Renal water handling at early stages of autosomal dominant polycystic kidney disease

Renal water handling at early stages of autosomal dominant polycystic kidney disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Renal water handling at early stages of autosomal dominant polycystic kidney disease Victor Manuel Garcia Nieto, Juan David Gonzalez Rodriguez, Matilde Gil Villena, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9294920/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 5 You are reading this latest preprint version Abstract Background Previous publications in children with autosomal dominant polycystic kidney disease (ADPKD) have described that there is an alteration of renal water handling in a large percentage of cases, with a striking reduction in maximum urinary osmolality (UOsm). The aim of the present work is to analyze this kidney function in children and adolescents with ADPKD and describe the evolution at two points of their disease. Patients and methods We included 31 patients (15 man, 16 woman) with bilateral renal cysts and a family history of ADPKD, who had, at least, their urinary volume (V/GFR) quantified and a renal ultrasound performed both in the first period (P1; age 8.9 ± 4.8 years) and in the second (P2; age 16.5 ± 2.7 years). UOsm was determined after desmopressin stimulation and GFR was estimated (eGFR) using creatinine-based equations. Results Significant differences were observed in the the longitudinal diameter of both kidneys at P2 compared to P1. No differences were observed in UOsm, eGFR, V/GFR and albuminuria between both periods. UOsm was reduced in 8/28 cases at P1 and in 5/23 cases at P2. Furthermore, V/GFR values were slightly lower than the mean values normal for age. Conclusions In our series the alterations in UOsm were scarce and of little entity. Excessive kidney growth in ADPKD in the first two decades of life does not seem to be directly influenced by vasopressin since there are no evident pathophysiological reasons for its stimulation. Autosomal dominant polycystic kidney disease Urinary volume Maximum urinary osmolality Renal water handling Introduction Autosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder characterized by the formation and growth of cysts in the kidneys that progressively replace normal renal parenchyma, along with areas of fibrosis and interstitial inflammation. It is a ciliopathy caused mainly by heterozygous mutations in the PKD1 and PKD2 genes, although several minor genes account for a small percentage of patients [ 1 , 2 ]. No more than 1–5% of nephrons develop cysts despite the fact that each renal tubular cell carries a germline mutation of the gene encoding a polycystin [ 3 ]. The mechanism proposed to explain this phenomenon would be the existence of a second somatic mutation acquired in a cell already containing the germline mutation [ 4 ]. A recent international cohort study reported that the most frequent symptoms or signs in children and adolescents with ADPKD are abdominal pain, urinary tract infection, hematuria, hypertension, enuresis or dysfunctional voiding, proteinuria and urolithiasis [ 5 ]. Reduced urinary concentrating ability has also been reported to be one of the first signs seen in children with ADPKD and, although not confirmed, has been suggested to be present in a large percentage of affected children [ 6 ]. Tolvaptan, a selective vasopressin V2 receptor (V2R) antagonist, is the first drug approved for the treatment of ADPKD. Its utility is based on the hypothesis suggesting that the impaired urinary concentrating ability present in patients with ADPKD would alter extracellular fluid conservation due to periods of hypohydration when urinary fluid loss is not adequately compensated by water intake. The blood hyperosmotic stimulus would favor the release of vasopressin that would induce an overactivation of renal V2R receptors contributing to cyst expansion [ 7 ]. However, it is not well established whether this mechanism is present in the pediatric age. The aim of this work is to observe the evolution of kidney size, estimated glomerular filtration rate (eGFR), albuminuria and renal water handling in a group of children and adolescents with ADPKD in two periods of the evolution of their disease. Patients and methods Design We designed a retrospective longitudinal cohort study including pediatric and adolescents patients diagnosed with ADPKD and monitored in the Pediatric Nephrology Unit of the first author´s hospital. Diagnosis was made by the presence of bilateral renal cysts and family history of ADPKD and/or genetic study if available. In the cases where a genetic study has been carried out, it was using next-generation sequencing (NGS) in the patients with unknown mutation in the family, and Sanger in the patients with previously known familial mutation. To be included, patients had to have at least two assessments spaced apart in time. Another inclusion criteria was to have data available to assess renal water handling, whether the urinary volume corrected by 100 ml GFR (V/GFR) and/or maximum urinary osmolality (UOsm) in both periods. We determinated the maximum UOsm following stimulation with sublingual desmopressin oral lyophilisate (MELT). The methodology of the renal concentration test performed with desmopressin stimulation has been described previously [ 8 , 9 ]. Above one year of age, the lower limit of normal for maximum UOsm is considered to be 850 Osm/kg [ 8 , 9 ]. The z-value of the kidney longitudinal diameter was calculated from the data according to age of both kidneys given in the publication of Rosenbaum et al. [ 10 ]. Blood pressure (BP) data were also collected based on ambulatory blood pressure monitoring (ABPM) performed after repeat office measurements, when BP was in the high normal range (> 75th percentile) [ 11 – 13 ]. Laboratory determinations and calculations The analytical determination of creatinine (Cr) was performed by the creatininase enzymatic method using a Roche/Hitachi Cobas c 701/702 autoanalyzer. UOsm was quantified by determination of freezing point depression on an Osmostat Osmometer (Menarini Diagnostics). Urinary albumin was measured by nephelometric techniques. The values of the albumin/creatinine ratio in first urine of the day were expressed in mg/g and levels above 30 mg/g creatinine were considered indicative of albuminuria [ 14 ]. GFR was estimated using the “Bedside Schwartz” [ 15 ] and the creatinine-based of the European Kidney Function Consortium (EKFC) equation [ 16 ], as recommended in the last KDIGO guidelines [ 17 ]. Values below 90 ml/min/1.73 m 2 were considered abnormal. It was also confirmed that none of the patients had eGFR less than 70 ml/min/1.73 m 2 in any of the periods. V/GFR was calculated with the following formula: V/GFR= (Plasma Cr x 100) /Urinary Cr. In children, normal values are 0.59 ± 0.22 ml/100 ml GFR and in adults 0.73 ± 0.26 ml/100 ml GFR [ 18 – 21 ]. Statistical analysis Descriptive statistics were initially performed. Kolmogorov-Smirnov test was used to study the distribution of the sample. Quantitative variables that followed a normal distribution were expressed as mean and standard deviation. For the comparison of differences between paired variables corresponding to the two periods, the “t” test for related samples was used. Pearson's test was used to study the correlation between quantitative variables. A p-value < 0.05 was considered statistically significant. Data were analysed using SPSS version 21.0 (SPSS Inc., Chicago, IL, USA). Ethical statement The procedures and protocols involved in this study met the ethical, administrative, and data protection requirements of our hospitals. Approval from the hospital Ethics Committee was also obtained with the code CHUNSC_2022_72. The ethics committee granted a waiver for informed consent since this research study was conducted retrospectively from data obtained for clinical purposes and samples from healthy children were not obtained specifically for this work. Results The study included 31 patients (15 men, 16 women). Genetic study was performed in 27 cases and was positive for PKD1 in 25 patients and for PKD2 in the remaining two. All but two families carried a different mutation. The mean patient age in the first period (P1) was 8.9 ± 4.8 years (range 1–17.6) and in the second analyzed period (P2) was 16.5 ± 2.7 years (range 8.9-18.8). Table 1 shows the kidney longitudinal diameters and z-value corresponding to both kidneys and periods. Statistically significant differences were observed in the z-value of the longitudinal diameter of both kidneys between the second period (P2) compared to the measurement in the first period (P1). Table 2 shows the values corresponding to renal water handling, eGFR and albumin/creatinine ratio. No differences were observed for any of the parameters studied corresponding to both periods, with the exception of eGFR calculated using the Bedside Schwartz equation. In P1, eGFR using Schwartz equation was normal in all patients, but in P2 was less than 90 ml/min/1.73 m² in eleven patients. As for EFKC eGFR, it was reduced in two patients in P1 (range 88.1-125.6 ml/min/1.73 m²) and in six in P2 (range 77.9-116.8 ml/min/1.73 m²). On P2, there were no differences between eGFR calculated according to the Schwartz equation and values obtained with the creatinine-based EKFC equation, with concordance in 83.3% of cases. Likewise, a direct correlation was observed between the eGFR values by EKFC calculated in P1 and P2 (r: 0.61; p= 0.001). UOsm was reduced in 8/28 of the cases at P1 (28.6%) (range 434-1290 mOsm/Kg); in three of them, the concentration defect was maintained at the end of the follow-up period (P2) and in the remaining it normalized. In P2, UOsm was reduced in 5/23 cases (21.7%) (range 773-1254 mOsm/Kg). V/GFR was increased in only one patient in P1 (range 0.2–1.2 ml/100 ml GFR) and in no cases in P2 (range 0.21–0.99). The mean V/GFR values were slightly lower than the mean values normal for age. Only a weak negative correlation was observed between the initial maximum UOsm and the final z-value of the longitudinal diameter of the right kidney at P2 (r: -0.47; p= 0.02). On the other hand, albuminuria was detected in 7/31 cases at P1 (22.6%) and in 7/29 cases at P2 (24.1%). ABPM was performed in nine patients based on the office measurements. In seven of them, hypertension was confirmed in both periods, day and night, except for one case that only presented nocturnal diastolic hypertension. All patients with elevated BP on ABPM had normal V/GFR in P1 y P2, while UOsm was reduced in 1/7 cases in P1 and in 2/7 cases in P2 of those with hypertension. Discussion Impaired ability to concentrate has been described in patients with ADPKD with some frequency in recent decades. Initially, it was determined in adults [22,23] or in children carrying both forms of polycystic disease [24]. Gabow et al. studied 87 adult subjects with ADPKD and observed that greater architectural severity assessed by the number and size of cysts was associated with greater impairment of renal concentrating ability [25]. Ho et al. in 2012 studied 10 adults and 10 children with ADPKD who had their plasma osmolality and vasopressin levels determined after overnight water deprivation, concluding that patients with ADPKD have a defect in osmoregulation, with limited vasopressin release [26]. These data were not subsequently confirmed by determining copeptin as a marker of vasopressin levels [27,28]. Thus, Zittema et al. in 2012 studied fifteen ADPKD patients with eGFR ≥60 ml/min/1.73 m 2 and concluded that in early stages of the disease ADPKD, patients show impaired renal concentrating ability leading to increased plasma vasopressin levels as a compensatory response, i.e. without evidence of an altered hypothalamic response [27]. In 2004, Seeman et al. found a reduction in peak UOsm in 58% of children with ADPKD (n= 53; age: 11.8 ± 4.4 years). Moreover, the prevalence of elevated BP studied by ABPM was significantly higher in children with reduced renal concentrating ability (35%) than in those with normal renal concentrating ability (5%) [6]. Recently, the same authors have studied 18 children with autosomal recessive polycystic kidney disease (age 8.5 years; range: 1.3-16.8) and observed similar results to those with ADPKD, i.e. a defect in concentrating ability present in most patients, which was associated with decreased eGFR and elevated BP [29]. The discrepancy in the results obtained in our work regarding the study of renal water handling in relation to the two pediatric publications by Seeman et al [6,29] could be explained by several reasons. In both studies, these authors did not quantify urinary volume and they used desmopressin nasal drops, so it is possible that the reabsorptive stimulus was lower than that achieved with MELT tablets. In a previous study by our group in which we included 53 patients (30 men, 32 women), the maximum UOsm obtained with intranasal desmopressin was 726.4 ± 163.8 mOsm/kg and with oral desmopressin 782.1 ± 198.5 mOsm/kg (p= 0.003). Overall, therefore, the UOsm values achieved orally were significantly higher than those obtained after intranasal administration [30]. On the other hand, in the aforementioned paper of Seeman et al. published in 2023, twelve patients (67%) presented stage 2-4 of chronic kidney disease (CKD) [29]. It has long been known that CKD itself, regardless of the cause, is accompanied by a defect in renal concentrating ability until the isosthenuria characteristic of stage 5 CKD is reached [19,31-34]. In a recent study, we have confirmed that in children below 70 ml/min/1.73 m 2 , regardless of the cause of CKD, there is always a reduced maximum UOsm [35]. In this work, the differences in eGFR levels observed between the two periods using the Schwartz equation were not confirmed using the EFKC equation (Table 2). The validity of Schwartz’s bedside equation when applied to children with mild CKD or normal kidney function is unclear with some studies demonstrating worse performance [36]. The reduction in eGFR EFKC observed in P2 in six patients was very slight and had no influence on renal water handling. The frequency of concentration ability defect in our study (28.6% in P1 and 21.7% in P2) was much lower than that described previously in pediatric patients with polycystic kidney disease. Moreover, in our cases urinary volume was only increased in one patient in the first period, showing no alterations in the last evaluation. In our clinical experience we have observed that most children and adolescents with ADPKD do not have usually an excessive appetite for water consumption. Note in this regard that the mean urinary volume of our patients was even lower than that of healthy children and adults. The hypothesis formulated by some authors that the influence of increased plasma vasopressin levels as a compensatory response to supposed periods of hypohydration secondary to polyuria, which would play a preponderant role in the progression of the disease [7,27,28], is difficult to assume, at least in early stages. This would be valid in the absence of a real availability to achieve an appropriate and continuous supply in the usual fluid intake, but this is not the case in most environments. The polyuria that is eventually observed in ADPKD would not be very marked except in more advanced stages of the disease. For example, in the paper by Gabow et al. the urine volume in adult subjects with ADPKD was 1.97 ± 0.08 liters/day and the maximum UOms was only slightly below normal (680 ± 14 mOsm/kg) [25]. Likewise, in one of the papers signed by Zittema et al. urine volume was 2 ± 0.65 liters/day and vasopressin levels were 1.34 (0.25-3.07) pg/ml, with no statistically significant differences in relation to those of the controls [0.87 (0.28-2.38) pg/ml]. In the test consisting of a fluid deprivation, no differences were observed in vasopressin levels and very discrete differences in copeptin levels (p= 0.04) [27]. In summary, in any patient with eGFR <70 ml/min/1.73 m 2 there is a defect in concentrating ability and, consequently, copeptin levels should be increased. This assertion has been proven in several articles in which patients with CKD were included, in the sense that high copeptin levels are associated with the development and the progression of CKD [37,38]. Therefore, the explanation for the efficacy of tolvaptan in adult patients and experimental animals with ADPKD [39-41] must be different from that formulated so far, since the defect in the ability to concentrate in this disease is not very noticeable except in advanced stages of the disease. In a review on the subject, Chebib et al. summarized that the cause of this concentrating defect has not been fully elucidated [42]. We believe that an alternative explanation could be the existence of a high density in the number of V2R receptors located in the basolateral membrane of the collecting tubule cells. In this case, in ADPKD patients the functional capacity of vasopressin-V2R complexes would be increased with the negative consequences in cyst growth and on disease progression. In addition, an increase in the expression of V2R messenger RNA has been described in murine models of polycystic kidney disease [43]. It could be hypothesized that the existence of mutations in PKD1 in the cilia of the collecting tubule and the ineffective action of the V2R receptors present in these cilia [44] would lead to a compensatory increase in V2R synthesis on the basolateral side of the collecting tubule cells. This increase in V2R density would explain our observation in clinical experience that most children and adolescents with ADPKD do not tend to have an excessive appetite for water consumption and that the mean urine volume of our patients was even lower than that of healthy children. The efficacy of tolvaptan in pediatric patients has not been well established [45]. Recently, a paper dedicated to establishing the characteristics necessary to determine the risk of rapid disease progression in children has been published [46]. In 2023, the first data from a randomized, double-blind, clinical trial involving 91 controlled patients at 20 pediatric nephrology centers were published. Tolvaptan showed a reduction in UOsm compared to placebo. The authors concluded that the effects on urinary volume increase were manageable, with few discontinuations, although it is too soon to know whether the drug is useful in the long-term progression of the disease [47]. In conclusion, in our series of patients the mean V/GFR values in both periods were slightly lower than the mean normal values for age and the alterations in UOsm were scarce and of little entity, especially at the end of the follow-up period. Consequently, excessive renal growth in ADPKD in the first two decades of life does not seem to be directly influenced by vasopressin since there are no obvious pathophysiological reasons for its release to be stimulated, so the explanation of the efficacy of tolvaptan in ADPKD should be reassessed. Declarations Conflict of interest The authors declare no competing interests. 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J Am Soc Nephrol 19:102–108. https://doi.org/10.1681/ASN.2007060688 Torres VE, Higashihara E, Devuyst O, Chapman AB, Gansevoort RT, Grantham JJ et al (2016) Effect of tolvaptan in autosomal dominant polycystic kidney disease by CKD stage: Results from the TEMPO 3:4 trial. Clin J Am Soc Nephrol 11:803–811. https://doi.org/10.2215/CJN.06300615 . TEMPO 3:4 Trial Investigators Wang X, Constans MM, Chebib FT, Torres VE, Pellegrini L (2019) Effect of a vasopressin V2 receptor antagonist on polycystic kidney disease development in a rat model. Am J Nephrol 49:487–493. https://doi.org/10.1159/000500667 Chebib FT, Sussman CR, Wang X, Harris PC, Torres VE (2015) Vasopressin and disruption of calcium signalling in polycystic kidney disease. Nat Rev Nephrol 11:451–464. https://doi.org/10.1038/nrneph.2015.39 Gattone VH 2nd, Maser RL, Tian C, Rosenberg JM, Branden MG (1999) Developmental expression of urine concentration-associated genes and their altered expression in murine infantile-type polycystic kidney disease. Dev Genet 24:309–318. https://doi.org/10.1002/(SICI)1520-6408(1999)24:3/4%3C309::AID-DVG14%3E3.0.CO;2-5 Raychowdhury MK, Ramos AJ, Zhang P, McLaughin M, Dai XQ, Chen XZ et al (2009) Vasopressin receptor-mediated functional signaling pathway in primary cilia of renal epithelial cells. Am J Physiol Ren Physiol 296:F87–F97. https://doi.org/10.1152/ajprenal.90509.2008 Liu F, Feng C, Shen H, Fu H, Mao J (2021) Tolvaptan in pediatric autosomal dominant polycystic kidney disease: From here to where? Kidney Dis (Basel) 7:343–349. https://doi.org/10.1159/000517186 Mekahli D, Guay-Woodford LM, Cadnapaphornchai MA, Goldstein SL, Dandurand A, Jiang H et al (2024) Estimating risk of rapid disease progression in pediatric patients with autosomal dominant polycystic kidney disease: a randomized trial of tolvaptan. Pediatr Nephrol 39:1481–1490. https://doi.org/10.1007/s00467-023-06239-8 Mekahli D, Guay-Woodford L, Cadnapaphornchai MA, Greenbaum LA, Litwin M, Seeman T et al (2023) Tolvaptan for children and adolescents with autosomal dominant polycystic kidney disease: randomized controlled trial. Clin J Am Soc Nephrol 18:36–46. https://doi.org/10.2215/CJN.0000000000000022 Tables Table 1 . Renal longitudinal diameters and their z-values in periods P1 and P2. First ultrasound Last ultrasound p Longitudinal diameter of the left kidney (cm) 9.6 ± 1.9 12.0 ± 1.9 - Longitudinal diameter of the left kidney (z-value) 1.3 ± 1.8 2.5 ± 2.0 <0.001 Longitudinal diameter of the right kidney (cm) 9.4 ± 1.9 12.0 ± 2.6 - Longitudinal diameter of the right kidney (z-value) 0.9 ± 1.9 2.5 ± 2.8 <0.001 Table 2 . Maximum UOsm, V/GFR, eGFR and albuminuria values at both time points of the study. P1 P2 p Maximum UOsm (mOsm/Kg) 908.7 ± 199.3 (n= 23) 964.8 ± 137.8 (n= 23) ns V/GFR (ml/100 ml GFR) 0.48 ± 0.23 (n= 31) 0.47 ± 0.17 (n= 31) ns eGFR Bedside Schwartz (ml/min/1,73 m 2 ) 143.4 ± 53.1 (n= 28) 101.5 ± 20.9 (n= 28) <0.001 eGFR EFKC Cr (ml/min/1,73 m 2 ) 106. ± 9.4 (n= 26) 102.2 ± 12.7 (n= 26) ns Urine albumin/creatinine (mg/g) 32.7 ± 67.3 (n= 29) 15.9 ± 3.3 (n= 29) ns Cr: creatinine. eGFR: estimated glomerular filtration rate. EKFC: European Kidney Function Consortium. ns: not significant. Uosm: urinary osmolality. V/GFR: urinary volume corrected by 100 ml GFR. Supplementary Files GraphicalAbstract.GarciaNietoetal.2026.pptx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Major Revisions Needed 02 May, 2026 Reviewers agreed at journal 08 Apr, 2026 Reviewers invited by journal 08 Apr, 2026 Editor assigned by journal 07 Apr, 2026 First submitted to journal 01 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9294920","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":619660526,"identity":"89588416-3c6f-4c02-b4e8-b3b8d09fbb20","order_by":0,"name":"Victor Manuel Garcia Nieto","email":"","orcid":"","institution":"Hospital Universitario Nuestra Senora de la Candelaria","correspondingAuthor":false,"prefix":"","firstName":"Victor","middleName":"Manuel Garcia","lastName":"Nieto","suffix":""},{"id":619660527,"identity":"775139a9-c1b6-4747-b837-5d9234c48c79","order_by":1,"name":"Juan David Gonzalez Rodriguez","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIiWNgGAWjYBACxgYgwQNCByACMgwMzAdI0wJksyUQtooHRCC08BjgVc08I/nZgzc1h2X4DrBffFzwx46Hn//MN6kbDDb2OB02I83ccM6xwzySB3iKjWfwJPNINpzdJp3DkJbYgFNLgpk0D1saj8EBnjRpHglmHoODvSAth3F6iHFG+jdpnn8wLQb1PPaHeZ4BtfzH47AcM2neNhugFvZj0jwJh3kM2HjYgFoOMOJ0WM+bMsm5fTY8kod5mI15DhznkTjDZmydY5CM0y+G7enbJN58k7DnO97+8DHPn2o5/v7DD2/nVNjhdJgh3CxmlOjAEzXyCCb7A9zKRsEoGAWjYEQDAHaeTQRT4rqLAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-8863-2007","institution":"Hospital General Universitario Santa Lucía: Hospital Universitario General de Santa Lucia","correspondingAuthor":true,"prefix":"","firstName":"Juan","middleName":"David Gonzalez","lastName":"Rodriguez","suffix":""},{"id":619660528,"identity":"3c264a17-16b8-4421-9ab8-85a0220d4b3d","order_by":2,"name":"Matilde Gil Villena","email":"","orcid":"","institution":"Hospital Universitario Nuestra Senora de la Candelaria","correspondingAuthor":false,"prefix":"","firstName":"Matilde","middleName":"Gil","lastName":"Villena","suffix":""},{"id":619660529,"identity":"de41b84e-bd0e-4721-8aa0-36d84a674931","order_by":3,"name":"María isabel Luis Yanes","email":"","orcid":"","institution":"Hospital Universitario Nuestra Senora de la Candelaria","correspondingAuthor":false,"prefix":"","firstName":"María","middleName":"isabel Luis","lastName":"Yanes","suffix":""}],"badges":[],"createdAt":"2026-04-01 17:42:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9294920/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9294920/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107481842,"identity":"ebcd9539-9a55-4968-81e2-e5672da3150c","added_by":"auto","created_at":"2026-04-22 02:20:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":323943,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9294920/v1/e9518890-5fc5-4763-9566-9ac42bd3c2ef.pdf"},{"id":107104963,"identity":"52464823-ca56-4db8-be2d-4e2ff34fc82f","added_by":"auto","created_at":"2026-04-16 20:36:14","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23514,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalAbstract.GarciaNietoetal.2026.pptx","url":"https://assets-eu.researchsquare.com/files/rs-9294920/v1/1ddd3f56a7d45fcc2c18d9d6.pptx"}],"financialInterests":"","formattedTitle":"Renal water handling at early stages of autosomal dominant polycystic kidney disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAutosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder characterized by the formation and growth of cysts in the kidneys that progressively replace normal renal parenchyma, along with areas of fibrosis and interstitial inflammation. It is a ciliopathy caused mainly by heterozygous mutations in the PKD1 and PKD2 genes, although several minor genes account for a small percentage of patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. No more than 1\u0026ndash;5% of nephrons develop cysts despite the fact that each renal tubular cell carries a germline mutation of the gene encoding a polycystin [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The mechanism proposed to explain this phenomenon would be the existence of a second somatic mutation acquired in a cell already containing the germline mutation [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA recent international cohort study reported that the most frequent symptoms or signs in children and adolescents with ADPKD are abdominal pain, urinary tract infection, hematuria, hypertension, enuresis or dysfunctional voiding, proteinuria and urolithiasis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Reduced urinary concentrating ability has also been reported to be one of the first signs seen in children with ADPKD and, although not confirmed, has been suggested to be present in a large percentage of affected children [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTolvaptan, a selective vasopressin V2 receptor (V2R) antagonist, is the first drug approved for the treatment of ADPKD. Its utility is based on the hypothesis suggesting that the impaired urinary concentrating ability present in patients with ADPKD would alter extracellular fluid conservation due to periods of hypohydration when urinary fluid loss is not adequately compensated by water intake. The blood hyperosmotic stimulus would favor the release of vasopressin that would induce an overactivation of renal V2R receptors contributing to cyst expansion [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, it is not well established whether this mechanism is present in the pediatric age.\u003c/p\u003e \u003cp\u003eThe aim of this work is to observe the evolution of kidney size, estimated glomerular filtration rate (eGFR), albuminuria and renal water handling in a group of children and adolescents with ADPKD in two periods of the evolution of their disease.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDesign\u003c/h2\u003e \u003cp\u003eWe designed a retrospective longitudinal cohort study including pediatric and adolescents patients diagnosed with ADPKD and monitored in the Pediatric Nephrology Unit of the first author\u0026acute;s hospital. Diagnosis was made by the presence of bilateral renal cysts and family history of ADPKD and/or genetic study if available. In the cases where a genetic study has been carried out, it was using next-generation sequencing (NGS) in the patients with unknown mutation in the family, and Sanger in the patients with previously known familial mutation.\u003c/p\u003e \u003cp\u003eTo be included, patients had to have at least two assessments spaced apart in time. Another inclusion criteria was to have data available to assess renal water handling, whether the urinary volume corrected by 100 ml GFR (V/GFR) and/or maximum urinary osmolality (UOsm) in both periods. We determinated the maximum UOsm following stimulation with sublingual desmopressin oral lyophilisate (MELT). The methodology of the renal concentration test performed with desmopressin stimulation has been described previously [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Above one year of age, the lower limit of normal for maximum UOsm is considered to be 850 Osm/kg [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe z-value of the kidney longitudinal diameter was calculated from the data according to age of both kidneys given in the publication of Rosenbaum et al. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Blood pressure (BP) data were also collected based on ambulatory blood pressure monitoring (ABPM) performed after repeat office measurements, when BP was in the high normal range (\u0026gt;\u0026thinsp;75th percentile) [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eLaboratory determinations and calculations\u003c/h3\u003e\n\u003cp\u003eThe analytical determination of creatinine (Cr) was performed by the creatininase enzymatic method using a Roche/Hitachi Cobas c 701/702 autoanalyzer. UOsm was quantified by determination of freezing point depression on an Osmostat Osmometer (Menarini Diagnostics). Urinary albumin was measured by nephelometric techniques.\u003c/p\u003e \u003cp\u003eThe values of the albumin/creatinine ratio in first urine of the day were expressed in mg/g and levels above 30 mg/g creatinine were considered indicative of albuminuria [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. GFR was estimated using the \u0026ldquo;Bedside Schwartz\u0026rdquo; [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and the creatinine-based of the European Kidney Function Consortium (EKFC) equation [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], as recommended in the last KDIGO guidelines [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Values below 90 ml/min/1.73 m\u003csup\u003e2\u003c/sup\u003e were considered abnormal. It was also confirmed that none of the patients had eGFR less than 70 ml/min/1.73 m\u003csup\u003e2\u003c/sup\u003e in any of the periods. V/GFR was calculated with the following formula: V/GFR= (Plasma Cr x 100) /Urinary Cr. In children, normal values are 0.59\u0026thinsp;\u0026plusmn;\u0026thinsp;0.22 ml/100 ml GFR and in adults 0.73\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26 ml/100 ml GFR [\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDescriptive statistics were initially performed. Kolmogorov-Smirnov test was used to study the distribution of the sample. Quantitative variables that followed a normal distribution were expressed as mean and standard deviation. For the comparison of differences between paired variables corresponding to the two periods, the \u0026ldquo;t\u0026rdquo; test for related samples was used. Pearson's test was used to study the correlation between quantitative variables. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Data were analysed using SPSS version 21.0 (SPSS Inc., Chicago, IL, USA).\u003c/p\u003e \u003c/div\u003e\u003cp\u003e\u003cstrong\u003eEthical statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe procedures and protocols involved in this study met the ethical, administrative, and data protection requirements of our hospitals. Approval from the hospital Ethics Committee was also obtained with the code CHUNSC_2022_72. The ethics committee granted a waiver for informed consent since this research study was conducted retrospectively from data obtained for clinical purposes and samples from healthy children were not obtained specifically for this work.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe study included 31 patients (15 men, 16 women). Genetic study was performed in 27 cases and was positive for PKD1 in 25 patients and for PKD2 in the remaining two. All but two families carried a different mutation. The mean patient age in the first period (P1) was 8.9 ± 4.8 years (range 1–17.6) and in the second analyzed period (P2) was 16.5 ± 2.7 years (range 8.9-18.8).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 1 shows the kidney longitudinal diameters and z-value corresponding to both kidneys and periods. Statistically significant differences were observed in the z-value of the longitudinal diameter of both kidneys between the second period (P2) compared to the measurement in the first period (P1). Table 2 shows the values corresponding to renal water handling, eGFR and albumin/creatinine ratio. No differences were observed for any of the parameters studied corresponding to both periods, with the exception of eGFR calculated using the Bedside Schwartz equation. In P1, eGFR using Schwartz equation was normal in all patients, but in P2 was less than 90 ml/min/1.73 m² in eleven patients. As for EFKC eGFR, it was reduced in two patients in P1 (range 88.1-125.6 ml/min/1.73 m²) and in six in P2 (range 77.9-116.8 ml/min/1.73 m²). On P2, there were no differences between eGFR calculated according to the Schwartz equation and values obtained with the creatinine-based EKFC equation, with concordance in 83.3% of cases. Likewise, a direct correlation was observed between the eGFR values by EKFC calculated in P1 and P2 (r: 0.61; p= 0.001).\u003c/p\u003e\n\u003cp\u003eUOsm was reduced in 8/28 of the cases at P1 (28.6%) (range 434-1290 mOsm/Kg); in three of them, the concentration defect was maintained at the end of the follow-up period (P2) and in the remaining it normalized. In P2, UOsm was reduced in 5/23 cases (21.7%) (range 773-1254 mOsm/Kg). V/GFR was increased in only one patient in P1 (range 0.2–1.2 ml/100 ml GFR) and in no cases in P2 (range 0.21–0.99). The mean V/GFR values were slightly lower than the mean values normal for age. Only a weak negative correlation was observed between the initial maximum UOsm and the final z-value of the longitudinal diameter of the right kidney at P2 (r: -0.47; p= 0.02).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOn the other hand, albuminuria was detected in 7/31 cases at P1 (22.6%) and in 7/29 cases at P2 (24.1%). ABPM was performed in nine patients based on the office measurements. In seven of them, hypertension was confirmed in both periods, day and night, except for one case that only presented nocturnal diastolic hypertension. All patients with elevated BP on ABPM had normal V/GFR in P1 y P2, while UOsm was reduced in 1/7 cases in P1 and in 2/7 cases in P2 of those with hypertension.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eImpaired ability to concentrate has been described in patients with ADPKD with some frequency in recent decades. Initially, it was determined in adults [22,23] or in children carrying both forms of polycystic disease [24]. Gabow et al. studied 87 adult subjects with ADPKD and observed that greater architectural severity assessed by the number and size of cysts was associated with greater impairment of renal concentrating ability [25]. Ho et al. in 2012 studied 10 adults and 10 children with ADPKD who had their plasma osmolality and vasopressin levels determined after overnight water deprivation, concluding that patients with ADPKD have a defect in osmoregulation, with limited vasopressin release [26]. These data were not subsequently confirmed by determining copeptin\u0026nbsp;as a marker of vasopressin levels [27,28]. Thus, Zittema et al. in 2012 studied fifteen ADPKD patients with eGFR ≥60 ml/min/1.73 m\u003csup\u003e2\u003c/sup\u003e and concluded that in early stages of the disease ADPKD, patients show impaired renal concentrating ability leading to increased plasma vasopressin levels as a compensatory response, i.e. without evidence of an altered hypothalamic response [27].\u003c/p\u003e\n\u003cp\u003eIn 2004, Seeman et al. found a reduction in peak UOsm in 58% of children with ADPKD (n= 53; age: 11.8 ± 4.4 years). Moreover, the prevalence of elevated BP studied by ABPM was significantly higher in children with reduced renal concentrating ability (35%) than in those with normal renal concentrating ability (5%) [6]. Recently, the same authors have studied 18 children with\u0026nbsp;autosomal recessive polycystic kidney disease\u0026nbsp;(age 8.5 years; range: 1.3-16.8) and observed similar results to those with ADPKD, i.e. a defect in concentrating ability present in most patients, which was associated with decreased eGFR and elevated BP [29].\u0026nbsp;The discrepancy in the results obtained in our work regarding the study of renal water handling in relation to the two pediatric publications by Seeman et al [6,29] could be explained by several reasons. In both studies, these authors did not quantify urinary volume and they used desmopressin nasal drops, so it is possible that the reabsorptive stimulus was lower than that achieved with MELT tablets. In a previous study by our group in which we included 53 patients (30 men, 32 women), the maximum UOsm obtained with intranasal desmopressin was 726.4 ± 163.8 mOsm/kg and with oral desmopressin 782.1 ± 198.5 mOsm/kg (p= 0.003). Overall, therefore, the UOsm values achieved orally were significantly higher than those obtained after intranasal administration [30]. On the other hand, in the aforementioned paper of Seeman et al. published in 2023, twelve patients (67%) presented stage 2-4 of chronic kidney disease (CKD) [29]. It has long been known that CKD itself, regardless of the cause, is accompanied by a defect in renal concentrating ability until the isosthenuria characteristic of stage 5 CKD is reached [19,31-34]. In a recent study, we have confirmed that in children below 70 ml/min/1.73 m\u003csup\u003e2\u003c/sup\u003e, regardless of the cause of CKD, there is always a reduced maximum UOsm [35].\u003c/p\u003e\n\u003cp\u003eIn this work, the differences in eGFR levels observed between the two periods using the Schwartz equation were not confirmed using the EFKC equation (Table 2). The validity of Schwartz’s bedside equation when applied to children with mild CKD or normal kidney function is unclear with some studies demonstrating worse performance [36]. The reduction in eGFR EFKC observed in P2 in six patients was very slight and had no influence on renal water handling. The frequency of concentration ability defect in our study (28.6% in P1 and 21.7% in P2) was much lower than that described previously in pediatric patients with\u0026nbsp;polycystic kidney disease. Moreover, in our cases urinary volume was only increased in\u0026nbsp;one patient in the first period, showing no alterations in the last evaluation. In our clinical experience we have observed that most children and adolescents with ADPKD do not have usually an excessive appetite for water consumption. Note in this regard that the mean urinary volume of our patients was even lower than that of healthy children and adults.\u003c/p\u003e\n\u003cp\u003eThe hypothesis formulated by some authors that the influence of increased plasma vasopressin levels as a compensatory response to supposed periods of hypohydration\u0026nbsp;secondary to polyuria, which would play a preponderant role in the progression of the disease [7,27,28], is difficult to assume, at least in early stages. This would be valid in the absence of a real availability to achieve an appropriate and continuous supply in the usual fluid intake, but this is not the case in most environments. The polyuria that is eventually observed in ADPKD would not be very marked except in more advanced stages of the disease. For example, in the paper by Gabow et al. the urine volume in adult subjects with ADPKD was 1.97 ± 0.08 liters/day and the maximum UOms was only slightly below normal (680 ± 14 mOsm/kg) [25]. Likewise, in one of the papers signed by Zittema et al. urine volume was 2 ± 0.65 liters/day and vasopressin levels were 1.34 (0.25-3.07) pg/ml, with no statistically significant differences in relation to those of the controls [0.87 (0.28-2.38) pg/ml]. In the test consisting of a fluid deprivation, no differences were observed in vasopressin levels and very discrete differences in copeptin levels (p= 0.04) [27].\u003c/p\u003e\n\u003cp\u003eIn summary, in any patient with eGFR \u0026lt;70 ml/min/1.73 m\u003csup\u003e2\u003c/sup\u003e there is a defect in concentrating ability and, consequently, copeptin levels should be increased. This assertion has been proven in several articles in which patients with CKD were included, in the sense that high copeptin levels are associated with the development and the progression of CKD [37,38]. Therefore, the explanation for the efficacy of tolvaptan in adult patients and experimental animals with ADPKD [39-41] must be different from that formulated so far, since the defect in the ability to concentrate in this disease is not very noticeable except in advanced stages of the disease. In a review on the subject, Chebib et al. summarized that the cause of this concentrating defect has not been fully elucidated [42]. We believe that an alternative explanation could be the existence of a high density in the number of V2R receptors located in the basolateral membrane of the collecting tubule cells. In this case, in ADPKD patients the functional capacity of vasopressin-V2R complexes would be increased with the negative consequences in cyst growth and on disease progression. In addition, an increase in the expression of V2R messenger RNA has been described in murine models of polycystic kidney disease [43]. It could be hypothesized that the existence of mutations in PKD1 in the cilia of the collecting tubule and the ineffective action of the V2R receptors present in these cilia [44] would lead to a compensatory increase in V2R synthesis on the basolateral side of the collecting tubule cells. This increase in V2R density would explain our observation in clinical experience that most children and adolescents with ADPKD do not tend to have an excessive appetite for water consumption and that the mean urine volume of our patients was even lower than that of healthy children.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe efficacy of tolvaptan in pediatric patients has not been well established [45]. Recently, a paper dedicated to establishing the characteristics necessary to determine the risk of rapid disease progression in children has been published [46]. In 2023, the first data from a randomized, double-blind, clinical trial involving 91 controlled patients at 20 pediatric nephrology centers were published. Tolvaptan showed a reduction in UOsm compared to placebo. The authors concluded that the effects on urinary volume increase were manageable, with few discontinuations, although it is too soon to know whether the drug is useful in the long-term progression of the disease [47].\u003c/p\u003e\n\u003cp\u003eIn conclusion, in our series of patients the mean V/GFR values in both periods were slightly lower than the mean normal values for age and the alterations in UOsm were scarce and of little entity, especially at the end of the follow-up period. Consequently, excessive renal growth in ADPKD in the first two decades of life does not seem to be directly influenced by vasopressin since there are no obvious pathophysiological reasons for its release to be stimulated, so the explanation of the efficacy of tolvaptan in ADPKD should be reassessed.\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eConflict of interest\u003c/strong\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDevuyst O, Ahn C, Barten TRM, Brosnahan G, Cadnapaphornchai MA, Chapman AB et al (2025) KDIGO 2025 clinical practice guideline for the evaluation, management, and treatment of autosomal dominant polycystic kidney disease (ADPKD). 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Clin J Am Soc Nephrol 18:36\u0026ndash;46. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2215/CJN.0000000000000022\u003c/span\u003e\u003cspan address=\"10.2215/CJN.0000000000000022\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eRenal longitudinal diameters and their z-values in periods P1 and P2.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 207px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFirst ultrasound\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLast ultrasound\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 207px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLongitudinal diameter of the left kidney (cm)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e9.6 \u0026plusmn; 1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e12.0 \u0026plusmn; 1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 207px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLongitudinal diameter of the left kidney (z-value)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e1.3 \u0026plusmn; 1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e2.5 \u0026plusmn; 2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 207px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLongitudinal diameter of the right kidney (cm)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e9.4 \u0026plusmn; 1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e12.0 \u0026plusmn; 2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 207px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLongitudinal diameter of the right kidney (z-value)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.9 \u0026plusmn; 1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e2.5 \u0026plusmn; 2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. \u0026nbsp;Maximum UOsm, V/GFR, eGFR and albuminuria values at both time points of the study.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMaximum UOsm (mOsm/Kg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e908.7 \u0026plusmn; 199.3\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n= 23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003e964.8 \u0026plusmn; 137.8\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n= 23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eV/GFR (ml/100 ml GFR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e0.48 \u0026plusmn; 0.23\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n= 31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003e0.47 \u0026plusmn; 0.17\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n= 31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eeGFR Bedside Schwartz (ml/min/1,73 m\u003csup\u003e2\u003c/sup\u003e)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e143.4 \u0026plusmn; 53.1\u003c/p\u003e\n \u003cp\u003e(n= 28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003e101.5 \u0026plusmn; 20.9\u003c/p\u003e\n \u003cp\u003e(n= 28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eeGFR EFKC Cr (ml/min/1,73 m\u003csup\u003e2\u003c/sup\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e106. \u0026plusmn; 9.4\u003c/p\u003e\n \u003cp\u003e(n= 26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003e102.2 \u0026plusmn; 12.7\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n= 26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUrine albumin/creatinine (mg/g)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e32.7 \u0026plusmn; 67.3\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n= 29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003e15.9 \u0026plusmn; 3.3\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n= 29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCr: creatinine. eGFR: estimated glomerular filtration rate. EKFC: European Kidney Function Consortium. ns: not significant. Uosm: urinary osmolality. V/GFR: urinary volume corrected by 100 ml GFR.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Autosomal dominant polycystic kidney disease, Urinary volume, Maximum urinary osmolality, Renal water handling","lastPublishedDoi":"10.21203/rs.3.rs-9294920/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9294920/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePrevious publications in children with autosomal dominant polycystic kidney disease (ADPKD) have described that there is an alteration of renal water handling in a large percentage of cases, with a striking reduction in maximum urinary osmolality (UOsm). The aim of the present work is to analyze this kidney function in children and adolescents with ADPKD and describe the evolution at two points of their disease.\u003c/p\u003e\u003ch2\u003ePatients and methods\u003c/h2\u003e \u003cp\u003eWe included 31 patients (15 man, 16 woman) with bilateral renal cysts and a family history of ADPKD, who had, at least, their urinary volume (V/GFR) quantified and a renal ultrasound performed both in the first period (P1; age 8.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8 years) and in the second (P2; age 16.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7 years). UOsm was determined after desmopressin stimulation and GFR was estimated (eGFR) using creatinine-based equations.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSignificant differences were observed in the the longitudinal diameter of both kidneys at P2 compared to P1. No differences were observed in UOsm, eGFR, V/GFR and albuminuria between both periods. UOsm was reduced in 8/28 cases at P1 and in 5/23 cases at P2. Furthermore, V/GFR values were slightly lower than the mean values normal for age.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn our series the alterations in UOsm were scarce and of little entity. Excessive kidney growth in ADPKD in the first two decades of life does not seem to be directly influenced by vasopressin since there are no evident pathophysiological reasons for its stimulation.\u003c/p\u003e","manuscriptTitle":"Renal water handling at early stages of autosomal dominant polycystic kidney disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-16 20:36:07","doi":"10.21203/rs.3.rs-9294920/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revisions Needed","date":"2026-05-02T10:33:36+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2026-04-08T13:11:14+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-08T12:46:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-07T22:32:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Nephrology","date":"2026-04-01T13:41:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"996ff5bf-8720-48c4-966f-9e6fd0696dc6","owner":[],"postedDate":"April 16th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Major Revisions Needed","date":"2026-05-02T10:33:36+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-02T14:34:05+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-16 20:36:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9294920","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9294920","identity":"rs-9294920","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}