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Nephrology

Presentation: Child or young person with unexplained end-stage renal disease

Over a third of children presenting with unexplained end-stage renal disease may have an underlying monogenic cause. Establishing a genetic diagnosis can inform management, treatment and genomic counselling decisions.

Example clinical scenario

A 13-year-old girl presents to her GP with symptoms of leg pain, polyuria and lethargy. Clinically the child appears well, however blood tests are consistent with chronic kidney disease stage 5 and she is subsequently admitted to hospital. A renal ultrasound shows small kidneys and a renal biopsy was inconclusive. No clear cause is identified and management options, including dialysis and transplantation, are discussed with the family.

When to consider genomic testing

  • Consider genomic testing in the following cases:
    • Unexplained young-onset end-stage renal disease under the age of 36, if no cause has been identified by clinical assessment, biochemistry, imaging or renal biopsy.
    • Unexplained end-stage renal disease associated with:
      • atypical growth patterns (overgrowth, asymmetric growth);
      • extra-renal features (for example ocular, hearing loss, neurological, gastrointestinal);
      • a family history of a renal condition or syndrome;
      • dysmorphic facial features or congenital malformations (where targeted testing is not possible); and/or
      • a syndrome, or atypical growth, with intellectual disability or developmental delay.
    • Unexplained end-stage renal disease in patients over the age of 36 if there is a strong clinical suspicion of a monogenic disorder after expert clinical review.
  • Semi-rapid testing can be requested in acutely unwell children or adults where monogenic young onset end-stage renal disease is considered highly likely to be the primary cause of the phenotype. Cases should meet the standard eligibility criteria for test R257 in the National Genomic Test Directory (see more information below). The clinical team should establish that:
    • testing will or could provide an immediate change to treatment or clinical management of the patient, for example by informing decisions about renal transplant, therapeutic intervention or prenatal testing for an ongoing at risk pregnancy; and
    • the patient is either not eligible for the R14 pathway for acutely unwell children or rapid R257 testing is considered to be the more appropriate test.

What do you need to do?

  • 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.
  • Decide which of the available tests best suits the needs of your patient/family:
    • R257 Unexplained young onset end-stage renal disease: This indication should be considered for patients under 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 is carried out using whole genome sequencing (WGS).
    • If there are additional features that suggest a particular diagnosis, consider the following tests:
      • R199 Congenital anomalies of the kidney and urinary tract – familial: This indication should be used if there are clinically significant non-syndromic congenital anomalies of the kidney and urinary tract (CAKUT) and the patient has a first-degree relative with CAKUT or unexplained kidney failure. See ‘Child with an ectopic kidney’. This test uses microarray.
      • R194 Haematuria: This indication should be used if you think your patient has features suggestive of Alport syndrome, including a first-degree relative with haematuria or unexplained renal failure. This is a small panel test. See ‘Adult with microscopic haematuria‘ and ‘Child with haematuria (blood in the urine)‘.
      • R195 Proteinuric renal disease: Use this indication if your patient has: steroid-resistant nephrotic syndrome presenting at any age; proteinuria with a histological picture of focal segmental glomerulosclerosis (FSGS); or diffuse mesangial sclerosis (DMS) with no identifiable cause. This test uses WGS. See ‘Adult with steroid-resistant nephrotic syndrome’, ‘Adult with non-nephrotic range proteinuria’ and ‘Child with non-nephrotic range proteinuria’.
      • R196 CFHR5 nephropathy: This indication is for a single gene test and should be considered if your patient has C3 glomerulopathy, unexplained haematuria or renal failure and is of Cypriot ancestry. See ‘Patient of Cypriot descent presents with reduced renal function and microscopic haematuria‘.
      • R197 Membranoproliferative glomerulonephritis including C3 glomerulopathy: This indication should be considered in the context of idiopathic membranoproliferative glomerulonephritis (MPGN) or C3 glomerulopathy with onset before the age of 18. This is a small panel test using multiplex ligation-dependent probe amplification (MLPA). See ‘Young person with idiopathic C3 glomerulopathy’.
      • R202 Tubulointerstitial kidney disease: This indication is suitable if your patient has tubulointerstitial fibrosis with no glomerular lesion and no identifiable cause, often associated with medullary cysts, hyperuricaemia, or gout, if they have a first-degree relative with tubulointerstitial kidney disease (TIKD) or unexplained end-stage renal disease. See ‘Adult with unexplained chronic kidney disease’.
      • R27 Paediatric disorders and R89 Ultra-rare and atypical monogenic disorders: These indications should be considered for individuals with complex or syndromic presentations. R27 includes microarray and a WGS ‘super-panel’. R89 includes microarray and WGS panels selected by the requesting clinician. Both require authorisation from clinical genetics.
      • R240 Diagnostic testing for known mutation(s): This indication is suitable for those who are clinically affected with renal disease and have a family member with a known pathogenic or likely pathogenic 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 for those who are unaffected but have a relative with a known pathogenic or likely pathogenic variant. This test requires authorisation from clinical genetics.
  • For WGS-based tests, including R257, R27, R195 and R89 you will need to:
  • For tests that do not include WGS, including R199, R194, R196, R197, R202, R240 and R242:
  • These tests are DNA-based, so an EDTA sample (purple-topped tube) is required.

Resources

For clinicians

References:

For patients

  • infoKID (information for parents and carers of children with kidney conditions)
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  • Last reviewed: 13/06/2024
  • Next review due: 13/06/2025
  • Authors: Dr Felicity Beal
  • Reviewers: Dr Danielle Bogue, Professor R Sandford, Professor John A Sayer

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