Presentation: Young person with nephrocalcinosis

An 18-year-old man presents with distal renal tubular acidosis (dRTA) and nephrocalcinosis on ultrasound. He had presented with hypokalaemia, low serum bicarbonate and acidic urine at two months of age and has been on sodium bicarbonate supplementation since. He has normal hearing, and there is no history of renal stones, previous fractures, osteoporosis or anaemia. There is no relevant family history. His parents are consanguineous.

• You should consider genomic testing when acquired causes have been excluded. Some of the more common acquired causes include:
  • autonomous hyperparathyroidism;
  • medullary sponge kidney;
  • idiopathic hypercalciuria;
  • autoimmune conditions (consider undertaking autoantibody screening; consider systemic lupus erythematosus (SLE) and Sjogren’s syndrome, especially);
  • renal papillary necrosis;
  • drugs including loop diuretics;
  • chronic hypokalaemia;
  •  sarcoidosis;
  • hypervitaminosis D/vitamin D therapy; and
  • milk alkali syndrome.
• A family history of nephrocalcinosis or nephrolithiasis increases the likelihood of a genetic cause but is not an essential requirement for genomic testing. Nephrolithiasis is common (1:12 lifetime risk).
• If there are features of medullary sponge kidney (MSK) on CT-KUB, genomic testing is not recommended. The exact cause of MSK is unknown and there is currently no known monogenic cause.

• Consult the National Genomic Test Directory. Here you can access the rare and inherited disease eligibility criteria document for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our Knowledge Hub resource ‘Genomic testing in the devolved nations’.
  • To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed-Off Panels Resource.
• Decide which of the panels best suits the needs of your patient/family. For patients with nephrocalcinosis there are a number of options, including:
  • R256 Nephrocalcinosis or nephrolithiasis: This indication can be used to investigate patients with nephrocalcinosis or nephrolithiasis when acquired causes have been excluded. This test uses a medium-sized gene panel – which may also be performed via whole exome sequencing (WES) – and multiplex ligation-dependent probe amplification (MLPA), to examine those genes associated with renal tract calcification.
  • R198 Renal tubulopathies: This indication is suitable for individuals presenting with features of tubulopathies. This test includes a medium-sized gene panel (which may also be done via WES) and MLPA and examines those genes associated with renal calcium malabsorption. See ‘Adult with hypokalaemic metabolic alkalosis’, ‘Patient with suspected pseudohypoaldosteronism type 2’, and ‘Patient with incidental finding of asymptomatic hypercalcaemia’.
  • R240 Diagnostic testing for known mutation(s): This indication may be suitable if a patient is clinically affected with nephrocalcinosis or nephrolithiasis and has a family member with a known pathogenic or likely pathogenic gene variant. In this situation, the laboratory will only test for the known familial variant.
  • R242 Predictive testing for known familial mutation(s): This indication is for a predictive (also known as presymptomatic) test and should be used if an unaffected individual has a family member with a known pathogenic or likely pathogenic variant. It can only be requested by clinical genetics.
• The tests listed above do not include whole genome sequencing (WGS). For these tests:
  •  You can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms.
  • When testing in children, parental samples may be needed for interpretation of the proband’s result, for example to determine whether a variant is de novo or inherited. These samples may be requested by the testing laboratory or you may wish to contact clinical genetics.
• Note that different forms are required for any test involving WGS.
• These tests are DNA-based, so an EDTA sample (purple-topped tube) is required.

For clinicians

• GeneReviews: Hereditary Distal Renal Tubular Acidosis
• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• NHS England: National Genomic Test Directory
• NHS Greater Glasgow and Clyde: Nephrolithiasis and/or nephrocalcinosis (management and evaluation)
• NICE Guidelines:  Renal and ureteric stones: assessment and management

References:

• Harris PC, Lieske JC, Sas DJ and others. ‘The genetics of kidney stone disease and nephrocalcinosis’. Nature Reviews Nephrology 2022: volume 18, pages 224–240. DOI: 10.1038/s41581-021-00513-4

For patients

• dRTA Support Group
• National Kidney Foundation: Distal Renal Tubular Acidosis (dRTA): What is dRTA and how is it diagnosed?