Chapter 3 - Genetic Kidney Diseases
Age of presentation and the number and distribution of cysts are key features distinguishing acquired from inherited cystic disease. Solitary cysts arising in adulthood are more likely to be benign, whilst numerous bilateral cysts in childhood or early adulthood are more suggestive of inherited disease¹⁹.
Inherited cystic kidney diseases arise from pathogenic variants in any of around 100 genes involved in renal cystogenesis²⁰. Presentations can range from simple cysts and dysplasia, as part of CAKUT, to polycystic kidney disease. Monogenic disorders tend to include the autosomal dominant forms of both polycystic & tubulointerstitial kidney diseases in adults, with children more commonly affected by the recessive forms²¹, however this is not always the case.
The dominant and recessive forms are quite distinct despite sounding similar, arising in different genes. Genomic testing for cystic disease is highly variable, with diagnostic yields ranging from 23.9 to 98% depending on the disease subtype and test option used.
Scroll down or select below for each sub-type of genetic cystic disease to learn more.
AD-PKD
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Being a dominant condition, AD-PKD only requires one pathogenic variant to be present in the PKD1 or PKD2 genes. Any parent with the condition has at least a 50% chance of passing the condition on. These variants can impact the production of polycystin-1 and polycystin-2, which like fibrocystin, are trans-membrane receptor-like proteins found in the primary cilia of the renal tubules. The interaction of polycystin-1 and 2 in the renal tubules are key to the normal development and function of the kidneys. The affected gene is also linked to prognosis, with pathogenic variants in PKD2 associated with milder forms of the condition.
AD-PKD is characterised by slow, progressive growth, with symptoms often not appearing until the mid-thirties when glomerular filtration starts to become compromised. The disease accounts for approximately 2.5% of all end-stage kidney disease and affects around 1 in 1000 people.
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Presenting features may include high blood pressure, chronic pain or heaviness, especially in the abdomen or flank, haematuria, urinary tract infections, kidney stones and infected kidney cysts.
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The objectives of care are to decrease renal cyst growth and reduce the risk of progression to end-stage kidney disease. Management involves lifestyle modifications to maintain a healthy weight and reductions in dietary sodium intake to 2.3g per day.
Pharmacological management includes symptomatic management of hypertension using antihypertensive and lipid lowering therapies, and Tolvaptan to slow the rate of cyst formation.
Patients who do progress to end-stage kidney disease are managed by either dialysis or renal transplant depending on individual suitability.
AD-TKD
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Previously known as medullary cystic kidney diseases, diseases associated with pathogenic variants in the MUC1 and UMOD genes were reclassified as tubulointerstitial diseases given cysts are only sometimes observed and do not exclusively form in the medulla. This reclassification allowed for the identification of several other disorders, all of which are characterised by progressive tubulointerstitial fibrosis and progression to end-stage kidney disease.
In addition to MUC1, and UMOD, pathogenic variants have been identified in HNF1β and REN, giving rise to four different forms of AD-TKD28:
• ADTKD-UMOD; uromodulin kidney disease
• ADTKD-MUC1; mucin-1 kidney disease
• ADTKD-REN; familial juvenile hyperuricemic nephropathy type 2 (FJHN2)
• ADTKD-HNF1β; maturity-onset diabetes mellitus of the young type 5 (MODY5)
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In addition to common clinical features, all four forms are inherited in an autosomal dominant manner, with multiple family members often affected given only a single pathogenic variant is required for the disease to manifest.
Hence a family history is an essential part of the diagnostic process, particularly given clinical features for AD-TKD can range from progressive chronic kidney disease to absent-to-mild proteinuria, bland urinary sediment, normal or slightly elevated blood pressure, and normal (or small) sized kidneys. ADTKD-HNF1β can also present with CAKUT.
AD-TKD is estimated to account for ~5% of monogenic disorders causing chronic kidney disease, with no evidence thus far of variations amongst national, geographic and ethnic populations, or between sexes.
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Currently, there are no specific treatments for AD-TKD beyond general measures for chronic kidney disease, and kidney transplantation is the preferred option when patients reach end-stage kidney disease.
Whilst the disease does not recur post-transplant, patients with the HNF1B form are prone to developing New Onset Diabetes After Transplantation (NODAT), the risks of which can be mitigated with alternative immunosuppressive agents and steroid-sparing regimens.
AR-PKD
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Polycystic kidney disease is the fourth most common cause of kidney failure in Australia, and the recessive form manifests when there are two pathogenic variants present in the PKHD1 gene, rendering the gene unable to correctly code for the protein fibrocystin. Fibrocystin is a trans-membrane receptor-like protein similar to polycystin whose production is impacted by the dominant form of the disease.
If only one copy of the allele is affected, the remaining ‘normal’ copy is able to code for fibrocystin, meaning that carriers of AR-PKD gene variants are generally unaffected by the disease.
It is estimated that 1 in 70 people in Australia are carriers for AR-PKD, however where both parents are carriers, there is a 1 in 4 chance of them both passing on their PKHD1 variant and having an affected child.
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Around 1 in 20,000 children are affected by AR-PKD, which can be detected on pre-natal ultrasound. Around one-third of presentations occur at birth, or in the first year of life, another third between 1 and 20 years of age, and the final third after age 2034.
Clinical manifestations also vary with age of presentation, with marked enlargement of the kidneys or related renal manifestations common in infants, variceal bleeding and symptoms of portal hypertension featuring in presentations between 1 and 20 years of age, and a variety of both renal and hepatic manifestations common in adult presentations.
Earlier diagnoses are associated with increased severity, with children diagnosed later in life often having less severe kidney problems but still presenting with high blood pressure, anaemia or haematuria.
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There is currently no cure for AR-PKD and treatment options focus on symptomatic management, with around half of all children requiring dialysis or renal transplant between 15-20 years of age.
NPHP
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Nephronophthisis and AD-TKD are often grouped together clinically as they share many phenotypic features, with the main differentiator being the inheritance pattern, age of onset of chronic kidney disease and the extra-renal presentations associated with NPHP.
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Nephronophthisis is inherited in an autosomal recessive manner, and accounts for up to 15% of all chronic kidney disease with ESKD in children and adults under 20 years of age.
There have been several genes associated with the disease, however pathogenic variants in the NPHP1 gene are the most common, being reported in around 20% of cases.
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Much like AD-TKD, there is no specific treatment for Nephronophthisis, with treatment options focussing on symptomatic management.
As for most cystic kidney diseases, the disease does not tend to recur in the newly transplanted kidney.