Presentation: Adult with non-nephrotic range proteinuria

A 20-year-old lady presents with frothy urine, non-nephrotic proteinuria (approximately 1g/day) and progressive decline in kidney function associated with hypertension. There is no haematuria, no history of hearing loss and no known family history of renal disease. Renal ultrasound is normal with no cysts. Renal biopsy shows focal segmental glomerulosclerosis (FSGS) with no tubular atrophy and immuno-staining is negative. She has been thinking about starting a family in the next few years.

There is a broad range of rare genetic causes of non-nephrotic range proteinuria presenting in adulthood. Monogenic forms of FSGS can present in adulthood and proteinuria can be below nephrotic range. For example genetic variants in INF2 are a cause of autosomal dominant FSGS.

Genomic testing could be valuable for anyone with a positive family history, in cases with early onset and when a genetic diagnosis could aid management, such as the use of immunosuppression.

Consider genomic testing for:

• steroid-resistant nephrotic syndrome presenting at any age; or
• proteinuria associated with:
  • FSGS or diffuse mesangial sclerosis (DMS) on biopsy;
  • no identifiable cause; and
  • where transplant or immunosuppression is planned.

• 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 non-nephrotic proteinuria in adults there are a number of available tests including:
  • R195 Proteinuric renal disease: This indication can be used for individuals who meet the criteria above. This includes a whole genome sequencing (WGS) panel.
  • R202 Tubulointerstitial kidney disease: This indication can be considered for individuals who have tubulointerstitial fibrosis with no glomerular lesion and no identifiable cause and a first-degree relative with tubulointerstitial kidney disease (TIKD) (often associated with medullary cysts, hyperuricaemia, or gout) or unexplained end-stage renal disease. This test includes a small gene panel and multiplex ligation-dependent probe amplification (MLPA). See ‘Adult with unexplained chronic kidney disease’.
  • R194 Haematuria: This indication can be used if the patient has persistent haematuria and one of the following: histological evidence of Alport syndrome or thin basement membrane disease; clinical features of Alport syndrome; or a first-degree relative with haematuria or unexplained chronic renal failure. See ‘Adult with microscopic haematuria’ and ‘Child with haematuria (blood in the urine)’.
  • R257 Unexplained young onset end-stage renal disease: This indication can be considered in individuals presenting with unexplained end-stage renal disease under the age of 36, where no cause has been identified by clinical assessment, biochemistry, imaging or biopsy. This 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 with non-nephrotic proteinuria, if a member of the family already has 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 predictive (also known as presymptomatic) testing for unaffected individuals who have a relative with a known pathogenic or likely pathogenic variant. This test can only be requested by clinical genetics.
• For WGS-based tests, including R195 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.
• For tests that do not include WGS, including R202, R194, R240 and R242:
  •  you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms.
• These tests are DNA-based, so an EDTA sample (purple-topped tube) is required.

For clinicians

• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• KDIGO: Clinical Practice Guideline for the Management of Glomerular Diseases
• NHS England: National Genomic Test Directory

References:

• Mabillard H, Olinger E, Sayer JA. ‘Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease’. Nephrology Dialysis Transplantation 2023: volume 38, issue 2, pages 271–282. DOI: 10.1093/ndt/gfab268
• Cameron-Christie S, Groopman E, Marasa M and others. ‘Diagnostic Utility of Exome Sequencing for Kidney Disease’. The New England Journal of Medicine 2019: volume 380, issue 2, pages 142–151. DOI: 10.1056/NEJMoa1806891
• Nguyen T, Snoek R, van der Zwaag B and others. ‘Importance of Genetic Diagnostics in Adult-Onset Focal Segmental Glomerulosclerosis’. Nephron 2019: volume 142, issue 4, pages 351–358. DOI: 10.1159/000499937

For patients

• Kidney Research UK: What is focal and segmental glomerulosclerosis?
• National Kidney Foundation: Focal Segmental Glomerulosclerosis (FSGS)
• UK Kidney Association: RaDaR (the rare disease registry) – information on the latest research