Autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) affects about one in 1,000 of the population. Progressive kidney cyst growth leads to chronic kidney disease. About half of patients with ADPKD reach end-stage kidney disease by the age of 60. People with ADPKD comprise about 10% of the kidney transplant population and about 10% of kidney failure patients.

Typical features of ADPKD include:

• Kidneys:
  • progressive growth of fluid-filled kidney cysts, causing progressive chronic kidney disease;
  • enlarged kidneys;
  • cyst haemorrhage and infection;
  • stone formation (50% uric acid, 50% calcium oxalate); and
  • micro-macro albuminuria.
• Liver:
  • progressive growth of fluid-filled liver cysts.
• Gastrointestinal:
  • diverticulosis/diverticulitis;
  • early satiety; and
  • gastro-oesophageal reflux disease (GORD).
• Cardiovascular:
  • increased prevalence of valvular heart disease, including mitral valve prolapse, dilatation of the aortic root and dissection of the thoracic aorta; and
  • intracranial aneurysm (seen in about 10% of patients where there is positive family history).
• Metabolic:
  • hypertension, including early-onset hypertension; and
  • high serum uric acid.
• Other features:
  • acute and chronic pain in the lower back, flank, abdomen and groin (present in up to 60% of patients with ADPKD);
  • hernia (hiatus, umbilical, groin, abdominal wall); and
  • cysts in the pancreas, seminal vesicles and arachnoid membrane.

• Up to 85% of patients with ADPKD have heterozygous pathogenic or likely pathogenic variants in PKD1, causing polycystic kidney disease-1 (PKD1) with or without polycystic liver disease. Those in PKD2 account for up to 15% of patients with ADPKD, causing polycystic kidney disease-2 (PKD2) with or without polycystic liver disease.
• On average, individuals with PKD2 reach kidney failure in their late seventies.
• Individuals with PKD1 will typically reach kidney failure at an earlier age, although there is considerable variability.
• Although genotype-phenotype correlation does exist, in ADPKD there is considerable intra- and inter-familial variability.
• Other factors, including hypertension, high body mass index and high salt intake are thought to affect disease progression and severity.
• There are currently five other genes associated with an ADPKD-like phenotype in 1%–2% of patients:
  • GANAB, causing polycystic kidney disease-3 with or without polycystic liver disease (PKD3);
  • DNAJB11, causing polycystic kidney disease-6 with or without polycystic liver disease (PKD6);
  • ALG5, causing polycystic kidney disease-7 (PKD7);
  • ALG9; and
  • IFT140.

• Most diagnoses of ADPKD are made based on finding typical features on imaging and a positive family history of cystic kidney disease.
• If a patient has no family history (either because family members have not undergone screening or the disease has arisen de novo) or ultrasound images that are not typical of ADPKD, genomic testing may be warranted, based on eligibility criteria in the National Genomic Test Directory (R193 Cystic renal disease).
• For information about testing see: ‘Child with cystic renal disease’, ‘Patient with polycystic kidney disease planning a pregnancy’ and ‘Adult with unexpected finding of multiple kidney cysts’.
• Up to 40% of patients with polycystic kidney diseases, without a positive family history, have causative variants in genes other than PKD1 or PKD2 (this is especially likely in younger patients).
• There are a significant number of genetic conditions associated with kidney cysts that require differentiation from ADPKD. For further information, see this article from the Journal of Clinical Medicine.
• ADPKD is diagnosed clinically based on the Pei Criteria, using age-specific ultrasound criteria. More recently, MRI criteria have also been developed to support with diagnosis. These criteria can help increase confidence in excluding the diagnosis, especially for potential living related kidney donors.
• PRO-PKD score and Mayo imaging classification are helpful prognostic tools. While the PRO-PKD score algorithm uses genomic information, Mayo imaging classification uses MRI to assess total kidney volume. Clinical factors that negatively impact prognosis include:
  • male sex;
  • a family history of kidney failure;
  • hypertension before the age of 35;
  • urological complications before the age of 35;
  • PKD1 loss of function variants; and
  • larger kidney volume.

• ADPKD is an autosomal dominant condition.
  • 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%).
  • ADPKD usually demonstrates complete penetrance.
• After family screening, about 10% of people with ADPKD are found to have no family history, and most likely represent de novo cases.
• ADPKD is generally a late-onset multisystem condition. Genomic counselling/testing should therefore be delayed until an appropriate age (at least the age of 16). There are, however, important management considerations for children and young people – see ‘Management’ below.
• When assessing potential living related kidney donors, The British Transplantation Society and Renal Association recommend that genomic testing (and counselling) is offered where available.

• Risk stratification to predict the age at which the patient might reach kidney failure, with the help of existing prognostic tools, is the first step in management. If the risk of developing kidney failure is high (rapidly progressive disease), treatment with a vasopressin V2-receptor antagonist (tolvaptan), to slow cyst growth, should be discussed.
• Meticulous blood pressure control using renin-angiotensin system (RAS) inhibitors is the main intervention to protect renal function.
• Other metabolic disorders, such as hyperlipidaemia, diabetes and high BMI, should be addressed.
• The symptoms of kidney cysts, including both acute and chronic kidney pain, should be managed to improve a patient’s quality of life.
• Assessment of the need for a kidney transplant, and any necessary referrals, should be timely. There is no risk of recurrence of ADPKD following transplantation.

Children and young people

• Addressing early-onset hypertension is important to slow the progression of chronic kidney disease. Bi-annual blood pressure checks should start between the ages of five and 10.
• Clinical guidelines for the diagnosis and management of ADPKD in children and young people and monitoring of children and young people with, or at risk of, developing ADPKD are available.

For clinicians

• DynaMed (clinical decision support and shared decision-making tools): Autosomal Dominant Polycystic Kidney Disease (ADPKD)
• GeneReviews: Polycystic Kidney Disease, Autosomal Dominant
• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• KDIGO: Clinical Practice Guideline for the Evaluation, Management, and Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)
• NHS England: National Genomic Test Directory
• National Institute for Health and Care Excellence: Tolvaptan for treating autosomal dominant polycystic kidney disease
• Online Mendelian Inheritance in Man (OMIM): #173900, #600666, #613095, #618061, #620056
• UK Kidney Association: Annual Report 2021
• UpToDate (clinical decision support resource): Autosomal dominant polycystic kidney disease (ADPKD): Treatment

References:

• Dudley J, Winyard P, Marlais M and others. ‘Clinical practice guideline monitoring children and young people with, or at risk of developing autosomal dominant polycystic kidney disease (ADPKD)‘. BMC Nephrology 2019: volume 20, issue 148. DOI: 10.1186/s12882-019-1285-2
• Gimpel C, Bergmann C, Bockenhauer D. ‘International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people‘. Nature Reviews Nephrology 2019: volume 15, pages 713–726. DOI: 10.1038/s41581-019-0155-2

For patients

• PKD Charity