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Genetics of Nephrolithiasis
Giovanni Gambaro
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• Hypercalciuria in 40-75% (?)
• Hyperoxaluria in ~5% (?)
• Hyperuricosuria in ~10% (URAT1)
• Hypocitraturia in ~20% (Na-DC1)
Stone risk
- FAMILIAL -
In up to 50% of SF
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Heritability of renal stones (Iceland)
(Edvardsson et al, Scand J Urol Nephrol, 2009)
Risk Ratio - 5954 all SF
Risk Ratio - 2959 Ca SF
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Goldfarb et al. A twin study of genetic and dietary influenceson nephrolithiasis: a report from the Vietnam Era Twin (VET) Registry. Kidney Int 67: 1053-61, 2005
Total
number of
pairs
Pairs
concordant
for stones
Pairs
discordant
for stones
Proband
concordance
Monozygotic 1928 39 163 32.4
Dizygotic 1463 17 162 17.3
Idiopthic calcium nephrolithiasis
Heritability 56%
Environmental effects 44%
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Idiopathic hypercalciuria & calcium stonedisease
• Monogenic forms of renal stone disease (calcium
and non-calcium stones) were previously thought to
account for just 2% of all renal stones
• PolygenicOne or few genes playing a major role
Additional genes contributing to the disease risk
Complex (multifactorial and polygenic) conditionIt is the consequence of dietary-environmental factors
in a genetically predisposed subject
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Genes previously associated with calcium
nephrolithiasis identified by genome-wide
association studies (GWAS)
CLDN14, Iceland-The Netherlands
AQP1, Japan
DGKH, Japan
Uromodulin, Iceland
ALPL (alkaline phosphatase isoenzyme), Iceland, China
CASR (possible association), Iceland
SLC34A1 (sodium-dependent phosphate cotransporter type
2), Iceland, Japan
TRPV5 (transient receptor potential cation channel V5, i.e.
epithelial calcium channel 1), Iceland
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Taguchi K et al. Genetic Risk Factors for Idiopathic
Urolithiasis: A Systematic Review of the Literature and
Causal Network Analysis. Eur Urol Focus 3(2017) 72-81
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GWAS studies in renal stone
disease: the Icelandic study
Oddsson et al Nat Comms 2015
GWAS using data from whole-genome sequencing of
Icelander
sample size of 5419 patients
identification of an intronic sequence variant (rs1256328) in
ALPL (encoding an alkaline phosphatase isoenzyme)
Common allele
Rare allele
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ALPL (alias TNAP tissue non-
specific Alk phosphatase)
Hydrolyses pyrophosphate to free
phosphate
Rare loss of function mutations in
patients with hypophosphatasia
(syndrome with decreased ALP and
elevated urine pyrophosphate, early
loss of teeth, chondrocalcinosis, poor
bone mineralisation)
ALPL expressed in proximal tubule
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Mutations in ABCC6 lead to pseudoksanthoma elasticum,
low pyrophosphate levels and soft tissue calcification
Affect skin, retina and arteries but many pts get renal stones
Humans and KO mice had papillary calcifications (Randall’s
plaques)
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exon sequencing in gene panels
30 genes were investigated (candidate genes)
whole exome sequencing
WES evaluates all 20,000 human genes
How to discover the monogenic
forms of nephrolithiasis?
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Recent genetic studies by the same consortium
show that the likelyhood to identify monogenic
forms of renal stone disease depend on patient
selection
Halbritter J et al. Fourteen monogenic genesaccount for 15% of nephrolithiasis/nephrocalcinosis. J Am SocNephrol. 26:543-551, 2015
Braun et al. Monogenetic Genes in Early-Onset Urinary Stone Disease. Clin J Am Soc Nephrol 11: 664–672, 2016
Daga et al. Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis. Kidney Int 2017 35%
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Fourteen monogenic genes cause ~15% of stones
256 consecutive recurrent SF;
16 nephrocalcinosis;
166 adults
106 children
30 genesGLUT9 NHERF1 NaPi2c Adenylate cyclase 10
Paediatric
Adult
(Halbritter et al, JASN, 2015)
40 cases of inherited
disorders
14 different disorders
(22 cystinuria)
Cys tp B 19 cases Cys tp A 3 cases
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Lieske et al. Stone composition as a function of
age and sex. Clin J Am Soc Nephrol. 2014 Dec
5;9(12):2141-6.
No. of stone
analyzed
% cystine
stones
Spivacow
SR
Argentina, 2016 715 0.6
Rellum
DM
The Netherlands
2014
71 children 10
Sun X China 2011 189 children 9
Zafar MN Pakistan 2017 976 children 1.2
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Genetic disorders1. dRTA with deafness
2. Hypophosphatemic nephrolithiasis/osteoporosis-1, NPHLOP1 / Fanconi
renotubular syndrome 2
3. Renal hypouricemia, RHUC2
4. Dent disease, tp 1
5. Familial hypomagnesemia with hypercalciuria & nephrocalcinosis
6. Hypophosphatemic nephrolithiasis/osteoporosis-2, NPHLOP2
7. Primary hyperoxaluria, type 1
8. 1,25-(OH) D-24 hydroxylase deficiency , infantile Hypercalcemia
9. Hypophosphatemic rickets with hypercalciuria
10. Renal hypouricemia, RHUC1
11. Cystinuria, type B
12. Primary dRTA, dominant / recessive
13. Cystinuria, type A
14. Idiopathic (absorptive) hypercalciuria, susceptibility
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65 individuals from 51 families (some with consanguinity)
with NL or a finding of NC (27 cases) on renal ultrasound or
both, who manifested before the age of 25 years.
1. Families with pts with recurrent
NL
2. Families with NC
3. Consanguinity
4. NL/NC manifested before the
age of 25 years
Daga et al. Whole exome sequencing frequently
detects a monogenic cause in early onset
nephrolithiasis and nephrocalcinosis Kidney Int 2017
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Daga et al. Whole exome sequencing frequently
detects a monogenic cause in early onset
nephrolithiasis and nephrocalcinosis Kidney Int 2017
10 genes
were mutated Total cases solved 34%
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Finding in a Pakistani
cohort
7%
2/3 of cases: Idiopathic infantile
hypercalcemia (with hypercalciuria)
(NaP 2a carrier; SLC34A1)
1 cystinuria
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The ability to identify causative
mutations by genetic tests
depends on the selection criteria
of the studied population.
HIGHER DETECTION RATES IN:
• YOUNGER AGE OF ONSET OF NL/NC (<3 YRS: 58%)
• PRESENCE OF MULTIPLE MEMBERS AFFECTED IN A
FAMILY (41%)
• PRESENCE OF CONSANGUINITY (75%)
• TERTIARY REFERRAL CENTER
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Toka HR, Genovese G, Mount DB, Pollak MR, Curhan GC.
Frequency of rare allelic variation in candidate genes among
individuals with low and high urinary calcium excretion.
PLoS One. 2013
association of rare allelic variants with extremes of 24-hour urinary calcium excretion …. 40 candidate genes potentially related to urinary calcium excretion …….480 hypercalciuric stone formers from the Nurses’ Health Studies I & II and the Health Professionals Follow-up Study…..primers were designed to target all 497 exons of the 40 candidate genes, including, 50 bp of intronic sequence flanking each exon.
Our study does not support the hypothesis that rare, presumably functional allelic variants in the
tested genes influence urinary Ca2+
excretion.
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In stone formers diagnosing a monogenic disease allows to
provide a specific etiologic diagnosis in NL/NC
delay progression to CKD/ESRD
enable personalization of the treatment plan
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A detailed clinical and biochemical phenotyping of renal stone formers and the familial pattern of inheritance are still very important since they can point toward an underlying molecular genetic diagnosis.
Send all stones for analysis
Measure Calcium, PTH
Spot urine for cystine is useful in all
Beware ESKD with a history of
stones/nephrocalcinosis/crystal deposition on renal
biopsy
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Clues of inherited renal stones
Early onset
Family cases
Consanguinity of parents
Highly active stone disease (bilateral, multiple stones, very recurrent)
Associated nephrocalcinosis
Renal hyperechogenicity
Tubular dysfunction and related manifestations (statural growth deficit, poliuria)
Renal failure
Extrarenal manifestations (Sensorineural hearing disorders, ocular abnormalities, neurological disorders)
Stone composition
Crystalluria
Monohydrate CaOx (whewellite)
Cystine
Dihydroxyadenine
Xanthine
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Which approach to genetics in
diagnosing nephrolithiasis?
Rapidly evolving
Targeted panel/Candidate gene approach will solve 10-20%
GWAS Individualised genetic risk profile
(SNP/WES/WGS) will give “predictive” info on
remaining
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Which approach to genetics in
diagnosing nephrolithiasis?
Rapidly evolving
Targeted panel/Candidate gene approach will solve 10-20% in selected cases
GWAS Individualised genetic risk profile
(SNP/WES/WGS) will give “predictive” info on
remaining