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  • Renal Physiology

    Control of Urinary Drainage and Voiding

    Warren G. Hill

    AbstractUrine differs greatly in ion and solute composition from plasma and contains harmful and noxious substances thatmust be stored for hours and then eliminatedwhen it is socially convenient to do so. The urinary tract that handlesthis output is composed of a series of pressurizable muscular compartments separated by sphincteric structures.With neural input, these structures coordinate the delivery, collection, and, ultimately, expulsion of urine.Despite large osmotic and chemical gradients in this waste fluid, the bladder maintains a highly impermeablesurface in the face of a physically demanding biomechanical environment, which mandates recurring cycles ofsurface area expansion and increased wall tension during filling, followed by rapid wall compression duringvoiding. Afferent neuronal inflow from mucosa and submucosa communicates sensory information aboutbladder fullness, and voiding is initiated consciously through coordinated central and spinal efferent outflow tothe detrusor, trigonal internal sphincter, and external urethral sphincter after periods of relative quiescence.Provocative new findings suggest that in some cases, lower urinary tract symptoms, such as incontinence,urgency, frequency, overactivity, and pain may be viewed as a consequence of urothelial defects (eitherurothelial barrier breakdown or inappropriate signaling from urothelial cells to underlying sensory afferents andpotentially interstitial cells). This review describes the physiologic and anatomic mechanisms by which urine ismoved from the kidney to the bladder, stored, and then released. Relevant clinical examples of urinary tractdysfunction are also discussed.

    Clin J Am Soc Nephrol 10: cccccc, 2015. doi: 10.2215/CJN.04520413

    Anatomy of the Lower Urinary TractUrinary drainage from the kidneys occurs through theureters (2530 cm long in adults), which enter the blad-der distally via a specialized region near the base ofthe bladder called the trigone. Unidirectional flowfrom the kidney pelvis into the ureter and from theureter to the bladder is assisted by two constrictionsat opposite ends: the ureteropelvic junction (UPJ) andthe ureterovesical junction (UVJ), respectively. Theseunique fibromuscular structures, which are notstrictly classic sphincters, provide antireflux protec-tion in order to ensure that urine transport occurs inonly one direction. The ureters consist of stratifiedlayers composed of epithelium (the urothelium), lam-ina propria, and smooth muscle.

    Ureteral smooth muscle cells are arranged in longitu-dinal, circular, and spiral bundles to facilitate peristalticmovement of urine toward the bladder. As urine isforced past the UPJ by calyceal and renal pelvis smoothmuscular contraction, it enters the ureters as a bolus thattravels down to the UVJ and is then extruded into thebladder. Distally, the ureters insert into the bladderat an oblique angle and traverse the muscle over adistance of approximately 1.5 cm. Beginning abovethe entry point to the detrusor, the ureter is sheathedby a layer of longitudinal smooth muscle. This sheathpasses through the vesical wall and then diverges tomerge with the deep trigone (1). The intravesicalureter forms a valve, which is important in the pre-vention of reflux. It also protects the kidney fromretrograde exposure to the high pressures generated

    by the bladder at voiding and also from infectionslocalized in the bladder. The physical relationship ofthe UVJ in terms of its length, diameter, and posi-tioning relative to the trigone prevents retrogradeflow. Damage to the trigone, congenital abnormali-ties, or trigonal muscular weakness are all primarycauses of vesicoureteral reflux. The complexity of theUVJ makes it the most difficult anastomosis to per-form in renal transplantation (2).The bladder is a highly deformable muscular sac

    that has two primary functions: storage and expul-sion. It features a layered structure similar to that ofthe ureters, with a highly impermeable urothelium,an intermediate vascularized lamina propria com-posed of connective tissue, several fibroblastic celltypes, and a thick smooth muscle coat called the de-trusor. Figure 1 illustrates the laminar nature of theselayers and the surface topography of the bladder,which is highly folded and ridged when not fullystretched.The urethra begins at the lower apex of the bladder

    neck and is formed of several layers of muscle. Figure 2shows the anatomy of male and female urethrae. Theurethra, on average, is 3.55 cm long in women,whereas it is approximately 20 cm long in men. Theurethral tube is formed from an inner longitudinalsmooth muscle, which, in turn, is surrounded by a thin-ner circular smooth muscle layer. Urinary continence ismaintained in both sexes by an involuntary internalsphincter and a voluntary external urethral sphincter(EUS), sometimes called the rhabdosphincter.

    Laboratory of VoidingDysfunction,Department ofMedicine, Beth IsraelDeaconess MedicalCenter and HarvardMedical School,Boston, Massachusetts

    Correspondence:Dr. Warren G. Hill,Laboratory of VoidingDysfunction, BethIsrael DeaconessMedical Center,RN349 99 BrooklineAvenue, Boston, MA02215. Email: Vol 10 March, 2015 Copyright 2014 by the American Society of Nephrology 1

    . Published on May 1, 2014 as doi: 10.2215/CJN.04520413CJASN ePress

  • Physiology of the UretersUrine flow through the ureters occurs by peristalsis, which

    facilitates unidirectional flow. At normal urine productionrates, contraction of the renal pelvis forces a bolus of urine intothe ureter, upon which waves of contraction (2080 cmH2O;26 times/min) occur behind the bolus and force it distallyinto relaxed sections with baseline pressures of only 05cmH2O. When urine production rates become particularlyhigh, boluses can become larger and then merge and mayultimately become essentially a column of fluid. Upon expul-sion of urine through the UVJ, the peristaltic wave dissipates.Ureteral obstruction raises the intraluminal pressure

    above the obstruction and is usually accompanied by anincrease in peristaltic frequency as well as changes inureteral dimensions. In response to this distal pressure, theureter becomes dilated and increases in length due to theretention of urine and tissue stretching. If the obstruction isnot cleared, the contractions diminish, intraluminal pres-sures will subsequently diminish to almost baseline levels,and the ureter can ultimately decompensate, losing the abilityto contract even if the obstruction is removed. Hence, theearly response to calculi is an increase in peristaltic pressure,resulting in increased proximal pressure on the stone andsimultaneous relaxation at, and distal to, the blockage. Intandem, these responses are designed to aid in stone passage.However, if this does not prove successful and blockage ismaintained, irreversible damage can occur.Smooth muscle contractions occur in response to increases

    in intracellular calcium (Ca21); conversely, relaxation occurswhen Ca21 drops. This has been exploited therapeuticallyvia the use of calcium channel blockers (e.g., nifedipine),which augment relaxation and thereby assist with stone pas-sage, in an approach known as medical expulsive therapy(3,4). Smooth muscle contracts either as a response to neuro-transmitters released from firing of motor neurons (neuro-genic contractility) or as a result of local intrinsic networksignaling originating within the muscle (myogenic or spon-taneous contractility).

    Figure 1. | Mouse bladder sectioned and counterstained with toluidine blue. The layers of the bladder and their relative dimensions are easilyvisualized by different degrees of red/blue coloration.

    Figure 2. | Lower urinary tract anatomy including bladder and ure-thra. (A) Human male and (B) female.

    2 Clinical Journal of the American Society of Nephrology

  • Myogenic ContractilityElectrical activity within the pyeloureters causes smooth

    muscle contractility at the kidney pelvis and results incoordinated peristalsis. This activity originates in a pace-maker cell network composed of atypical smooth musclecells (SMCs) and interstitial cells of Cajal-like (ICC-like)cells. These pacemaker cells spontaneously generate elec-trical activity. Although the precise contribution of thesetwo cell types is not yet defined in ureters, atypical SMCsappear to be the primary pacemakers at the UPJ (59). Thesecells exhibit spontaneous high-frequency Ca21 spikes re-leased from internal stores that propagate through gap junc-tions to induce transient membrane depolarization in typicalSMCs. Depolarization activates an influx of Ca21 throughvoltage-gated L-type calcium channels on the plasma mem-brane, which then initiates tonic cytosolic Ca21 oscillationsresulting in SMC contraction (10). The role of ICC-like cells isnot clear because they form a separate, but interacting,electrically active network, which may be important inperistaltic contraction in distal regions of the ureter (8).Loss of ICC-like cells has been noted in studies of congenitalUPJ obstruction (1114). It is not clear, however, whetherthis reduction in cell number is a cause of the obstructionor a secondary consequence.

    Neurogenic ContractilityUreters are innervated directly by afferent and efferent

    fibers. However, peristalsis persists in the presence oftetrodotoxin, which blocks voltage-gated sodium channelsand, hence, action potentials. Furthermore, ureters trans-planted along with transplant kidneys, which lose theirinnervation, continue to exhibit peristalsis (15). Thisstrongly suggests that neurogenic regulation is likely tobe modulatory in nature (16). Neurotransmitter signalingpathways from both sympathetic and para