Presentation: Adult with unexplained chronic kidney disease

A 44-year-old man is referred to hospital due to progressive decline in his kidney function. His eGFR has dropped from 60 ml/min/1.73m2 to 36 ml/min/1.73m2 in the last ten years. A kidney biopsy shows tubulointerstitial fibrosis and kidney ultrasound shows small, echogenic kidneys. He does not have haematuria and urine PCR is 28 mg/mmol Cr.  He has had multiple episodes of gout, the first of which was in 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.

Note that: Exceptions may be made for patients where the clinical presentation is suggestive of a monogenic aetiology but the family history is unknown, for example if the patient was adopted.

• 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:
  • 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.
  • 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.
• Note: Testing for variants in MUC1, which are a major cause of autosomal dominant tubulointerstitial kidney disease, is not currently available through the test directory. Please contact your local Genomic Laboratory Hub (GLH) for information about alternative testing routes.
• For tests that do not include WGS, including R202, R240 and R242:
  • You can use your local GLH test order and consent (record of discussion) forms.
• For WGS-based tests, including R193 and R257, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband). Include 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); and
  • complete an NHS GMS record of discussion form for each person being tested. (This is typically one form for an affected individual, but 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 record of discussion form for support.
• These tests are DNA-based, so an EDTA sample (purple-topped tube) is required.

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)
• UK Kidney Association: Autosomal Dominant Tubulointerstitial Kidney Disease