Tubulointerstitial kidney disease

The clinical presentation of tubulointerstitial kidney disease (TKD) is non-specific, with often normal (bland) urinalysis and progressive chronic kidney disease. Renal biopsy may show interstitial fibrosis and/or tubular atrophy but biopsy results are often non-specific and may not be required for diagnosis. Adult-onset TKDs are typically inherited as autosomal dominant disorders and childhood-onset TKDs are typically autosomal recessive.

In adults

• Slow decline in kidney function starting in teens or early adulthood progressing to kidney failure/end-stage renal disease (ESRD) in mid-to-late adulthood.
• Typically no haematuria or significant proteinuria (bland urinalysis).
• Hyperuricemia and/or gout, often before a significant decline in kidney function is apparent.
• First-degree relative(s) with a similar presentation or unexplained ESRD.
• Renal ultrasound scan is often unremarkable early in the course of the disease, although medullary cysts may be noted in advanced disease. Renal size is usually normal or reduced.
• Non-specific findings including interstitial fibrosis and tubular atrophy on renal biopsy (not necessary for diagnosis).

In children

Nephronophthisis, an autosomal recessive condition, with isolated kidney disease is the most common presentation of TKD in childhood. Presenting features in children include:

• Polyuria and polydipsia resulting from reduced urine-concentrating ability.
• Chronic anaemia and/or growth restriction.
• Proteinuria (usually mild) due to hypertension (usually a late finding).
• Normal or small-sized kidneys with increased echogenicity and reduced corticomedullary differentiation on renal ultrasound.
• Non-specific findings from renal biopsy, which is not necessary for diagnosis.
• 10%–20% of cases may also have some additional extrarenal features such as liver disease, retinal dystrophy, intellectual disability, skeletal dysplasia and/or polydactyly.

Note that children with infantile-onset nephronophthisis may present with features of oligohydramnios sequence in the neonatal period with severe hypertension and rapid progression to kidney failure/end-stage renal disease. Renal ultrasound scanning typically shows bilateral enlarged, cystic kidneys.

Pathogenic variants in UMOD and MUC1 are responsible for the majority of cases of adult-onset TKD. Other genes with overlapping clinical presentation include HNF1B, DNAJB11, REN and SEC61A1. These conditions are autosomal dominant and there is often a family history of chronic kidney disease across multiple generations.

Genes for TKDs can be routinely tested through the use of the following gene panel: R202: Tubulointerstitial kidney disease. However, a recurrent variant in MUC1 is responsible for most MUC1 associated cases and cannot be routinely detected using this approach as it lies within a complex variable number tandem repeats (VNTR) region. Testing may be available in a small number of laboratories worldwide by special arrangement.

In contrast, most childhood-onset TKDs are inherited as autosomal recessive conditions. Childhood-onset nephronophthisis most commonly results from biallelic variants in NPHP1, with a high proportion of patients homozygous for a common 290kb deletion at chromosome 2q13 including the NPHP1 gene. Many other genes account individually for a small proportion of patients with syndromic or non-syndromic presentation of children with nephronophthisis.

For information about genomic testing, see ‘Adult with unexplained chronic kidney disease’. This includes expert assessment of the clinical presentation, renal biopsy findings if available and the results of genomic testing. The R202 gene panel is used where there is a strong suspicion of ADTKD, although it will not identify patients with MUC1-kidney disease as there are still technical challenges for identifying variants in this gene that occur in a complex region of multiple VNTR. Please discuss availability of alternative routes of testing with your local Genomic Laboratory Hub (GLH).

Adult-onset TKDs are usually inherited as autosomal dominant disorders.

• Individuals affected by an autosomal dominant condition have one working copy of the gene and one with a pathogenic variant.
• The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
• Incomplete penetrance can occur, meaning that not everyone who has the variant will develop the disease.

Children presenting with nephronophthisis usually have an autosomal recessive disorder.  If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:

• 25% (1-in-4) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
• 50% (1-in-2) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a carrier; and a
• 25% (1-in-4) chance of a child inheriting both unaffected copies and being neither affected nor a carrier.

In adults

• Baseline assessment of blood pressure, serum creatinine, serum urate and renal ultrasound scanning to establish disease severity.
• Prevention of gout with allopurinol.
• Monitoring of kidney function and preparation for renal replacement therapy when end-stage renal disease is likely.
• Progress of chronic kidney disease is usually slow, allowing adequate time for planned renal transplantation. Primary disease does not recur in the transplanted kidney.

In children

• Baseline assessment of blood pressure, serum creatinine, haemoglobin, liver function, growth and developmental parameters to establish disease severity.
• Abdominal ultrasound scan to detect renal, liver or biliary tract abnormalities.
• Based on genetic diagnosis and/or clinical history, further assessment for extra-renal manifestations in syndromic nephronophthisis may include:
  • neurologic assessment including brain MRI; and
  • echocardiography and/or ophthalmic assessment for retinal dystrophy.
• Renal transplantation when ESRD is reached. Nephronophthisis does not recur in the transplanted kidney.

For clinicians

• GeneReviews: Autosomal Dominant Tubulointerstitial Kidney Disease – MUC1
• GeneReviews: Autosomal Dominant Tubulointerstitial Kidney Disease – UMOD
• GeneReviews: Nephronophthisis-Related Ciliopathies
• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• NHS England: National Genomic Test Directory

For patients

Adults:

• Kidney Care UK: Autosomal dominant tubulointerstitial kidney disease (ADTKD)
• UK Kidney Association: Autosomal Dominant Tubulointerstitial Kidney Disease

Children:

• UK Kidney Association: Nephronophthisis