, often progressive
• Fanconi syndrome variable, CRF possible
• Dent /Lowe syndrome often progressive CRF
• Primary metabolic disorders in general rather poor
• Distal renal tubular acidosis little risk of CRF
Underlying disorders in pediatric NC/NL – Outcome ?
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• Idiopathic Hypercalciuria unknown good?
• Antenatal Bartter syndrome good, except BSND defects
• FHHNC (claudin defects) poor, ESRF frequent
• Primary hyperoxaluria I poor, often progressive
• Fanconi syndrome variable, CRF possible
• Dent /Lowe syndrome often progressive CRF
• Primary metabolic disorders in general rather poor
• Distal renal tubular acidosis little risk of CRF
Underlying disorders in pediatric NC/NL – Outcome ?
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Pediatric NC / NL – CAVEAT
Antenatal Bartter syndrome
excessive hypercalciuria, early NC grade III
NO THIAZIDES !
DCT is important for compensating salt loss
Hypercalciuria related to CASR mutations (FHH)
hypocalcemic hypercalciuria
calcium / vit D suppl induce massive NC
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Thank you !