Martin Konrad has documented that he has no relevant financial relationships to disclose or conflict of interest to resolve.

Nephrocalcinosis

Clinical / Genetic Work-up and Outcome

Martin Konrad

University Children‘s Hospital

Münster, Germany

48th ESPN Meeting, Brussels 2015

Nephrocalcinosis in Children

• Introduction

• Diagnostic / genetic work-up

• Outcome

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

55 – 70%

5 – 7 %

20 –

25 %

2 %

Renal tubular calcium reabsorption

free Calcium

Introduction – Nephrocalcinosis

Is the differentiation between nephrocalcinosis and

kidney stones disease always helpful?

This question certainly is a question

of the right perspective.

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...

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?

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 %).

• 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

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

• ........

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

• Introduction

• Diagnostic / genetic work-up

• Outcome

Nephrocalcinosis in Children

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

• Ultrasound

kidney morphology

size, echogenicity

nephrocalcinosis, concrements

• Radiography / CT scan

rarely necessary (e.g. ureteral stones)

Pediatric nephrocalcinosis: work-up

U. Vester, Essen

Pediatric NC: cortical nephrocalcinosis

Preterm infant,

CLDN16 mutation

Hypomagnesemia

Hypercalciuria

High risk of CRF

16 mo, ♀, Williams Beuren syndrome, serume Ca > 3 mmol/l, hypercalciuria

medullary nephrocalcinosis, grade IIa

♂, proximal tubular

dysfunction after

polychemotherapy

medullary nephrocalcinosis, grade IIa

10 y, ♂,

Idiopathic

hypercalciuria

medullary nephrocalcinosis, grade IIb

♀, CLDN16 mutation

medullary nephrocalcinosis, grade III

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.

9 weeks, advanced renal failure, primary hyperoxaluria type I

diffuse nephrocalcinosis

ESRD, primary hyperoxaluria type I

diffuse nephrocalcinosis

U. Vester, Essen

• Lab examination

Pediatric Nephrocalcinosis: work-up

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

glucose

amino acids

uric acid

Ca++

PO4-,

Na+,

K+

salt

water,

Mg++

Ca++

Salt

Mg++

Ca++

Pediatric Nephrocalcinosis: work-up

• 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

• 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

• 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

• 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

Nephrocalcinosis / Kidney Stones in Children

• Introduction

• Diagnostic / genetic work-up

• Outcome

Pediatric NC / NL – Outcome (in Adult Life)

• main risk factors:

hypercalciuria

hyperoxaluria

hypocitraturia

strong genetic background

monogenic disorders

♀, 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 ?

Calcium reabsorption in the TAL

ROMK

CLDN16

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

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

• 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 ?

• 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 ?

• 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 ?

• 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 ?

• 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 ?

• 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 ?

• 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 ?

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

Thank you !