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Conditions

Unexplained young-onset end-stage renal disease

It is important to consider possible monogenic causes when dealing with young people who have end-stage renal disease (often called kidney failure) without a known underlying cause.

Overview

Those under the age of 36 who have symptoms of end-stage renal disease requiring supportive treatment with renal replacement therapy (dialysis and/or transplantation) may present as ‘clinically silent’ with non-specific symptoms. The diagnostic odyssey includes ruling out common causes of kidney disease such as diabetes, hypertension and autoimmune diseases. Determining the cause is difficult due to the lack of identifiable risk factors and the potential for a wide range of rare or emerging aetiologies. Genomic testing may be valuable to determine an underlying genomic cause that explains the phenotype.

Clinical features

The clinical features of end-stage renal disease in young people can be wide-ranging and include:

  • lethargy;
  • difficulty concentrating;
  • nausea;
  • poor growth (height);
  • change in urine output (oliguria or polyuria);
  • oedema;
  • hypertension;
  • a history of recurrent urinary tract infections;
  • extra-renal manifestations (for example, hearing loss);
  • anomalies on urine dipstick testing (protein/blood); and
  • a known family history of kidney disease, haematuria or hearing loss.

Genomics

Pathogenic variants in nearly 600 genes have been implicated in monogenic kidney disease and it is estimated that 20%–40% of children waiting for a kidney transplant have an underlying genomic diagnosis. Registry studies show that 10%–15% of adults requiring renal replacement also have a genomic diagnosis.

Conditions associated with end-stage renal disease are clinically and genetically very heterogeneous. Some are associated with syndromic features (for example ciliopathy syndrome, Joubert’s syndrome and HNF1B-related renal cysts and diabetes syndrome) and others with an isolated renal phenotype (for example, the stone-forming condition, cystinuria and the tubular condition, Dent disease).

The following table, which categorises genetic kidney diseases, may be helpful:

Diagnostic category Example diagnosis (with examples of implicated genes)
Congenital anomalies of the kidneys and urinary tract (CAKUT) Renal hypodysplasia (PAX2)

Renal cysts and diabetes syndrome (HNF1B)
Glomerular disease Congenital nephrotic syndrome (NPHS1, NPHS2)
Tubulointerstitial disease Autosomal dominant tubulointerstitial kidney disease (UMOD)

Dent disease (CLCN5)
Cystic kidney disease Autosomal dominant polycystic kidney disease (PKD1)
Syndromic Tuberous sclerosis (TSC1)

Deny’s-Drash syndrome (WT1)

Joubert syndrome (ARL13B)

Bardet-Biedl syndrome (BBS1)
Metabolic Cystinosis (CTNS)

Hyperoxaluria (AGXT)
Immunological Atypical haemolytic uraemic syndrome (CFH)

 

Diagnosis

Common causes of kidney disease, such as diabetes, hypertension and autoimmune diseases should be ruled out by undertaking a medical history, physical examination, laboratory tests and imaging studies. When there is no identifiable cause detectable by renal biopsy, biochemistry, imaging or clinical assessment, genomic testing may be beneficial to determine an underlying cause – especially for patients with early-onset disease, extrarenal features/phenotypes, early onset and a family history.

For information about organising genomic testing see ‘Child or young person with unexplained end-stage renal disease’ and ‘Neonate with unexplained end-stage renal disease’.

Inheritance and genomic counselling

Genetic conditions linked to unexplained end-stage renal disease with onset in children and young adults are varied and have a range of inheritance patterns: autosomal dominant (monoallelic), autosomal recessive (biallelic), X-linked and mitochondrial. Genomic testing using large gene panels reveals a genetic diagnosis in up to a third of individuals tested. The most commonly identified conditions are those linked to COL4 gene variants, nephronophthisis and autosomal dominant tubulointerstitial disease. A broad range of rare monogenic conditions account for the majority of diagnoses, however.

Management

The management of children and young adults with end-stage renal disease is complex and condition-specific. Multi-disciplinary care is essential and patients will almost universally require input from a tertiary paediatric nephrology centre at some stage.

Renal replacement therapy (RRT) in the form of dialysis and/or transplantation is a key component. Besides RRT, medical care focuses on managing the complications associated with end-stage renal disease, which include: renal anaemia, mineral bone disease (CKD-MBD) and cardiovascular disease (hypertension, hyperlipidaemia) as well as other, extrarenal features such as liver disease, vision and hearing loss.

Gene-directed therapies/trials

There are a number of clinical drug trials currently underway for genetic causes of kidney disease, for example for Alport syndrome (ELX-02), hyperoxaluria (nedisoran small interfering RNA therapy) and proteinuric renal disease (sparsentan). For further information, please explore the US National Library of Medicine’s clinical trials resource.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 01/11/2024
  • Next review due: 01/11/2026
  • Authors: Dr Caroline Platt
  • Reviewers: Professor Richard Sandford, Professor John Sayer