Ciliopathies are inherited conditions caused by faults in cilia, tiny antenna-like structures on cells. Many of them, including ARPKD and ADPKD, can affect the liver as well as the kidneys. This review explains how faulty cilia disturb the development of the liver's bile ducts and describes the main liver patterns: scarring of the liver and high pressure in its blood vessels in ARPKD, liver cysts in ADPKD, which usually appear in adulthood, and other patterns in rarer syndromes. Genetic testing with large gene panels or genome sequencing is increasingly used to find the cause. It is a review of existing knowledge, not a new study.
Narrative review with a paediatric focus. Ciliary dysfunction in cholangiocytes and hepatic progenitors disrupts ductal plate remodelling, causing ductal plate malformation, aberrant biliary branching and progressive periductal fibrosis. PKHD1, PKD1 and PKD2 remain central; ER/glycosylation genes (GANAB, ALG8, PRKCSH, SEC63, DNAJB11) and trafficking/IFT-A and WDR/dynein-2 components (TULP3, WDR family) are increasingly recognised. Phenotypes: congenital hepatic fibrosis and portal hypertension in ARPKD; hepatic cysts in ADPKD and ADPLD, usually adult onset; steatotic liver disease in Bardet-Biedl syndrome; transaminitis or fibrocystic liver disease in Joubert and WDR-related disorders. DCDC2 and PKD1L1 are implicated in neonatal cholestasis and biliary atresia. Diagnosis increasingly relies on multigene panels or exome/genome sequencing, with functional assays to interpret novel alleles.
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Should my child's liver be checked as well as their kidneys, and how often?
Kidney disease that starts early in life has been linked to problems with thinking and learning, and to changes in how the body handles iron. This study used young mice with a form of PKD that causes severe kidney disease within weeks of birth. Brain scans and tissue staining showed more iron in several brain areas than in healthy mice, although brain size was the same. This is an animal study; it does not show that the same happens in children, and it gives researchers a model to study the question.
Preclinical imaging study. Conditional Pkd2 knockout mice reached a mean BUN of 141 mg/dL and 83.1% cyst burden by postnatal day 19 (both p < 0.01). Longitudinal brain volumetrics did not differ from controls, but T2* relaxation times were shorter across total brain, grey and white matter, cerebral cortex, cerebellum, brainstem, hippocampus and globus pallidus, indicating increased iron deposition; Perls Prussian blue staining confirmed more iron in the cortex. First animal data on brain iron in early-life CKD, extending human CKD neuroimaging findings. Model of severe early uraemia; relevance to children with ADPKD is untested.
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Is there anything we should watch for in our child's learning or development, given their kidney condition?
Kidney cyst infections are a serious complication of ADPKD. This study looked back at the records of 416 people with ADPKD who had kidney arterial embolization, a procedure that blocks blood vessels inside the kidney through a thin tube so that the kidney shrinks. After the procedure, cyst infections became about three times less frequent, and people who had had infections before spent fewer days in hospital. The benefit was larger when the kidney shrank more. The study compared each person before and after the procedure, so it cannot prove the procedure caused the drop. Whether this procedure suits anyone depends on their own situation and their care team.
Retrospective cohort of 416 ADPKD patients undergoing kidney TAE, 70 with a previous cyst infection. Annual cyst-infection frequency fell from 0.291 to 0.087 episodes/year (P < 0.001); in the prior-infection subgroup from 1.73 ± 1.18 to 0.49 ± 0.96, with hospital days falling from 34.1 ± 26.1 to 9.90 ± 24.4 per year (P < 0.001). Benefit tracked with TKV reduction rate; no infections occurred with TKV-RR > 75%. Independent predictors of post-TAE recurrence: pre-TAE infection frequency, lower TKV-RR and antibiotic use at the time of TAE. The authors suggest performing TAE after full remission off antibiotics. Within-patient pre/post comparison; not randomised.
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If I keep getting kidney cyst infections, what options are there besides antibiotics, and could any of them suit me?
Mitochondria are the parts of a cell that make energy. In PKD they tend to break into small pieces, and this study looked at why. In kidney cells that had lost the PKD proteins, a switch-like protein called RhoA drove this breaking up. Blocking RhoA, or the proteins it acts through, prevented or reversed it, including in cells from people with PKD. The broken-up mitochondria also encouraged scarring processes. This is laboratory research on cells; no treatment based on it exists yet.
Mechanistic cell study. RhoA activation alone induced DRP1-mediated mitochondrial fission in tubular cells. Genetic or pharmacological inhibition of RhoA or its effectors (ROCK/LIM kinase/cofilin, phospho-myosin or formins) prevented or reversed PC1/PC2 loss-induced fragmentation; formin-driven fragmentation required F-actin polymerising capacity but not binding to INF2. PC1 re-expression or RhoA/effector inhibition restored mitochondrial morphology in human PKD cells, and fragmentation facilitated fibrogenesis. Positions RhoA-mediated actin polymerisation and myosin activation as a central mechanism of PKD-associated mitochondrial fragmentation. Cell-based data only.
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How do researchers decide which laboratory findings are worth testing as treatments for PKD?
Many people with polycystic liver disease have no symptoms, but some develop a swollen belly, pain or infected liver cysts. A nationwide survey of hospital departments in Japan estimated that about 3,570 people were being treated or followed for symptomatic polycystic liver disease in 2023, around 29 per million people. Among 557 patients with detailed data, most were women and about two thirds also had polycystic kidney disease. More than half had treatment for their liver cysts, and many needed care from more than one department or hospital. The study describes the condition in one country; it does not test treatments.
Nationwide two-stage questionnaire survey (3127 departments sampled). Symptomatic PLD defined as ≥ 10 hepatic cysts with cyst-related symptoms or complications. Estimated 6500 patients in 2021–2023 and 3570 in 2023, an annual prevalence of 28.6 per million. Of 557 with clinical data: 62% female, 67.2% met PKD diagnostic criteria; abdominal distension, pain and cyst infection were most frequent; more than half had hepatic cyst treatment; 60.4% needed consultation with other departments or institutions. Cyst infection and liver failure accounted for a subset of deaths; mortality differed by Gigot type and was highest in type III. Survey-based estimates in a Japanese setting.
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I have cysts in my liver as well as my kidneys. Which symptoms should make me contact my team?
Apelin is a natural hormone involved in blood pressure and heart function. Children and young adults with ADPKD had lower apelin levels than healthy peers, even with normal kidney function. Giving apelin to mice with PKD shrank their kidneys and cysts and improved kidney function, similar to a tolvaptan-like drug but without causing heavy urination. This is early animal research; no apelin-based treatment exists for people yet.
Translational study. Circulating apelin peptides reduced in young ADPKD patients with normal eGFR. Apelin and the small-molecule agonist azelaprag inhibited 3D cyst growth of primary human ADPKD cells. In Pkd1RC/RC;Pkd2+/− mice (27 days), apelin and mozavaptan lowered kidney weight, cystic index, BUN and renal cAMP; azelaprag did not. Apelin down-regulated Lcn2, Postn and Havcr1 and, unlike mozavaptan, caused no aquaresis. Proposes the apelin receptor as a target without aquaretic burden — short-duration preclinical data only.
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If tolvaptan’s side effects are hard for me, are there clinical trials of other approaches that I could be considered for?
People with ADPKD are more likely to have brain aneurysms, but there is no agreed plan for how often to re-scan small, untreated ones. Two Japanese centres built a simple 4-point score using three facts: having more than one aneurysm, high blood pressure, and a family history of ADPKD. Over 5 years, no one in the low-risk group had an aneurysm grow, change or bleed, versus nearly half in the high-risk group. It needs testing elsewhere before routine use.
Retrospective two-centre Japanese cohort: of 1,267 ADPKD adults imaged 2003–2024, 132 with untreated intracranial aneurysms and follow-up imaging. Composite outcome: growth, morphological change, de novo formation or rupture. Predictors: multiple aneurysms (OR 5.56), hypertension (OR 3.60) and family history of ADPKD (OR 2.24) → 4-point score; optimism-corrected AUC 0.73. Five-year composite incidence 0% / 12% / 46% (low / moderate / high risk) in validation cohort. Internal validation only, selection bias likely — external validation needed before guiding surveillance intervals.
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If I have a small brain aneurysm, how would my number of aneurysms, blood pressure and family history affect how often I should be scanned?
Tolvaptan makes urine more dilute. Re-analysing the large TEMPO 3:4 trial, researchers asked whether how much urine concentration drops in the first 3 weeks predicts long-term benefit. In non-Japanese participants, a bigger early drop went with better kidney function at 3 years; in the smaller Japanese group, the link was not clear. Either way, tolvaptan slowed kidney growth in both groups. A simple urine test might one day help gauge response.
Post hoc causal mediation analysis of TEMPO 3:4 (3-year RCT). Week-3 change in urine osmolality significantly mediated the tolvaptan effect on month-36 eGFR in non-Japanese participants (ACME 2.4; 95% CI 1.2–3.6; n=948) but not in Japanese participants (ACME −0.3; n=138), where the direct effect on eGFR was significant (ADE 8.4). Direct effect on %TKV change significant in both cohorts (−8.3 and −12.0). Supports early Uosm change as a candidate response biomarker; not validated for individual dose titration or stopping decisions.
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If I take tolvaptan, would checking my urine concentration early on help us understand whether it is working for me?
Researchers mapped which genes are switched on inside kidney cysts while keeping track of where each cyst sits in the tissue. They used kidney tissue from people with ADPKD and combined three ways of reading gene activity. Cyst cells showed signals that may be linked to scarring, inflammation and low oxygen, and to growth pathways already known in PKD. The team also picked out a gene, musculin, that marks cyst cells. This is laboratory research meant to guide future studies; it does not change care today.
Translational transcriptomics. 10X Visium spatial transcriptomics of an ADPKD kidney sample identified cysts by morphology; anchor genes were validated in snRNA-seq and cyst bulk RNA-seq across cysts of different sizes and across ADPKD samples, with confocal confirmation at protein level. The cyst interactome may be enriched for hypoxia, fibrotic ECM and TGF-β, TNF and IFN-γ signalling. Cyst–fibroblast ligand–receptor pairs suggest osteopontin and MIF signals from cysts and TWEAK, tenascin-C and pleiotrophin signals into cysts. Cystic principal cells implicate Hippo (YAP/TAZ), TGF-β/SMAD3 and mTORC2/SGK1; musculin is prioritised as a cystic anchor gene. Hypothesis-generating; spatial data from a single patient sample.
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Is any of the research on what makes cysts grow close to being tested in people?
Polycystic liver disease can run in families through changes in at least seven genes, which can also cause a few kidney cysts but rarely kidney failure. Using large public gene databases, researchers estimated that roughly 1 in 91 to 1 in 130 people carry a likely harmful change in one of these genes, more often in some ancestries. Many carriers never develop liver or kidney cysts, so a positive result needs careful interpretation.
gnomAD v2.1.1 (ANNOVAR: LoF, structural/CNV, null and conserved rare damaging missense) and gnomAD v4.1 ClinVar P/LP for GANAB, ALG8, ALG9, PRKCSH, SEC63, LRP5 and SEC61B. Predicted pathogenic carriers ~1 in 91 (v2.1.1) and 1 in 130 (ClinVar); LRP5 and ALG8 (milder phenotypes) most frequent. Higher in admixed American (1/91), Finnish (1/110) and African/African American (1/43) vs European (1/187). Incomplete penetrance and variable expressivity — interpret panel findings with phenotype and family history.
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If a gene panel finds a variant linked to polycystic liver disease, what does it mean for me and my relatives if we have few or no cysts?
PAPP-A is a protein that frees a growth signal called IGF-1, and polycystic kidneys have more of it. Researchers made new human antibodies that block PAPP-A and tested them in two mouse models of PKD, one with advanced and one with early disease. In male mice, all doses tested reduced cyst disease, inflammation and scarring in the kidney. In one of the models, female mice were protected less than males. These are mouse results; the authors say the difference between sexes should be taken into account when planning trials in people.
Preclinical therapeutic study. PAPPA cleaves IGFBP2, 4 and 5, releasing IGF1, and is overexpressed in polycystic kidneys. Human PAPPA-mAbs generated on yeast-based platforms blocked PAPPA-mediated cleavage of IGFBP2, 4 and 5; HDX and cryo-EM mapped the protected PAPPA regions. PAPPA-mAb1 (15 or 50 mg/kg/week) and -mAb2 (1, 5 or 50 mg/kg/week) were given intraperitoneally to male jck mice with advanced PKD from 6 to 12 weeks; -mAb2 (0.3, 3 or 30 mg/kg/week) to male and female Pkd1RC/RC mice with early PKD from 4 to 16 weeks. All doses in males showed target engagement, ameliorated cystic disease, inflammation and fibrosis, and inhibited IGF1Rβ and downstream signalling; females were less protected than males. Both mAbs compared favourably with the earlier Ansh Labs mAb. The authors flag low-dose effectiveness and sexual dimorphism for clinical trial design.
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How do researchers check that a medicine that works in mice is safe to test in people?
Organoids are tiny structures grown in the lab from stem cells that copy parts of an organ. Researchers developed a way to grow thousands of kidney organoids that form cysts like those in ADPKD, so that many possible drugs can be tested at once. The cysts responded to some experimental compounds but not to tolvaptan, which the authors linked to the organoids having little of the receptor that tolvaptan acts on. Testing a small set of compounds pointed to TLR4, a protein involved in the immune response, as a possible target. This is a laboratory tool for finding drug candidates; none of these compounds is a treatment for people.
Preclinical platform. Day-12 nephron organoids from wild-type and PKD2-deficient hiPSC lines were dissociated and grown in suspension under ureteric bud (UB) conditions, yielding up to 2000 UB organoids from about 50 nephron organoids within 7 days (AQP2, WNT9B and KRT8 positive). PKD2-deficient UB organoids began cystogenesis within 7 days, with very high cyst-forming efficiency by about 20 days. Cysts expressed ADPKD markers and responded to JQ1 (bromodomain inhibitor) and QNZ (NF-κB inhibitor) but not tolvaptan, consistent with low AVPR2 expression. A small-molecule screen identified M1, a putative TLR4 antagonist, that reduced cyst size; TAK-242 reduced and lipopolysaccharide increased cyst formation, consistent with TLR4-driven cystogenesis. In vitro data only.
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Are there clinical trials for ADPKD that are testing new kinds of medicines?
The body runs on an internal 24-hour clock, and organs such as the kidney have their own clocks too. In mice with PKD, the daily rhythm of drinking and passing urine became more disrupted as cysts grew. In cystic kidneys, the clock genes swung less and fell out of step, and losing the PKD1 gene also weakened the clock in kidney cells grown in the lab. This suggests PKD1 matters for the kidney's own clock, although the authors say more work is needed to separate direct effects from changes caused by the cysts. This is animal and cell research.
Preclinical study at organism, organ and cell level. Slowly progressive Pkd1RC/RC mice showed progressive disruption of diurnal water intake and urine output rhythms, paralleling cystic burden. Cystic kidneys had dampened, desynchronised core clock gene oscillations and PER2::LUC bioluminescence in explants, more pronounced in rapidly progressive Pkd1-KO mice. Pkd1 loss blunted clock gene oscillations in synchronised proximal tubular and inner medullary collecting duct cells in vitro, indicating cell-autonomous dysfunction independent of systemic cues. Builds on the group's earlier finding that renal clock disruption accelerates cyst growth. Direct effects of Pkd1 loss versus secondary cystic remodelling in vivo remain to be separated.
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Does my daily routine, such as sleep or when I drink fluids, matter for my kidneys?