Autosomal dominant polycystic kidney disease.

# Autosomal dominant polycystic kidney disease *The Lancet 2026* Review interventions such as a ketogenic diet, metformin, sodium- p 3). Extrapolations of the results of TEMPO 3:4 and glucose cotransporter-2 inhibitors, and GLP-1 receptor REPRISE have given estimates that tolvaptan could delay agonists have been used to treat diabetes, obesity, and progression to stage 5 chronic kidney disease by 7·3, 4·4, metabolic syndrome, their efficacy for slowing progression 2·9, and 1·5 years if pretreatment eGFR was 90, 60, 45, in ADPKD is currently unknown. Therefore, these and 30 mL/min, respectively.11 The KDIGO ADPKD interventions should not be used for this purpose until guideline recommends the MIC as the preferred tool to results from adequately powered and long-term clinical identify high-risk patients for tolvaptan therapy. Non- trials become available (table 1).11,78 Finally, systematic contrast CT for total kidney volume measurement can be screening for extrarenal manifesta tions such as liver cysts, used for patients in whom MRI is contraindicated (eg, intracranial aneurysms, and cardiac valve abnormalities patients with claustrophobia or a non-removable metal and routine psychol ogical assessment are also key for the part in body). Initiation of tolvaptan is a joint decision comprehensive management of ADPKD.11 with the patient after discussion of its potential risks and benefits. Tolvaptan should be initiated with a daily dose Kidney replacement therapy of 45 mg upon waking and 15 mg 8 h later, titrated Kidney replacement therapy is the primary treatment gradually to a maximum dose of 90 mg and 30 mg, for stage 5 chronic kidney disease and includes according to individual tolerance. Regular monitoring haemodialysis, peritoneal dialysis, and kidney trans- should include kidney function, serum sodium, uric plantation.118 Despite concerns about constrained acid, and liver function tests. Patients should be educated abdominal space and increased pressure due to enlarged to stop the drug during any acute illness associated with kidneys in ADPKD, the mortality rate is similar between fluid loss or reduced fluid intake. Common side-effects both dialysis techniques, with overall low certainty of of tolvaptan include thirst, polyuria, nocturia, and liver evidence. Patients with ADPKD using peritoneal dialysis function test elevation.123 Real life experience with generally face fewer complications.119,120 An individualised tolvaptan use in patients with ADPKD indicates that approach with careful attention to potential risks such as polyuria up to 6–9 L per day might limit long-term abdominal hernia and leakage is recommended. Kidney treatment adherence in some patients.124–127 Tolvaptan- transplantation is generally preferred for quality of life, induced polyuria is influenced by urinary osmolar load; especially since patients with ADPKD have better mean thiazide diuretics can reduce urine volume by lowering long-term post-transplant survival rates compared with osmolality and improve tolerance.128,129 However, more other causes of kidney failure.11 After transplantation, studies are needed to evaluate the long-term effects of native kidneys can diminish in size, reducing so-called thiazide diuretics on GFR decline and overall kidney mass effect (eg, bloating, early satiety, acid reflux, protection. Idiosyncratic drug-induced liver injury can abdominal fullness, and pain) symptoms.121 Native occur with tolvaptan in up to 5% of patients; therefore, nephrectomy in patients with ADPKD receiving kidney monthly liver monitoring during the first 18 months transplantation should only be performed after shared followed by quarterly assessments is necessary to detect decision making with multidisciplinary consultation, liver function test changes early.130,131 Other side-effects of preferably during or after transplantation. Potential tolvaptan include hyperuricaemia and rarely, gout.11 indications of nephrectomy include severe mass effect symptoms, recurrent kidney infection or bleeding, Management of other selected complications complicated kidney stones, intractable pain, suspected Patients can experience various complications during renal cell carcinoma, and insufficient space for the their lifetime, among which kidney and liver cyst kidney allograft.118 Whenever possible, laparoscopic infections, pain, intracranial aneurysms, and polycystic surgery is preferred to open surgery, and the decision liver disease are potentially the most clinically important. between unilateral or bilateral nephrectomy should be made based on individual clinical circumstances.11,122 Kidney and liver cyst infections Cyst infection is a common complication that can lead to Disease modifying treatment acute pain and sepsis in ADPKD. Patients diagnosed Two large RCTs have shown that tolvaptan reduced with suspected kidney or liver cyst infection should be kidney growth by 45% and eGFR declined by 26% in promptly investigated based on history, clinical, and patients with early to mid-stage ADPKD over a 3-year laboratory tests including abdominal imaging (appendix period (TEMPO 3:4)60 and eGFR declined by 35% in p 4).132 Suspected or confirmed kidney or liver cyst patients with later disease stages over 1 year (REPRISE).61 infection should be treated with a lipid-soluble antibiotic Collectively, these data have led to the regulatory approval (ie, fluoroquinolone or trimethoprim-sulfamethoxazole) of tolvaptan for treatment of ADPKD in many countries.11 that has better cystic penetration than non-lipid soluble Tolvaptan is indicated for the treatment of patients with antibiotics for 4–6 weeks to ensure a high treatment ADPKD who are deemed to be at high risk for progression success rate. If fever persists for more than 48–72 h, to stage 5 chronic kidney disease generally by MIC, imaging tests should be repeated to rule out possible PROPKD score, or ERA eGFR slope algorithms (appendix complications (such as a perirenal abscess or urinary 8 www.thelancet.com Published online February 27, 2026 https://doi.org/10.1016/S0140-6736(26)00046-2 Review obstruction). In difficult cases,111 an indium white blood and limitations is important to facilitate informed cell scan or [¹⁸F]fluorodeoxyglucose-PET-CT might be decision making. Screened positive cases should be useful for confirming and locating the infection. Infected referred to the neurosurgical team for assessment and cysts larger than 5 cm that are unresponsive to antibiotic discussion of management options, including treatment could require percutaneous or surgical observation, coiling, clipping, and flow-diverter therapy. drainage. In severe cases, surgical intervention such as Rescreening every 5–10 years should be individualised for nephrectomy might be necessary.11 Empirical antibiotic those initially screened negative but at high-risk of treatment should not be prescribed for patients with intracranial aneurysm.11 acute kidney or liver pain without fever, elevated white cell counts, and CRP levels. In such cases, other causes Polycystic liver disease such as cyst haemorrhage should be considered.11 Although approximately 80% of patients with ADPKD will have liver cysts by age 40 years, only 5–10% develop Pain management symptomatic polycystic liver disease.141,142 Symptomatic Pain is a major burden in patients with ADPKD, with polycystic liver disease is more common in women, acute episodes often triggered by infections, kidney generally associated with a liver volume greater than stones, or cyst rupture, and chronic pain originating 1800 mL or double the normal size, and typically presents from kidney or liver capsule distension or pressure on with mass effect symptoms but not liver failure.141,142 surrounding organs. Pain is best managed by an Massive liver enlargement can severely affect quality of interdisciplinary team. Therapeutic strategies should life, body image, physical activities, sexual life, and even follow a stepwise approach starting with non- nutritional intake. When abdominal MRI or CT is pharmacologic measures, followed by oral medications performed for ADPKD, kidney and liver images should (eg, non-opioid and opioids) and minimally invasive be included to assess both kidney and liver cystic therapies (eg, foam sclerotherapy). For refractory cases, burden.11 Early screening could identify individuals at more invasive options (eg, celiac plexus block, increased risk of progressive polycystic liver disease, nephrectomy, and hepatectomy) could be considered.133,134 particularly young women with multiple liver cysts in whom oestrogen exposure should be avoided. Patients Intracranial aneurysms with symptomatic polycystic liver disease143,144 should be The prevalence of intracranial aneurysms in patients with assessed for sarcopenia and malnutrition and referred to ADPKD is four times higher in people with a family a centre of expertise for consultation and management.11 history of intracranial aneurysm or subarachnoid For symptomatic polycystic liver disease, treatment with haemorrhage than those without such a family history; a long-acting somatostatin analogue can reduce liver most are small (<5 mm), predominantly located in large volume by 2–8% over 6–36 months.145,146 Somatostatin calibre arteries in the anterior circulation.135,136 Although analogues also slow the total kidney volume growth but the majority of intracranial aneurysms are asymptomatic have no effect on kidney function decline.147 Depending and might not rupture,137 rupture can result in significant on the size and distribution of the liver cysts, different morbidity and mortality. It is vital to educate patients on radiological or surgical treatments can be used, including the increased risk and modifiable risk factors such as foam sclerotherapy, cyst fenestration, segmental hepatic smoking cessation and stringent blood pressure control resection, and liver transplantation (appendix p 6).11 For (appendix p 5).138,139 Patients with ADPKD should be patients with ADPKD, liver transplantation is considered educated to recognise the clinical significance of a when there is a massively enlarged liver combined with thunderclap headache, a sudden onset, typically unilateral at least one of the following: severe portal hypertension, headache that reaches maximal intensity within seconds hepatic decompensation, malnutrition, or severe to minutes. This unusual headache is typically due to a sarcopenia.148 For patients with an eGFR below minor bleed preceding intracranial aneurysm rupture 30 mL/min, a combined kidney and liver transplant and should alert the patient to seek emergency assessment might be recommended. Treatment options should also immediately.11 Headache in patients with ADPKD can take into consideration that liver volume growth tends to also be due to spinal meningeal diverticula or spontaneous plateau after menopause in females.149,150 spinal cerebrospinal fluid leak resulting in spontaneous The effect of polycystic liver disease on female intracranial hypotension.140 Screening by time-of-flight reproductive health is considerable. Hormonal therapies, magnetic resonance angiography or high-resolution CT including oral contraceptives, hormone replacement angiography is recommended in high-risk individuals therapy during menopause, and oestrogens and gestagens with a positive personal history of intracranial aneurysm for in vitro fertilisation should be used with caution in or subarachnoid haemorrhage or a family history of patients with clinically significant polycystic liver disease, intracranial aneurysm, subarachnoid haemorrhage, or as higher oestrogen exposure has been associated with unexplained sudden death who are eligible for treatment increased cyst growth. If hormonal agents are used, and have a reasonable life expectancy.11,138 Comprehensive oestrogen-free or low-oestrogen preparations are discussion of the option of screening and its advantages preferred. In women with enlarged liver considering www.thelancet.com Published online February 27, 2026 https://doi.org/10.1016/S0140-6736(26)00046-2 9 Review reproductive options, referral to an expert centre for 2 Blanchette CM, Iorga ŞR, Altan A, et al. Healthcare resource consultation is recommended.151 utilization and costs associated with autosomal dominant polycystic kidney disease. J Health Econ Outcomes Res 2014; 2: 63–74. 3 Lanktree MB, Haghighi A, Guiard E, et al. Prevalence estimates of Patient-centred care polycystic kidney and liver disease by population sequencing. There is increasing interest in developing multi- J Am Soc Nephrol 2018; 29: 2593–600. 4 Willey CJ, Blais JD, Hall AK, Krasa HB, Makin AJ, Czerwiec FS. disciplinary care pathways,152 identifying future research Prevalence of autosomal dominant polycystic kidney disease in the priorities,153 and defining clinical trial outcomes154 for European Union. Nephrol Dial Transplant 2017; 32: 1356–63. ADPKD that are truly patient-centred through patient- 5 Willey C, Kamat S, Stellhorn R, Blais J. Analysis of nationwide data initiated or patient-embedded studies. Clear advantages to determine the incidence and diagnosed prevalence of autosomal dominant polycystic kidney disease in the USA: 2013–2015. include addressing major patient priorities, patient Kidney Dis 2019; 5: 107–17. perceptions, and the most relevant research questions, 6 Grantham JJ, Torres VE, Chapman AB, et al, and the CRISP thus promoting patient engagement in self-management Investigators. Volume progression in polycystic kidney disease. N Engl J Med 2006; 354: 2122–30. and research.155,156 The top research priority identified by a 7 Lavu S, Vaughan LE, Senum SR, et al, and the HALT PKD and patient-initiated research priority setting partnership was CRISP Study Investigators. The value of genotypic and imaging to develop treatments to slow or prevent kidney function information to predict functional and structural outcomes in ADPKD. JCI Insight 2020; 5: e138724. decline.153 A second common issue was the importance of 8 Torres VE, Chapman AB, Perrone RD, et al, and the HALT PKD kidney pain as a neglected symptom that has a major Study Group. Analysis of baseline parameters in the HALT effect on quality of life.157 The optimal organisation of polycystic kidney disease trials. Kidney Int 2012; 81: 577–85. 9 Perrone RD, Oberdhan D, Ouyang J, et al. OVERTURE: medical care was identified by a systematic review and a worldwide, prospective, observational study of disease ranked as the third highest priority.153 Appendix (p 7) characteristics in patients with ADPKD. Kidney Int Rep 2023; summarises a patient-centred care pathway model for 8: 989–1001. comprehensive management of ADPKD. 10 Cadnapaphornchai MA, Ong ACM. Hypertension in young adults with autosomal dominant polycystic kidney disease: a case for early screening? Clin Kidney J 2023; 16: 901–04. Current challenges and future directions 11 Torres VE, Ahn C, Barten TRM, et al. KDIGO 2025 clinical practice Advances in kidney imaging and NGS-based genetic guideline for the evaluation, management, and treatment of autosomal dominant polycystic kidney disease (ADPKD): executive technologies over the past decade have provided clinicians summary. Kidney Int 2025; 107: 234–54. with better diagnostic and prognostication tools to 12 Qian Q, Li A, King BF, et al. Clinical profile of autosomal dominant improve clinical management. Recognition of milder polycystic liver disease. Hepatology 2003; 37: 164–71. 13 McNicholas BA, Kotaro Y, Martin W, et al. Pancreatic cysts and ADPKD-like phenotypes associated with several intraductal papillary mucinous neoplasm in autosomal dominant minor cystic genes requires minor modification of polycystic kidney disease. Pancreas 2019; 48: 698–705. the established imaging-based diagnostic criteria. 14 Torra R, Sarquella J, Calabia J, et al. Prevalence of cysts in seminal tract and abnormal semen parameters in patients with autosomal Although tolvaptan is currently the only approved disease- dominant polycystic kidney disease. Clin J Am Soc Nephrol 2008; modifying treatment for patients with rapidly progressive 3: 790–93. disease, new concepts of disease mechanisms (figure 2) 15 Driscoll JA, Bhalla S, Liapis H, Ibricevic A, Brody SL. Autosomal are leading testing of promising new therapies. Looking dominant polycystic kidney disease is associated with an increased prevalence of radiographic bronchiectasis. Chest 2008; ahead, a patient-centred model of care together with 133: 1181–88. implementation and refinement of these new clinical 16 Perrone RD, Malek AM, Watnick T. Vascular complications in tools and continued development of disease mechanism- autosomal dominant polycystic kidney disease. Nat Rev Nephrol 2015; 11: 589–98. based therapeutics have the exciting potential to delay or 17 Sung PH, Yang YH, Chiang HJ, et al. Risk of aortic aneurysm and arrest kidney failure, reduce symptom burden, and dissection in patients with autosomal-dominant polycystic kidney improve quality of life for patients with ADPKD. disease: a nationwide population-based cohort study. Oncotarget 2017; 8: 57594–604. Contributors 18 Luciano RL, Dahl NK. Extra-renal manifestations of autosomal All authors participated in the development, review, and revision of the dominant polycystic kidney disease (ADPKD): considerations for Review and gave approval to submit the final version for publication. routine screening and management. Nephrol Dial Transplant 2014; 29: 247–54. Declaration of interests 19 Reig B, Blumenfeld J, Donahue S, Prince MR. Seminal megavesicle ACMO reports consulting fees from Crinetics, Galapagos, GSK, Janssen, in autosomal dominant polycystic kidney disease. Clin Imaging Mironid, Palladio, Sanofi-Genzyme, Torque Bio, and Vertex paid to his 2015; 39: 289–92. institution; SC received funding from the US Polycystic Kidney Disease 20 Iliuta IA, Kalatharan V, Wang K, et al. Polycystic kidney disease Foundation for a postdoctoral research fellowship outside the submitted without an apparent family history. J Am Soc Nephrol 2017; work; BMM received a speaker’s fee from Otsuka outside the submitted 28: 2768–76. work; RT reports consulting fees from Amicus, AstraZeneca, Boehringer 21 Jawaid T, Elbarougy DE, Lavu S, et al.. Characterization of the cystic Ingelheim, Chiesi, CSL Vifor, Kyowa Kirin, GSK, Otsuka, and Takeda phenotype associated with monoallelic ALG8 and ALG9 pathogenic outside the submitted work; YP reports consulting fees from AstraZeneca, variants. J Am Soc Nephrol 2025; 36: 1056–71. Biossil, Calico-Abbvie, GSK, Mironid, Otsuka Canada, and Vertex outside 22 Harris PC, Bae KT, Rossetti S, et al. Cyst number but not the rate of the submitted work. cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2006; References 17: 3013–19. 1 Gagnon-Sanschagrin P, Liang Y, Sanon M, Oberdhan D, Guérin A, Cloutier M. Excess healthcare costs in patients with autosomal 23 Cornec-Le Gall E, Audrézet MP, Chen JM, et al. Type of PKD1 dominant polycystic kidney disease by renal dysfunction stage. mutation influences renal outcome in ADPKD. J Am Soc Nephrol J Med Econ 2021; 24: 193–201. 2013; 24: 1006–13. 10 www.thelancet.com Published online February 27, 2026 https://doi.org/10.1016/S0140-6736(26)00046-2 Review 24 Hwang YH, Conklin J, Chan W, et al. Refining genotype-phenotype 46 Harris PC, Torres VE. Genetic mechanisms and signaling pathways correlation in autosomal dominant polycystic kidney disease. in autosomal dominant polycystic kidney disease. J Clin Invest 2014; J Am Soc Nephrol 2016; 27: 1861–68. 124: 2315–24. 25 Cornec-Le Gall E, Torres VE, Harris PC. Genetic complexity of 47 Grantham JJ, Mulamalla S, Swenson-Fields KI. Why kidneys fail in autosomal dominant polycystic kidney and liver diseases. autosomal dominant polycystic kidney disease. Nat Rev Nephrol J Am Soc Nephrol 2018; 29: 13–23. 2011; 7: 556–66. 26 Porath B, Gainullin VG, Cornec-Le Gall E, et al, and the Genkyst 48 Baert L. Hereditary polycystic kidney disease (adult form): Study Group, HALT Progression of Polycystic Kidney Disease a microdissection study of two cases at an early stage of the disease. Group, and the Consortium for Radiologic Imaging Studies of Kidney Int 1978; 13: 519–25. Polycystic Kidney Disease. Mutations in GANAB, encoding the 49 Watnick TJ, Torres VE, Gandolph MA, et al. Somatic mutation in glucosidase IIα subunit, cause autosomal-dominant polycystic individual liver cysts supports a two-hit model of cystogenesis in kidney and liver disease. Am J Hum Genet 2016; 98: 1193–207. autosomal dominant polycystic kidney disease. Mol Cell 1998; 27 Besse W, Dong K, Choi J, et al. Isolated polycystic liver disease 2: 247–51. genes define effectors of polycystin-1 function. J Clin Invest 2017; 50 Pei Y, Watnick T, He N, et al. Somatic PKD2 mutations in individual 127: 1772–85. kidney and liver cysts support a “two-hit” model of cystogenesis in 28 Lemoine H, Raud L, Foulquier F, et al, and the Genomics England type 2 autosomal dominant polycystic kidney disease. Research Consortium, and the Genkyst Study Group. Monoallelic J Am Soc Nephrol 1999; 10: 1524–29. pathogenic ALG5 variants cause atypical polycystic kidney disease 51 Watnick T, He N, Wang K, et al. Mutations of PKD1 in ADPKD2 and interstitial fibrosis. Am J Hum Genet 2022; 109: 1484–99. cysts suggest a pathogenic effect of trans-heterozygous mutations. 29 Besse W, Chang AR, Luo JZ, et al, and the Regeneron Genetics Nat Genet 2000; 25: 143–44. Center. ALG9 mutation carriers develop kidney and liver cysts. 52 Zhang Z, Bai H, Blumenfeld J, et al. Detection of PKD1 and PKD2 J Am Soc Nephrol 2019; 30: 2091–102. somatic variants in autosomal dominant polycystic kidney cyst 30 Senum SR, Li YSM, Benson KA, et al, and the Genomics England epithelial cells by whole-genome sequencing. J Am Soc Nephrol Research Consortium. Monoallelic IFT140 pathogenic variants are 2021; 32: 3114–29. an important cause of the autosomal dominant polycystic kidney- 53 Wu G, Markowitz GS, Li L, et al. Cardiac defects and renal failure in spectrum phenotype. Am J Hum Genet 2022; 109: 136–56. mice with targeted mutations in PKD2. Nat Genet 2000; 24: 75–78. 31 Cornec-Le Gall E, Olson RJ, Besse W, et al, and the Genkyst Study 54 Tan AY, Zhang T, Michaeel A, et al. Somatic mutations in renal cyst Group, and the HALT Progression of Polycystic Kidney Disease epithelium in autosomal dominant polycystic kidney disease. Group, and the Consortium for Radiologic Imaging Studies of J Am Soc Nephrol 2018; 29: 2139–56. Polycystic Kidney Disease. Monoallelic mutations to DNAJB11 55 Lantinga-van Leeuwen IS, Dauwerse JG, Baelde HJ, et al. Lowering cause atypical autosomal-dominant polycystic kidney disease. of PKD1 expression is sufficient to cause polycystic kidney disease. Am J Hum Genet 2018; 102: 832–44. Hum Mol Genet 2004; 13: 3069–77. 32 Cnossen WR, te Morsche RH, Hoischen A, et al. LRP5 variants may 56 Ong AC, Harris PC. A polycystin-centric view of cyst formation and contribute to ADPKD. Eur J Hum Genet 2016; 24: 237–42. disease: the polycystins revisited. Kidney Int 2015; 88: 699–710. 33 Song X, Haghighi A, Iliuta I-A, Pei Y. Molecular diagnosis of 57 Hopp K, Ward CJ, Hommerding CJ, et al. Functional polycystin-1 autosomal dominant polycystic kidney disease. dosage governs autosomal dominant polycystic kidney disease Expert Rev Mol Diagn 2017; 17: 885–95. severity. J Clin Invest 2012; 122: 4257–73. 34 Lanktree MB, Haghighi A, di Bari I, Song X, Pei Y. Insights into 58 Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH 2nd. polycystic kidney disease from genetic studies. Effective treatment of an orthologous model of autosomal dominant Clin J Am Soc Nephrol 2021; 16: 790–99. polycystic kidney disease. Nat Med 2004; 10: 363–64. 35 Paterson AD, Magistroni R, He N, et al. Progressive loss of renal 59 Wang X, Wu Y, Ward CJ, Harris PC, Torres VE. Vasopressin directly function is an age-dependent heritable trait in type 1 autosomal regulates cyst growth in polycystic kidney disease. J Am Soc Nephrol dominant polycystic kidney disease. J Am Soc Nephrol 2005; 2008; 19: 102–08. 16: 755–62. 60 Torres VE, Chapman AB, Devuyst O, et al, and the TEMPO 3:4 Trial 36 Lanktree MB, Guiard E, Li W, et al. Intrafamilial variability of Investigators. Tolvaptan in patients with autosomal dominant ADPKD. Kidney Int Rep 2019; 4: 995–1003. polycystic kidney disease. N Engl J Med 2012; 367: 2407–18. 37 Pei Y, Paterson AD, Wang KR, et al. Bilineal disease and trans- 61 Torres VE, Chapman AB, Devuyst O, et al, and the REPRISE Trial heterozygotes in autosomal dominant polycystic kidney disease. Investigators. Tolvaptan in later-stage autosomal dominant Am J Hum Genet 2001; 68: 355–63. polycystic kidney disease. N Engl J Med 2017; 377: 1930–42. 38 Pei Y, Lan Z, Wang K, et al. A missense mutation in PKD1 62 Chang MY, C M Ong A. Targeting new cellular disease pathways in attenuates the severity of renal disease. Kidney Int 2012; 81: 412–17. autosomal dominant polycystic kidney disease. 39 Rossetti S, Kubly VJ, Consugar MB, et al. Incompletely penetrant Nephrol Dial Transplant 2018; 33: 1310–16. PKD1 alleles suggest a role for gene dosage in cyst initiation in 63 Ma M, Tian X, Igarashi P, Pazour GJ, Somlo S. Loss of cilia polycystic kidney disease. Kidney Int 2009; 75: 848–55. suppresses cyst growth in genetic models of autosomal dominant 40 Durkie M, Chong J, Valluru MK, Harris PC, Ong ACM. Biallelic polycystic kidney disease. Nat Genet 2013; 45: 1004–12. inheritance of hypomorphic PKD1 variants is highly prevalent in 64 Shao L, El-Jouni W, Kong F, et al. Genetic reduction of cilium very early onset polycystic kidney disease. Genet Med 2021; length by targeting intraflagellar transport 88 protein impedes 23: 689–97. kidney and liver cyst formation in mouse models of autosomal 41 Durkie M, Watson CM, Winship P, et al. The common PKD polycystic kidney disease. Kidney Int 2020; 98: 1225–41. P.(Ile3167Phe) variant is hypomorphic and associated with very 65 Luo L, Roy S, Li L, Ma M. Polycystic kidney disease: novel insights early onset, biallelic polycystic kidney disease. Hum Mutat 2023; into polycystin function. Trends Mol Med 2023; 29: 268–81. 2023: 5597005. 66 Zhang C, Rehman M, Tian X, et al. Glis2 is an early effector of 42 Lanktree MB, Guiard E, Akbari P, et al. Patients with protein- polycystin signaling and a target for therapy in polycystic kidney truncating PKD1 mutations and mild ADPKD. disease. Nat Commun 2024; 15: 3698. Clin J Am Soc Nephrol 2021; 16: 374–83. 67 Vander Heiden MG, Cantley LC, Thompson CB. Understanding the 43 Iliuta IA, Win AZ, Lanktree MB, et al. Atypical polycystic kidney Warburg effect: the metabolic requirements of cell proliferation. disease as defined by imaging. Sci Rep 2023; 13: 2952. Science 2009; 324: 1029–33. 44 Hopp K, Cornec-Le Gall E, Senum SR, et al, and the HALT 68 Rowe I, Chiaravalli M, Mannella V, et al. Defective glucose Progression of Polycystic Kidney Disease Group. Detection and metabolism in polycystic kidney disease identifies a new therapeutic characterization of mosaicism in autosomal dominant polycystic strategy. Nat Med 2013; 19: 488–93. kidney disease. Kidney Int 2020; 97: 370–82. 69 Song X, Pickel L, Sung HK, Scholey J, Pei Y. Reprogramming of 45 Devuyst O, Pei Y. Next-generation sequencing for detection of energy metabolism in human PKD1 polycystic kidney disease: somatic mosaicism in autosomal dominant polycystic kidney a systems biology analysis. Int J Mol Sci 2024; 25: 13. disease. Kidney Int 2020; 97: 261–63. www.thelancet.com Published online February 27, 2026 https://doi.org/10.1016/S0140-6736(26)00046-2 11 Review 70 Podrini C, Rowe I, Pagliarini R, et al. Dissection of metabolic 93 Nowak KL, Copeland TP, Ku E, et al. Overweight status, obesity, and reprogramming in polycystic kidney disease reveals coordinated progression to ESKD in patients with autosomal dominant rewiring of bioenergetic pathways. Commun Biol 2018; 1: 194. polycystic kidney disease. Clin J Am Soc Nephrol 2025; 20: 520–28. 71 Padovano V, Podrini C, Boletta A, Caplan MJ. Metabolism and 94 Carriazo S, Pei Y. Do overweight status and obesity affect mitochondria in polycystic kidney disease research and therapy. progression to ESKD in autosomal dominant polycystic kidney Nat Rev Nephrol 2018; 14: 678–87. disease? Clin J Am Soc Nephrol 2025; 20: 471–73. 72 Takiar V, Nishio S, Seo-Mayer P, et al. Activating AMP-activated 95 Yu ASL, Shen C, Landsittel DP, et al, and the Consortium for protein kinase (AMPK) slows renal cystogenesis. Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP). Proc Natl Acad Sci USA 2011; 108: 2462–67. Long-term trajectory of kidney function in autosomal-dominant 73 Leonhard WN, Song X, Kanhai AA, et al. Salsalate, but not polycystic kidney disease. Kidney Int 2019; 95: 1253–61. metformin or canagliflozin, slows kidney cyst growth in an adult- 96 Perrone RD, Mouksassi MS, Romero K, et al. Total kidney volume onset mouse model of polycystic kidney disease. EBioMedicine 2019; is a prognostic biomarker of renal function decline and progression 47: 436–45. to end-stage renal disease in patients with autosomal dominant 74 Lakhia R, Yheskel M, Flaten A, Quittner-Strom EB, Holland WL, polycystic kidney disease. Kidney Int Rep 2017; 2: 442–50. Patel V. PPARα agonist fenofibrate enhances fatty acid β-oxidation 97 Irazabal MV, Rangel LJ, Bergstralh EJ, et al, and the CRISP and attenuates polycystic kidney and liver disease in mice. Investigators. Imaging classification of autosomal dominant Am J Physiol Renal Physiol 2018; 314: F122–31. polycystic kidney disease: a simple model for selecting patients for 75 Dong K, Zhang C, Tian X, et al. Renal plasticity revealed through clinical trials. J Am Soc Nephrol 2015; 26: 160–72. reversal of polycystic kidney disease in mice. Nat Genet 2021; 98 Akbari P, Nasri F, Deng S, et al. Total kidney volume measurements 53: 1649–63. in autosomal dominant polycystic kidney disease by 3D and 76 Hajarnis S, Lakhia R, Yheskel M, et al. microRNA-17 family ellipsoid ultrasound in comparison to magnetic resonance imaging. promotes polycystic kidney disease progression through Clin J Am Soc Nephrol 2022; 17: 827–34. modulation of mitochondrial metabolism. Nat Commun 2017; 99 van Gastel MDA, Edwards ME, Torres VE, Erickson BJ, 8: 14395. Gansevoort RT, Kline TL. Automatic measurement of kidney and liver 77 Lakhia R, Ramalingam H, Chang CM, et al. PKD1 and PKD2 volumes from MR images of patients affected by autosomal dominant mRNA cis-inhibition drives polycystic kidney disease progression. polycystic kidney disease. J Am Soc Nephrol 2019; 30: 1514–22. Nat Commun 2022; 13: 4765. 100 Simms RJ, Doshi T, Metherall P, et al. A rapid high-performance 78 Zhou JX, Torres VE. Autosomal dominant polycystic kidney semi-automated tool to measure total kidney volume from MRI in disease therapies on the horizon. Adv Kidney Dis Health 2023; autosomal dominant polycystic kidney disease. Eur Radiol 2019; 30: 245–60. 29: 4188–97. 79 Pei Y, Obaji J, Dupuis A, et al. Unified criteria for ultrasonographic 101 Potretzke TA, Korfiatis P, Blezek DJ, et al. Clinical implementation diagnosis of ADPKD. J Am Soc Nephrol 2009; 20: 205–12. of an artificial intelligence algorithm for magnetic resonance-derived 80 Pei Y, Hwang YH, Conklin J, et al. Imaging-based diagnosis of measurement of total kidney volume. Mayo Clin Proc 2023; autosomal dominant polycystic kidney disease. J Am Soc Nephrol 98: 689–700. 2015; 26: 746–53. 102 Taylor J, Thomas R, Metherall P, et al. An artificial intelligence 81 Živná M, Kidd KO, Barešová V, Hůlková H, Kmoch S, Bleyer AJ Sr. generated automated algorithm to measure total kidney volume in Autosomal dominant tubulointerstitial kidney disease: a review. ADPKD. Kidney Int Rep 2023; 9: 249–56. Am J Med Genet C Semin Med Genet 2022; 190: 309–24. 103 Kim Y, Bu S, Tao C, Bae KT, Group HPKDS, and the HALT Polycystic 82 Burgmaier K, Broekaert IJ, Liebau MC. Autosomal recessive Kidney Disease Study Group. Deep learning-based automated polycystic kidney disease: diagnosis, prognosis, and management. imaging classification of ADPKD. Kidney Int Rep 2024; 9: 1802–09. Adv Kidney Dis Health 2023; 30: 468–76. 104 Siedek F, Grundmann F, Weiss K, et al. Magnetic resonance kidney 83 Sekine A, Hidaka S, Moriyama T, et al. Cystic kidney diseases that parenchyma-T2 as a novel imaging biomarker for autosomal require a differential diagnosis from autosomal dominant polycystic dominant polycystic kidney disease. Invest Radiol 2020; 55: 217–25. kidney disease (ADPKD). J Clin Med 2022; 11: 6528. 105 Gregory AV, Anaam DA, Vercnocke AJ, et al. Semantic instance 84 Lanktree MB, Iliuta IA, Haghighi A, Song X, Pei Y. Evolving role of segmentation of kidney cysts in MR images: a fully automated 3D genetic testing for the clinical management of autosomal dominant approach developed through active learning. J Digit Imaging 2021; polycystic kidney disease. Nephrol Dial Transplant 2019; 34: 1453–60. 34: 773–87. 85 Cornec-Le Gall E, Ong ACM. Genetic testing in autosomal 106 Gregory AV, Chebib FT, Poudyal B, et al. Utility of new image- dominant polycystic kidney disease: why it matters in 2025. derived biomarkers for autosomal dominant polycystic kidney Clin Kidney J 2025; 18 (suppl 2): ii17–25. disease prognosis using automated instance cyst segmentation. Kidney Int 2023; 104: 334–42. 86 Bogdanova N, Markoff A, Gerke V, McCluskey M, Horst J, Dworniczak B. Homologues to the first gene for autosomal dominant 107 Bhutani H, Smith V, Rahbari-Oskoui F, et al, and the CRISP polycystic kidney disease are pseudogenes. Genomics 2001; 74: 333–41. Investigators. A comparison of ultrasound and magnetic resonance imaging shows that kidney length predicts chronic kidney disease 87 Richards S, Aziz N, Bale S, et al, and the ACMG Laboratory Quality in autosomal dominant polycystic kidney disease. Kidney Int 2015; Assurance Committee. Standards and guidelines for the 88: 146–51. interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and 108 Cornec-Le Gall E, Audrézet MP, Rousseau A, et al. The PROPKD Genomics and the Association for Molecular Pathology. Genet Med score: a new algorithm to predict renal survival in autosomal 2015; 17: 405–24. dominant polycystic kidney disease. J Am Soc Nephrol 2016; 27: 942–51. 88 Schrier RW, Brosnahan G, Cadnapaphornchai MA, et al. Predictors 109 Müller RU, Messchendorp AL, Birn H, et al. An update on the use of autosomal dominant polycystic kidney disease progression. of tolvaptan for autosomal dominant polycystic kidney disease: J Am Soc Nephrol 2014; 25: 2399–418. consensus statement on behalf of the ERA Working Group on Inherited Kidney Disorders, the European Rare Kidney Disease 89 Chebib FT, Nowak KL, Chonchol MB, et al. Polycystic kidney Reference Network and Polycystic Kidney Disease International. disease diet: what is known and what is safe. Clin J Am Soc Nephrol Nephrol Dial Transplant 2022; 37: 825–39. 2024; 19: 664–82. 110 Lee SH, Cam MM, Dehkharghanian T, et al. Patients with mild 90 Pahlavani N, Azizi-Soleiman F. The effect of dietary protein on the ADPKD by kidney imaging but low estimated GFR. progression of polycystic kidney disease – a review on current Kidney Int Rep 2025; 10: 1855–63. evidence. Clin Nutr Open Sci 2023; 51: 128–35. 111 Rangan GK, Wong ATY, Munt A, et al. Prescribed water intake in 91 Nowak KL, You Z, Gitomer B, et al. Overweight and obesity are autosomal dominant polycystic kidney disease. N Eng J Med Evid predictors of progression in early autosomal dominant polycystic 2022; 1: EVIDoa2100021. kidney disease. J Am Soc Nephrol 2018; 29: 571–78. 112 Kramers BJ, Koorevaar IW, Drenth JPH, et al. Salt, but not protein 92 Nowak KL, Steele C, Gitomer B, Wang W, Ouyang J, Chonchol MB. intake, is associated with accelerated disease progression in autosomal Overweight and obesity and progression of ADPKD. dominant polycystic kidney disease. Kidney Int 2020; 98: 989–98. Clin J Am Soc Nephrol 2021; 16: 908–15. 12 www.thelancet.com Published online February 27, 2026 https://doi.org/10.1016/S0140-6736(26)00046-2 Review 113 Torres VE, Abebe KZ, Schrier RW, et al. Dietary salt restriction is 133 Casteleijn NF, van Gastel MD, Blankestijn PJ, et al, and the DIPAK beneficial to the management of autosomal dominant polycystic Consortium. Novel treatment protocol for ameliorating refractory, kidney disease. Kidney Int 2017; 91: 493–500. chronic pain in patients with autosomal dominant polycystic kidney 114 Schrier RW, Abebe KZ, Perrone RD, et al, and the HALT-PKD Trial disease. Kidney Int 2017; 91: 972–81. Investigators. Blood pressure in early autosomal dominant polycystic 134 van Luijk F, Gansevoort RT, Blokzijl H, et al. Multidisciplinary kidney disease. N Engl J Med 2014; 371: 2255–66. management of chronic refractory pain in autosomal dominant 115 Irazabal MV, Abebe KZ, Bae KT, et al, and the HALT Investigators. polycystic kidney disease. Nephrol Dial Transplant 2023; 38: 618–29. Prognostic enrichment design in clinical trials for autosomal 135 Sanchis IM, Shukoor S, Irazabal MV, et al. Presymptomatic dominant polycystic kidney disease: the HALT-PKD clinical trial. screening for intracranial aneurysms in patients with autosomal Nephrol Dial Transplant 2017; 32: 1857–65. dominant polycystic kidney disease. Clin J Am Soc Nephrol 2019; 116 Cheung AK, Chang TI, Cushman WC, et al, and the Kidney 14: 1151–60. Disease: Improving Global Outcomes (KDIGO) Blood Pressure 136 Haemmerli J, Morel S, Georges M, et al. Characteristics and Work Group. KDIGO 2021 clinical practice guideline for the distribution of intracranial aneurysms in patients with autosomal management of blood pressure in chronic kidney disease. dominant polycystic kidney disease compared with the general Kidney Int 2021; 99: S1–87. population: a meta-analysis. Kidney360 2023; 4: e466–75. 117 Torres VE, Abebe KZ, Chapman AB, et al, and the HALT-PKD Trial 137 Irazabal MV, Huston J 3rd, Kubly V, et al. Extended follow-up of Investigators. Angiotensin blockade in late autosomal dominant unruptured intracranial aneurysms detected by presymptomatic polycystic kidney disease. N Engl J Med 2014; 371: 2267–76. screening in patients with autosomal dominant polycystic kidney 118 de Chickera S, Alam A. Dialysis and transplant considerations in disease. Clin J Am Soc Nephrol 2011; 6: 1274–85. autosomal dominant polycystic kidney disease. 138 Nguyen BA, Halpin B, Olson V, et al. Risk factors for unruptured Adv Kidney Dis Health 2023; 30: 461–67. intracranial aneurysms in asymptomatic patients with autosomal 119 Sigogne M, Kanagaratnam L, Dupont V, et al. Outcome of dominant polycystic kidney disease: who needs screening? autosomal dominant polycystic kidney disease patients on A systematic review and meta-analysis. J Neurosurg 2025; 143: 220–31. peritoneal dialysis: a national retrospective study based on 139 Hoh BL, Ko NU, Amin-Hanjani S, et al. 2023 guideline for the two French registries (the French Language Peritoneal Dialysis management of patients with aneurysmal subarachnoid Registry and the French Renal Epidemiology and Information hemorrhage: a guideline from the American Heart Association/ Network). Nephrol Dial Transplant 2018; 33: 2020–26. American Stroke Association. Stroke 2023; 54: e314–70. 120 Sanchez JE, Ulloa C, Bueno CM, Astudillo E, Rodríguez-Suárez C. 140 Sattar U, Yin X, Luo X, et al. Prevalence of spinal meningeal Impact of peritoneal dialysis strategy on technique and patient diverticula in autosomal dominant polycystic kidney disease. survival. Clin Kidney J 2023; 16: 2523–29. AJNR Am J Neuroradiol 2025; 46: 200–06. 121 Yamamoto T, Watarai Y, Kobayashi T, et al. Kidney volume changes 141 van Aerts RMM, van de Laarschot LFM, Banales JM, Drenth JPH. in patients with autosomal dominant polycystic kidney disease after Clinical management of polycystic liver disease. J Hepatol 2018; renal transplantation. Transplantation 2012; 93: 794–98. 68: 827–37. 122 Geertsema P, Gansevoort RT, Arici M, et al, and the members of the 142 Bugazia S, Hogan MC. Polycystic liver disease and its study group. Nephrectomy in autosomal dominant polycystic complications. Adv Kidney Dis Health 2023; 30: 440–53. kidney disease: a consensus statement of the ERA Genes & Kidney 143 Neijenhuis MK, Gevers TJ, Hogan MC, et al. Development and Working Group. Nephrol Dial Transplant 2025; 40: 1032–54. validation of a disease-specific questionnaire to assess patient- 123 Roca Oporto FJ, Andrades Gómez C, Montilla Cosano G, reported symptoms in polycystic liver disease. Hepatology 2016; Aguilera AL, Rocha JL. Prospective study on individualized dose 64: 151–60. adjustment of tolvaptan based on urinary osmolality in patients 144 Temmerman F, Dobbels F, Ho TA, et al. Development and with ADPKD. Kidney Int Rep 2024; 9: 1031–39. validation of a polycystic liver disease complaint-specific assessment 124 Calvaruso L, Yau K, Akbari P, et al. Real-life use of tolvaptan in (POLCA). J Hepatol 2014; 61: 1143–50. ADPKD: a retrospective analysis of a large Canadian cohort. 145 van Aerts RMM, Kievit W, D’Agnolo HMA, et al, and the DIPAK-1 Sci Rep 2023; 13: 22257. Investigators. Lanreotide reduces liver growth in patients with 125 Chong J, Harris T, Ong ACM. Regional variation in tolvaptan autosomal dominant polycystic liver and kidney disease. prescribing across England: national data and retrospective Gastroenterology 2019; 157: 481–91. evaluation from an expert centre. Clin Kidney J 2022; 16: 61–68. 146 Suwabe T, Barrera FJ, Rodriguez-Gutierrez R, Ubara Y, Hogan MC. 126 Kramers BJ, van Gastel MDA, Boertien WE, Meijer E, Gansevoort Somatostatin analog therapy effectiveness on the progression of RT. Determinants of urine volume in ADPKD patients using the polycystic kidney and liver disease: a systematic review and meta- vasopressin V2 receptor antagonist tolvaptan. Am J Kidney Dis 2019; analysis of randomized clinical trials. PLoS One 2021; 16: e0257606. 73: 354–62. 147 St Pierre K, Cashmore BA, Bolignano D, et al. Interventions for 127 Todorova P, Arjune S, Hendrix C, et al. Interaction between preventing the progression of autosomal dominant polycystic determinants governing urine volume in patients with ADPKD on kidney disease. Cochrane Database Syst Rev 2024; 10: CD010294. tolvaptan and its impact on quality of life. Kidney Int Rep 2023; 148 Mehta S, Rosenstengle CA. Policy corner: polycystic liver disease 8: 1616–26. MELD exception update. Liver Transpl 2024; 30: 960–61. 128 Kramers BJ, Koorevaar IW, van Gastel MDA, et al. Effects of 149 Chebib FT, Jung Y, Heyer CM, et al. Effect of genotype on the hydrochlorothiazide and metformin on aquaresis and severity and volume progression of polycystic liver disease in nephroprotection by a vasopressin V2 receptor antagonist in ADPKD: autosomal dominant polycystic kidney disease. a randomized crossover trial. Clin J Am Soc Nephrol 2022; 17: 507–17. Nephrol Dial Transplant 2016; 31: 952–60. 129 Uchiyama K, Kitayama C, Yanai A, Ishibashi Y. The effect of 150 Sherstha R, McKinley C, Russ P, et al. Postmenopausal estrogen trichlormethiazide in autosomal dominant polycystic kidney disease therapy selectively stimulates hepatic enlargement in women with patients receiving tolvaptan: a randomized crossover controlled autosomal dominant polycystic kidney disease. Hepatology 1997; trial. Sci Rep 2021; 11: 17666. 26: 1282–86. 130 Capelli I, Lerario S, Ciurli F, et al. Investigational agents for 151 Bazojoo V, Davoudi V, Blumenfeld JD, et al. Effects of pregnancy on autosomal dominant polycystic kidney disease: preclinical and liver and kidney cyst growth rates in autosomal dominant polycystic early phase study insights. Expert Opin Investig Drugs 2024; kidney disease: a pilot study. J Clin Med 2025; 14: 3688. 33: 469–84. 152 EAF co-chairs, Harris T, Sandford R, et al. European ADPKD 131 Alpers DH, Lewis JH, Hunt CM, et al. Clinical pattern of tolvaptan- Forum multidisciplinary position statement on autosomal associated liver injury in trial participants with autosomal dominant dominant polycystic kidney disease care: European ADPKD Forum polycystic kidney disease (ADPKD): an analysis of pivotal clinical and Multispecialist Roundtable participants. Nephrol Dial Transplant trials. Am J Kidney Dis 2023; 81: 281–93.e1. 2017; 33: 563–73. 132 Lantinga MA, Darding AJ, de Sévaux RG, et al, and the Delphi 153 Harris T, Bridges HR, Brown WD, et al. Research priorities for collaborators. International multi-specialty delphi survey: autosomal dominant polycystic kidney: a UK priority setting identification of diagnostic criteria for hepatic and renal cyst partnership. BMJ Open 2022: 12: e055780. infection. Nephron J 2016; 134: 205–14. www.thelancet.com Published online February 27, 2026 https://doi.org/10.1016/S0140-6736(26)00046-2 13 Review 154 Cho Y, Tong A, Craig JC, et al, and the SONG-PKD Workshop 157 Winterbottom J, Simms RJ, Caroli A, et al. Flank pain has a Investigators. Establishing a core outcome set for autosomal significant adverse impact on quality of life in ADPKD: dominant polycystic kidney disease: report of the Standardized the CYSTic-QoL study. Clin Kidney J 2022; 15: 2063–71. Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD) consensus workshop. Am J Kidney Dis 2021; 77: 255–63. Copyright © 2026 Elsevier Ltd. All rights reserved, including those for 155 Gittus M, Harris T, Ong AC. Patient perspectives on ADPKD. text and data mining, AI training, and similar technologies. Adv Kidney Dis Health 2023; 30: 294–302. 156 Logeman C, Cho Y, Sautenet B, et al. ‘A sword of Damocles’: patient and caregiver beliefs, attitudes and perspectives on presymptomatic testing for autosomal dominant polycystic kidney disease: a focus group study. BMJ Open 2020; 10: e038005. 14 www.thelancet.com Published online February 27, 2026 https://doi.org/10.1016/S0140-6736(26)00046-2 --- [PDF原文](https://sci-net.xyz/storage/7298661/ffcd655e2bac24a7ae9c758f2c210c777e338335a8f7a46fdbb4ad80b5b41129/Autosomal-dominant-polycystic-kidney-disease.pdf) DOI: 10.1016/S0140-6736(26)00046-2