Autosomal Dominant Polycystic Kidney Disease

The ADPKD spectrum associated with PKD1, PKD2 and minor genes (IFT140, GANAB, DNAJB11, ALG9, ALG5), including TSC2/PKD1 contiguous gene syndrome and biallelic forms with very early onset.

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Autosomal dominant polycystic kidney disease is the most common potentially lethal monogenic disease and the most common hereditary kidney disease associated with kidney failure [1, 2]. According to the estimate cited by KDIGO, it affects up to 12 million people worldwide and is the fourth leading global cause of kidney replacement therapy [3, 22]. It is a systemic disease: the kidneys determine prognosis, but the liver, cerebral circulation, heart and abdominal wall also contribute to its manifestations, and severity varies both between and within families [1, 9].

The prevalence estimate of 1:1000 derives from Dalgaard's population study in Copenhagen, published in the 1950s, which estimated genetic prevalence at birth from the theoretical disease risk over an 80-year lifespan rather than from a point-prevalence count of patients; KDIGO cites this as the classic study of the disease's epidemiology [2]. In 1985, Reeders and colleagues demonstrated linkage between the locus for what was then called adult polycystic kidney disease and the alpha-globin locus on the short arm of chromosome 16 (LOD score 25.85; recombination fraction 0.05). The same paper described the diagnostic limitations of the time: death from kidney failure occurred at a mean age of 51 without dialysis or transplantation, patients accounted for 9% of chronic dialysis requirements, and 34% of at-risk individuals in their second decade and 14% in their third would develop cysts after a negative ultrasound, preventing early ultrasound exclusion and prenatal diagnosis [23].

Positional cloning of PKD1 was reported in 1994 by the European Polycystic Kidney Disease Consortium, using a translocation that disrupted a gene with a 14 kb transcript adjacent to TSC2, in a genomic region reiterated more proximally on 16p; duplication of this region still accounts for some of the technical difficulties of genetic testing [24]. That same year, Brook-Carter and colleagues described large deletions simultaneously inactivating TSC2 and PKD1 in six patients with severe childhood-onset polycystic kidney disease, defining the contiguous gene syndrome [25]. In 1996, Mochizuki and colleagues identified PKD2, whose 968-amino-acid product has six transmembrane segments and similarities to voltage-dependent calcium channels [26]. In 1999, the European PKD1–PKD2 Study Group compared 333 patients from 31 PKD1 families with 291 patients from 31 PKD2 families and 398 controls: median age at death or end-stage kidney disease was 53.0 years for PKD1, 69.1 years for PKD2 and 78.0 years in controls, establishing that the PKD2 form is milder but reduces life expectancy [27].

From 2016 onwards, minor genes were described that encode endoplasmic reticulum proteins required for polycystin-1 maturation (GANAB, DNAJB11, ALG9, ALG5) and, in 2022, an intraflagellar transport protein (IFT140) [28–32]. Targeted treatment emerged with the TEMPO 3:4 trial (2012), which showed that tolvaptan, a vasopressin V2 receptor antagonist, reduces total kidney volume growth and loss of kidney function, and the REPRISE trial (2017) in more advanced disease [33, 34]. In 2025, KDIGO published its first guideline dedicated to a genetic kidney disease, introducing nomenclature based on the causal gene, recommending the Mayo Imaging Classification for prognosis and defining criteria for tolvaptan use [2, 3].

2. Molecular Genetics and Pathophysiology

2.1. Genes, proteins and proportion of families

ADPKD is genetically heterogeneous. PKD1, at 16p13.3, encodes polycystin-1 (PC1), an integral membrane glycoprotein with an extensive extracellular region, multiple transmembrane segments and a cytoplasmic tail; PKD2, at 4q22.1, encodes polycystin-2 (PC2, TRPP2), a non-selective cation channel present in the primary ciliary membrane, endoplasmic reticulum and plasma membrane [1, 10]. Pathogenic PKD1 variants explain approximately 78% of families and PKD2 approximately 15%; older estimates in the Oxford Desk Reference were approximately 77% and 14% [1, 9]. Minor genes were identified mainly in genetically unresolved families, which accounted for approximately 7% of cases after testing PKD1 and PKD2 [29, 31].

KDIGO distinguishes genes with well-supported pathogenicity (PKD1, PKD2, IFT140, ALG5, ALG9, GANAB, DNAJB11 and NEK8) from those whose association with ADPKD remains uncertain (ALG6, ALG8 and heterozygous PKHD1). In patients with a variant in these latter genes, without genetic testing, or with inconclusive results, the recommended designation remains ‘ADPKD’, without a gene suffix; the designation should also not be based on a likely pathogenic variant in a minor gene when the clinical diagnosis is uncertain [3]. In a study of more than 3900 families with renal and/or hepatic cysts, pathogenic ALG8 variants were found in 1.3% and ALG9 variants in 0.6% of families, frequencies approximately 10 and 24 times higher than in controls without polycystic kidney disease; the renal phenotype was mild to moderate and kidney failure was rare, whereas ALG8 may cause severe polycystic liver disease [36].

2.2. Polycystin function and disease mechanism

PC1 and PC2 form a functional complex whose cryo-electron microscopy structure contains three PC2 molecules and one PC1 molecule; this interaction is required for maturation and localisation of both proteins [1]. Both are located in the primary cilium, placing ADPKD among the ciliopathies, and loss of the cilium is associated with cystic disease [1, 37]. The primary cilium acts as a sensory organelle coordinating signalling pathways such as sonic hedgehog and Wnt [37]. The precise role of the polycystin complex in relation to the cilium remains debated: proposed sensory, mechanosensory or receptor functions are regulated by tubular flow, Wnt ligand binding or the PC1 N-terminal region, with downstream signalling involving calcium, cAMP and G proteins [1]. Simultaneous inactivation of polycystins and cilia produces a milder cystic phenotype than isolated polycystin loss, interpreted as evidence that the complex regulates a cyst-promoting ciliary pathway; in animal models, re-expression of Pkd1 or Pkd2 after cystogenesis had begun reversed cystic disease [1].

Renal and hepatic cysts appear to result from clonal proliferation following a second somatic mutation [9]. Functional protein dosage is also important: incompletely penetrant PKD1 alleles that reduce rather than abolish function cause few cysts individually, typical-to-severe disease when two such alleles are combined, and early-onset disease when associated in trans with an inactivating allele [38]. ClinGen assigns PKD1 and PKD2 a haploinsufficiency score of 3 (sufficient evidence) and a triplosensitivity score of 0 [10]. Some non-truncating hypomorphic PKD1 variants cause defective PC1 folding and trafficking [1].

Minor genes converge on PC1 biogenesis. GANAB encodes the glucosidase II alpha subunit, which removes glucose residues from glycans and participates in the calnexin/calreticulin cycle; cells lacking GANAB cannot complete PC1 and PC2 maturation or ciliary and surface localisation, and heterozygous cells have less mature PC1 [28]. DNAJB11 encodes a BiP cofactor controlling the folding, trafficking and degradation of secreted and membrane proteins, with defective maturation of PC1 and proteins involved in tubulointerstitial diseases, such as uromodulin [29]. ALG9 adds specific mannose residues to N-glycan precursors, and its inactivation impairs PC1 maturation and glycosylation [30]; ALG5 is required for PC1 maturation and membrane and ciliary localisation, and haploinsufficiency alone alters N-glycan chain synthesis in renal epithelial cells [31]. IFT140 is a core component of the IFT-A complex, responsible for retrograde ciliary trafficking and entry of membrane proteins into the cilium [32].

2.3. From molecular injury to renal physiology

Impaired urinary concentrating ability and ammonia excretion develop early. Reduced ammoniagenesis, low urinary pH and hypocitraturia favour uric acid and calcium oxalate stones, and crystal deposition may in turn accelerate cystogenesis [1]. The concentrating defect and elevated serum vasopressin appear to contribute to cystogenesis, glomerular hyperfiltration in children and young adults, hypertension and progression of chronic kidney disease (CKD); plasma copeptin, a marker of endogenous vasopressin, correlates positively with total kidney volume (TKV) and albuminuria and negatively with glomerular filtration rate (GFR) [1]. V2 receptor blockade reduces cAMP-dependent cyst fluid secretion, providing the basis for tolvaptan treatment [3, 10].

Reduced renal blood flow precedes hypertension and independently predicts functional decline. Angiotensin II, transforming growth factor beta and reactive oxygen species participate in vascular remodelling and interstitial fibrosis [1]. ADPKD hypertension is characterised by increased renal vascular resistance and filtration fraction, normal or elevated plasma renin activity, resetting of the pressure–natriuresis relationship, salt sensitivity and normal or increased extracellular volume, partially corrected by angiotensin-converting enzyme inhibition [1]. Parenchymal compression by cysts, vascular sclerosis, interstitial inflammation and fibrosis, and tubular epithelial apoptosis explain loss of function [1]. Polycystin expression in the vascular system suggests that reduced levels of these proteins underlie intracranial aneurysms [1].

2.4. Genotype–phenotype correlations

PKD1-associated disease is more severe than PKD2-associated disease because cysts form earlier and in greater numbers, rather than growing faster [1]. Mean age at end-stage kidney disease is 58.0 years in PKD1 and 74.8 years in PKD2; most carriers of fully penetrant PKD1 variants develop kidney failure by age 70, whereas more than half of PKD2 carriers retain adequate kidney function at that age [1]. In the 1999 European comparison, median age at presentation with kidney failure was 54.3 years in PKD1 and 74.0 years in PKD2, and PKD2 patients were less likely to have hypertension (OR 0.25), urinary tract infection (OR 0.50) or haematuria (OR 0.59) [27].

Within PKD1, mean age at end-stage kidney disease is 55.6 years with truncating variants and 67.9 years with non-truncating variants. Non-truncating variants are divided into ‘mutation strength’ groups: non-conservative substitutions at conserved sites (MSG2 or NT1) have severity similar to truncating variants in estimated GFR (eGFR) and height-adjusted TKV (htTKV), whereas more conservative substitutions at less conserved sites (MSG3 or NT2) are hypomorphic; approximately half of missense and other in-frame variants are estimated to be fully penetrant [1]. KDIGO recommends stating in the report whether a PKD1 variant is truncating or non-truncating, without incorporating this into the disease designation [2]. Variant position within PKD1 has also been associated with the vascular phenotype, with vascular disease more common for variants at the 5' end [9]. In PKD2, truncating variants are associated with lower eGFR than non-truncating variants, and only one hypomorphic allele has been described [1].

The most extensively studied reduced-penetrance PKD1 allele is NM_001009944.3:c.9829C>T, p.(Arg3277Cys), validated in VariantValidator against the MANE Select transcript (NC_000016.10:g.2099955G>A, GRCh38) [1, 39]. In heterozygous individuals, it causes few cysts or no signs of disease; in a consanguineous family, two homozygous siblings developed end-stage kidney disease at ages 75 and 62, whereas six heterozygotes had few cysts, and in families with in utero onset it was found in trans with a truncating variant [38]. In ClinVar, record VCV000192320 has conflicting pathogenicity classifications, illustrating the difficulty of applying ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) categories to incompletely penetrant alleles [8, 40].

2.5. Biallelic forms, digenic inheritance and mosaicism

Fully penetrant biallelic PKD1 or PKD2 variants are considered incompatible with live birth, as in murine knockout models, which are embryonically lethal; combinations including at least one hypomorphic allele are compatible with life and cause prenatal-onset disease or, when both alleles are hypomorphic, early disease with an apparently negative family history that may be mistaken for ARPKD [1]. Neonatal disease due to homozygosity for a hypomorphic PKD2 allele resulting from uniparental disomy has also been described [1]. In an international paediatric referral cohort from 2010 to 2020, likely causal PKD1 or PKD2 variants were found in 30 infants with very early-onset disease (16 presenting in utero); 21 (70%) had two variants, with biallelic inheritance in trans confirmed in 16, one had biallelic PKD2 variants and two had digenic PKD1/PKD2 variants; 43% of families had no known ADPKD history [8].

Digenic inheritance has been demonstrated in double heterozygotes for PKD1 and PKD2, with more severe kidney disease than in relatives carrying a single variant, and suggested with HNF1B, COL4A1, PKHD1 and the polycystic liver disease genes PRKCSH and SEC63 [1]. Mosaicism explains some variability and apparently de novo cases: in a series of 20 families, all mosaic cases involved PKD1, the variant was transmitted in five families and sporadic in 15, patients had milder disease than a PKD1 control group and few showed evident asymmetry; next-generation sequencing-detectable mosaicism accounted for approximately 1% of typical cases and approximately 10% of genetically unresolved cases with uncertain family history [7]. Parental mosaicism has been estimated at approximately 0.25% of families [1].

2.6. Allelic diseases and contiguous gene syndrome

No distinct allelic phenotypes caused by germline intragenic variants are known for PKD1, PKD2 or ALG5 [1]; Smith's Recognizable Patterns does, however, include rare PKD2 variants among the causes of rare cases of laterality defects in humans [41]. The proximity of IFT140 to PKD1 (approximately 0.5 Mb at 16p13.3) may cause diagnostic confusion, and PKD1 variants may modify the IFT140 phenotype [32]. KDIGO notes that some ADPKD genes are also associated with recessive disorders; pathogenic variant carriers should therefore be informed, and partners may undergo carrier testing when planning reproduction [2].

2.7. Penetrance

Penetrance depends on age and genotype. Multiple bilateral renal cysts approach 100% penetrance in older adults, but cysts may be sparse in childhood and young adulthood, particularly with non-truncating PKD1 variants, PKD2 or minor genes [1]. In the Geisinger population cohort, 77.8% (42/54) of truncating PKD1 variant carriers and 70.8% (17/24) of truncating PKD2 variant carriers had an ADPKD diagnostic code, compared with 2.5% for IFT140 and 7.1% for GANAB, indicating much lower clinical penetrance for minor genes [2].

3. Clinical Spectrum and System-Specific Manifestations

3.1. Kidneys: cyst growth and functional progression

All patients develop renal cysts, but severity varies between families and, to a lesser extent, within families [1]. In CRISP (Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease), which followed 241 non-azotaemic patients with annual magnetic resonance imaging, TKV and cyst volume increased exponentially: baseline TKV was 1060 ± 642 mL and increased by a mean of 204 mL over three years, or 5.3% annually; baseline volume predicted subsequent growth rate, and GFR declined in patients with baseline TKV above 1500 mL [1]. In KDIGO's analysis, CRISP patients with TKV >1500 mL had a mean GFR decline of −4.33 mL/min per year, whereas those with TKV between 750 and 1500 mL showed no significant decline; over 13 years of follow-up, each 100 mL/m increase in baseline htTKV was associated with an odds ratio of 1.38 for reaching CKD G3 [2]. An htTKV ≥600 mL/m has high predictive value for kidney impairment over the following eight years [1].

GFR decline was traditionally described as late, with a loss of 4–6 mL/min per year once established; more recent studies show an almost linear trajectory from young adulthood in patients with larger kidneys and inactivating PKD1 variants, and a curvilinear trajectory with later decline in those with smaller kidneys [1, 42]. Approximately 50% of patients have end-stage kidney disease by age 60 [1, 4]. Lower incidence in women suggests greater severity in men: in PKD1 disease, mean age at end-stage kidney disease was 58.1 years in men and 59.5 years in women; in a PKD1/PKD2 cohort, it was 58.2 and 63.9 years, respectively [1]. Poor prognostic factors listed by GeneReviews include diagnosis before age 30, first haematuria before age 30, hypertension before age 35, hyperlipidaemia, high body mass index, high urinary sodium excretion, low renal blood flow, low HDL cholesterol, high TKV and a truncating PKD1 variant [1].

Hypertension develops in young adults and even in childhood, usually before GFR falls; diagnosis is often delayed, and ambulatory monitoring in children and young people may reveal elevated blood pressure, attenuated nocturnal dipping and an exaggerated exercise response, sometimes with left ventricular hypertrophy and diastolic dysfunction [1]. Cardiovascular disease is the leading cause of death, and uncontrolled hypertension increases the risk of proteinuria, haematuria, faster kidney function decline, valvular and aneurysmal morbidity and pregnancy complications [1]. The KDOQI commentary estimates hypertension in 70–80% of patients [19].

Pain is common and may result from cyst haemorrhage, stones, cyst infection, rarely a tumour, or renal distension; most episodes are self-limiting and resolve within two to seven days, and retroperitoneal haemorrhage requiring transfusion is rare [1]. Visible haematuria may accompany cyst haemorrhage or stones or occur in isolation [1]. Nephrolithiasis affects approximately 20% of patients, mainly with uric acid and/or calcium oxalate stones; Orphanet reports up to one-third of adults [1, 4]. The frequency of urinary tract infections was probably overestimated historically because of sterile pyuria; women are more often affected, the predominant organisms are E. coli and other Enterobacteriaceae, and cyst infections account for approximately 9% of hospitalisations [1]. The association between ADPKD and renal cell carcinoma remains controversial; when present, it tends to occur earlier, with constitutional symptoms and a higher proportion of sarcomatoid, bilateral, multicentric and metastatic tumours, and the increased risk observed during dialysis is explained by advanced kidney disease [1]. KDIGO concludes that there is no clear association with increased risk, but clinicians should recognise atypical presentations [3]. Massive kidney enlargement may compress the inferior vena cava or cause gastric outlet obstruction [1]. Haemoglobin tends to be higher than in other forms of CKD, and erythrocytosis may develop (haematocrit >51% or haemoglobin >17 g/dL), rarely before kidney failure and more commonly after transplantation [3].

3.2. Liver and pancreas

Polycystic liver disease is the most common extrarenal manifestation [1]. Hepatic cysts are rare in childhood; in CRISP, magnetic resonance imaging prevalence was 58% at ages 15–24, 85% at ages 25–34 and 94% at ages 35–46 [1]. KDIGO reports hepatic cysts in more than 80% by age 30 and symptomatic polycystic liver disease in fewer than 5%, predominantly women [3]. Liver disease develops earlier in women, worsens with multiple pregnancies and oestrogen replacement therapy, and often regresses after menopause; in an analysis of severe disease (height-adjusted total liver volume of 1.8 L), more than 80% of patients were women, with no difference between truncating or non-truncating PKD1 and PKD2 variants [1]. Cysts rarely compromise hepatic synthetic function; symptoms result from mass effect (abdominal distension and pain, early satiety, dyspnoea, back pain) or compression of the inferior vena cava, hepatic veins or bile ducts [1, 3]. Cyst epithelium produces CA 19-9, whose serum level correlates with liver volume; haemorrhage, infection and rupture are the main cyst complications, and 18F-fluorodeoxyglucose positron emission tomography is the most sensitive technique for infection [1]. Bile duct dilatation, congenital hepatic fibrosis, cholangiocarcinoma and ampullary adenomas are rare [1].

Pancreatic cysts occur in 19% of patients and intraductal papillary mucinous neoplasms in 1%, according to GeneReviews; KDIGO estimates approximately 10% and recommends follow-up of complex or multiple cysts to exclude malignancy, particularly von Hippel-Lindau disease [1, 3].

3.3. Intracranial aneurysms and other vascular manifestations

Intracranial aneurysms are the most serious extrarenal complication. Estimates depend on methodology and patient selection: approximately 6% in the Oxford Desk Reference (general population 1–2%); approximately 10% in GeneReviews, with 22% in patients with a family history of aneurysm or subarachnoid haemorrhage and 6% without such history; and 12.9% (389/3031) in KDIGO's meta-analysis of presymptomatic screening, with low-certainty evidence [1, 2, 9]. In the French Genkyst study, 4.7% of participants had a diagnosed aneurysm, 47% of whom had a family history; prevalence reached 8.1% at age 70 (10.8% in women and 5.4% in men) [1]. Among patients with aneurysms, 15–25% have multiple aneurysms; 50–60% of patients with an aneurysm and approximately 40% of those experiencing rupture have no family history [2].

The absolute rupture rate is low, at 0.57 per 1000 patient-years, but approximately seven times that in the general population, and median age at rupture is approximately 41 years, compared with 52 in the general population [2]. GeneReviews reports 39 versus 51 years [1]. Rupture is associated with mortality above 30% and morbidity of 50% [2]. At rupture, most patients have normal kidney function and up to 30% have normal blood pressure [1]. Size-based rupture risk estimates cited by GeneReviews come from the international study of unruptured aneurysms in patients without ADPKD: 0.05% per year below 10 mm, approximately 1% per year between 10 and 24 mm, and 6% in the first year at 25 mm or above, without previous rupture elsewhere; with previous rupture, 0.5–1% per year irrespective of size [1]. The Oxford Desk Reference emphasises that the risk of interval rupture in ADPKD is unknown and management has been extrapolated from these data [9]. Familial clustering occurs: aneurysm detection is approximately three times higher with a family history of rupture [9], and likelihood approximately four times higher in the family-history group, where screening frequency is around 17% [2]. Patients with PKD2 variants are also at risk [9].

Other vascular manifestations include intracranial dolichoectasia (0.7–5%), aortic root dilatation, thoracic aortic dissection (approximately 1.5% for thoracic aortic aneurysm in the KDIGO table), carotid, vertebral and coronary dissections, and retinal arterial and venous occlusions [1, 3]. There is evidence of familial clustering of thoracic aortic dissections [1]. Patients may have increased risks of vasospasm and transient ischaemic complications following cerebral angiography [1].

3.4. Heart

Mitral valve prolapse was reported in up to 25% of patients in older echocardiographic studies [1]; KDIGO notes that, using the current definition, prevalence is 1% in paediatric cohorts and 3.4% in adults, similar to the general population [3]. Increased left ventricular mass, diastolic dysfunction, endothelial dysfunction and increased carotid intima–media thickness have been described even in normotensive young people; in a study of 543 patients with GFR >60 mL/min/1.73 m² and early treatment, left ventricular hypertrophy on magnetic resonance imaging was rare [1]. Pericardial effusion is more common (approximately 20%) and usually has no consequences [1, 3]. Dilated cardiomyopathy (5.8%), hypertrophic cardiomyopathy (2.5%) and non-compaction (0.3%) were described in a series with probable referral bias, and congenital heart disease appears more common (1.4% versus 0.4%) [1, 3]. Laterality defects, including complete situs inversus, have been described in a small number of patients, mainly with PKD2 [3].

3.5. Other organs

Seminal vesicle cysts occur in approximately 40% of men and rarely cause infertility; impaired sperm motility is another possible cause of male infertility, although KDIGO concludes that these abnormalities do not appear to compromise fertility [1, 3]. Arachnoid cysts occur in 8–15% and may increase subdural haematoma risk; spinal meningeal diverticula may cause intracranial hypotension through a cerebrospinal fluid fistula [1, 3]. Ovarian cysts are not associated with ADPKD [1]. Colonic diverticular disease is more common in ADPKD patients with end-stage kidney disease than in other nephropathies, and abdominal wall hernias are common [1, 3]. KDIGO includes bronchiectasis (19–37%) and extrahepatic bile duct dilatation (approximately 40%) among reported findings, most of limited clinical relevance [3].

3.6. Childhood and prenatal presentation

ADPKD is considered an adult disease, but a minority present in childhood [9]. Orphanet estimates that 2–5% of cases manifest before age 15 [4]. KDIGO defines very early-onset ADPKD as clinical abnormalities before 18 months and early-onset disease between 18 months and 15 years, considering these rare, distinct subentities [3]. Rarely (approximately 1%), prenatal ultrasound detects enlarged, hyperechogenic kidneys or intrarenal cysts [9]. Sources differ regarding prognosis: the Oxford Desk Reference ADPKD chapter states that approximately 30% of these children die in the first months without renal support, and survivors have a high risk of early hypertension and kidney impairment; conversely, the renal abnormalities chapter in the same book and GeneReviews describe an often favourable fetal and childhood prognosis, except with oligohydramnios, with declining kidney volume and preserved function, but earlier kidney failure than in adult disease [1, 9, 43]. These descriptions probably reflect series with different severity, and KDIGO associates oligohydramnios and severe bilateral structural disease with worse neonatal prognosis [3]. When a child in a family has presented prenatally, affected siblings are more likely to present early too, possibly reflecting co-inheritance of a hypomorphic allele from an apparently unaffected parent [9, 43].

3.7. Minor-gene phenotypes

Minor genes have distinctive phenotypes that should not be confused with the course of PKD1. In IFT140 carriers, identified in 1.9% of families without previous genetic testing and 2.1% of probands with cystic kidney disease in the 100,000 Genomes Project, kidney disease is mild, with large cysts, limited kidney impairment and few hepatic cysts [32]. In DNAJB11, among 77 patients from 27 families, 32 developed end-stage kidney disease between ages 55 and 89 (median 75), without a sex difference; cysts were inconsistently identified before age 45, and four families had vascular phenotypes (intracranial aneurysms, thoracic aortic dilatation and carotid dissection) [35]. In ALG5, the 23 affected members of five families had non-enlarged kidneys with multiple cysts and few or no hepatic cysts, and eight developed end-stage kidney disease between ages 62 and 91 [31]. In GANAB, the 20 patients from seven ADPKD families and two polycystic liver disease families had mild kidney disease and variable, sometimes severe, liver disease [28]. In ALG9, seven of eight population-identified carriers imaged after age 50 had at least four renal cysts, compared with none of the controls [30]. KDIGO notes that intracranial aneurysm risk for minor genes is uncertain [3].

4. Clinical Recognition and Warning Signs

ADPKD should be suspected with multiple bilateral renal cysts without manifestations suggesting another cystic disease; cysts in other organs, particularly the liver but also seminal vesicles, pancreas and arachnoid; palpable kidneys or liver; hypertension before age 35; an intracranial aneurysm; or a family history consistent with autosomal dominant transmission, with men and women affected across generations [1]. Absence of a family history does not exclude the diagnosis: 10–15% of patients lack one according to Orphanet, and 10–20% have a de novo variant according to GeneReviews [1, 4]. The history may appear negative because disease was unrecognised in relatives, a parent died before symptoms developed, or disease began late in that parent [1].

The genetics consultation should include a three-generation pedigree, with specific questions about affected relatives, age and reason for diagnosis, age at kidney failure onset, subarachnoid haemorrhage and cause of death; history-taking should document back pain, haematuria and recurrent urinary tract infections; examination should include blood pressure, kidney and liver palpation and cardiac auscultation for a midsystolic murmur or mitral prolapse [9]. KDIGO adds enquiry about unexplained sudden death in the family, as this forms part of aneurysm screening criteria [3].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Principles and prior counselling

KDIGO recommends placing the person's values and preferences at the centre of decision-making, providing counselling on benefits and risks before and throughout any imaging or genetic screening, and multidisciplinary support for families with complex disease [2]. Potential consequences include insurance and employment implications, which should be discussed before testing [1]. ADPKD is diagnosed through age-specific imaging criteria associated with an affected first-degree relative or identification of a heterozygous pathogenic variant in an ADPKD gene [1].

5.2. Ultrasound criteria in at-risk individuals

KDIGO recommends abdominal ultrasound as the first investigation for screening at-risk adults, in the context of family history, kidney function and comorbidities (recommendation 1.3.1, grade 1B) [2]. Pei's unified criteria were derived from 577 and 371 at-risk individuals from 58 PKD1 and 39 PKD2 families, with molecular genotyping [12].

*GeneReviews gives the age range as 15–30 years and the Oxford Desk Reference as 15–29 years, with rounded values (94%, 69%, 82%); positive predictive value is 100% in all age groups between 15 and 59 years [1, 9, 12]. The criterion of ≥4 cysts in each kidney from age 60 appears in the original paper, the Oxford Desk Reference and KDIGO [3, 9, 12].

For exclusion, KDIGO considers the diagnosis ruled out with ≤1 cyst between ages 15 and 39 and ≤2 cysts in total between ages 40 and 59 [3]. Pei's criteria state that fewer than two cysts from age 40 are sufficient to exclude disease [9, 12]. Without a known familial variant, normal kidneys between ages 30 and 39 or at most one cyst from age 40 have a negative predictive value of 100% [1]. Absence of cysts virtually excludes disease due to a truncating PKD1 variant between ages 15 and 30 (negative predictive value 99.1%) and above age 30 (100%), but does not exclude it before age 40 in families with reduced-penetrance non-truncating variants, PKD2 or minor genes [1]. The criteria assume an affected relative and apply only to PKD1 or PKD2 families [3, 10]. Thresholds are stricter for related living donors:

Source: GeneReviews, Table 2, derived from Pei et al. 2009 (NPV, negative predictive value) [1].

5.3. Magnetic resonance imaging, computed tomography and simple cysts

Magnetic resonance imaging is useful when ultrasound is equivocal: between ages 16 and 40, in people with an affected first-degree relative, more than 10 cysts suffice for diagnosis [1]. In Pei's prospective study (126 at-risk individuals, 110 with molecularly defined status, and 45 controls), >10 cysts had 100% sensitivity and specificity below age 30, with similar results between ages 30 and 40; high-resolution ultrasound with ≥3 cysts had approximately 97% sensitivity and 98% specificity [13]. KDIGO adds that fewer than 5 cysts on magnetic resonance imaging between ages 16 and 40 exclude the diagnosis [3]. Contrast-enhanced computed tomography and magnetic resonance imaging, routinely used in transplant centres, provide greater confidence in exclusion for donor candidates [1, 9].

The sensitivity of modern techniques requires interpretation of simple cysts: among potential donors assessed by contrast-enhanced computed tomography, 39%, 22%, 7.9% and 1.6% of people aged 19–49 had at least one cyst ≥2, ≥5, ≥10 and ≥20 mm, respectively, compared with 63%, 43%, 22% and 7.8% at ages 50–75 [1]. In adults with incidentally detected cysts and no family history, KDIGO proposes ultrasound of relatives, magnetic resonance imaging using criteria for a negative family history, and genetic testing for atypical presentations; few cysts, normal kidney function and size, and no extrarenal manifestations make ADPKD uncertain before age 40 and unlikely thereafter, with reassessment after approximately two years [3].

5.4. Genetic testing: indications, methods and limitations

KDIGO considers genetic testing particularly useful with few cysts, marked intrafamilial variability (including very early onset), discordance between imaging and GFR, a negative family history, related living donor candidates below age 30, and family planning involving preimplantation diagnosis [3]. In families with a known variant, targeted testing for the familial variant is usually sufficient [3]. The indications for genetic testing in adults with chronic kidney disease of undetermined cause and the technical limits of renal panels are common to the hereditary nephropathies.

Technical design is crucial. The PKD1 genomic region underwent complex segmental duplication: six copies of the 5' three-quarters of the gene exist as pseudogenes elsewhere on chromosome 16 [1]. Next-generation sequencing panels must therefore be designed to capture PKD1 specifically; exome sequencing may not detect all PKD1 variants; and deletion/duplication analysis requires methods such as MLPA (multiplex ligation-dependent probe amplification) or a chromosomal microarray covering the segment [1]. KDIGO considers a targeted ADPKD or nephrology gene panel the most effective and cost-effective method, advises against very limited Sanger or NGS approaches, accepts genome sequencing, which covers intronic and intergenic regions, and recommends copy-number testing with confirmation by MLPA or an equivalent method [2]. Sequencing detects approximately 97% of pathogenic PKD1 and PKD2 variants and deletion/duplication analysis approximately 3%; for minor genes, sequencing detects more than 95%, and a deletion encompassing GANAB has been described [1].

Results should be classified according to ACMG/AMP standards [2]. The report should identify the gene, versioned transcript (e.g., NM_001009944.3 for PKD1 and NM_000297.4 for PKD2, both MANE Select), HGVS (Human Genome Variation Society) nomenclature at coding DNA and protein levels, zygosity, classification and technical limitations, particularly coverage of duplicated PKD1 regions and sensitivity for mosaicism [2, 39]. In a patient with a typical clinical presentation, a negative or uncertain result does not exclude a hereditary form [2]. Low-level mosaicism may escape testing in leucocytes, and exclusively germline mosaicism is not detectable in blood [1, 2]. In the Geisinger population, a possible genetic cause was found in 180 of 235 ADPKD patients (76.6%), with 8.1% having variants in other cystic disease genes [2]; the Oxford Desk Reference reports identification of a pathogenic variant in approximately 90% of cases, with careful assessment of missense variants [9]. These are diagnostic yields in specific populations and do not equal analytical test sensitivity.

5.5. Prognostic assessment: Mayo Imaging Classification and PROPKD score

According to KDIGO, height-adjusted TKV is currently the best prognostic biomarker, measured most accurately by magnetic resonance imaging or computed tomography with automated or semi-automated tools; the ellipsoid formula (π/6 × length × width × depth) is an alternative [2]. KDIGO recommends using the Mayo Imaging Classification to predict future kidney function decline and timing of kidney failure (recommendation 1.4.2.1, grade 1B) [2].

The classification was developed in 590 Mayo Clinic patients with imaging and at least three eGFR measurements over ≥6 months (538 typical, 52 atypical) and externally validated in 173 CRISP participants [14]. Class 1 (typical) represents bilateral diffuse disease in which all cysts contribute similarly to TKV; class 2 (atypical) includes unilateral, segmental, asymmetric and lopsided forms (2A) and forms with unilateral or bilateral renal atrophy (2B), in which htTKV does not predict progression [2]. In class 1, starting from a theoretical value of 150 mL/m at birth, subclasses correspond to annual htTKV growth rates below 1.5% (1A), 1.5–3.0% (1B), 3.0–4.5% (1C), 4.5–6.0% (1D) and above 6.0% (1E) [2].

Sources: Irazabal 2015 and KDIGO 2025, citing Lavu 2020 for ages at kidney failure [2, 14, 42]. In the younger CRISP cohort, end-stage kidney disease frequency at 10 years ranged from 2.2% (1C) to 22.3% (1E) [14]. In Lavu's analysis, kidney failure risk during a mean follow-up of 16.8 years was 97%, 92%, 78% and 71% lower in subclasses 1A, 1B, 1C and 1D than in 1E [2]. The classification should not be used for atypical forms or patients with pathogenic variants in genes other than PKD1 and PKD2, often classified as 2A (IFT140) or 2B (DNAJB11, ALG5); without genetic information and with typical kidneys, predictions may be applied [2]. Ultrasound with the ellipsoid formula underestimated TKV by 11% and misclassified 22% of patients, but predicted subclasses 1C–1E with positive predictive value 98%, specificity 99%, negative predictive value 95% and sensitivity 94%; mean kidney length >16.5 cm predicted 1C–1E only up to age 45 [2].

The PROPKD score was developed in 1341 patients from the French Genkyst cohort and assigns 1 point for male sex, 2 for hypertension before age 35, 2 for the first urological event before age 35 (visible haematuria or cyst haemorrhage, cyst infection or cyst-related back pain), and 0, 2 or 4 for a PKD2, non-truncating PKD1 or truncating PKD1 variant [2, 15]. Low- (0–3), intermediate- (4–6) and high-risk (7–9) groups had median ages at end-stage kidney disease of 70.6, 56.9 and 49 years; a score ≤3 excludes end-stage kidney disease before age 60 with negative predictive value 81.4%, and a score >6 predicts it with positive predictive value 90.9% [15]. The score requires a genotype and does not reliably classify people below age 35 without hypertension or urological events [2]. Combining genotype and imaging improves prediction (C-index 0.845 in a multivariable model) [42].

5.6. Initial assessment after diagnosis

6. Differential Diagnosis

Without a family history or with an atypical presentation, the differential includes benign simple cysts and other hereditary and acquired cystic diseases [1]. Several differential diagnoses share genes or mechanisms with ADPKD, and some can be distinguished only by genetic testing [1, 3].

Distinguishing very early-onset ADPKD from ARPKD is particularly difficult. ARPKD features symmetrically enlarged, highly echogenic kidneys, with individual cysts not detectable on prenatal ultrasound, progressive oligohydramnios and liver involvement in all patients; individual cysts may be visible in fetal ADPKD, and prognosis is good in fetal life and early childhood except with oligohydramnios [43]. In PKHD1-related ARPKD, all patients with two truncating variants have a severe phenotype with perinatal or neonatal death, and neonatal survivors have at least one missense variant [43]. As biallelic ADPKD with hypomorphic alleles may occur without a family history, ARPKD should not be assumed without genetic testing including PKD1, PKD2 and PKHD1 [1, 8]. Ultrasound of parents, or grandparents when parents are below age 40, helps uncover an unknown family history [3].

7. Treatments and Risk Management Strategies

7.1. Organisation of care

Treatment aims to slow kidney function loss and reduce morbidity and mortality from renal and extrarenal complications [1]. KDIGO proposes a continuous multidisciplinary care pathway based on shared decision-making: complete clinical and imaging assessment, prognostic stratification (imaging, risk score, genetic testing when indicated), self-management and blood pressure control, nephroprotective treatment when indicated and according to local access, annual nephrology or shared-care follow-up with re-referral for complications or eGFR <60 mL/min/1.73 m², timely preparation for kidney replacement therapy, and participation in registries and trials [3]. Health systems should provide coordinated care, culturally adapted self-management programmes and access to patient organisations [3].

7.2. Blood pressure

KDIGO recommends standardised office blood pressure measurement (1B), supplemented by home or ambulatory measurement (2B) [2]. Targets vary with age and stage:

Renin–angiotensin system inhibitors, an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB), are first-line treatment (1C), and any combination of ACEI, ARB and direct renin inhibitor should be avoided (1B) [2]. Resistant hypertension requiring three or more drugs should prompt investigation for other causes, and high-grade proteinuria for coexisting nephropathy [3]. GeneReviews, predating KDIGO, proposes ≤110/75 mmHg at ages 18–50 with GFR >60 mL/min and ≤130/85 mmHg otherwise [1]. The KDOQI commentary agrees with the targets and emphasises practical difficulties with standardised measurement and the cost of ambulatory monitoring in the USA, proposing home measurement as an alternative [19].

In HALT-PKD study A (558 hypertensive patients aged 15–49 with eGFR >60), the low target (95/60–110/75 mmHg) reduced annual TKV growth (5.6% versus 6.6%), left ventricular mass index and albuminuria, without an overall eGFR difference, at the cost of more dizziness (80.7% versus 69.4%); lisinopril–telmisartan was not superior to lisinopril alone [49]. In study B (486 patients aged 18–64 with eGFR 25–60), dual inhibition did not change the composite outcome of death, end-stage kidney disease or a 50% eGFR reduction (HR 1.08; 95% CI 0.82–1.42) [50]. The Oxford Desk Reference recommends annual blood pressure measurement from adolescence and GeneReviews every three years from age 5 in normotensive individuals; the more recent KDIGO recommends annual measurement from age 5 in children with or at risk of ADPKD (see section 7.13) [1, 3, 9].

7.3. Tolvaptan

Mechanism and indication. Tolvaptan is a selective vasopressin V2 receptor antagonist that reduces cAMP-dependent cyst fluid secretion [10, 51]. KDIGO recommends initiating tolvaptan in adults with ADPKD, eGFR ≥25 mL/min/1.73 m² and risk of rapidly progressive disease (recommendation 4.1.1.1, grade 1B) [2]. Rapid progression means having reached, or being predicted to reach, kidney failure from ADPKD before approximately age 60, identified by Mayo class 1C–1E or a historical eGFR decline ≥3 mL/min/1.73 m² per year, established from multiple measurements over 3–5 years; in borderline class 1C, decisions should consider eGFR decline, PROPKD score >6, family history of kidney replacement therapy before age 60 in at least two first-degree relatives, or new biomarkers [2]. Other causes of eGFR loss (vascular disease, uncontrolled hypertension, diabetic nephropathy, proteinuria ≥1 g/day, acute kidney injury) should be excluded before concluding rapid progression [2]. The KDOQI commentary agrees and adds heart failure, nephrotoxic drugs and a causal variant in a gene other than PKD1/PKD2 as alternative explanations [19]. Above age 55, initiation should be individualised through shared decision-making (practice point 4.1.1.1): in REPRISE, the subgroup above 55 (190 patients) had no statistically significant eGFR benefit [2, 19]. Established treatment may continue after age 55 or with eGFR <25 mL/min/1.73 m² if well tolerated [2]. The 2022 ERA/ERKNet/PKD International consensus updated the European selection algorithm using REPRISE data [21].

Dosage (FDA label and European SmPC). Tablets of 15, 30, 45, 60 and 90 mg. The initial dose is 60 mg/day, divided into 45 mg on waking and 15 mg eight hours later, titrated to 60 mg + 30 mg and then to the target dose of 90 mg + 30 mg (120 mg/day, maximum recommended dose; indication in adults), at intervals of at least one week, and reduced according to tolerability [18, 51]. The European SmPC states that the morning dose should be taken at least 30 minutes before breakfast, that the patient should maintain the highest tolerated dose, drink one to two glasses of fluid before bedtime and replace fluid with each episode of nocturia, avoid grapefruit juice, and that treatment should be discontinued if the disease progresses to CKD stage 5 [18]. KDIGO and KDOQI adopt the same titration; KDIGO permits starting at 15 mg + 15 mg or 30 mg + 15 mg in special circumstances, and KDOQI suggests starting at 15 mg + 15 mg when interactions are expected to increase exposure; both prefer titration to the highest tolerated dose, as in the trials, over titration to morning urine osmolality ≤280 mOsm/kg, viewing this measurement as an adjunct when tolerability is problematic [2, 19]. Tolvaptan should be stopped before pregnancy, during breastfeeding and before the start of kidney replacement therapy; withdrawal may be associated with a 5–10% increase in eGFR [2].

Sources: FDA label, section 2.4, and Jinarc SmPC, section 4.2 [18, 51].

Hepatotoxicity and monitoring. Tolvaptan causes potentially fatal idiosyncratic liver injury; acute liver failure requiring transplantation has been reported post-marketing [18, 51]. In the two controlled trials, ALT elevations >3 times the upper limit of normal occurred in 4.9% (80/1637) with tolvaptan versus 1.1% (13/1166) with placebo, mainly within the first 18 months, and usually resolved within 1–4 months of withdrawal; in TEMPO 3:4 and its extension, severe hepatocellular injury (transaminases ≥3 times and bilirubin ≥2 times the upper limit) occurred in 0.2% (3/1487) [51]. The US label requires ALT, AST and bilirubin before initiation, at 2 and 4 weeks, monthly for 18 months and quarterly thereafter; the European SmPC requires baseline, monthly testing for 18 months and quarterly thereafter, and KDIGO notes that some regulators require testing at 2 and 4 weeks [2, 18, 51]. With symptoms or an elevation >2 times the upper limit (or >2 times baseline), treatment should be stopped and tests repeated within 48–72 hours; the US label prohibits reintroduction when ALT or AST exceeded 3 times the upper limit or signs of injury occurred, unless there is another explanation and resolution [3, 51]. The European SmPC lists permanent discontinuation criteria as ALT or AST >8 times the upper limit, >5 times for more than 2 weeks, >3 times with bilirubin >2 times or INR >1.5, or >3 times with persistent symptoms [18]. In the USA, the drug is dispensed only through the shared REMS (Risk Evaluation and Mitigation Strategy) programme, with certified prescribers and pharmacies and patient enrolment [51].

Aquaretic and other adverse effects. In TEMPO 3:4, increased urination occurred in 69.5% versus 28.0%, thirst in 63.7% versus 23.4%, dry mouth in 16.0% versus 12.4%, fatigue in 13.6% versus 9.7%, and hyperuricaemia in 3.9% versus 1.9%; aquaretic effects were the most common reason for discontinuation (6.6% versus 0.2%), and adverse events led to withdrawal in 15.4% versus 5.0% [51]. Hypernatraemia (>150 mEq/L) occurred in 4.0% versus 0.6% (TEMPO 3:4) and 1.4% versus 0% (REPRISE) [51]. KDIGO recommends teaching patients to respond to thirst with water, drink sugar- and fat-free fluids, reduce sodium (modestly reducing polyuria), maintain a ‘sick-day plan’ to withhold doses when at risk of volume depletion (diarrhoea, vomiting, fever, heat, limited water access, long journeys), and adapt dosing times to activities; evidence is insufficient to use thiazides to mitigate aquaresis [2]. Tolvaptan may raise uric acid and should be used cautiously in patients with gout [2]. KDIGO absolute contraindications are planned or current pregnancy, breastfeeding, high-risk conditions for volume depletion, inability to perceive or respond to thirst, hypernatraemia, urinary obstruction, strong CYP3A inhibitors and significant liver disease not due to polycystic liver disease; relative contraindications are eGFR <25 at initiation, gout or hyperuricaemia, CYP3A and P-glycoprotein inhibitors, grapefruit and bitter orange, and urinary incontinence [3].

Real-world adherence. In the three years following US approval, 6711 patients received prescriptions, and real-world data show approximately 75% continuation at 1–3 years; KDOQI identifies risk stratification, magnetic resonance imaging access, frequent monitoring, cost and inflexible working arrangements as barriers [19].

Marketing authorisation does not guarantee reimbursement or availability in each country; the consulted sources provided no information on reimbursement status in Portugal or incorporation into public healthcare in Brazil.

7.4. Water, diet and lifestyle

Without tolvaptan, KDIGO suggests adjusting fluid intake, spread throughout the day, to at least 2–3 L of water daily in patients with eGFR ≥30 mL/min/1.73 m² without contraindications to excreting a water load (2D), with caution for drugs increasing hyponatraemia risk (selective serotonin reuptake inhibitors, tricyclic antidepressants, thiazides) [2, 3]. KDIGO's CKD G1–G4 nutrition table includes water ≥2 L/day with second-morning urine osmolality <280 mOsm/kg, sodium <2 g/day (<90 mmol or <5 g salt), protein 0.8–1 g/kg/day (potential harm above 1.3 g/kg/day and preference for plant proteins), 25–35 kcal/kg/day, fat <30% of energy and fibre 25–38 g/day [2]. Body mass index should use adjusted weight, subtracting estimated polycystic kidney and liver weight (1 L ≈ 1 kg) and adding normal organ weight (approximately 0.27 kg/0.23 kg for kidneys and 1.6 kg/1.3 kg for liver, in men/women) [2]. Moderate physical activity of at least 150 minutes weekly and strength training twice weekly are recommended, with advice on direct-trauma risks to enlarged kidneys and liver [2]. All tobacco forms should be avoided; alcohol limited to ≤1 drink/day in women and ≤2 in men; excessive caffeine (particularly in pregnancy), cannabis, recreational drugs and anabolic steroids should be avoided [3]. GeneReviews adds targets of LDL cholesterol ≤100 mg/dL, serum bicarbonate ≥22 mEq/L and moderate dietary phosphorus (800 mg/day), and notes that in CRISP, body mass index ≥30 kg/m² was associated with faster kidney growth and GFR loss [1]. Sodium restriction has been associated with benefit in ADPKD [9]. Patients with gout should be treated according to the 2020 American College of Rheumatology guideline, without pharmacological treatment for asymptomatic hyperuricaemia [3]. KDIGO recommends lipid-lowering therapy for cardiovascular prevention according to its lipid guideline, but not statins specifically to slow renal progression (2D) [2, 3].

7.5. Therapies not indicated to slow progression

KDIGO recommends against mTOR inhibitors (1C) or metformin in patients without diabetes (1B) to slow progression, suggests against somatostatin analogues solely to slow eGFR decline (2B), although these may be considered for severe symptoms from massive kidneys without alternatives, and suggests against sodium–glucose cotransporter 2 inhibitors (SGLT2 inhibitors), GLP-1 receptor agonists or ketogenic diets for this purpose until evidence is available [2, 3]. With coexisting diabetes, KDIGO advises against SGLT2 inhibitors because of insufficient evidence and prefers metformin with eGFR ≥30 mL/min/1.73 m² or a GLP-1 agonist with eGFR <30 or when metformin is not tolerated or insufficient [3]. Trials of mTOR inhibitors showed no effect, an effect on TKV with faster eGFR decline, or worsening of both, with significant toxicity; bosutinib reduced TKV growth without affecting eGFR, with high withdrawal rates [1]. Supplements and complementary medicines should not replace standard treatment [3].

7.6. Pain, cyst haemorrhage, stones and infections

Pain. Flank, abdominal or back pain should be investigated to determine renal origin; after excluding causes requiring intervention (infection, stones, tumour), management begins with non-pharmacological measures and non-opioid analgesics, avoiding prolonged NSAID and combination analgesic use; tricyclic antidepressants are useful and well tolerated, and opioids should be reserved for acute episodes [1, 3]. Refractory pain requires multidisciplinary management and invasive intervention in a specialist centre: aspiration or sclerotherapy of one or a few dominant cysts, coeliac plexus block alone or followed by greater splanchnic nerve block, percutaneous renal denervation, spinal cord stimulation in selected cases, and nephrectomy for intractable pain, usually with advanced disease or after kidney failure [3]. Aspiration helps establish the relationship between a cyst and pain but rarely provides sustained relief because fluid reaccumulates; 95% ethanol sclerotherapy achieved 90% success in benign cysts; surgical decompression was effective in 80–90% of patients at one year and 62–77% beyond two years, neither accelerating nor preserving kidney function [1].

Cyst haemorrhage and visible haematuria. These are usually self-limiting and respond to rest, analgesia and adequate hydration to avoid obstructing clots; severe haemorrhage with subcapsular or retroperitoneal haematoma and haemodynamic instability requires hospitalisation, transfusion and computed tomography or angiography, with segmental arterial embolisation or surgery for persistent cases; some reports suggest a role for tranexamic acid in life-threatening haematuria [1]. KDIGO recommends explaining the possibility, causes and natural course of visible haematuria at diagnosis to avoid unnecessary anxiety [3].

Stones. Medical treatment follows general-population practice, and obstructing stones should be treated in experienced centres because management is more difficult in ADPKD [3]. KDIGO adopts the general recommendation of urine output 2.5 L/day for stone formers (2B) [2]. Small uric acid stones are best detected by computed tomography, without and with contrast, to distinguish them from parenchymal calcifications; high fluid intake and potassium citrate are the treatments of choice for uric acid stones, calcium oxalate stones with hypocitraturia and distal acidification defects; extracorporeal lithotripsy and percutaneous nephrolithotomy may be used without excess complications [1].

Urinary tract infection and renal cyst infection. KDIGO adopts general recommendations: do not treat asymptomatic bacteriuria (1B), use nitrofurantoin, trimethoprim–sulfamethoxazole or fosfomycin for symptomatic cystitis in women according to local susceptibility patterns (1B), treat recurrent cystitis episodes for the shortest reasonable duration, generally up to 7 days (2B), and consider prophylaxis in women with previous infections (2B) [2]. Recurrent infections should prompt investigation for a predisposing factor, and blood cultures are necessary when upper tract or cyst infection is suspected [3]. The KDIGO algorithm considers cyst infection probable with fever >38 °C, acute abdominal pain and C-reactive protein ≥50 mg/L or leucocytosis >11 × 10⁹/L, with at least two criteria from two categories (clinical, microbiological, imaging or treatment response), reserving 18F-FDG positron emission tomography for cases requiring confirmation [3]. KDIGO suggests 4–6 weeks of antibiotics (2D), preferably a lipid-soluble agent (trimethoprim–sulfamethoxazole or a fluoroquinolone), noting that fluoroquinolones are associated with tendinopathy and aortic aneurysms and dissections [3]. GeneReviews explains that ‘gradient’ cysts allow only lipid-soluble drugs to pass through tight junctions, also cites clindamycin, vancomycin and metronidazole as agents with good penetration, and recommends percutaneous or surgical drainage if fever persists after one to two weeks of appropriate antibiotics [1].

7.7. Intracranial aneurysms

KDIGO recommends informing all adults about increased aneurysm and subarachnoid haemorrhage risk, risk factors, screening, preventive measures and warning symptoms (1C), emphasising thunderclap headache, smoking cessation and blood pressure control [2]. It recommends screening patients with previous subarachnoid haemorrhage or a family history of aneurysm, subarachnoid haemorrhage or unexplained sudden death if eligible for treatment and with reasonable life expectancy (1D) [2]. Screening should be discussed in de novo ADPKD, with unknown or uninformative family history or a personal or familial extracerebral vascular phenotype; it may be considered before kidney or liver transplantation or major elective surgery; it should be available to anyone who prefers it after full information; and in women with an indication, it should be discussed before pregnancy [3]. The method is time-of-flight magnetic resonance angiography without gadolinium, with high-resolution computed tomography angiography as an alternative; after negative screening in high-risk patients, repeat testing should be individualised at 5–10-year intervals, and detected aneurysms assessed in high-volume multidisciplinary centres [3]. KDIGO notes life-insurance implications and anxiety associated with detecting lesions not requiring treatment [3].

Earlier sources differ in detail. GeneReviews proposes considering magnetic resonance angiography every 10 years in risk groups, including high-risk occupations such as airline pilots and significant anxiety despite adequate information, and cites a study in which 1 of 76 patients with normal initial magnetic resonance angiography developed a new aneurysm after mean follow-up of 9.8 years [1]. The Oxford Desk Reference suggests repetition every 5 years after a negative examination and every 2 years with a previous aneurysm or haemorrhage, stressing that screening should be organised only with neurosurgery so a plan exists before testing [9]. For treatment, GeneReviews describes surgical neck clipping as the mainstay for ruptured or symptomatic aneurysms, initially annual observation of asymptomatic aneurysms ≤5 mm, controversy at 6–9 mm and usual intervention above 10 mm, with detachable platinum coils for patients at high surgical risk [1]. The Oxford Desk Reference recommends conservative treatment below 10 mm and surgery above, with intervention mortality of 1% and morbidity of 3–7% [9]. KDIGO sets no thresholds and refers decisions between surveillance, microvascular or endovascular repair to multidisciplinary teams [3].

7.8. Polycystic liver disease

The liver should be included in abdominal imaging (magnetic resonance imaging, computed tomography or, if unavailable, ultrasound) to measure volume and characterise severity; symptoms should be recorded using disease-specific questionnaires, and symptomatic patients assessed for sarcopenia and malnutrition [3]. Most patients require no treatment [1]. KDIGO recommends long-acting somatostatin analogues for marked cystic hepatomegaly with severe volume-related symptoms (1B), assessing response at 6–12 months and stopping without benefit; four randomised trials with at least one year of follow-up showed reduced liver volume growth, and adverse effects include gastrointestinal symptoms, gallstones, bradycardia and hyperglycaemia, the latter more common with pasireotide [2, 3]. Somatostatin analogues are not authorised for this indication in the consulted labels, making use off-label; the consulted source specifies no dose for liver disease.

Source: KDIGO 2025, executive summary Table 3 [3]. Combined liver–kidney transplantation is indicated when liver transplantation is indicated and eGFR <30 mL/min/1.73 m² [3]. Patients with severe liver disease usually have normal liver function and low MELD (Model for End-Stage Liver Disease) scores, placing them at a disadvantage in organ allocation [1].

For hepatic cyst infection, empirical therapy should target Enterobacteriaceae with an intravenous third-generation cephalosporin, with or without a fluoroquinolone, switching to an oral fluoroquinolone after stabilisation, for at least 4 weeks; percutaneous drainage should be considered for resistant organisms, immunosuppression, infected cysts >8 cm, haemodynamic instability or sepsis, and lack of response within 48–72 hours requires reassessment; empirical antibiotics should not be used for localised liver pain without fever and with normal white cells and C-reactive protein [3].

Sex hormones and contraception. Oestrogens and possibly progestogens should be avoided in severe polycystic liver disease [1]. KDIGO specifies that oestrogen-containing oral contraceptives may worsen liver disease; effects of combined patches or rings and progestogen-only methods are unknown, but systemic exposure from the levonorgestrel intrauterine device is 4–13% of that from combined oral contraceptives; low-dose combined methods may be used with no or mild liver disease; the progestogen-only device is probably safe in moderately severe disease; non-hormonal methods (barrier, copper device) are safest in severe disease; and contraception should not be restricted in adolescents and young adult women [3]. Liver imaging should be offered before deciding on hormonal therapy [3].

7.9. Advanced chronic kidney disease, dialysis and transplantation

CKD management follows general guidelines [3]. Kidney transplantation, preferably pre-emptive and from a living donor, is the preferred treatment for kidney failure; assessment should subtract estimated kidney and liver weight from body weight, consider renal imaging within the preceding year to exclude solid or complex cystic lesions, and use the same immunosuppression as for other recipients [3]. KDIGO suggests native nephrectomy only for a specific indication (symptoms from massive kidneys, severe or recurrent infection or bleeding, complicated stones, intractable pain, suspected carcinoma, inadequate graft space, severe ventral hernia), unilateral rather than bilateral when appropriate (2D), at or after transplantation rather than beforehand (2C), and hand-assisted laparoscopic rather than open surgery (2D) [2]. The KDOQI commentary disagrees with this last suggestion and proposes that the surgical team decide the approach, citing risks of infected cyst rupture and dissemination of undiagnosed carcinoma during laparoscopy of large kidneys; it also recommends individualising unilateral versus bilateral nephrectomy because robust data are lacking [19]. Patient and graft survival after transplantation are similar to other aetiologies; new-onset diabetes, erythrocytosis, worsening valvular disease, aortic root dilatation, subarachnoid haemorrhage, thromboembolic events, skin cancers, cyst infections and diverticulitis were more common in some studies [1, 3]. Post-transplant erythrocytosis is initially treated with an ACEI or ARB, targeting haematocrit <51% and haemoglobin <17 g/dL, with phlebotomy if these are contraindicated or ineffective [3].

ADPKD patients have better dialysis outcomes than patients with other causes of kidney failure [1]. Peritoneal dialysis is viable, with caution for massive kidneys or liver or abdominal wall hernias, which should be surgically repaired in patients choosing it; modality selection depends on the patient and resources (2C) [2, 3]. Haemodialysis may rarely be complicated by hypotension from inferior vena cava compression by a cyst [1].

7.10. Other extrarenal manifestations

Routine screening for aneurysms of major extracranial arteries is not indicated without a family history of aneurysms or dissections; with a family history of aortic root or thoracic aortic aneurysm, first-degree relatives should be screened, and aortic dilatation should prompt smoking cessation, a statin and antihypertensives including a beta-blocker and/or ACEI or ARB [3]. GeneReviews proposes echocardiography or thoracic magnetic resonance imaging every 2–3 years in adults with a first-degree relative with thoracic aortic dissection, and aortic replacement when the root reaches 55–60 mm [1]. Non-surgical treatment should be discussed for asymptomatic abdominal wall hernias with large kidneys or kidney failure, with teaching on signs of incarceration [3].

7.11. Agents and circumstances to avoid

Prolonged nephrotoxic treatment (combination analgesics, NSAIDs), large amounts of caffeine, high-salt diets, smoking, obesity and, in severe polycystic liver disease, oestrogens and possibly progestogens should be avoided [1]. The Oxford Desk Reference recommends avoiding NSAIDs with impaired kidney function and adjusting all drugs to kidney function [9]. Vasopressin analogues should not be used for nocturnal enuresis in children with or at risk of ADPKD [3]. ACEIs, ARBs, tolvaptan and other teratogenic drugs should be stopped before conception [3].

7.12. Clinical trials underpinning decisions

These trials measure different outcomes (TKV, eGFR at 1 or 3 years, composite outcomes, pharmacodynamic markers) in populations at different stages, so their numbers should not be compared to rank drugs. Tolvaptan provides an absolute reduction of approximately 1–1.3 mL/min/1.73 m² per year in eGFR decline; treated patients continue losing function, and KDIGO accepts eGFR decline rate as a reliable surrogate for delaying kidney failure, without a trial using kidney failure as an outcome [3, 34]. The TEMPO 3:4 TKV difference developed mainly in the first year and was not maintained in extension years 4 and 5 when both groups received tolvaptan [51]. REPRISE selected patients tolerating the two highest doses during pre-randomisation, limiting generalisation of adverse event rates [51]. Neither pivotal trial required molecular diagnosis; in TEMPO 3:4, among 770 participants genotyped in the extension, 88% had PKD1 and 12% PKD2 variants, and the data do not support extrapolation to minor genes [10, 51]. DIPAK 1 and ALADIN 2 showed reduced kidney growth without an eGFR effect, illustrating possible dissociation between these outcomes [1, 53]. POSITANO results are available in the registry, with no peer-reviewed publication located in the consulted sources. Trial populations were predominantly white: 84% Caucasian in TEMPO 3:4 and 92% in REPRISE, with few black patients [51].

7.13. Children and adolescents

No validated models identify children with rapid progression and no therapies are approved specifically for this population; KDIGO considers evidence insufficient for disease-modifying treatment in children beyond antihypertensive treatment [3]. The 2019 international paediatric consensus allowed off-label vasopressin antagonist use in selected children, did not recommend mTOR inhibitors or somatostatin analogues, and reached no consensus on statins [20]. Standardised blood pressure measurement should be annual from age 5, with annual ambulatory monitoring (from age 5 and height 120 cm) in very early- or early-onset forms and when pressure is ≥75th percentile; hypertension should prompt consideration of other causes, echocardiography to exclude left ventricular hypertrophy, and initiation of an ACEI or ARB (1D) under paediatric nephrology guidance [2, 3]. Renal follow-up is adapted to clinical findings, blood pressure, kidney function, urine and ultrasound, without routine extrarenal screening; urinary infection, pain, stones and proteinuria are treated as in children without ADPKD, with ultrasound for atypical infection courses [3]. A formal transition process to adult care should be established [3]. In the paediatric tolvaptan trial, the drug had pharmacodynamic activity and manageable aquaretic effects, but the 12-month htTKV difference was not significant [54]; paediatric use remains off-label in the USA and EU [18, 51].

7.14. Investigational therapies and developments in the last 12 months

Between October 2025 and October 2026, identified regulatory and clinical developments were publication of the North American KDOQI commentary (April 2026); FDA approval of new ADPKD-indicated tolvaptan generics (Alkem, 21/04/2026; Teva, 21/07/2026); the European variation of 10/04/2026 closing the 7.5-year post-authorisation safety study; the Jynarque® labelling supplement approved on 15/09/2026; initiation of VX-407 (phase 2a) and STOP-PKD (phase 3) trials; and posting of POSITANO results on ClinicalTrials.gov in June 2026 [16, 17, 19, 52, 58, 59, 61]. None of these programmes yet constitutes authorisation of a new ADPKD drug.

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

In most families, ADPKD results from a heterozygous PKD1 or PKD2 variant transmitted in an autosomal dominant manner, and each child of a heterozygote has a 50% chance of inheriting it [1]. Most probands have an affected parent; 10–20% have a de novo variant [1]. The Oxford Desk Reference estimated de novo variants at approximately 10% [9]. When the proband's variant is absent from both parents' leucocyte DNA, with parentage confirmed, de novo occurrence or parental mosaicism (somatic and germline, or germline only), estimated in approximately 0.25% of families, should be considered; sibling risk is then slightly above population risk [1]. If parental genetic status is unknown and imaging appears normal, sibling risk remains above population risk because a parent may have late-onset disease or mosaicism [1]. Assessment of parents of an apparently de novo proband should include imaging, preferably magnetic resonance imaging or computed tomography in families with mild kidney disease, and testing for the variant when known [1].

In biallelic or digenic ADPKD families, risk depends on the segregating variants, and testing relatives should include both [1]. Severe in utero-onset disease has a substantial sibling recurrence risk, potentially resulting from co-inheritance of a hypomorphic allele from an apparently unaffected parent [9]. In Durkie's series, the high frequency of biallelic inheritance in infants with very early-onset disease has direct reproductive counselling implications despite difficulties classifying these alleles under ACMG/AMP rules [8]. With a dual aetiology, such as PKD1 and PRKCSH on different chromosomes, each child has a 25% chance of inheriting both variants and 50% of inheriting one [45]. For genes also causing recessive disease (e.g., ALG9, DNAJB11, IFT140), carriers should be informed and their partners offered carrier testing when planning reproduction [1, 2].

8.2. Predictive testing and testing minors

Cascade screening of adult relatives is justified by the benefits of blood pressure control and morbidity of undiagnosed kidney impairment [9]. GeneReviews recommends clarifying the status of adult relatives (≥18 years) for education, surveillance, early detection, treatment and trial inclusion, by imaging or familial variant testing; a ‘negative’ genetic test without a known familial variant does not exclude disease [1]. Formal counselling should precede predictive testing, including potential insurance and employment effects [1].

For asymptomatic minors, sources differ in emphasis. GeneReviews considers testing asymptomatic children currently unindicated, but testing symptomatic children with polycystic kidney disease appropriate [1]. The 2019 paediatric consensus considers surveillance of treatable manifestations without diagnostic testing and immediate diagnostic screening equally valid, recommending genetic testing in infants with symptomatic very early-onset disease and children with a negative family history and progressive disease [20]. KDIGO calls for shared decisions with parents and sufficiently mature children, counselling by a team including a paediatric nephrologist and geneticist, and ultrasound as the preferred method; it explains that a single cyst in an at-risk child below age 15 is highly suggestive, but absent cysts do not exclude diagnosis; it offers genetic testing for very early-onset disease, atypical presentation, cystic kidneys with negative family history, or screening of at-risk children after shared decision-making [3]. Orphanet states that presymptomatic screening of at-risk children is currently not recommended [4]. Whichever option is chosen, children with a family history should have blood pressure surveillance [3, 20].

8.3. Kidney donation within families

At-risk relatives volunteering as donors should undergo complete renal imaging (ultrasound, contrast-enhanced computed tomography and/or magnetic resonance imaging) and, if the familial variant is known, molecular testing; only those without it should proceed. Without a known familial variant, assessment relies on imaging, and a gene panel may help candidates with few cysts [1]. KDIGO highlights genetic testing in donor candidates below age 30 and with equivocal imaging [2, 3]. For minor genes such as DNAJB11, donor selection is particularly sensitive because a relative with non-enlarged kidneys and few cysts may be wrongly considered unaffected [35].

8.4. Reproductive options

The ideal time to establish genetic risk and discuss prenatal and preimplantation diagnosis is before pregnancy [1]. KDIGO recommends preconception counselling for men and women by a multidisciplinary team in a reference centre, covering all options: accepting the 50% risk without testing, preimplantation genetic diagnosis when the causal variant is known and parents accept discarding embryos, prenatal diagnosis when parents would consider pregnancy termination (with discussion of legal availability), gamete donation or adoption [3]. Prenatal diagnosis is technically possible from chorionic villi if the variant is known, but has rarely been requested; preimplantation diagnosis is requested more often [9]. In families without a molecular diagnosis, banking proband DNA is useful, particularly for atypical presentations such as lethal in utero-onset disease [1]. Different perspectives on prenatal and preimplantation diagnosis should be discussed non-directively [1].

8.5. Contraception, pregnancy and postpartum care

Pregnancy is usually well tolerated, with stable kidney function, but requires specialist surveillance of hypertension, which may worsen, and increased pre-eclampsia risk [9]. KDIGO recommends follow-up by a multidisciplinary team in a specialist centre; monitoring blood pressure (preferably weekly at home), kidney function, proteinuria and, when available, the sFlt-1/PlGF ratio from 24 weeks and every 4–6 weeks; monthly urinalysis with treatment of positive cultures even if asymptomatic; a blood pressure target ≤130/85 mmHg with labetalol, extended-release nifedipine, hydralazine, clonidine or methyldopa; low-dose acetylsalicylic acid from the 12th to 36th week; ultrasound or magnetic resonance imaging for acute abdominal pain; and unrestricted vaginal delivery [3]. ACEIs, ARBs and tolvaptan should be stopped before pregnancy and resumed only after breastfeeding ends [3]. Women should have nephrology assessment at 6 weeks and up to 6 months postpartum, and be offered pelvic floor physiotherapy for bladder instability or incontinence [3]. GeneReviews advises second-trimester prenatal ultrasound when a parent has ADPKD to assess fetal kidney size and echogenicity, cysts and amniotic fluid [1]. Mild fetal renal findings do not imply poor prognosis, whereas severe bilateral cystic disease and oligohydramnios are associated with worse neonatal outcomes; normal fetal ultrasound does not exclude diagnosis [3].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Genetic, birth and diagnosed prevalence

Estimates vary more than fivefold according to whether genetic prevalence, birth prevalence or diagnosed disease prevalence is measured [2]. The value 1:1000 derives from Dalgaard's study and represents theoretical risk over 80 years (8 per 10,000), rather than point prevalence [2]. GeneReviews reports birth prevalence of approximately 1:1000 and approximately 300,000 affected people in the USA; the Oxford Desk Reference gives 1:2000 across ethnic groups; Orphanet gives 1–5/10 000 and approximately 1:2500 in Europe [1, 4, 9]. KDIGO summarises diagnosed disease prevalence: 3.96 per 10,000 in the European Union in 2012, 2–4 per 10,000 in several US studies, 5.7 per 10,000 in the Seychelles, 6.8 per 10,000 (definite or probable cases) in Olmsted County, Minnesota, during 1980–2016, rising to 12.4 per 10,000 including possible cases, and 13.5 per 10,000 in a Pennsylvania health system using code selection and clinical confirmation [2]. Sequencing unselected populations (gnomAD and BRAVO, more than 200,000 individuals) found high-confidence PKD1 and PKD2 variants in 9.3 per 10,000 sequenced individuals, a lower bound for lifetime prevalence, with 6.8 and 2.6 per 10,000 for PKD1 and PKD2 (ratio 2.6), and truncating polycystic liver disease gene variants in 20.2 per 10,000 [2, 11]. The PKD1/PKD2 ratio above 4 in nephrology clinics probably reflects milder PKD2 disease [2]. For DNAJB11, estimated genetic prevalence from gnomAD was 0.85 per 10,000, and pathogenic variants were found in 9 of 3934 probands with kidney and urinary disorders in the 100,000 Genomes Project [35]. These values are carrier or recorded-case proportions in specific populations and should not be interpreted as clinical disease prevalence or transferred to minor genes.

9.2. Burden in kidney replacement therapy

In the USA in 2020, 3396 people with cystic kidneys started kidney replacement therapy (2.60% of new entrants), and 40,968 were receiving treatment (5.07% of the total, 115 per million; 63% transplanted, 29% on haemodialysis and 8% on peritoneal dialysis); 55.6% received nephrology care at least 12 months before kidney failure [2]. In the 2020 ERA (European Renal Association) registry, prevalence was 137 per million, 5% of the kidney replacement population and 9% below age 65, with 67% transplanted, 30% on haemodialysis and 3% on peritoneal dialysis [2]. Mean ages at kidney failure used by KDIGO to define rapid progression derive from registries and cohorts across continents: 58 years in ERA-EDTA, 61.7 in the French Genkyst cohort, 62 in the Mayo database, 62 in a Korean national cohort and 60 in the Australian and New Zealand ANZDATA registry [2]. In 1985, ADPKD accounted for 9% of chronic dialysis requirements in Reeders' series [23].

9.3. Population diversity and founder effects

ADPKD affects all populations, with no common pathogenic variant enriching disease in a region or ethnic group except a Taiwan-specific PKD2 variant [2]. Prevalence appears higher in European-ancestry populations, potentially reflecting a founder effect or underdiagnosis in black populations; few prevalence studies exist in Asia and Africa [2]. High allelic heterogeneity means the causal variant is often unique to a family [45]. Cohorts underpinning the Mayo Imaging Classification and pivotal trials are predominantly European-ancestry (84% Caucasian in TEMPO 3:4 and 92% in REPRISE), and KDIGO notes the need to validate prognostic models in more diverse populations [2, 51]. Aneurysm prevalence and subarachnoid haemorrhage incidence vary between countries, and KDIGO recommends considering ethnic and local differences in screening decisions [2]. No Portugal- or Brazil-specific epidemiological data were found in the consulted sources.

9.4. Special populations and access

Developed with patient partners, KDIGO addresses resource disparities: when magnetic resonance imaging and computed tomography are unavailable, it permits ultrasound with the ellipsoid formula and historical eGFR decline to stratify risk [2]. In the USA, KDOQI identifies barriers in genetic testing and tolvaptan costs, insurance coverage and access to volumetry [19]. ERKNet is the European reference network for rare kidney diseases, and patient organisations include the PKD Foundation (USA), Polycystic Kidney Disease Charity (UK), PKD International, Ciliopathy Alliance, Kidney Foundation of Canada and National Kidney Foundation [1, 4, 9]. Orphanet also lists French national protocols (PNDS of 2018 and 2024) among ADPKD-associated guidelines [4].

10. Illustrative Clinical Case

10.1. Dual monogenic aetiology: ADPKD-PKD1 and PRKCSH-related polycystic liver disease

Brossart and colleagues described in 2026 a 50-year-old woman of European ancestry with a previous clinical ADPKD diagnosis, hypertension and preserved kidney function who sought nephrology care for abdominal discomfort and distension consistent with hepatomegaly and difficulty eating [45]. Computed tomography showed numerous renal and hepatic cysts (Figure 2 of the original article, axial and coronal computed tomography sections). Family history included clinical ADPKD in her mother, maternal grandmother and the grandmother's siblings; her mother developed kidney failure in her late seventh decade, received a transplant and died in her eighth decade from COVID-19 complications, with a few small hepatic cysts on late imaging; her maternal grandmother died at 82 from ADPKD complications; another first-degree relative had a few renal cysts with normal function; no relative had significant liver disease [45].

Because liver disease was disproportionate to kidney disease and inconsistent with the family's course, a 385-gene hereditary kidney disease panel was requested, with hybrid capture of exons and exon–intron junctions, GRCh37 alignment, ACMG/AMP classification and orthogonal confirmation by Sanger or MLPA/qPCR [45]. Two heterozygous truncating pathogenic variants were identified: NM_001009944.3(PKD1):c.3957_3994dup, p.(Asp1332GlyfsTer27), in exon 15 (ClinVar VCV003376509.1), and NM_001289104.2(PRKCSH):c.374_375del, in exon 6 (ClinVar VCV001048653.34), described in the paper as p.(Glu125fs) [45]. Both were confirmed in VariantValidator against MANE Select transcripts, and the PRKCSH variant corresponds to NP_001276033.1:p.(Glu125ValfsTer21) [39]. The PKD1 variant was absent from gnomAD v4.1.0 and previously described; the PRKCSH variant had been identified in two autosomal dominant polycystic liver disease families [45].

The authors interpreted the pronounced hepatic phenotype as a possible PC1 dosage effect because hepatocystin (the glucosidase II beta subunit) participates in polycystin maturation, and emphasised counselling implications: the variants segregate independently, each child has a 25% chance of inheriting both and 50% of inheriting one, and relatives should be tested for both [45]. Maternal origin of the PKD1 variant was only presumed because both parents had died and segregation could not be studied, and the PRKCSH variant may be de novo or inherited from a mildly affected parent [45]. Three authors were employees of the laboratory marketing the panel, and a fourth had been employed there during the study [45].

This case illustrates three points of this article: dominant polycystic liver disease belongs in the differential diagnosis and may coexist with ADPKD; genetic testing is more informative when the presentation is discordant with the family history; and counselling of relatives depends on the complete molecular diagnosis [3, 45]. The mechanistic interpretation of the interaction between the two variants is a hypothesis of the authors, without a functional study. The authors' recommendation to avoid oestrogen- and progestogen-containing contraceptives and hormonal intrauterine devices in liver disease is stricter than KDIGO, which considers the progestogen-only device probably safe in moderately severe disease and reserves non-hormonal methods for severe disease [3, 45]. The authors cite KDIGO in support of expanded panel testing; in the guideline, this guidance is an ungraded practice point [2, 45].

10.2. Very early-onset ADPKD from a de novo PKD1 variant

Kim and colleagues described in 2026 a Korean male newborn, the second child of non-consanguineous parents without renal or endocrine history, referred on day 8 for neonatal screening 17-hydroxyprogesterone of 51.4 ng/mL; he had hyponatraemia (129 mmol/L), hyperkalaemia (6.5 mmol/L), ACTH 370 pg/mL and scrotal and labial hyperpigmentation, and started hydrocortisone, fludrocortisone and sodium chloride for salt-wasting congenital adrenal hyperplasia [64]. Prenatal ultrasound had shown a 1.3 cm right renal cyst; at 11 days, there were multiple small left renal cysts and two right renal cysts, with normal kidney size, and both parents' renal ultrasounds were normal [64]. The cystogenesis gene panel identified NM_001009944.3(PKD1):c.12013C>T, p.(Gln4005Ter), absent in both parents, supporting de novo occurrence; CYP21A2 sequencing identified c.293-13C>G and c.955C>T, p.(Gln319Ter), without confirmed allelic phase [64]. The PKD1 variant was confirmed in VariantValidator against the MANE Select transcript (NC_000016.10:g.2090799G>A) [39].

Over five years, cysts enlarged (largest cyst 0.2–0.4 cm at 11 days and 2.5 cm at age 5), medullary nephrocalcinosis appeared at 6 months with progressive worsening, and stones <3 mm developed at age 5 (Figure 1 of the original article, sequential ultrasound examinations from the neonatal period to age 5); mild proteinuria persisted from age 3 (protein/creatinine ratio 0.20–0.25 mg/mg), kidney length remained normal, and kidney function, stable overall, declined modestly late in follow-up [64]. At 3 years and 7 months, blood pressure reached 122/86 mmHg (stage 2 hypertension under American Academy of Pediatrics criteria) on unchanged corticosteroid doses; renal Doppler was normal; enalapril was started and fludrocortisone halved, reducing pressure to approximately 99/60 mmHg and allowing enalapril withdrawal six months later [64]. The authors considered nephrocalcinosis and stones multifactorial [64].

The case shows that ADPKD may manifest fetally and neonatally without a family history, normal parental ultrasound does not exclude disease in the child, and genetic testing establishes de novo occurrence, with implications for sibling recurrence risk (low but above population risk because of possible germline mosaicism) and a 50% risk to the patient's future offspring [1, 3, 64]. Antihypertensive management was influenced by coexisting adrenal hyperplasia and should not be generalised; general guidance for children with ADPKD and hypertension appears in section 7.13 [2].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Approximately half of patients develop end-stage kidney disease by age 60, but the range is broad: age depends on gene (PKD1 58.0 years; PKD2 74.8), PKD1 variant type (truncating 55.6 years; non-truncating 67.9), sex and environmental factors such as obesity and salt intake [1, 2]. The Mayo Imaging Classification and PROPKD score estimate likely age at kidney failure (section 5.5), and combining imaging and genotype improves discrimination [14, 15, 42]. Family disease severity provides an approximate guide, with significant intrafamilial variability [1, 2]. Minor genes generally progress more slowly, but DNAJB11 and ALG5 are associated with kidney failure in the eighth and ninth decades and NEK8 with childhood kidney failure [3, 31, 35]. Orphanet reports that proteinuria and hypertension in affected children correlate with more severe progression [4]. Cardiovascular disease is the leading cause of death [1]. After transplantation, patient and graft survival are similar to other causes of kidney failure [1].

11.2. Follow-up plan

Patients should be encouraged to participate in registries, cohort studies and clinical trials [3].

12. Summary and Final Considerations

ADPKD is the most common monogenic kidney disease associated with kidney failure, with genetic prevalence of approximately 9 per 10,000 sequenced individuals and diagnosed disease prevalence of 2–4 per 10,000 in US studies and 3.96 per 10,000 in the European Union [2, 11]. PKD1 (approximately 78%) and PKD2 (approximately 15%) variants explain most families, and minor genes involved in PC1 biogenesis or intraflagellar transport (IFT140, GANAB, DNAJB11, ALG9, ALG5, NEK8) explain a small proportion, with distinctive phenotypes and generally slower progression [1, 3]. Functional polycystin dosage is a central determinant of severity, explaining very early-onset disease from hypomorphic alleles in trans and mosaicism-associated variability [7, 8, 38].

Diagnosis relies on age- and family-history-dependent imaging criteria valid for PKD1 and PKD2, and genetic testing designed to address duplicated PKD1 regions, copy-number variations and mosaicism [1, 2, 12]. KDIGO 2025 introduced ‘ADPKD-gene’ nomenclature, recommends the Mayo Imaging Classification for prognosis, and defines rapid progression (classes 1C–1E or eGFR decline ≥3 mL/min/1.73 m² annually) as a criterion for starting tolvaptan in adults with eGFR ≥25 mL/min/1.73 m² [2]. Tolvaptan reduces eGFR decline by approximately 1.0–1.3 mL/min/1.73 m² annually and requires liver monitoring; US and EU labels differ in initial monitoring, strong CYP3A inhibitors and pregnancy and breastfeeding status [18, 33, 34, 51]. Blood pressure control with age-dependent targets, water intake, sodium restriction, complication management, targeted intracranial aneurysm screening and treatment of symptomatic polycystic liver disease complete management [3].

Genetic counselling should cover the 50% risk, particular features of de novo, mosaic, biallelic and digenic forms, differing positions on testing minors, living donor selection and reproductive options [1, 3, 20]. Current research includes polycystin dosage-targeted therapies (farabursen), genotype-selected PC1 folding correctors (VX-407), PAPP-A antibodies and repurposing of SGLT2 inhibitors and metformin, with no new drug authorised at the article's date [56, 59, 61].

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