F1000Research 2019, 8(F1000 Faculty Rev):116 Last updated: 29 JAN 2019 REVIEW Recent advances in the clinical management of autosomal dominant polycystic kidney disease [version 1; referees: 2 approved] Roser Torra Inherited Renal Disorders, Nephrology Department, Fundació Puigvert, REDINREN, IIB Sant Pau, Universitat Autònoma de Barcelona, Barcelona, 08025, Spain First published: 29 Jan 2019, 8(F1000 Faculty Rev):116 ( Open Peer Review v1 https://doi.org/10.12688/f1000research.17109.1) Latest published: 29 Jan 2019, 8(F1000 Faculty Rev):116 ( https://doi.org/10.12688/f1000research.17109.1) Referee Status: Abstract Invited Referees Autosomal dominant polycystic kidney disease (ADPKD) is a genetic systemic 1 2 disorder causing the development of renal and hepatic cysts and decline in renal function. It affects around 1 in 1,000 live births. Early hypertension and version 1 progressive renal failure due to massive enlargement of cysts and fibrosis are published hallmarks of the disease. This article reviews recent advances in ADPKD and 29 Jan 2019 focuses mainly on diagnosis, management, and prediction of the course of the disease. F1000 Faculty Reviews are commissioned Keywords from members of the prestigious F1000 ADPKD, diagnosis, management, treatment, prediction Faculty. In order to make these reviews as comprehensive and accessible as possible, peer review takes place before publication; the referees are listed below, but their reports are not formally published. 1 Chang-Lin Mei, Shanghai Changzheng Hospital, Second Military Medical University, China 2 John Sayer , Newcastle University, UK Discuss this article Comments (0) Page 1 of 8 F1000Research 2019, 8(F1000 Faculty Rev):116 Last updated: 29 JAN 2019 Corresponding author: Roser Torra (rtorra@fundacio-puigvert.es) Author roles: Torra R: Conceptualization, Project Administration, Resources, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests: The author has received speaking fees and travel funding from Otsuka pharmaceutical. The author was member of the IDMC of the TEMPO trial. Grant information: This work was funded by the ISCIII: RETIC REDINREN RD16/0009 FIS FEDER FUNDS (PI15/01824 and PI16/01998) and the Catalan Government (AGAUR 2014/SGR-1441). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2019 Torra R. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite this article: Torra R. Recent advances in the clinical management of autosomal dominant polycystic kidney disease [version 1; referees: 2 approved] F1000Research 2019, 8(F1000 Faculty Rev):116 (https://doi.org/10.12688/f1000research.17109.1) First published: 29 Jan 2019, 8(F1000 Faculty Rev):116 (https://doi.org/10.12688/f1000research.17109.1) Page 2 of 8 F1000Research 2019, 8(F1000 Faculty Rev):116 Last updated: 29 JAN 2019 Introduction A further advantage of this relatively new technique is that gene Autosomal dominant polycystic kidney disease (ADPKD) is panels or whole exome sequencing can be used, allowing the the most common monogenic cause of kidney failure, occur- detection of mutations in ultrarare genes that account for a ring in more than 1 in 400 to 1,000 live births and accord- very small number of cases of renal cystic disease17. The draw- ingly representing a major socioeconomic medical problem back of testing PKD1 is the huge number of variants of unknown globally1. ADPKD arises owing to mutations in the PKD1 gene significance (VUSs) that can be identified, around 10 per (about 85% of cases) or the PKD2 gene (about 15% of cases), patient18. Some of these VUSs have previously been published as which encode the proteins polycystin-1 (PC1) and -2 (PC2), mutations, but for many pathogenicity is still to be elucidated19. respectively2,3. Compared with patients who have PKD1 muta- This is of the utmost relevance when a patient seeks preimplan- tions, those with PKD2 mutations have a milder phenotype and tation genetic diagnosis (PGD) or when a disease-modifying reach end-stage renal disease (ESRD) about 20 years later4–6. treatment for ADPKD can be offered but there is uncertainty ADPKD is characterized by progressive development and over the diagnosis. PGD has evolved over recent years to enlargement of cysts in all nephron segments but preferentially become a valuable technique to offer patients with severe genetic in the collecting duct, and ESRD occurs in 50% of patients by diseases, although there are ethical issues regarding its use for the age of 60 years1. It is associated with cyst formation in other non-severe genetic diseases. ADPKD is halfway between these organs, primarily the liver and pancreas, and with cardiovascular categories, and genetic counseling is highly recommended anomalies such as intracranial arterial aneurysms and vascular to ensure sound understanding of the pros and cons of such a dissections. Huge variation is observed in disease phenotype procedure20. Probably, each case or family should be counseled and progression, even within families; the reason for this is differently according to the severity of the disease, but patient poorly understood, but genetic modifiers, including hypomorphic attitudes to PGD vary considerably depending on how well the alleles, probably play a significant role. family is dealing with the disease, religious aspects, age, disease severity, and so on. Although a definitive curative treatment is not currently avail- able, there is a disease-modifying therapy using a V2 receptor Progression of autosomal dominant polycystic antagonist (tolvaptan)7,8. This article guides the reader through kidney disease recent achievements, and the clinical consequences, within A large number of factors have been identified as influencing the field of ADPKD. disease progression21, and whereas some are modifiable, many are not22. Among the latter are male sex, PKD1 mutations (worse Genetics and genetic testing if protein-truncating (PT)), early development of renal symp- Mutations in other genes, such as GANAB and DNAJB11, have toms, early detection of high blood pressure23, and large kidney recently been identified in a small subgroup of patients9,10, volumes in relation to age and height24,25. Modifiable factors that but the phenotypes related to these mutations are not exactly should be highlighted in patients with ADPKD include smoking; the same as those caused by mutations in PKD1 or PKD2. This blood pressure; lipid levels; water, protein, and calorie intake; may suggest that, instead of using the name “ADPKD”, it and body mass index (BMI)26–31. Also, some biomarkers, such as would be appropriate to name these diseases after the mutated MCP-1, FGF23, and copeptin, have been found to be predictive gene, as has been done, for example, for ADTKD11. Whereas factors of ADPKD progression32–34. mutations in GANAB give rise to a mild form of cystic disease that does not progress to ESRD9, mutations in DNAJB11 cause The prediction of which patients will have a rapid progression cystic disease in the context of which ESRD may develop in is crucial not only for the decision of whether to use a disease- the absence of marked kidney enlargement10. modifying drug but also for the recruitment of patients to clini- cal trials35. Although in the past few years many attempts have Genetic testing has undergone remarkable progress, as is very evi- been made to provide tools predictive of rapid disease progres- dent if one considers the case of ADPKD. When the PKD1 and sion, to date there is no gold standard. Some of these predictive PKD2 genes were first identified, genetic testing was performed tools employ imaging; an example is the Mayo Clinic ADPKD by means of linkage analysis5. Not only was this time consum- calculator, which uses the height-adapted total kidney volume ing but also, more importantly, several affected and non-affected (htTKV) to classify patients into one of five classes (A–E) on the family members were needed in order to identify the risk basis of growth rates: less than 1.5%, 1.5–3%, 3–4.5%, 4.5–6%, haplotype. As soon as the PKD1 gene was identified, it became or more than 6% per year36. Measuring TKV for use as a prog- evident that genetic testing for the gene would be burden- nostic biomarker does not require high precision. Measurement by some owing to the large transcript size (>14 kb) and reiteration the ellipsoid equation as well as by means of various imaging of the genomic area encoding about 75% of the protein on the modalities is possible27,37. Another imaging approach that can be same chromosome12. The group of Harris then developed a used to predict PKD progression involves the measurement of technique that used long-range polymerase chain reaction and renal length. Bhutani et al. demonstrated that a renal diameter of benefited from the few non-repeated nucleotides13. Although 16.8 cm is predictive of chronic kidney disease (CKD) stage 3 this allowed diagnosis of a single individual, it remained time within 8 years38. An alternative to imaging-based prognostic consuming and was also expensive. Over the past 3 years, next- strategies is the Predicting Renal Outcome in Polycystic Kidney generation sequencing (NGS) has changed the scenario14–16. Disease (PROPKD) scoring system, as shown in a large cohort The use of NGS for genetic diseases such as ADPKD has reduced from Brittany, France23. This scoring system uses both clinical costs, improved sensitivity, and reduced turnaround time17,18. and genetic data to stratify risk of disease progression. Patients Page 3 of 8 F1000Research 2019, 8(F1000 Faculty Rev):116 Last updated: 29 JAN 2019 may reach a score suggestive of rapid progression if they have dihydropyridine class) should be considered if blood pressure is hypertension or early urinary symptoms before the age of not controlled by the other agents27. The CRISP (Consortium for 35 years plus a PT mutation. Male sex is also included in the Radiologic Imaging Studies of Polycystic Kidney Disease) and scoring system. Obvious drawbacks of this predictive tool are HALT studies suggest that moderate dietary sodium restriction the need to perform genetic testing, which may not be avail- (2.3–3 g) be recommended to patients with ADPKD22. able in many centers, and the impossibility of employing it in patients younger than 35 who are asymptomatic. In addition, In patients with cyst infection, a positron emission tomography/ it is subject to the need to establish a relationship between computed tomography scan is recommended to enable deter- early symptoms and ADPKD and the limitation that many mination of the location of cysts for the purpose of diagnosis rapid progressors with PT mutations do not develop early or drainage43. Fluoroquinolones remain the first-line antibiotic symptoms. treatment, but their side effects and the increasing prevalence of fluoroquinolone-resistant Gram-negative bacilli mean that cyst The European Renal Association-European Dialysis and Trans- infections frequently represent a very large burden. plant Association (ERA-EDTA) Working Groups on Inherited Kidney Disorders and European Renal Best Practice (WGIKD/ Until more information becomes available44,45, moderate enhance- ERBP) developed a hierarchical decision-making algorithm that ment of hydration, spread out over the course of 24 hours, is may offer guidance on the identification and prediction of rapid recommended with the goal of maintaining an average urine disease progression in patients with ADPKD and subsequently osmolality of not more than 280 mOsm/L27,46. identify candidates for tolvaptan treatment39. When this algorithm was tested in a cohort of 305 patients, it was found that 15.7% Based on experimental studies and lessons learned from CKD fulfilled the ERA-EDTA criteria and that the overall propor- in general, a daily protein intake of 0.8–1.0 g/kg ideal body tion of patients with rapid progression rose to 27% upon incor- weight seems appropriate in ADPKD27. Although protein-restricted poration of expanded criteria based on data from the REPRISE diets are usually already low in phosphorus, patient educa- (Replicating Evidence of Preserved Renal Function: an Inves- tion on the need to avoid processed foods that contain readily tigation of Tolvaptan Safety and Efficacy in ADPKD) trial40 absorbed inorganic phosphates is appropriate. Sodium bicarbo- (that is, age of less than 56 years and estimated glomerular nate supplementation is recommended in order to treat metabolic filtration rate [eGFR] of more than 30 mL/min/m2)41. This study, acidosis, and the aim is to maintain the plasma bicarbonate together with a recent assessment of an unpublished large series level at a minimum of 22 mmol/L27. of patients, calls into question the suitability of the algorithm, especially in its first steps when limiting for age/eGFR and Mild to moderate food restriction has been found to markedly using retrospective eGFR. Each country, even region, in Europe reduce cystogenesis in animal models of PKD47,48. This fact, has either approved the use of the drug on these terms or pro- together with evidence that excess food intake has a detrimen- posed some changes. For example, the National Institute for tal effect both in PKD trials and in CKD in general, means that Health and Care Excellence (NICE) decision in the UK was to moderation of caloric intake and avoidance of an above-average treat on the basis of these criteria but only patients with CKD BMIshould be recommended to patients with ADPKD29. stage 2 to 3 without limiting age, whereas in Scotland they approved its use in stage 1. In the US, the preferred approach A small trial with statins in children has yielded positive for definition of a rapid progressor is based on htTKV, age, results49, but a post-hoc analysis of the HALT-PKD trials failed and eGFR, basically using the Mayo ADPKD calculator42. to demonstrate a benefit of statin therapy on renal outcomes50. Risk assessment in ADPKD is an evolving process However, evidence in ADPKD22,31, and in CKD in general, that will undergo further refinement as new clinical data are indicates that it is appropriate to keep the low-density lipoprotein obtained and prediction tools are developed. The performance (LDL) cholesterol level at not more than 100 mg/dL. of risk assessment guidelines needs to be evaluated and validated by real-life clinical data, but it is probable that the Disease-modifying treatments use of a composite tool including age, renal function, imaging, In the TEMPO (Tolvaptan Efficacy and Safety in Management family history and possibly genetic testing will be able to of Autosomal Dominant Polycystic Kidney Disease and Its define rapid progression very accurately. Outcomes) 3:4 trial, the vasopressin receptor antagonist tolvaptan was shown to slow the growth of cystic kidneys and the dete- Basic renal protective measures rioration of renal function7. Based on these results, the European Based on the HALT-PKD (Halt Progression of Polycystic Medicines Agency in 2015 approved tolvaptan to slow the Kidney Disease) trial, the recommendations regarding blood progression of cyst development and renal insufficiency in ADPKD pressure control for ADPKD were recently lowered26. The target in adults with CKD stages 1–3 at initiation of treatment and should now be 95–110/60–75 mmHg in 15- to 49-year-old evidence of rapidly progressing disease51. TEMPO 4:4 showed patients with an eGFR of more than 60 mL/min/1.73 m2. First- that benefit is sustained over time52. line management of hypertension should include a blocker of the renin–angiotensin–aldosterone system (angiotensin-converting In 2018, tolvaptan was approved by the US Food and Drug enzyme inhibitors and angiotensin-II receptor blockers)27. Administration for the purpose of slowing decline in kidney Second- and third-line treatments should be diuretics and function in adults at risk of rapidly progressing ADPKD. This beta-blockers. Calcium channel blockers (particularly the decision was based on additional information provided by the Page 4 of 8 F1000Research 2019, 8(F1000 Faculty Rev):116 Last updated: 29 JAN 2019 REPRISE trial, which demonstrated slowing in the deterioration discontinuation53. This rare drug-induced liver injury led to of renal function, even in the later stages of renal failure8. the institution of a risk evaluation and mitigation strategy with monthly liver enzyme tests for the first 18 months and then at Currently, more than 6,000 patients with ADPKD are being 3-month intervals. treated with tolvaptan around the world. However, tolvaptan does have side effects. It markedly impairs urinary concentrating A few other drugs, such as mammalian target of rapamycin ability and therefore patients experience polyuria, nocturia, (mTOR) inhibitors, somatostatin analogues, and bosutinib, and polydipsia7,8. In addition, a small proportion of patients also underwent clinical trials but failed to show any positive develop liver function abnormalities; it appears that whereas some effect on disease progression54–57. Recommendations for the of these abnormalities can be significant, all resolve upon drug management of ADPKD are shown in Figure 1. 1PTTJCMF"%1,% $POGJSNEJBHOPTJT r *NBHJOH r 'BNJMZ)JTUPSZ r $MJOJDBMGJOEJOHT r -BC5FTU %FGJOJUF %PVCUGVM "TTFTTCMPPEQSFTTVSF6TF (FOFUJDUFTUJOH "$&"3#TBTGJSTUDIPJDFJG )5/(PBMśNN)HJG ZPBOEF('3NMNJO PUIFSXJTF 1PTJUJWF /FHBUJWF r .BJOUBJO6PTN N0TN,HCZNPEFSBUFMZ FOIBODJOHIZESBUJPO r 4PEJVNSFTUSJDUJPO HE 'PMMPXVQ r .PEFSBUFQIPTQIPSVTJOUBLF r .PEFSBUFDBMPSJDJOUBLF NBJOUBJOOPSNBM#.* r -JQJEDPOUSPM BJNGPS-%-ś NHE* I5,7 .BZPDMBTT "TTFTTSBQJE EJTFBTFQSPHSFTTJPO 1301,%TDPSF &3"&%5"BMHPSJUIN 4MPXQSPHSFTTPS 3BQJEQSPHSFTTPS 3FBTTVSBODFDPOGJSN $POTJEFSEJTFBTF SBUFPGQSPHSFTTJPOJO NPEJGZJOHUSFBUNFOU ZFBST Figure 1. Diagnosis and management of autosomal dominant polycystic kidney disease. ACE/ARB, angiotensin-converting enzyme/angiotensin receptor blocker; ADPKD, autosomal dominant polycystic kidney disease; BMI, body mass index; eGFR, estimated glomerular filtration rate; ERA-EDTA, European Renal Association-European Dialysis and Transplant Association; hTKV, height-adapted total kidney volume; HTN, hypertension; LDL, low-density lipoprotein; PROPKD, Predicting Renal Outcome in Polycystic Kidney Disease; Uosm, urine osmolality. Modified from Chebib et al.27 and Chebib et al.42. Page 5 of 8 F1000Research 2019, 8(F1000 Faculty Rev):116 Last updated: 29 JAN 2019 Many new drugs are being tested, and it is probable that more Grant information than one drug will be needed to target the different abnormal This work was funded by the ISCIII: RETIC REDINREN pathways found in PKD cells. RD16/0009 FIS FEDER FUNDS (PI15/01824 and PI16/01998) and the Catalan Government (AGAUR 2014/SGR-1441). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. References F1000 recommended 1. Grantham JJ: Clinical practice. Autosomal dominant polycystic kidney disease. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation N Engl J Med. 2008; 359(14): 1477–85. 17. Bullich G, Domingo-Gallego A, Vargas I, et al.: A kidney-disease gene panel PubMed Abstract | Publisher Full Text allows a comprehensive genetic diagnosis of cystic and glomerular inherited 2. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies kidney diseases. Kidney Int. 2018; 94(2): 363–71. within a duplicated region on chromosome 16. The European Polycystic PubMed Abstract | Publisher Full Text Kidney Disease Consortium. Cell. 1994; 78(4): 725. PubMed Abstract 18. Bergmann C: Recent advances in the molecular diagnosis of polycystic kidney disease. Expert Rev Mol Diagn. 2017; 17(12): 1037–54. 3. Mochizuki T, Wu G, Hayashi T, et al.: PKD2, a Gene for Polycystic Kidney PubMed Abstract | Publisher Full Text | F1000 Recommendation Disease That Encodes an Integral Membrane Protein. Science. 1996; 272(5266): 1339–42. 19. Cornec-Le Gall E, Torres VE, Harris PC: Genetic Complexity of Autosomal PubMed Abstract | Publisher Full Text Dominant Polycystic Kidney and Liver Diseases. J Am Soc Nephrol. 2018; 29(1): 13–23. 4. Audrézet MP, Cornec-Le Gall E, Chen JM, et al.: Autosomal dominant PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation polycystic kidney disease: Comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Hum Mutat. 2012; 33(8): 1239–50. 20. Swift O, Vilar E, Rahman B, et al.: Attitudes in Patients with Autosomal PubMed Abstract | Publisher Full Text | F1000 Recommendation Dominant Polycystic Kidney Disease Toward Prenatal Diagnosis and 5. Torra R, Badenas C, Darnell A, et al.: Linkage, clinical features, and Preimplantation Genetic Diagnosis. Genet Test Mol Biomarkers. 2016; 20(12): prognosis of autosomal dominant polycystic kidney disease types 1 and 2. 741–6. J Am Soc Nephrol. 1996; 7(10): 2142–51. PubMed Abstract | Publisher Full Text | F1000 Recommendation PubMed Abstract | F1000 Recommendation 21. Schrier RW, Brosnahan G, Cadnapaphornchai MA, et al.: Predictors of autosomal 6. Cornec-Le Gall E, Audrézet MP, Le Meur Y, et al.: Genetics and Pathogenesis dominant polycystic kidney disease progression. J Am Soc Nephrol. 2014; of Autosomal Dominant Polycystic Kidney Disease: 20 Years On. Hum Mutat. 25(11): 2399–418. 2014; 35(12): 1393–406. PubMed Abstract | Publisher Full Text | Free Full Text PubMed Abstract | Publisher Full Text 22. Torres VE, Grantham JJ, Chapman AB, et al.: Potentially modifiable factors 7. Torres VE, Chapman AB, Devuyst O, et al.: Tolvaptan in Patients with affecting the progression of autosomal dominant polycystic kidney disease. Autosomal Dominant Polycystic Kidney Disease. N Engl J Med. 2012; 367(25): Clin J Am Soc Nephrol. 2011; 6(3): 640–7. 2407–18. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation 23. Cornec-Le Gall E, Audrézet MP, Rousseau A, et al.: The PROPKD Score: A 8. Torres VE, Chapman AB, Devuyst O, et al.: Tolvaptan in Later-Stage New Algorithm to Predict Renal Survival in Autosomal Dominant Polycystic Autosomal Dominant Polycystic Kidney Disease. N Engl J Med. 2017; 377(20): Kidney Disease. J Am Soc Nephrol. 2016; 27(3): 942–51. 1930–1942. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation PubMed Abstract | Publisher Full Text | F1000 Recommendation 24. Grantham JJ, Torres VE: The importance of total kidney volume in 9. Porath B, Gainullin VG, Cornec-Le Gall E, et al.: Mutations in GANAB, evaluating progression of polycystic kidney disease. Nat Rev Nephrol. 2016; Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic 12(11): 667–77. Kidney and Liver Disease. Am J Hum Genet. 2016; 98(6): 1193–1207. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation 25. Yu ASL, Shen C, Landsittel DP, et al.: Baseline total kidney volume and the rate of kidney growth are associated with chronic kidney disease progression 10. Cornec-Le Gall E, Olson RJ, Besse W, et al.: Monoallelic Mutations to in Autosomal Dominant Polycystic Kidney Disease. Kidney Int. 2018; 93(3): DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease. 691–9. Am J Hum Genet. 2018; 102(5): 832–844. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation 11. Eckardt KU, Alper SL, Antignac C, et al.: Autosomal dominant tubulointerstitial 26. Schrier RW, Abebe KZ, Perrone RD, et al.: Blood pressure in early kidney disease: diagnosis, classification, and management--A KDIGO autosomal dominant polycystic kidney disease. N Engl J Med. 2014; 371(24): consensus report. Kidney Int. 2015; 88(4): 676–83. 2255–66. PubMed Abstract | Publisher Full Text PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation 12. Perales MA, Schwartz DH, Fabry JA, et al.: A vaccinia-gp160-based vaccine 27. Chebib FT, Torres VE: Recent Advances in the Management of Autosomal but not a gp160 protein vaccine elicits anti-gp160 cytotoxic T lymphocytes Dominant Polycystic Kidney Disease. Clin J Am Soc Nephrol. 2018; 13(11): in some HIV-1 seronegative vaccinees. J Acquir Immune Defic Syndr Hum 1765–76. Retrovirol. 1995; 10(1): 27–35. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation PubMed Abstract | Publisher Full Text 28. Torres VE, Abebe KZ, Chapman AB, et al.: Angiotensin blockade in late 13. Peral B, Gamble V, Strong C, et al.: Identification of mutations in the duplicated autosomal dominant polycystic kidney disease. N Engl J Med. 2014; 371(24): region of the polycystic kidney disease 1 gene (PKD1) by a novel approach. 2267–76. Am J Hum Genet. 1997; 60(6): 1399–410. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation PubMed Abstract | Publisher Full Text | Free Full Text 29. Nowak KL, You Z, Gitomer B, et al.: Overweight and Obesity Are Predictors 14. Carrera E, Maeder-Ingvar M, Rossetti AO, et al.: Trends in risk factors, patterns of Progression in Early Autosomal Dominant Polycystic Kidney Disease. J Am and causes in hospitalized strokes over 25 years: The Lausanne Stroke Soc Nephrol. 2018; 29(2): 571–8. Registry. Cerebrovasc Dis. 2007; 24(1): 97–103. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation PubMed Abstract | Publisher Full Text 30. Torres VE, Bankir L, Grantham JJ: A case for water in the treatment of 15. Cornec-Le Gall E, Chebib FT, Madsen CD, et al.: The Value of Genetic polycystic kidney disease. Clin J Am Soc Nephrol. 2009; 4(6): 1140–50. Testing in Polycystic Kidney Diseases Illustrated by a Family With PKD2 and PubMed Abstract | Publisher Full Text COL4A1 Mutations. Am J Kidney Dis. 2018; 72(2): 302–8. 31. Klahr S, Breyer JA, Beck GJ, et al.: Dietary protein restriction, blood pressure PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation control, and the progression of polycystic kidney disease. Modification of Diet 16. Rossetti S, Hopp K, Sikkink RA, et al.: Identification of gene mutations in Renal Disease Study Group. J Am Soc Nephrol. 1995; 5(12): 2037–47. in autosomal dominant polycystic kidney disease through targeted PubMed Abstract resequencing. J Am Soc Nephrol. 2012; 23(5): 915–33. 32. Messchendorp AL, Meijer E, Boertien WE, et al.: Urinary Biomarkers to Page 6 of 8 F1000Research 2019, 8(F1000 Faculty Rev):116 Last updated: 29 JAN 2019 Identify Autosomal Dominant Polycystic Kidney Disease Patients With a High determine the efficacy and safety of prescribed water intake to prevent kidney Likelihood of Disease Progression. Kidney Int Rep. 2018; 3(2): 291–301. failure due to autosomal dominant polycystic kidney disease (PREVENT- PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation ADPKD). BMJ Open. 2018; 8(1): e018794. PubMed Abstract | Free Full Text 33. Pavik I, Jaeger P, Ebner L, et al.: Soluble klotho and autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2012; 7(2): 248–57. 46. Clark WF, Sontrop JM, Huang SH, et al.: Hydration and Chronic Kidney PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation Disease Progression: A Critical Review of the Evidence. Am J Nephrol. 2016; 34. Meijer E, Bakker SJL, van der Jagt EJ, et al.: Copeptin, a surrogate marker of 43(4): 281–92. vasopressin, is associated with disease severity in autosomal dominant PubMed Abstract | Publisher Full Text | F1000 Recommendation polycystic kidney disease. Clin J Am Soc Nephrol. 2011; 6(2): 361–8. 47. Warner G, Hein KZ, Nin V, et al.: Food Restriction Ameliorates the PubMed Abstract | Publisher Full Text | Free Full Text Development of Polycystic Kidney Disease. J Am Soc Nephrol. 2016; 27(5): 35. Cornec-Le Gall E, Blais JD, Irazabal MV, et al.: Can we further enrich 1437–47. autosomal dominant polycystic kidney disease clinical trials for rapidly PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation progressive patients? Application of the PROPKD score in the TEMPO trial. 48. Kipp KR, Rezaei M, Lin L, et al.: A mild reduction of food intake slows Nephrol Dial Transplant. 2017. disease progression in an orthologous mouse model of polycystic kidney PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation disease. Am J Physiol Renal Physiol. 2016; 310(8): F726–F731. 36. Irazabal MV, Rangel LJ, Bergstralh EJ, et al.: Imaging classification of PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation autosomal dominant polycystic kidney disease: a simple model for selecting 49. Cadnapaphornchai MA, George DM, McFann K, et al.: Effect of pravastatin patients for clinical trials. J Am Soc Nephrol. 2015; 26(1): 160–72. on total kidney volume, left ventricular mass index, and microalbuminuria PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation in pediatric autosomal dominant polycystic kidney disease. Clin J Am Soc 37. Magistroni R, Corsi C, Martí T, et al.: A Review of the Imaging Techniques for Nephrol. 2014; 9(5): 889–96. Measuring Kidney and Cyst Volume in Establishing Autosomal Dominant PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation Polycystic Kidney Disease Progression. Am J Nephrol. 2018; 48(1): 67–78. 50. Brosnahan GM, Abebe KZ, Rahbari-Oskoui FF, et al.: Effect of Statin Therapy PubMed Abstract | Publisher Full Text on the Progression of Autosomal Dominant Polycystic Kidney Disease. A 38. Bhutani H, Smith V, Rahbari-Oskoui F, et al.: A comparison of ultrasound Secondary Analysis of the HALT PKD Trials. Curr Hypertens Rev. 2017; 13(2): and magnetic resonance imaging shows that kidney length predicts chronic 109–20. kidney disease in autosomal dominant polycystic kidney disease. Kidney Int. PubMed Abstract | Publisher Full Text | Free Full Text 2015; 88(1): 146–51. 51. European Medicines Agency: Assessment report: Jinarc. Procedure No. EMEA/ PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation H/C/002788/0000. EMA/154879/2015. London, England: European Medicines 39. Gansevoort RT, Arici M, Benzing T, et al.: Recommendations for the use of Agency: 2015. tolvaptan in autosomal dominant polycystic kidney disease: a position Reference Source statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney 52. Torres VE, Chapman AB, Devuyst O, et al.: Multicenter, open-label, Disorders and European Renal Best Practice. Nephrol Dial Transplant. 2016; extension trial to evaluate the long-term efficacy and safety of early versus 31(3): 337–48. delayed treatment with tolvaptan in autosomal dominant polycystic kidney PubMed Abstract | Publisher Full Text | Free Full Text disease: the TEMPO 4:4 Trial. Nephrol Dial Transplant. 2018; 33(3): 477–489. 40. Wyatt CM, Le Meur Y: REPRISE: tolvaptan in advanced polycystic kidney PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation disease. Kidney Int. 2018; 93(2): 292–5. 53. Watkins PB, Lewis JH, Kaplowitz N, et al.: Clinical Pattern of Tolvaptan- PubMed Abstract | Publisher Full Text Associated Liver Injury in Subjects with Autosomal Dominant Polycystic 41. Furlano M, Loscos I, Martí T, et al.: Autosomal Dominant Polycystic Kidney Kidney Disease: Analysis of Clinical Trials Database. Drug Saf. 2015; 38(1): Disease: Clinical Assessment of Rapid Progression. Am J Nephrol. 2018; 48(4): 1103–13. 308–17. PubMed Abstract | Publisher Full Text | Free Full Text PubMed Abstract | Publisher Full Text 54. Serra AL, Poster D, Kistler AD, et al.: Sirolimus and kidney growth in 42. Chebib FT, Perrone RD, Chapman AB, et al.: A Practical Guide for Treatment autosomal dominant polycystic kidney disease. N Engl J Med. 2010; 363(9): 820–9. of Rapidly Progressive ADPKD with Tolvaptan. J Am Soc Nephrol. 2018; 29(10): PubMed Abstract | Publisher Full Text | F1000 Recommendation 2458–70. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation 55. Tesar V, Ciechanowski K, Pei Y, et al.: Bosutinib versus Placebo for Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol. 2017; 28(11): 3404–13. 43. Lantinga MA, Casteleijn NF, Geudens A, et al.: Management of renal cyst PubMed Abstract | Publisher Full Text | Free Full Text infection in patients with autosomal dominant polycystic kidney disease: a 56. Walz G, Budde K, Mannaa M, et al.: Everolimus in patients with autosomal systematic review. Nephrol Dial Transplant. 2017; 32(1): 144–50. dominant polycystic kidney disease. N Engl J Med. 2010; 363(9): 830–40. PubMed Abstract | Publisher Full Text | F1000 Recommendation PubMed Abstract | Publisher Full Text | F1000 Recommendation 44. El-Damanawi R, Harris T, Sandford RN, et al.: Patient Survey of current water Intake practices in autosomal dominant Polycystic kidney disease: the SIPs 57. Meijer E, Visser FW, van Aerts RMM, et al.: Effect of Lanreotide on Kidney survey. Clin Kidney J. 2017; 10(3): 305–9. Function in Patients With Autosomal Dominant Polycystic Kidney Disease: The PubMed Abstract | Publisher Full Text | Free Full Text DIPAK 1 Randomized Clinical Trial. JAMA. 2018; 320(19): 2010–9. 45. Wong ATY, Mannix C, Grantham JJ, et al.: Randomised controlled trial to PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation Page 7 of 8 F1000Research 2019, 8(F1000 Faculty Rev):116 Last updated: 29 JAN 2019 Open Peer Review Current Referee Status: Editorial Note on the Review Process F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions (any comments will already have been addressed in the published version). The referees who approved this article are: Version 1 1 John Sayer Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK Competing Interests: No competing interests were disclosed. 2 Chang-Lin Mei Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China Competing Interests: No competing interests were disclosed. The benefits of publishing with F1000Research: Your article is published within days, with no editorial bias You can publish traditional articles, null/negative results, case reports, data notes and more The peer review process is transparent and collaborative Your article is indexed in PubMed after passing peer review Dedicated customer support at every stage For pre-submission enquiries, contact research@f1000.com Page 8 of 8