The purpose of this study is to develop nocturia phenotypes that can be used to construct diagnostic and treatment pathways and to offer clues to identifying underlying causes.

This is a retrospective multicenter study of patients evaluated for lower urinary tract symptoms (LUTS) who completed a 24-hour bladder diary (24HBD), the lower urinary tract symptoms score (LUTSS) questionnaire on a mobile app, website and/or paper, and uroflow (Q) and post-void residual urine (PVR). Those with nocturia once or more at night on a 24HBD were included. A panel of experts was convened to design the conceptual framework around which nocturia phenotypes could be constructed. The panel considered two general approaches – classifying patients according to age, sex, disease states such as benign prostatic hyperplasia, overactive bladder, pelvic organ prolapse, sleep apnea, peripheral edema, etc, or, according to physiologic variables such as 24-hour voided volume, bladder capacity, uroflow and post void residual urine. The panel chose the latter approach because it was their opinion that it is the underlying pathophysiology that dictates the rationale for treatment and that there is a commonality of therapeutic choices that transcends disease states. The phenotype classification system is depicted in table 1.

331 patients, 197 men and 134 women, completed the LUTSS and a contemporaneous 24H BD. 36 patients did not have contemporaneous Q and PVR results and were excluded , leaving 295 for analysis (201 men and 94 women). Nocturia, as defined as ≥1 nighttime void, was present in 228 (77%) of these patients (154 men and 74 women). Nocturia, ≥ 2 nighttime voids, was present in 50% of the cohort (148 patients). Demographic and clinical data is presented in table 2.  The panel selected these variables for inclusion in the phenotype modelling: 24-hour voided volume (24HV), maximum voided volume (MVV), nocturnal voids, insomnia voids, nocturnal polyuria index (NPi), and uroflow and post void residual urine. Subjects were divided into five major phenotypes as depicted in table 1, according to the 24HBD as follows: polyuria (P), nocturnal polyuria (NP), small bladder capacity (SBC), mismatches (M), and sleep disorders (SD). Definitions are provided in table 1. Each major phenotype was subdivided based on MVV, Q and PVR, resulting in a total of 30 phenotypes. 6 phenotypes are excluded because they cannot exist; patients with a small bladder (MVV < 150 mL) have 2 possible phenotypes, and ‘mismatches’ must have a normal bladder capacity (MVV > 150 mL), leaving only 4 possible phenotypes, resulting in 22 total phenotypes.

Because the ultimate goal of this research is to use these phenotypic descriptions to develop treatment pathways, the 22 phenotypes described herein were developed by the panel based on expert opinion with respect to how they might be utilized to construct treatment paradigms. Further, they are not all mutually exclusive. For example, patients with P could also have NP. The panel did not make NP a subdivision of P because they believed that treatment of P alone is effective in reducing both NP and P in the vast majority of patients. Of course, 22 phenotypic groups are impractical for directing diagnosis and treatment in routine clinical practice. However, several factors have convinced us that this will ultimately prove to be a useful approach. Firstly, the categories are hypothetical and some phenotypes may be eliminated.  Secondly, at the present time, there are limited OAB treatment options, so many of the categories will likely be lumped together to follow a single treatment path. Thirdly, the mere existence of some of these categories may stimulate further research to develop new treatment options. Finally, using artificial intelligence techniques, it is likely that diagnostic and treatment algorithms will be developed that can handle a large number of diverse phenotypes and present the physician with straightforward diagnostic and treatment paths without the need for the physician to be conversant in the phenotypic classification.

A phenotype classification system for nocturia based on expert opinion was devised, resulting in 22 phenotypes that were not all mutually exclusive. It is our goal to utilize and refine the data to provide the substrate for further research into the etiology of nocturia, new treatments and more precise treatment algorithms and clinical pathways.