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Diagnosing Nocturnal Polyuria from a Single Nocturnal Urine Sample
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available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Voiding Dysfunction
Diagnosing Nocturnal Polyuria from a Single Nocturnal Urine Sample Thomas F. Monaghan a,*, Joseph G. Verbalis b, Rebecca Haddad c,d, Kim Pauwaert c, Christina W. Agudelo a, An-Sofie Goessaert c, Marie-Astrid Denys c, Jason M. Lazar e, Donald L. Bliwise f, Johan Vande Walle g, Alan J. Wein h, Jeffrey P. Weiss a, Karel Everaert c a
Department of Urology, State University of New York Downstate Health Sciences University, Brooklyn, NY, USA; b Division of Endocrinology and Metabolism,
Department of Medicine, Georgetown University Medical Center, Washington, DC, USA; c Department of Urology, Ghent University Hospital, Ghent, Belgium; d
Sorbonne Université, UPMC Univ Paris 06, AP-HP, GRC 01, Groupe de Recherche Clinique en Neuro-Urologie (GREEN), Service de Rééducation Neurologique,
AP-HP, Hôpitaux Universitaires Est Parisien, Paris, France; e Division of Cardiovascular Medicine, Department of Medicine, SUNY Downstate Health Sciences University, Brooklyn, NY, USA; f Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA; g Department of Pediatric Nephrology, Ghent University Hospital, Ghent, Belgium; h Department of Urology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Article info Associate Editor: Malte Rieken
Keywords: Adherence Conductivity Nocturia Nocturnal polyuria Osmolality Volume
Abstract Background: Patients with nocturnal polyuria (NP) experience a unique surge in nocturnal diuresis rate during the early hours of sleep. Objective: To determine the diagnostic utility of the volume and osmolality of a single early nocturnal urine sample in detecting NP. Design, setting, and participants: Analysis of 1 AM urine samples obtained from two prospective observational studies at Ghent University Hospital involving participants recruited from a urology ambulatory care unit and those who consulted a continence clinic. Nocturic participants (one or more nocturnal void[s]; n = 176) were stratified based on the presence (n = 87) or absence (n = 89) of NP (>90 ml/h). Outcome measurements and statistical analysis: Receiver operating characteristic curves with Youden’s Index were used to determine cutoff values for urine volume and urine osmolality (Uosm). Results and limitations: Individuals with NP demonstrated higher 1 AM volume (400 [interquartile range 300–515] vs 210 [160–300] ml, area under the curve [AUC] = 0.843, p < 0.001, cutoff = 350 ml) and lower Uosm (274 [201–348] vs 430 [320–664] mOsm/kg H2O, AUC = 0.774, p < 0.001, cutoff = 314 mOsm/kg H2O) than those without NP. In combining cutoffs, the criteria of either 1 AM volume 350 ml or Uosm 314 mOsm/kg H2O were 85% sensitive and 75% specific for NP, while criteria of both 1 AM volume 350 ml and Uosm 314 mOsm/kg H2O were 60% sensitive and 92% specific for NP. Comparable AUC values, sensitivities, and specificities were observed in both men and women. Limitations include post hoc design and a relatively small study sample. Conclusions: Individuals with NP are more likely than those without NP to produce a higher volume of more dilute urine (ie, “aquaresis”) in the early hours of sleep. Analysis of easily measurable parameters of the first nocturnal void (for which 1 AM values serve as a surrogate) in men and women with nocturia can predict a diagnosis of NP with a reasonably high degree of sensitivity and specificity.
* Corresponding author. Department of Urology, SUNY Downstate Health Sciences University, 450 Clarkson Avenue, Box 79, Brooklyn, NY 11203, USA. Tel.: +1 (518) 729-0070. E-mail address: [email protected] (T.F. Monaghan).
https://doi.org/10.1016/j.euf.2019.10.002 2405-4569/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Monaghan TF, et al. Diagnosing Nocturnal Polyuria from a Single Nocturnal Urine Sample. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.10.002
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Patient summary: Urologists often try to understand the specific reason why people wake up to urinate at night by asking them to record the amount of urine they make every time they go to the bathroom (also known as a “voiding diary”) during the nighttime as well as the daytime—typically for a total of 1–3 days. In this study, we showed that an analysis of the composition of the urine that people produce when they first wake up to urinate at night might be sufficient to determine whether their symptoms are caused by excessive urine production or something else, and some people might find this urine study easier than keeping a voiding diary. © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
1.
2.2.
Introduction
The voiding diary is a gold standard in the evaluation and management of nocturia [1]. However, as evidenced by the fact that only 55% of patients with documented nocturnal polyuria (NP)—thought to be the most common overall cause of nocturia [2]—are diagnosed using a voiding diary [3], many patients find the diary to be cumbersome, and adherence to voiding diaries is a pervasive obstacle in the clinical setting [4]. Notably, while the voiding dairy requires a careful record of the timing and volume of every micturition over the duration of the diary (which, depending on provider preference, is typically 24–72 h), the early hours of sleep appear to be particularly central to the pathogenesis of NP. Recently, individuals with NP have been shown to demonstrate significantly higher free water clearance and lower urine osmolality (Uosm) than those without NP [5]. Moreover, among patients with nocturia owing to NP and no identifiable contributory comorbidities, there was a notable surge in nocturnal diuresis rate before the time of first awakening, such that early nocturnal urine production (NUP) disproportionately contributes to the total nocturnal urine volume [6]. The present analysis expanded this work by examining the extent to which early nocturnal urine samples, obtained at the time of first nocturnal awakening in patients with nocturia, may represent a rational substitute to voiding diaries for diagnosing nocturia owing to NP. Specifically, the primary aim of this study was to test the hypothesis that individuals with nocturia owing to NP will produce a greater volume of more dilute urine in the early nocturnal period. Secondarily, this study aimed to determine the sensitivity and specificity of the volume and Uosm of a single early nocturnal urine sample in diagnosing NP in a population of individuals with nocturia. 2.
Participants and methods
2.1.
Study design
The present study is a post hoc analysis of 1
AM
urine samples obtained
from two prospective observational studies conducted at Ghent University Hospital from 2011 to 2016. Ethical approval was obtained from the Ghent University Hospital ethics committee (EC/2011/565; EC/ 2013/950), and all participants provided written informed consent in accordance with the Declaration of Helsinki.
Participants
The first protocol enrolled individuals (n = 135) recruited by the urology ambulatory care unit [5]. The second protocol (n = 95) recruited individuals aged 65 yr who consulted the continence clinic [7]. Baseline nocturia was not a prerequisite for inclusion in either protocol.
2.3.
Test methods
For both protocols, participants completed 24–72-h voiding diaries, and subsequently collected urine samples at 3-h intervals (Q3H) for 24 h. The participants also provided a blood sample upon completion of the Q3H urine sampling. For the urine samples, the participants were instructed to void at fixed 3-h intervals and record the accompanying voided volumes. In total, five daytime (10
AM,
1
PM,
4
PM,
7
PM,
and 10
PM)
and
three nighttime (1 AM, 4 AM, and 7 AM) samples were obtained, and voided volumes for interim micturitions were also recorded. Uosm was determined by freezing point depression in an Osmo Station OM6050 osmometer (Menarini Diagnostics Benelux, Machelen, Belgium). Fluid intake was not regulated in either protocol. The methods of both aforementioned studies have previously been described elsewhere in detail [5,7]. The
inclusion
and
exclusion
criteria
are
outlined
in
Figure 1. Nocturia was defined as one or more nocturnal void(s) on voiding diary analysis. Individuals were excluded if they did not report nocturia on the voiding diary or if Q3H urine sampling data were absent/incomplete. Included participants were stratified based on the presence or absence of NP from the Q3H urine collection using a cutoff of NUP > 90 ml/h (voided volume + incontinence weight), as this criterion is more robust than commonly used proportion-based (ie, nocturnal volume/24-h volume >0.33) cutoffs [8].
2.4.
Analysis
The easyROC web tool was utilized to create receiver operating characteristic curves, determine the area under the curve (AUC) for 1 AM urine volume and Uosm between participants with (cases) and without (reference group) NP [9], and employ Youden’s Index to establish optimal cut points [9,10]. This analysis was repeated separately in men and women to explore potential sex differences.
3.
Results
3.1.
Participants
A total of 176 individuals were included for analysis, of whom 87 met the criteria for NP and 89 fell below this threshold (Table 1). Body mass index was higher in all participants with NP (p < 0.001) and women with NP (p < 0.001) compared with their counterparts who fell
Please cite this article in press as: Monaghan TF, et al. Diagnosing Nocturnal Polyuria from a Single Nocturnal Urine Sample. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.10.002
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Database characteristics:
Participants completing 24-72-h voiding diaries derived from either of two sources: 1) Patients recruited from urology ambulatory care unit 2) Patients ≥65 yr consulting the continence clinic Total database entries (n = 230)
Excluded (n = 53) - Zero nocturnal voids on voiding diary (n = 53) - Incomplete/absent data (n = 0)
Baseline nocturia ( ≥1 nocturnal voids on voiding diary) (n = 177) Excluded (n=1)
Complete Q3H urine sampling data 1) 1 AM urine osmolality 2) 1AM urine volume 3) Nocturnal urine production rate (ml/h)
- Missing 1AM urine osmolality (n = 1) - Missing 1AM urine volume (n = 0) - Missing nocturnal urine production (n = 0)
(n=176)
Nocturnal polyuria (Nocturnal urine production >90ml/h on Q3H urine sampling)
No nocturnal polyuria (Nocturnal urine production <90 ml/h on Q3H urine sampling)
(n = 87)
(n = 89)
Fig. 1 – Flow chart of enrollment characteristics. Q3H = 3-h interval.
below the threshold for NP. No significant differences were observed in participant age by NP status. 3.2.
Test results
In accordance with the predefined cutoff for NP, individuals with NP demonstrated significantly greater NUP versus those without NP. Among participants with NP, urine volume was higher (400 [interquartile range 300–515] vs 210 [160–300] ml, p < 0.001) and Uosm was lower (274 [201–348] vs 430 [320–664] mOsm/kg H2O, p < 0.001) compared with those without NP. The 24-h urine productionwas significantly greater in the NP cohort for all participants (p < 0.001), men (p < 0.001), and women (p = 0.001). For 1 AM urine volume, the AUC was 0.843 (p < 0.001), with highest sensitivity (69%) and specificity (91%) at 350 ml (Fig. 2). For 1 AM Uosm, the AUC was 0.774 (p < 0.001), with the highest sensitivity (72%) and specificity (76%) at 314 mOsm/kg H2O. Combining these two cutoffs, criteria of either 1 AM volume 350 ml or Uosm 314 mOsm/ kg H2O resulted in 85% sensitivity and 75% specificity for NP, while criteria of both 1 AM volume 350 ml and Uosm 314 mOsm/kg H2O resulted in 60% sensitivity and 92% specificity for NP. By sex, comparable AUC values, sensitivities, and specificities were observed in both men and women (Fig. 1). For men, combining the optimal cutoffs (350 ml
and 370 mOsm/kg H2O) resulted in “either/or” sensitivity of 80% and specificity of 79%, and “both/and” sensitivity of 60% and specificity of 96% for NP. For women, combining the optimal cutoffs (320 ml and 309 mOsm/kg H2O) resulted in “either/or” sensitivity of 90% and specificity of 68%, and “both/and” sensitivity of 65% and specificity of 89% for NP.
4.
Discussion
Individuals with NP are more likely than those without NP to produce a higher volume of more dilute urine in the early hours of sleep. This finding is consistent with our own previous work, in which we demonstrated that participants with NP (with or without nocturia) experience higher 1 AM free water clearance and lower 1 AM Uosm than individuals without NP [5], and that patients with idiopathic NP demonstrate a unique surge in nocturnal diuresis rate during the early hours of sleep [6]. The results of the present study are novel because they are, to our knowledge, the first to demonstrate that analysis of easily measurable urinary parameters of the first nocturnal void (for which 1 AM values serve as a surrogate) in participants with nocturia can predict a diagnosis of NP with a reasonably high degree of sensitivity and specificity. These findings have sizable clinical implications because of recent advances in urinalysis, which have enabled
Please cite this article in press as: Monaghan TF, et al. Diagnosing Nocturnal Polyuria from a Single Nocturnal Urine Sample. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.10.002
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0.2
0.4
0.6
0.8
0.8 0.4
NP (n = 87) = 274 No NP (n = 89) = 430 AUC = 0.774, p < 0.001 Optimal cutoff = 314 Sensitivity = 0.72 Specificity = 0.76
0.0
0.4 0.0
Sensitivity
0.8
1 AM urine osmolality
NP (n = 87) = 400 No NP (n = 89) = 200 AUC = 0.843, p < 0.001 Optimal cutoff = 350 Sensitivity = 0.69 Specificity = 0.91
0.0
Sensitivity
All participants
1 AM urine volume
1.0
0.0
0.2
0.2
0.4
0.6
0.8
0.2
0.6
0.8
1–specificity
1.0
0.6
0.8
1.0
0.8 0.4
NP (n = 52) = 247 No NP (n = 65) = 409 AUC = 0.794, p < 0.001 Optimal cutoff = 309 Sensitivity = 0.81 Specificity = 0.72
0.0
Sensitivity
0.8 0.4
Sensitivity
Women
0.0
0.4
0.4
1–specificity
NP (n = 52) = 400 No NP (n = 65) = 200 AUC = 0.840, p < 0.001 Optimal cutoff = 320 Sensitivity = 0.75 Specificity = 0.85
0.2
1.0
0.8 0.4 0.0
1.0
1–specificity
0.0
0.8
NP (n = 35) = 302 No NP (n = 24) = 636 AUC = 0.810, p < 0.001 Optimal cutoff = 370 Sensitivity = 0.71 Specificity = 0.79
0.0
Sensitivity
0.8 0.4 0.0
0.6
1–specificity
NP (n = 35) = 430 No NP (n = 24) = 205 AUC = 0.843, p < 0.001 Optimal cutoff = 350 Sensitivity = 0.69 Specificity = 0.96
0.0
Sensitivity
Men
1–specificity
0.4
0.0
0.2
0.4
0.6
0.8
1.0
1–specificity
Fig. 2 – NP defined as nocturnal urine production of >90 ml/h. Youden’s Index was used to determine cutoff values for 1 AM urine volume and Uosm between participants with (cases) and without (reference group) NP [9,10]. Urine volume is expressed in milliliters and urine osmolality in mOsm/kg H2O. AUC = area under the curve; NP = nocturnal polyuria; Uosm = urine osmolality.
clinicians to reliably estimate Uosm—a gold standard parameter for quantifying urine production [11,12]—using widely available laboratory techniques. Historically, measurement of Uosm utilized the freezing point depression method, which is a time-consuming technique that is not readily available to most physicians. Recently, Oyaert et al [13] compared measured osmolality (using the freezing-point depression technique) with a conductivity-based estimate of osmolality (using a routine
flow cytometry urine sediment analyzer) and determined that conductivity allows for a rough estimation of measured osmolality. Moreover, Oyaert and colleagues [13] were able to construct and validate a strong (r2 = 0.895) conductivitybased osmolality predication model by incorporating only parameters (specific gravity and creatinine) that are available on a standard commercial urine test strip. In contrast to osmometers, conductivity meters can be incorporated into modern urine analyzers. In fact, conductivity meters are
Please cite this article in press as: Monaghan TF, et al. Diagnosing Nocturnal Polyuria from a Single Nocturnal Urine Sample. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.10.002
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BMI = body mass index; NP = nocturnal polyuria; Q3H = every 3 h. Data of 24–72-h voiding diary, which were used to determine the presence of nocturia/number of nocturnal voids, were collected prior to the Q3H 24-h urine collection, which was used to stratify participants by NP status and analyze the 1 AM measurements reported in this table. Data are presented as median (interquartile range). Of the included participants, one value was missing for BMI and four values were missing for 24-h urine production. * Statistical significance.
<0.001* <0.001* <0.001* 0.001* 200 (150–300) 409 (285–579) 63 (52–75) 27.9 (22.8–35.1) 400 (315–500) 247 (175–296) 110 (100–136) 35.1 (28.7–42.4) <0.001* <0.001* <0.001* <0.001* 430 (300–564) 302 (257–409) 114 (103–145) 31.9 (26.4–40.0) 210 (160–300) 430 (320–664) 64 (52–75) 26.9 (20.2–33.8) 400 (300–515) 274 (201–348) 112 (100–140) 33.6 (27.2–42.1)
<0.001* <0.001* <0.001* <0.001*
205 (180–285) 636 (392–756) 67 (56–79) 22.1 (17.8–27.1)
0.714 2 (1–2) 2 (1–2) 0.446 2 (1–2.3) 2 (1–3) 2 (1–2) 2 (1–2.5)
0.662
0.232 <0.001* 69 (51–77) 24.0 (21.6–26.3) 71 (67–76) 27.1 (24.8–31.4) 0.192 0.552 67 (59–72) 26.2 (23.7–27.5) 68 (64–76) 25.1 (24.3–29.6) 0.100 <0.001* 69 (66–76) 24.4 (22.3–27.1) 69 (55–75) 26.6 (24.5–30.6)
Demographics Age (yr) BMI (kg/m2) 24–72-h voiding diary Number of nighttime voids Q3H urine sampling 1 AM urine volume (ml) 1 AM urine osmolality (mOsm/kg H2O) Nocturnal urine production (ml/h) 24-h urine production (ml/kg/h)
No NP (n = 65) No NP (n = 24) p Value No NP (n = 89) NP (n = 87)
All participants
Table 1 – Demographic data and voiding diary results by nocturnal polyuria status.
NP (n = 35)
Men
p Value
NP (n = 52)
Women
p Value
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5
increasingly flexible and inexpensive, and measurements could reasonably be performed by nocturic patients using a portable bedside sensor (along with a urine dipstick and volume measurement). Nocturia is a complex and often multifactorial condition, but experts agree that voiding diaries are a standard of care in the initial clinical assessment of bothersome nocturia, irrespective of the suspected causality [1]. However, in a representative multinational cross-sectional study of practice trends, Oelke et al [3] recognized that 45% of documented NP diagnoses are made without the use of a diary. Notably, voiding diary results are critical in delineating between underlying mechanisms of nocturia, and are thus used to support individualized lifestyle and/or pharmacologic treatment plans [1]. Consistently, in patients with nocturia, Oelke and colleagues [3] also reported a substantial time lapse from diagnosis to the initiation of first therapy (lifestyle advice and behavioral therapy included) among both men and women, ranging from 27 to 41 wks. Nonadherent patients offer a wide array of reasons for failing to complete a voiding diary, including a lack of understanding of the benefits or instructions, the time commitment required to complete the diary, interference with their work/daily routine, and forgetfulness [4]. In recent years, several changes have been proposed to the nocturia treatment algorithm in order to make it more patient centered, which we would expect to improve patient adherence to voiding diaries. Notable initiatives have included analyses of nocturnal-only voiding diaries [14], validation of user-friendly electronic voiding diary applications [15,16], and new, resource-conscientious practice patterns centering on electronic diaries and remote office visits [17]. Beyond these recent efforts, it stands to reason that greater attention to the diagnostic utility of single-void nocturnal urine samples may contribute to a treatment paradigm for nocturia, which further reduces patient burden and, in turn, improves adherence to diagnosis and management. Beyond the diagnostic utility of Uosm and urine volume in delineating nocturic patients by NP status, our finding of a higher volume of more dilute urine (ie, “aquaresis”) in the early sleep period among individuals with NP is consistent with the reduced diurnal variation in plasma arginine vasopressin (AVP) levels found in some studies of nocturnal enuresis [18] and nocturia [19]. This is particularly relevant in view of the fact that the treatment of nocturia is rapidly evolving, with multiple formulations of synthetic AVP now approved in several countries for patients with nocturia owing to NP. Desmopressin is a synthetic analog of AVP, which is produced by the posterior pituitary gland and acts primarily on the collecting duct of the renal inner medulla to increase trafficking of aquaporin-2 integral membrane proteins to the apical plasma membrane to reduce free water diuresis [20]. As such, the role of antidiuretic therapy in alleviating NP severity is mediated, in large part, by a decrease in NUP [21]. Moreover, given the short half-life of current formulations of desmopressin
Please cite this article in press as: Monaghan TF, et al. Diagnosing Nocturnal Polyuria from a Single Nocturnal Urine Sample. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.10.002
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[22], it stands to reason that antidiuretic therapy predominantly exerts its effect on NUP during the early hours of sleep. Accordingly, the significantly greater 1 AM aquaresis observed among patients with NP is consistent with both the pharmacokinetics and the pharmacodynamics of short-acting antidiuretic therapy taken at bedtime for the treatment of NP. Future research is warranted to determine whether the volume and Uosm of the first nocturnal void can predict response to antidiuretic replacement therapy, particularly in view of differential responses to antidiuretics as a function of age and gender, and the fact that rebound diuresis in older women (who constitute the majority of the present cohort) may be considerably delayed. The present study is subject to the inherent limitations of a single-institution analysis with a limited number of participants. Moreover, this was a convenience sample, and we had no information about their sleep patterns at the time the data were collected. Owing to this, first nocturnal voided samples collected after the patients initially went to sleep, as would be obtained in clinical practice, could not be analyzed. Fixed 1 AM urine samples, as were available from both protocols, are only a proxy for early NUP as well as for the first uninterrupted sleep period. Sleep was interrupted as per the investigational procedure for Q3H urine sampling, which may have interfered with normal nocturnal blood pressure trajectories, such that the study protocol itself could have given rise to NP. While voiding diaries more closely approximate nocturnal voiding patterns as compared with Q3H urine sampling, documentation of nocturnal voiding was not a prerequisite for either protocol, so nocturia duration and severity could not be assessed. Additionally, comorbidities including obstructive sleep apnea, diabetes mellitus, and nondipping hypertension, as well as medication usage and timing, were not taken into account. Although combined criteria of either 1 AM volume 350 ml or Uosm 314 mOsm/kg H2O resulted in 85% sensitivity for NP, criteria of both 1 AM volume 350 ml and Uosm 314 mOsm/kg H2O resulted in sensitivity of only 60%, and the sensitivity was likewise relatively low using individual optimal cutoffs for both 1 AM urine volume (69%) and 1 AM Uosm (72%). At present, more than 15 definitions have been proposed for NP [23], and these results may not necessarily extend to other NP definitions—particularly the proportion-based criteria (ie, nocturnal volume/24-h volume >0.33), which are markedly less discriminatory for NP at the population level [8]. Larger study samples with well-defined NP patient subgroups are required to evaluate the effect of these factors, and to establish reproducible cutoff values for first nocturnal voided volume and Uosm by NP status. The findings of this study necessitate future translational research involving Uosm analysis, as well as the development of more sophisticated medical devices for in-home conductivity monitoring, as these measures would promote more patient-centered practice patterns and allow the urology community to refine and perhaps simplify its current diagnostic algorithm for nocturia.
5.
Conclusions
In the appropriate clinical context, analysis of a single urine sample produced at the time of first nocturnal awakening could facilitate the detection of nocturia owing to NP, and may also provide a means of predicting response or monitoring treatment with antidiuretic replacement therapy.
Author contributions: Thomas F. Monaghan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Monaghan, Verbalis, Haddad, Agudelo, Lazar, Bliwise, Weiss, Everaert. Acquisition of data: Goessaert, Denys. Analysis and interpretation of data: Monaghan, Verbalis, Agudelo, Lazar, Bliwise, Weiss, Everaert. Drafting of the manuscript: Monaghan. Critical revision of the manuscript for important intellectual content: Monaghan, Verbalis, Haddad, Pauwaert, Agudelo, Goessaert, Denys, Lazar, Bliwise, Vande Walle, Wein, Weiss, Everaert. Statistical analysis: Monaghan. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Verbalis, Lazar, Bliwise, Vande Walle, Wein, Weiss, Everaert. Other: None.
Financial disclosures: Thomas F. Monaghan certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Thomas F. Monaghan has no direct or indirect commercial incentive associated with publishing this article. Dr. Verbalis is a consultant for Ferring and has served on the Ferring Desmopressin Safety Board. Dr. Haddad reports grants from Fonds de dotation Renaitre and from Société Interdisciplinaire Francophone d’UroDynamique et de Pelvi Périnéologie, during the conduct of the study; personal fees and nonfinancial support from Astellas; personal fees from MedDay Pharmaceuticals and Novartis Pharma SAS; nonfinancial support from Dentsply Sirona France, Pierre Fabre Medicament, Allergan France, Bayer HealthCare, SAS and Vifor France SA, outside the submitted work. Dr. Pauwaert has received research grants from Ferring. Dr. Goessaert reports institutional grants from Allergan, Astellas, and Ferring, outside the submitted work. Dr. Denys reports institutional grants from Allergan, Astellas, and Ferring, outside the submitted work. Dr. Bliwise has served as a consultant for Merck, Jazz, Ferring, Eisai, and Respicardia, and a speaker for Merck during the last 3 yr, outside the submitted work. Johan Vande Walle reports institutional grants from Allergan, Astellas, and Ferring, and is a consultant and lecturer for Ferring and Astellas, outside the submitted work. Dr. Wein has served as an advisor/consultant for Avadel, GTX, Acquinox, Urovant, Medtronic, and Serenity during the last 3 yr, outside the submitted work. Dr. Weiss is a consultant for Ferring and the Institute for Bladder and Prostate Research, outside the submitted work. Dr. Everaert is a consultant and lecturer for Medtronic and Ferring, and reports institutional grants from Allergan, Ferring, Astellas, and Medtronic, outside the submitted work. The remaining authors have nothing to disclose.
Funding/Support and role of the sponsor: None.
Please cite this article in press as: Monaghan TF, et al. Diagnosing Nocturnal Polyuria from a Single Nocturnal Urine Sample. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.10.002
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[5] Goessaert AS, Krott L, Hoebeke P, Walle JV, Everaert K. Diagnosing
new paradigm for outpatient diagnosis and treatment of lower
the pathophysiologic mechanisms of nocturnal polyuria. Eur Urol
urinary tract symptoms utilizing a mobile app/software platform
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and remote patient visits: feasibility study. S30 (pelvic floor muscle
[6] Monaghan TF, Suss NR, Epstein MR, et al. Differential nocturnal diuresis rates among patients with and without nocturnal polyuria syndrome. Eur Urol Focus. In press. https://doi.org/10.1016/j.euf. 2018.10.015. [7] Denys MA, Decalf V, Kumps C, Petrovic M, Goessaert AS, Everaert K.
assessment and treatment), 9/6/2019. https://www.ics.org/2019/ abstract/550. [18] Rittig S, Knudsen UB, Nørgaard JP, Pedersen EB, Djurhuus JC. Abnormal diurnal rhythm of plasma vasopressin and urinary output in patients with enuresis. Am J Physiol 1989;256:F664–71.
Pathophysiology of nocturnal lower urinary tract symptoms in
[19] Hvistendahl GM, Frøkiaer J, Nielsen S, Djurhuus JC. Gender differ-
older patients with urinary incontinence. Int J Urol 2017;24:808–15.
ences in nighttime plasma arginine vasopressin and delayed com-
[8] van Doorn B, Blanker MH, Kok ET, Westers P, Bosch JL. Prevalence,
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incidence, and resolution of nocturnal polyuria in a longitudinal community-based study in older men: the Krimpen study. Eur Urol 2013;63:542–7. [9] Goksuluk D, Korkmaz S, Zararsiz G, Karaagaoglu AE. easyROC: an interactive web-tool for ROC curve analysis using R language environment. R J 2016;8:213–30. [10] Lopez-Raton M, Rodriguez-Alvarez MX, Suarez CC, Sampedro FG. OptimalCutpoints: an R package for selecting optimal cutpoints in diagnostic tests. J Stat Softw 2014;61:1–36. [11] European Confederation of Laboratory Medicine. European urinalysis guidelines. Scand J Clin Lab Invest Suppl 2000;60:1–96. [12] Delanghe J, Speeckaert M. Preanalytics in urinalysis. Clin Biochem 2016;49:1346–50.
sin. J Urol 2007;178:2671–6. [20] Inoue T, Terris J, Ecelbarger CA, Chou CL, Nielsen S, Knepper MA. Vasopressin regulates apical targeting of aquaporin-2 but not of UT1 urea transporter in renal collecting duct. Am J Physiol 1999;276 (4 Pt 2):F559–66. [21] Asplund R, Sundberg B, Bengtsson P. Desmopressin for the treatment of nocturnal polyuria in the elderly: a dose titration study. Br J Urol 1998;82:642–6. [22] U.S. Food and Drug Administration. Summary review Noctiva. Reference ID 4064111. www.accessdata.fda.gov/drugsatfda_docs/ summary_review/2017/201656orig1s000sumr.pdf. [23] Madersbacher S, Cornu JN. Nocturnal polyuria: it’s all about definition, and be patient! Eur Urol 2013;63:548–50.
Please cite this article in press as: Monaghan TF, et al. Diagnosing Nocturnal Polyuria from a Single Nocturnal Urine Sample. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.10.002
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Voiding Dysfunction
Diagnosing Nocturnal Polyuria from a Single Nocturnal Urine Sample Thomas F. Monaghan a,*, Joseph G. Verbalis b, Rebecca Haddad c,d, Kim Pauwaert c, Christina W. Agudelo a, An-Sofie Goessaert c, Marie-Astrid Denys c, Jason M. Lazar e, Donald L. Bliwise f, Johan Vande Walle g, Alan J. Wein h, Jeffrey P. Weiss a, Karel Everaert c a
Department of Urology, State University of New York Downstate Health Sciences University, Brooklyn, NY, USA; b Division of Endocrinology and Metabolism,
Department of Medicine, Georgetown University Medical Center, Washington, DC, USA; c Department of Urology, Ghent University Hospital, Ghent, Belgium; d
Sorbonne Université, UPMC Univ Paris 06, AP-HP, GRC 01, Groupe de Recherche Clinique en Neuro-Urologie (GREEN), Service de Rééducation Neurologique,
AP-HP, Hôpitaux Universitaires Est Parisien, Paris, France; e Division of Cardiovascular Medicine, Department of Medicine, SUNY Downstate Health Sciences University, Brooklyn, NY, USA; f Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA; g Department of Pediatric Nephrology, Ghent University Hospital, Ghent, Belgium; h Department of Urology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Article info Associate Editor: Malte Rieken
Keywords: Adherence Conductivity Nocturia Nocturnal polyuria Osmolality Volume
Abstract Background: Patients with nocturnal polyuria (NP) experience a unique surge in nocturnal diuresis rate during the early hours of sleep. Objective: To determine the diagnostic utility of the volume and osmolality of a single early nocturnal urine sample in detecting NP. Design, setting, and participants: Analysis of 1 AM urine samples obtained from two prospective observational studies at Ghent University Hospital involving participants recruited from a urology ambulatory care unit and those who consulted a continence clinic. Nocturic participants (one or more nocturnal void[s]; n = 176) were stratified based on the presence (n = 87) or absence (n = 89) of NP (>90 ml/h). Outcome measurements and statistical analysis: Receiver operating characteristic curves with Youden’s Index were used to determine cutoff values for urine volume and urine osmolality (Uosm). Results and limitations: Individuals with NP demonstrated higher 1 AM volume (400 [interquartile range 300–515] vs 210 [160–300] ml, area under the curve [AUC] = 0.843, p < 0.001, cutoff = 350 ml) and lower Uosm (274 [201–348] vs 430 [320–664] mOsm/kg H2O, AUC = 0.774, p < 0.001, cutoff = 314 mOsm/kg H2O) than those without NP. In combining cutoffs, the criteria of either 1 AM volume 350 ml or Uosm 314 mOsm/kg H2O were 85% sensitive and 75% specific for NP, while criteria of both 1 AM volume 350 ml and Uosm 314 mOsm/kg H2O were 60% sensitive and 92% specific for NP. Comparable AUC values, sensitivities, and specificities were observed in both men and women. Limitations include post hoc design and a relatively small study sample. Conclusions: Individuals with NP are more likely than those without NP to produce a higher volume of more dilute urine (ie, “aquaresis”) in the early hours of sleep. Analysis of easily measurable parameters of the first nocturnal void (for which 1 AM values serve as a surrogate) in men and women with nocturia can predict a diagnosis of NP with a reasonably high degree of sensitivity and specificity.
* Corresponding author. Department of Urology, SUNY Downstate Health Sciences University, 450 Clarkson Avenue, Box 79, Brooklyn, NY 11203, USA. Tel.: +1 (518) 729-0070. E-mail address: [email protected] (T.F. Monaghan).
https://doi.org/10.1016/j.euf.2019.10.002 2405-4569/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Monaghan TF, et al. Diagnosing Nocturnal Polyuria from a Single Nocturnal Urine Sample. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.10.002
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Patient summary: Urologists often try to understand the specific reason why people wake up to urinate at night by asking them to record the amount of urine they make every time they go to the bathroom (also known as a “voiding diary”) during the nighttime as well as the daytime—typically for a total of 1–3 days. In this study, we showed that an analysis of the composition of the urine that people produce when they first wake up to urinate at night might be sufficient to determine whether their symptoms are caused by excessive urine production or something else, and some people might find this urine study easier than keeping a voiding diary. © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
1.
2.2.
Introduction
The voiding diary is a gold standard in the evaluation and management of nocturia [1]. However, as evidenced by the fact that only 55% of patients with documented nocturnal polyuria (NP)—thought to be the most common overall cause of nocturia [2]—are diagnosed using a voiding diary [3], many patients find the diary to be cumbersome, and adherence to voiding diaries is a pervasive obstacle in the clinical setting [4]. Notably, while the voiding dairy requires a careful record of the timing and volume of every micturition over the duration of the diary (which, depending on provider preference, is typically 24–72 h), the early hours of sleep appear to be particularly central to the pathogenesis of NP. Recently, individuals with NP have been shown to demonstrate significantly higher free water clearance and lower urine osmolality (Uosm) than those without NP [5]. Moreover, among patients with nocturia owing to NP and no identifiable contributory comorbidities, there was a notable surge in nocturnal diuresis rate before the time of first awakening, such that early nocturnal urine production (NUP) disproportionately contributes to the total nocturnal urine volume [6]. The present analysis expanded this work by examining the extent to which early nocturnal urine samples, obtained at the time of first nocturnal awakening in patients with nocturia, may represent a rational substitute to voiding diaries for diagnosing nocturia owing to NP. Specifically, the primary aim of this study was to test the hypothesis that individuals with nocturia owing to NP will produce a greater volume of more dilute urine in the early nocturnal period. Secondarily, this study aimed to determine the sensitivity and specificity of the volume and Uosm of a single early nocturnal urine sample in diagnosing NP in a population of individuals with nocturia. 2.
Participants and methods
2.1.
Study design
The present study is a post hoc analysis of 1
AM
urine samples obtained
from two prospective observational studies conducted at Ghent University Hospital from 2011 to 2016. Ethical approval was obtained from the Ghent University Hospital ethics committee (EC/2011/565; EC/ 2013/950), and all participants provided written informed consent in accordance with the Declaration of Helsinki.
Participants
The first protocol enrolled individuals (n = 135) recruited by the urology ambulatory care unit [5]. The second protocol (n = 95) recruited individuals aged 65 yr who consulted the continence clinic [7]. Baseline nocturia was not a prerequisite for inclusion in either protocol.
2.3.
Test methods
For both protocols, participants completed 24–72-h voiding diaries, and subsequently collected urine samples at 3-h intervals (Q3H) for 24 h. The participants also provided a blood sample upon completion of the Q3H urine sampling. For the urine samples, the participants were instructed to void at fixed 3-h intervals and record the accompanying voided volumes. In total, five daytime (10
AM,
1
PM,
4
PM,
7
PM,
and 10
PM)
and
three nighttime (1 AM, 4 AM, and 7 AM) samples were obtained, and voided volumes for interim micturitions were also recorded. Uosm was determined by freezing point depression in an Osmo Station OM6050 osmometer (Menarini Diagnostics Benelux, Machelen, Belgium). Fluid intake was not regulated in either protocol. The methods of both aforementioned studies have previously been described elsewhere in detail [5,7]. The
inclusion
and
exclusion
criteria
are
outlined
in
Figure 1. Nocturia was defined as one or more nocturnal void(s) on voiding diary analysis. Individuals were excluded if they did not report nocturia on the voiding diary or if Q3H urine sampling data were absent/incomplete. Included participants were stratified based on the presence or absence of NP from the Q3H urine collection using a cutoff of NUP > 90 ml/h (voided volume + incontinence weight), as this criterion is more robust than commonly used proportion-based (ie, nocturnal volume/24-h volume >0.33) cutoffs [8].
2.4.
Analysis
The easyROC web tool was utilized to create receiver operating characteristic curves, determine the area under the curve (AUC) for 1 AM urine volume and Uosm between participants with (cases) and without (reference group) NP [9], and employ Youden’s Index to establish optimal cut points [9,10]. This analysis was repeated separately in men and women to explore potential sex differences.
3.
Results
3.1.
Participants
A total of 176 individuals were included for analysis, of whom 87 met the criteria for NP and 89 fell below this threshold (Table 1). Body mass index was higher in all participants with NP (p < 0.001) and women with NP (p < 0.001) compared with their counterparts who fell
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Database characteristics:
Participants completing 24-72-h voiding diaries derived from either of two sources: 1) Patients recruited from urology ambulatory care unit 2) Patients ≥65 yr consulting the continence clinic Total database entries (n = 230)
Excluded (n = 53) - Zero nocturnal voids on voiding diary (n = 53) - Incomplete/absent data (n = 0)
Baseline nocturia ( ≥1 nocturnal voids on voiding diary) (n = 177) Excluded (n=1)
Complete Q3H urine sampling data 1) 1 AM urine osmolality 2) 1AM urine volume 3) Nocturnal urine production rate (ml/h)
- Missing 1AM urine osmolality (n = 1) - Missing 1AM urine volume (n = 0) - Missing nocturnal urine production (n = 0)
(n=176)
Nocturnal polyuria (Nocturnal urine production >90ml/h on Q3H urine sampling)
No nocturnal polyuria (Nocturnal urine production <90 ml/h on Q3H urine sampling)
(n = 87)
(n = 89)
Fig. 1 – Flow chart of enrollment characteristics. Q3H = 3-h interval.
below the threshold for NP. No significant differences were observed in participant age by NP status. 3.2.
Test results
In accordance with the predefined cutoff for NP, individuals with NP demonstrated significantly greater NUP versus those without NP. Among participants with NP, urine volume was higher (400 [interquartile range 300–515] vs 210 [160–300] ml, p < 0.001) and Uosm was lower (274 [201–348] vs 430 [320–664] mOsm/kg H2O, p < 0.001) compared with those without NP. The 24-h urine productionwas significantly greater in the NP cohort for all participants (p < 0.001), men (p < 0.001), and women (p = 0.001). For 1 AM urine volume, the AUC was 0.843 (p < 0.001), with highest sensitivity (69%) and specificity (91%) at 350 ml (Fig. 2). For 1 AM Uosm, the AUC was 0.774 (p < 0.001), with the highest sensitivity (72%) and specificity (76%) at 314 mOsm/kg H2O. Combining these two cutoffs, criteria of either 1 AM volume 350 ml or Uosm 314 mOsm/ kg H2O resulted in 85% sensitivity and 75% specificity for NP, while criteria of both 1 AM volume 350 ml and Uosm 314 mOsm/kg H2O resulted in 60% sensitivity and 92% specificity for NP. By sex, comparable AUC values, sensitivities, and specificities were observed in both men and women (Fig. 1). For men, combining the optimal cutoffs (350 ml
and 370 mOsm/kg H2O) resulted in “either/or” sensitivity of 80% and specificity of 79%, and “both/and” sensitivity of 60% and specificity of 96% for NP. For women, combining the optimal cutoffs (320 ml and 309 mOsm/kg H2O) resulted in “either/or” sensitivity of 90% and specificity of 68%, and “both/and” sensitivity of 65% and specificity of 89% for NP.
4.
Discussion
Individuals with NP are more likely than those without NP to produce a higher volume of more dilute urine in the early hours of sleep. This finding is consistent with our own previous work, in which we demonstrated that participants with NP (with or without nocturia) experience higher 1 AM free water clearance and lower 1 AM Uosm than individuals without NP [5], and that patients with idiopathic NP demonstrate a unique surge in nocturnal diuresis rate during the early hours of sleep [6]. The results of the present study are novel because they are, to our knowledge, the first to demonstrate that analysis of easily measurable urinary parameters of the first nocturnal void (for which 1 AM values serve as a surrogate) in participants with nocturia can predict a diagnosis of NP with a reasonably high degree of sensitivity and specificity. These findings have sizable clinical implications because of recent advances in urinalysis, which have enabled
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0.2
0.4
0.6
0.8
0.8 0.4
NP (n = 87) = 274 No NP (n = 89) = 430 AUC = 0.774, p < 0.001 Optimal cutoff = 314 Sensitivity = 0.72 Specificity = 0.76
0.0
0.4 0.0
Sensitivity
0.8
1 AM urine osmolality
NP (n = 87) = 400 No NP (n = 89) = 200 AUC = 0.843, p < 0.001 Optimal cutoff = 350 Sensitivity = 0.69 Specificity = 0.91
0.0
Sensitivity
All participants
1 AM urine volume
1.0
0.0
0.2
0.2
0.4
0.6
0.8
0.2
0.6
0.8
1–specificity
1.0
0.6
0.8
1.0
0.8 0.4
NP (n = 52) = 247 No NP (n = 65) = 409 AUC = 0.794, p < 0.001 Optimal cutoff = 309 Sensitivity = 0.81 Specificity = 0.72
0.0
Sensitivity
0.8 0.4
Sensitivity
Women
0.0
0.4
0.4
1–specificity
NP (n = 52) = 400 No NP (n = 65) = 200 AUC = 0.840, p < 0.001 Optimal cutoff = 320 Sensitivity = 0.75 Specificity = 0.85
0.2
1.0
0.8 0.4 0.0
1.0
1–specificity
0.0
0.8
NP (n = 35) = 302 No NP (n = 24) = 636 AUC = 0.810, p < 0.001 Optimal cutoff = 370 Sensitivity = 0.71 Specificity = 0.79
0.0
Sensitivity
0.8 0.4 0.0
0.6
1–specificity
NP (n = 35) = 430 No NP (n = 24) = 205 AUC = 0.843, p < 0.001 Optimal cutoff = 350 Sensitivity = 0.69 Specificity = 0.96
0.0
Sensitivity
Men
1–specificity
0.4
0.0
0.2
0.4
0.6
0.8
1.0
1–specificity
Fig. 2 – NP defined as nocturnal urine production of >90 ml/h. Youden’s Index was used to determine cutoff values for 1 AM urine volume and Uosm between participants with (cases) and without (reference group) NP [9,10]. Urine volume is expressed in milliliters and urine osmolality in mOsm/kg H2O. AUC = area under the curve; NP = nocturnal polyuria; Uosm = urine osmolality.
clinicians to reliably estimate Uosm—a gold standard parameter for quantifying urine production [11,12]—using widely available laboratory techniques. Historically, measurement of Uosm utilized the freezing point depression method, which is a time-consuming technique that is not readily available to most physicians. Recently, Oyaert et al [13] compared measured osmolality (using the freezing-point depression technique) with a conductivity-based estimate of osmolality (using a routine
flow cytometry urine sediment analyzer) and determined that conductivity allows for a rough estimation of measured osmolality. Moreover, Oyaert and colleagues [13] were able to construct and validate a strong (r2 = 0.895) conductivitybased osmolality predication model by incorporating only parameters (specific gravity and creatinine) that are available on a standard commercial urine test strip. In contrast to osmometers, conductivity meters can be incorporated into modern urine analyzers. In fact, conductivity meters are
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BMI = body mass index; NP = nocturnal polyuria; Q3H = every 3 h. Data of 24–72-h voiding diary, which were used to determine the presence of nocturia/number of nocturnal voids, were collected prior to the Q3H 24-h urine collection, which was used to stratify participants by NP status and analyze the 1 AM measurements reported in this table. Data are presented as median (interquartile range). Of the included participants, one value was missing for BMI and four values were missing for 24-h urine production. * Statistical significance.
<0.001* <0.001* <0.001* 0.001* 200 (150–300) 409 (285–579) 63 (52–75) 27.9 (22.8–35.1) 400 (315–500) 247 (175–296) 110 (100–136) 35.1 (28.7–42.4) <0.001* <0.001* <0.001* <0.001* 430 (300–564) 302 (257–409) 114 (103–145) 31.9 (26.4–40.0) 210 (160–300) 430 (320–664) 64 (52–75) 26.9 (20.2–33.8) 400 (300–515) 274 (201–348) 112 (100–140) 33.6 (27.2–42.1)
<0.001* <0.001* <0.001* <0.001*
205 (180–285) 636 (392–756) 67 (56–79) 22.1 (17.8–27.1)
0.714 2 (1–2) 2 (1–2) 0.446 2 (1–2.3) 2 (1–3) 2 (1–2) 2 (1–2.5)
0.662
0.232 <0.001* 69 (51–77) 24.0 (21.6–26.3) 71 (67–76) 27.1 (24.8–31.4) 0.192 0.552 67 (59–72) 26.2 (23.7–27.5) 68 (64–76) 25.1 (24.3–29.6) 0.100 <0.001* 69 (66–76) 24.4 (22.3–27.1) 69 (55–75) 26.6 (24.5–30.6)
Demographics Age (yr) BMI (kg/m2) 24–72-h voiding diary Number of nighttime voids Q3H urine sampling 1 AM urine volume (ml) 1 AM urine osmolality (mOsm/kg H2O) Nocturnal urine production (ml/h) 24-h urine production (ml/kg/h)
No NP (n = 65) No NP (n = 24) p Value No NP (n = 89) NP (n = 87)
All participants
Table 1 – Demographic data and voiding diary results by nocturnal polyuria status.
NP (n = 35)
Men
p Value
NP (n = 52)
Women
p Value
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5
increasingly flexible and inexpensive, and measurements could reasonably be performed by nocturic patients using a portable bedside sensor (along with a urine dipstick and volume measurement). Nocturia is a complex and often multifactorial condition, but experts agree that voiding diaries are a standard of care in the initial clinical assessment of bothersome nocturia, irrespective of the suspected causality [1]. However, in a representative multinational cross-sectional study of practice trends, Oelke et al [3] recognized that 45% of documented NP diagnoses are made without the use of a diary. Notably, voiding diary results are critical in delineating between underlying mechanisms of nocturia, and are thus used to support individualized lifestyle and/or pharmacologic treatment plans [1]. Consistently, in patients with nocturia, Oelke and colleagues [3] also reported a substantial time lapse from diagnosis to the initiation of first therapy (lifestyle advice and behavioral therapy included) among both men and women, ranging from 27 to 41 wks. Nonadherent patients offer a wide array of reasons for failing to complete a voiding diary, including a lack of understanding of the benefits or instructions, the time commitment required to complete the diary, interference with their work/daily routine, and forgetfulness [4]. In recent years, several changes have been proposed to the nocturia treatment algorithm in order to make it more patient centered, which we would expect to improve patient adherence to voiding diaries. Notable initiatives have included analyses of nocturnal-only voiding diaries [14], validation of user-friendly electronic voiding diary applications [15,16], and new, resource-conscientious practice patterns centering on electronic diaries and remote office visits [17]. Beyond these recent efforts, it stands to reason that greater attention to the diagnostic utility of single-void nocturnal urine samples may contribute to a treatment paradigm for nocturia, which further reduces patient burden and, in turn, improves adherence to diagnosis and management. Beyond the diagnostic utility of Uosm and urine volume in delineating nocturic patients by NP status, our finding of a higher volume of more dilute urine (ie, “aquaresis”) in the early sleep period among individuals with NP is consistent with the reduced diurnal variation in plasma arginine vasopressin (AVP) levels found in some studies of nocturnal enuresis [18] and nocturia [19]. This is particularly relevant in view of the fact that the treatment of nocturia is rapidly evolving, with multiple formulations of synthetic AVP now approved in several countries for patients with nocturia owing to NP. Desmopressin is a synthetic analog of AVP, which is produced by the posterior pituitary gland and acts primarily on the collecting duct of the renal inner medulla to increase trafficking of aquaporin-2 integral membrane proteins to the apical plasma membrane to reduce free water diuresis [20]. As such, the role of antidiuretic therapy in alleviating NP severity is mediated, in large part, by a decrease in NUP [21]. Moreover, given the short half-life of current formulations of desmopressin
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[22], it stands to reason that antidiuretic therapy predominantly exerts its effect on NUP during the early hours of sleep. Accordingly, the significantly greater 1 AM aquaresis observed among patients with NP is consistent with both the pharmacokinetics and the pharmacodynamics of short-acting antidiuretic therapy taken at bedtime for the treatment of NP. Future research is warranted to determine whether the volume and Uosm of the first nocturnal void can predict response to antidiuretic replacement therapy, particularly in view of differential responses to antidiuretics as a function of age and gender, and the fact that rebound diuresis in older women (who constitute the majority of the present cohort) may be considerably delayed. The present study is subject to the inherent limitations of a single-institution analysis with a limited number of participants. Moreover, this was a convenience sample, and we had no information about their sleep patterns at the time the data were collected. Owing to this, first nocturnal voided samples collected after the patients initially went to sleep, as would be obtained in clinical practice, could not be analyzed. Fixed 1 AM urine samples, as were available from both protocols, are only a proxy for early NUP as well as for the first uninterrupted sleep period. Sleep was interrupted as per the investigational procedure for Q3H urine sampling, which may have interfered with normal nocturnal blood pressure trajectories, such that the study protocol itself could have given rise to NP. While voiding diaries more closely approximate nocturnal voiding patterns as compared with Q3H urine sampling, documentation of nocturnal voiding was not a prerequisite for either protocol, so nocturia duration and severity could not be assessed. Additionally, comorbidities including obstructive sleep apnea, diabetes mellitus, and nondipping hypertension, as well as medication usage and timing, were not taken into account. Although combined criteria of either 1 AM volume 350 ml or Uosm 314 mOsm/kg H2O resulted in 85% sensitivity for NP, criteria of both 1 AM volume 350 ml and Uosm 314 mOsm/kg H2O resulted in sensitivity of only 60%, and the sensitivity was likewise relatively low using individual optimal cutoffs for both 1 AM urine volume (69%) and 1 AM Uosm (72%). At present, more than 15 definitions have been proposed for NP [23], and these results may not necessarily extend to other NP definitions—particularly the proportion-based criteria (ie, nocturnal volume/24-h volume >0.33), which are markedly less discriminatory for NP at the population level [8]. Larger study samples with well-defined NP patient subgroups are required to evaluate the effect of these factors, and to establish reproducible cutoff values for first nocturnal voided volume and Uosm by NP status. The findings of this study necessitate future translational research involving Uosm analysis, as well as the development of more sophisticated medical devices for in-home conductivity monitoring, as these measures would promote more patient-centered practice patterns and allow the urology community to refine and perhaps simplify its current diagnostic algorithm for nocturia.
5.
Conclusions
In the appropriate clinical context, analysis of a single urine sample produced at the time of first nocturnal awakening could facilitate the detection of nocturia owing to NP, and may also provide a means of predicting response or monitoring treatment with antidiuretic replacement therapy.
Author contributions: Thomas F. Monaghan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Monaghan, Verbalis, Haddad, Agudelo, Lazar, Bliwise, Weiss, Everaert. Acquisition of data: Goessaert, Denys. Analysis and interpretation of data: Monaghan, Verbalis, Agudelo, Lazar, Bliwise, Weiss, Everaert. Drafting of the manuscript: Monaghan. Critical revision of the manuscript for important intellectual content: Monaghan, Verbalis, Haddad, Pauwaert, Agudelo, Goessaert, Denys, Lazar, Bliwise, Vande Walle, Wein, Weiss, Everaert. Statistical analysis: Monaghan. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Verbalis, Lazar, Bliwise, Vande Walle, Wein, Weiss, Everaert. Other: None.
Financial disclosures: Thomas F. Monaghan certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Thomas F. Monaghan has no direct or indirect commercial incentive associated with publishing this article. Dr. Verbalis is a consultant for Ferring and has served on the Ferring Desmopressin Safety Board. Dr. Haddad reports grants from Fonds de dotation Renaitre and from Société Interdisciplinaire Francophone d’UroDynamique et de Pelvi Périnéologie, during the conduct of the study; personal fees and nonfinancial support from Astellas; personal fees from MedDay Pharmaceuticals and Novartis Pharma SAS; nonfinancial support from Dentsply Sirona France, Pierre Fabre Medicament, Allergan France, Bayer HealthCare, SAS and Vifor France SA, outside the submitted work. Dr. Pauwaert has received research grants from Ferring. Dr. Goessaert reports institutional grants from Allergan, Astellas, and Ferring, outside the submitted work. Dr. Denys reports institutional grants from Allergan, Astellas, and Ferring, outside the submitted work. Dr. Bliwise has served as a consultant for Merck, Jazz, Ferring, Eisai, and Respicardia, and a speaker for Merck during the last 3 yr, outside the submitted work. Johan Vande Walle reports institutional grants from Allergan, Astellas, and Ferring, and is a consultant and lecturer for Ferring and Astellas, outside the submitted work. Dr. Wein has served as an advisor/consultant for Avadel, GTX, Acquinox, Urovant, Medtronic, and Serenity during the last 3 yr, outside the submitted work. Dr. Weiss is a consultant for Ferring and the Institute for Bladder and Prostate Research, outside the submitted work. Dr. Everaert is a consultant and lecturer for Medtronic and Ferring, and reports institutional grants from Allergan, Ferring, Astellas, and Medtronic, outside the submitted work. The remaining authors have nothing to disclose.
Funding/Support and role of the sponsor: None.
Please cite this article in press as: Monaghan TF, et al. Diagnosing Nocturnal Polyuria from a Single Nocturnal Urine Sample. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.10.002
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Please cite this article in press as: Monaghan TF, et al. Diagnosing Nocturnal Polyuria from a Single Nocturnal Urine Sample. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.10.002