The Genetics of

Nephrolithiasis
DR. NOFFI JULIA
Introduction
Renal stone formation (or nephrolithiasis)  common problem worldwide
◦ Prevalence : 3.8% (1976–1980)  5.2% (1988–1994)

Renal stone formation  multifactorial

◦ Environmental : Diet (fructose)
◦ Anatomical
◦ Genetic factors : Hypertension, Metabolic syndrome

Type of stone : calcium-containing stones (75%)

Introduction

Table 1. Major risk factors for renal stone formation

Hypercalciuria
Common metabolic abnormality found in both adult and child stone formers
Urinary calcium concentration :
◦ Absorptive hypercalciuria : increased gastrointestinal calcium resorption
◦ Renal hypercalciuria : defects in renal tubules for calcium reabsorption
◦ Increased bony resorption

The genetic : 20% of patients with idiopathic hypercalciuria have a family history of stones
Absorptive Hypercalciuria caused by mutation on:
◦ Calcium-Sensing Receptor (CASR) Mutations and Hypercalciuria
◦ Vitamin D Receptor (VDR) Polymorphisms
◦ Claudin-16 Mutations
Hypercalciuria
Calcium-Sensing Receptor (CASR) Mutations and Hypercalciuria
◦ CASR gene encodes calcium-sensing receptor protein (parathyroid gland, bone, intestine, thyroid gland)
◦ CASR control serum calcium concentrations by stimulating PTH secretion.
◦ PTH stimulating conversion 25-hydroxyvitamin D - 1,25-dihydroxyvitamin D & promoting calcium
reabsorption in the distal convoluted tubule (DCT).
◦ Mutations in CASR  change the set-point of the sensor (increase feedback threshold)

Vitamin D Receptor (VDR) Polymorphisms

◦ VDR polymorphisms  ‘resorptive’ type hypercalciuria

Claudin-16 Mutations
◦ Paracellular calcium and magnesium resorption
Hyperoxaluria
Found in around 10 - 20% of stone formers
SLC26A6 genes : regulate serum oxalate concentrations
◦ Mechanism :
◦ Hyperabsorption of oxalate
◦ Failure of oxalate secretion into the gut
◦ raised serum oxalate

‘microbiome’ = gut organisms that influence bodies’ metabolism

◦ Oxalobacter formigenes (anaerobic commensal organism)  degrade oxalate from the diet using its
enzyme oxalyl-CoA decarboxylase.
◦ Low rates of colonization  hyperoxaluria
Hyperuricosuria
2–8% of children with nephrolithiasis
Human urate transporter 1 (hURAT1) and loss of function mutations have been found in subjects
with idiopathic renal hypouricaemia and nephrolithiasis
Other medical causes :
◦ Myeloproliferative disorders
◦ Chronic diarrhoeal states
◦ Insulin resistance
◦ Monogenic metabolic disorders
Cystinuria
5% of paediatric stones, 1–2% of adult stones
median age at onset : 12 years
An autosomal recessive disorder at SLC3A1 and SLC7A9 genes (25%)
◦ Plus 75% : other unknown gene defects
Hypocitraturia
Citrate : natural inhibitor of stone formation in the urine
Chronic metabolic acidosis  increase proximal tubular citrate absorption  stone formation.
Mutation : SLC13A5 genes
REMEMBER : monogenic forms of renal tubular acidosis  hypocitraturia and hypercalciuria 
nephrocalcinosis and nephrolithiasis.
Pyrophosphate Defects
Inorganic pyrophosphate (PPi) : normal component of urine  a potent inhibitor of calcification
◦ Bind to basic calcium phosphate crystals surface  blocks crystal growth.

Mutations Ppi transporter (ANKH)  Hypopyro phosphaturia, give severe phenotypes :

◦ Hypermineralisation disorder known as cranio-metaphyseal dysplasia
◦ Calcium pyrophosphate dihydrate deposition disease (CCAL2)
Other Genetic Considerations
Medullary sponge kidney  congenital collecting duct abnormalities  redispose to calcium
salt precipitation
Polymorphisms of matrix Gla protein (MGP)  calcification of extracellular matrix
Tamm-Horsfall Protein Defects
The most abundant urinary protein in man
Patients with mutations in gene encoding THP (UMOD), exhibit :
◦ Unexplained hyperuricaemia and gout,
◦ Medullary cystic kidney disease or
◦ Familial juvenile hyperuricaemic nephropathy.

Recurrent calcium stone-forming patients shown to excrete increased quantities of abnormal

THP, with a change in its chemical composition to include more sialic acid residues