The Aging Bladder

김 장 환연세의대 비뇨기과

Morphologic & Physiologic Changes

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Function of the Bladder

Urine Storage

Urine Excretion

Physiologic Changes with Age

Decreased -detrusor contractility -bladder capacity -MUCP(women)

Increased -PVR (50-100 ml) -detrusor overactivity

Definition of the Aging Detrusor

No definition of the functional norm of the aging or aged bladder

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Normal Morphology

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Smooth Muscle

• 3 layers – outer longitudinal – middle circular– inner longitudinal

Distinct 3 layers

Intertwining 3 layers

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Gross Morphologic Changes

• Trabeculation• Thin- or thick-walled bladder• edema• diffuse scarring• chronic inflammatory lesions

Bladder Trabeculation

a familiar gross finding at autopsyhallmark of bladder outlet obstruction

• Thickening , hypertrophy of muscle → compensate for the obstruction

traditionally

Nature of Bladder Trabeculation

• Obstructed bladder: may not be trabeculated• Overactive bladder: trabeculated in both sexes

whether unobstructed or obstructed• Unobstructed detrusor with impaired contractility• Neuropathic bladder• Bladder of children with enuresis

Elbadawi A, et al. (1993) J Urol 150: 1668-1680Elbadawi A, et al. (1993) J Urol 150: 1681-1695Booth CM, Gosling JA. (1983). Br J Urol 55: 367-370Barnard RJ et.al. (1981). In: Female incontinence. pg 285-288

Nature of Bladder Trabeculation

• Nonspecific phenomenon

• Reflects characteristics of its normal construction

• Cannot correlate with aging bladder

Elbadawi A, Yalla SV, Resnick NM (1993). J Urol 150: 1657-1667Booth CM, Gosling JA (1983). Br J Urol 55: 367-370

Gross Morphology

• No definite morphological characteristics of an aging bladder

Smooth muscle

• Widened spaces between muscle fibers• Change in collagen content

1) Deposition of collagen and fibrosis are recognized phenomena in the aging bladders of both men and women

→ loss in compliance2) The collagen content was increased in female bladders

but decreased in male bladders → collagen/muscle ratio

Swaiman KF, Bradley WE (1967). J Appl Physiol 22: 122-124Susset JG, et al, (1978) Collagen in 155 human bladders. Invest Urol 16: 204-206Hald T, Horn T. Br J Urol. 1998;82(suppl 1):59-64.

Collagen Content in Bladders

Muscle Ultrastructure

- > 65 yrs, urodynamically stable -normally contractile -unobstructed -an asymptomatic continent person -no neurologic deficit

⇒ Dense-band pattern

Elbadawi A, et al. (1993) J Urol 150: 1668-1680Elbadawi A, et al. (1993) J Urol 150: 1681-1695

Dense-Band Pattern • Muscle cell membranes dominated by

electron-dense, conspicuously long, dense bands with markedly depleted caveolae.

• Caveolae: – small (50–100 nanometer) invaginations of the

plasma membrane– Involved in signal transduction, endocytosis,

uptake of bacteria and viruses.Elbadawi A, et al. (1993) J Urol 150: 1668-1680Elbadawi A, et al. (1993) J Urol 150: 1681-1695

Dense-Band Pattern • Dedifferentiation

mature cells (active contractile) → immature cells(inactive syntheticphenotype )

ex) arteriosclerotic blood vessels postmenopausal myometrium

Elbadawi A, et al. (1993) J Urol 150: 1668-1680Elbadawi A, et al. (1993) J Urol 150: 1681-1695

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Connexin 43

Suadiacani S. BJU Int 2009

• Gap junction protein

• Involved in intercellular signaling

• Myogenic substrate for detrusor overactivity

Intrinsic Nerve

• Density of cholinergic nerve– Reduced cholinergic and overall intrinsic

innervation in obstructed human detrusor– No change in old rats (Ordway et al)– Increase in old rabbits (Latifpour et al)

Histologic Changes

• Collagen deposition

• Muscle degeneration

• Axonal degeneration

Neurochemcial Change

• Age associated Ach response– No change with age (Lluel et al)

– Contraction to Ach increase with age (Saito, Kolta)

– Response lower in elderly rats (Toyoshima et al)

Neurochemcial Change• Age associated NE change in bladder

– Contraction to NE increase with age (Saito)

– No change in response with age (Kolta et al)

• Detrusor contraction to alpha adrenergic stimulation increased

• Aging increased expression of AR1D (alpha1D adrenergic receptor ) in the bladder

• Changes in beta receptor density or sensitivity with aging is unknown in humans

• Bladder response to beta adrenergic stimulation & receptor reduced in old male rats

Hampel C et al. Urologe A. 2004 May;43(5):535-41Nishimoto et al. 1995

Neurochemcial Change

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Adrenergic Effect

• Increase in alpha adrenergic excitatory effect

• Decrease in beta adrenergic inhibitory response

Net contracting effect of norephinephrine in the aged bladder

Muscarinic & Purinergic Receptors

• Two major components of detrusor contraction 1) by muscarinic receptors (Ach) 2) by purinergic receptors (ATP)

Yoshida et al. Urology 2004 Andersson KE, Schroder A. Urologe A. 2004

Muscarinic & Purinergic Receptors

Yoshida et al. Urology 2004

Conclusions• Gross Appearance : non-specific changes• Microscopic Appearance: collagen increased, Cx43

• EM Appearance: dense-band pattern • Receptor Changes :

adrenergic, muscarinic ↓, purinergic↑, AR1D ↑

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Conclusions• Most studies using animals• Most animal studies are in vitro• Most human data involve bladders with

predisposing conditions (e.g. neurologic, BOO, etc)

• Small number in human studies• Lack of longitudinal human data

Immeasurable impact on the diagnosis and management of voiding disorders in the elderly