Presentation: Adult with unexplained chronic kidney disease

A 44-year-old man is referred due to a progressive decline in his kidney function (eGFR dropped from 60 ml/min/1.73m2 to 36 ml/min/1.73m2 over ten years). A biopsy shows tubulointerstitial fibrosis and ultrasound shows small, echogenic kidneys. Urine PCR is 28 mg/mmol Cr and he has no haematuria.  He has had multiple episodes of gout since his early 20s. His father and a paternal aunt (both deceased) had chronic kidney disease with uncertain cause and had dialysis in their 60s.

Genomic testing should be considered when there is:

• renal impairment/chronic kidney disease caused by tubulointerstitial fibrosis with no glomerular lesion, with no identifiable cause, often associated with medullary cysts, hyperuricaemia or gout; and
• a first-degree relative with tubulointerstitial kidney disorders (TIKD) or unexplained kidney failure.

If end stage renal disease has developed at a younger age (under 36), then additional/broader-scale genomic testing may be possible using a whole genome sequencing approach.

• Consult the National Genomic Test Directory. From this link 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 Genomic testing in the devolved nations.
  • For information about the genes that 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:
  • R202 Tubulointerstitial kidney disease: This indication should be the first choice when a patient meets the above criteria. It is a medium-sized gene panel test and includes multiplex ligation-dependent probe amplification (MLPA).
  • R193 Cystic renal disease: This indication should be used in the context of an adult presenting with renal cysts on ultrasound if the appearance suggests an alternative diagnosis to tubulointerstitial kidney disease. This includes a whole genome sequencing (WGS) panel. See ‘Adult with unexpected finding of multiple kidney cysts’.
  • R257 Unexplained young onset end-stage renal disease: This indication should be used for patients up to the age of 36 presenting with unexplained end-stage renal disease where no cause has been identified by clinical assessment, biochemistry, imaging or biopsy.  This test includes a WGS panel. See ‘Child or young person with unexplained end-stage renal disease’ and ‘Neonate with unexplained end-stage renal disease’.
  • R240 Diagnostic testing for known mutation(s): This indication can be used for a patient who is clinically affected by chronic kidney disease, gout or renal cysts if a member of the family already has a known pathogenic or likely pathogenic gene variant. The laboratory will only test for the known familial variant.
  • R242 Predictive testing for known familial mutation(s): This is a predictive (also known as presymptomatic) test that can be used for an unaffected individual if a pathogenic or likely pathogenic variant has already been identified in a relative. This test can only be requested by clinical genetics.
• For tests that do not include WGS, including R202, R240 and R242 you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms.
• For tests that are undertaken using WGS, including R193 and R257, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents where available, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for WGS for support in completing WGS-specific forms); and
  • complete an NHS GMS record of discussion (RoD) form for each person being tested – for example if you are undertaking trio testing of an affected individual and their parents, you will need to complete three forms (see How to complete a RoD form for support).
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• European Renal Association: Understanding the pathophysiology and genetics of Autosomal dominant tubulointerstitial kidney disease (ADTKD) e-seminar
• GeneReviews: Autosomal Dominant Tubulointerstitial Kidney Disease – MUC1
• GeneReviews: Autosomal Dominant Tubulointerstitial Kidney Disease – REN
• GeneReviews: Autosomal Dominant Tubulointerstitial Kidney Disease – UMOD
• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• NHS England: National Genomic Test Directory
• Orphanet (information about rare diseases and orphan drugs)
• US National Library of Medicine: Autosomal dominant tubulointerstital kidney disease

For patients

• • Kidney Care UK: Autosomal dominant tubulointerstitial kidney disease (ADTKD)
  • National Registry of Rare Kidney Diseases (RaDaR)
  • UK Kidney Association: Autosomal Dominant Tubulointerstitial Kidney Disease