**4.3 Post-voiding residual urine volume – Chronic urinary retention**

Chronic urinary retention is thought to be the dominant mechanism by which BPH can cause chronic renal failure (Rule, Lieber et al. 2005). Rule *et* al, defined chronic urinary retention (CUR) as a post-void residual urine (PVR) higher than 100 mL, and reported that CUR was significantly associated in CKD in community-dwelling men. For years it has been well described that large volumes (»300 mL) affect renal function in advanced BPH (Styles, Neal et al. 1988; Rule, Lieber et al. 2005; Yamasaki 2010).

Recent studies, however, demonstrate that the volume of residual urine (post void) necessary to impair renal function is not that elevated. Yamasaki et al, verified in their study a cut-off of 12 ml for PVR (Yamasaki 2010), confirming PVR as a significant and independent risk factor for CKD. This study showed for the first time that patients with BPH can develop impaired renal function with small amounts of post-void urine (PVR< 100 ml). Furthermore, these findings indicated a higher prevalence of CKD in patients with BPH, acknowledging it as a risk factor for CKD. However, the mechanism by which small PVR influence renal function remains unknown.

Although, as Yamasaki et al. demonstrated low post-void residual urine can cause deterioration of renal function it is scientifically accepted that large residual pos-void urine are in line more severe cases of renal function deterioration (Yamasaki 2010).

#### **4.3.1 Acute urinary retention**

Acute urinary retention (AUR) is defined as an acute complication of benign prostatic hyperplasia, patients suffers from an acute, sudden and painful inability to micturate. AUR represents an immediate indication for intervention or even surgery. Between 25% and 30% of men who underwent transurethral resection of prostate (TURP) had AUR as their main indication (Wein 2007). This complication is not exclusive for patients suffering from BPH, other causes can trigger acute urinary retention, like surgery, anaesthesia, trauma, medications, medical examination and urinary tract infections (mainly prostatitis).

Benign Prostate Hyperplasia and Chronic Kidney Disease 355

patients with low bladder compliance had renal failure (Comiter, Sullivan et al. 1997). Low bladder compliance and detrusor instability may be causal mechanisms for renal failure in

In other studies (animal experimental studies) in addition to obstruction-induced changes in the smooth muscle cell and collagen of the bladder wall, there was clear evidence that obstruction may modulate neural-detrusor responses, causing reduced bladder contractility

Bladder remodelling is a response to continued bladder obstruction, and detrusor smooth muscle cell is a key contributor to the complex symptoms associated with prostatic obstruction (Christ and Liebert 2005), namely in BPH/BPE (benign prostatic enlargement).

In general, ureterovesical junction obstruction caused by bladder remodelling in chronic urinary retention is a contributing mechanism for renal failure in BPH (Rule, Lieber et al. 2005). Upper tract dilation occurs as a consequence of a continuum bladder outlet obstruction and remodelling (detrusor hypertrophy and scarring) leading to anatomical ureterovesical junction obstruction (Jones, Ellis et al. 1991). Upper urinary tract dilation or hydronephrosis is consistent with chronic renal failure from obstructive uropathy. In men with BPH and increased serum creatinine, hydronephrosis is common (one third), and is found in 90% of men with BPH who are hospitalized for uremic symptoms (Sacks, Aparicio et al. 1989). In ultrasound evaluation it is common among patients with bilateral hydroureteronephrosis to observe compressing and thinning of renal cortex, with obvious impact in renal function. A history of enuresis, painless chronic retention, and palpable bladder should suggest a diagnosis of high pressure chronic retention with its attendant risk

Recurrent urinary tract infections in men with chronic urinary retention due to BPH may

Secondary hypertension due to chronic urinary retention is also a described complication of

Nephrogenic diabetes insipidus caused by partial or chronic urinary obstruction can result

Other clinical entities like diabetes and hypertension are independent factors that can lead to CKD (Gerber, Goldfischer et al. 1997). Patients with BPH are probable carriers of these pathologies that are likely to seriously aggravate renal function and must be taken into

BPH is a chronic and progressive condition (Jacobsen, Girman et al. 2001) patients generally have a history of lower urinary tract symptoms and indolent obstructive

men in chronic urinary retention (Rule, Lieber et al. 2005).

and altered sensation (Chai, Andersson et al. 2000)

**4.5 Ureterovesical junction and upper tract dilation** 

of hydroureteronephrosis (Sacks, Aparicio et al. 1989).

account as sombre conditioners of renal disease.

also contribute to chronic renal failure (Rule, Lieber et al. 2005).

BPH, leading to hypertensive kidney disease (Ghose and Harindra 1989).

**4.6 Other causes** 

in renal failure (Klahr 2001).

**5. Clinical presentation** 

uropathy.

In 2002 the self-reported rate of AUR in a cross sectional study in Spanish men was 5.1% (Hunter, Berra-Unamuno et al. 1996).

Acute urinary retention is not common in men under sixty years, and may be responsible for the majority of acute renal failure cases due to obstructive uropathy (Prakash, Saxena et al. 2001). Men in whom acute urinary retention is promptly relieved by bladder catheterization acute renal failure does not develop but long-term tubular dysfunction may still occur (Rule, Lieber et al. 2005). It is believed that acute urinary retention without prior history of chronic urinary retention do not lead to chronic renal failure. High bladder compliance allows men to maintain a normal GFR, however renal tubular dysfunction may persist after the acute urinary retention episode and probably result in progressive renal disease.

### **4.4 Bladder remodelling – Bladder response to urinary obstruction**

The bladder has a central role in pathophysiology of BPH and its complications.

Current evidence suggests that the bladder´s response to obstruction is largely an adaptative one, although it is only a partially adptative one. It is also clear for many authors and physicians that LUTS in men with BPH or prostate enlargement are more closely related to obstruction-induced changes in bladder function than to the outflow obstruction directly.

There are of two types of bladder changes. First, changes that lead to detrusor instability (clinically associated with symptoms of frequency and urgency). Second, changes associated with decreased detrusor contractility (emptying symptoms – low urinary stream, hesitancy, intermittency, increased residual urine) and detrusor failure (Wein 2007).

The development of bladder wall thickening (easily measurable by ultrasound) and trabeculation due to smooth muscle hypertrophy and connective tissue permeation is responsible for increased bladder pressure in patients with high pressure chronic retention (Jones, Ellis et al. 1991; Rule, Lieber et al. 2005). Gosling *et* al, were some of the first authors who established endoscopically that major detrusor changes and trabeculation were due to an increase in detrusor collagen (Gosling and Dixon 1980). Severe trabeculation is related to significant residual urine, suggesting that increased collagen in the bladder wall is probably responsible for incomplete bladder emptying to rather than impaired muscle function (Wein 2007). Detrusor hypertrophy is one of the first modifications in the bladder and, as in animal models, the initial response is the development of smooth muscle hypertrophy (Gosling, Kung et al. 2000; Levin, Haugaard et al. 2000). This is an adaptative response associated with intra and extracellular changes in the smooth muscle cells that leads to detrusor instability. Obstruction also induces changes in smooth muscle cells contractile protein expression, impairing cell-to-cell communication (Levin, Haugaard et al. 2000), with changes in myosin heavy chain isoform expression (Lin, Robertson et al. 2000) that lead to detrusor instability and in some cases to impaired contractility (Wein 2007).

Cellular and physiological changes in bladder muscle and collagen, contribute to a high pressure bladder that perpetuates itself with worsening ability to empty and causing kidney lesions.

These mechanisms of bladder remodelling develop in a hypofunctional bladder, with low compliance. Comiter *et* al. reported that in a series of men with symptomatic BPH, 78% of

In 2002 the self-reported rate of AUR in a cross sectional study in Spanish men was 5.1%

Acute urinary retention is not common in men under sixty years, and may be responsible for the majority of acute renal failure cases due to obstructive uropathy (Prakash, Saxena et al. 2001). Men in whom acute urinary retention is promptly relieved by bladder catheterization acute renal failure does not develop but long-term tubular dysfunction may still occur (Rule, Lieber et al. 2005). It is believed that acute urinary retention without prior history of chronic urinary retention do not lead to chronic renal failure. High bladder compliance allows men to maintain a normal GFR, however renal tubular dysfunction may persist after the acute urinary retention episode and probably result in progressive renal

**4.4 Bladder remodelling – Bladder response to urinary obstruction** 

intermittency, increased residual urine) and detrusor failure (Wein 2007).

and in some cases to impaired contractility (Wein 2007).

The bladder has a central role in pathophysiology of BPH and its complications.

Current evidence suggests that the bladder´s response to obstruction is largely an adaptative one, although it is only a partially adptative one. It is also clear for many authors and physicians that LUTS in men with BPH or prostate enlargement are more closely related to obstruction-induced changes in bladder function than to the outflow obstruction directly. There are of two types of bladder changes. First, changes that lead to detrusor instability (clinically associated with symptoms of frequency and urgency). Second, changes associated with decreased detrusor contractility (emptying symptoms – low urinary stream, hesitancy,

The development of bladder wall thickening (easily measurable by ultrasound) and trabeculation due to smooth muscle hypertrophy and connective tissue permeation is responsible for increased bladder pressure in patients with high pressure chronic retention (Jones, Ellis et al. 1991; Rule, Lieber et al. 2005). Gosling *et* al, were some of the first authors who established endoscopically that major detrusor changes and trabeculation were due to an increase in detrusor collagen (Gosling and Dixon 1980). Severe trabeculation is related to significant residual urine, suggesting that increased collagen in the bladder wall is probably responsible for incomplete bladder emptying to rather than impaired muscle function (Wein 2007). Detrusor hypertrophy is one of the first modifications in the bladder and, as in animal models, the initial response is the development of smooth muscle hypertrophy (Gosling, Kung et al. 2000; Levin, Haugaard et al. 2000). This is an adaptative response associated with intra and extracellular changes in the smooth muscle cells that leads to detrusor instability. Obstruction also induces changes in smooth muscle cells contractile protein expression, impairing cell-to-cell communication (Levin, Haugaard et al. 2000), with changes in myosin heavy chain isoform expression (Lin, Robertson et al. 2000) that lead to detrusor instability

Cellular and physiological changes in bladder muscle and collagen, contribute to a high pressure bladder that perpetuates itself with worsening ability to empty and causing kidney

These mechanisms of bladder remodelling develop in a hypofunctional bladder, with low compliance. Comiter *et* al. reported that in a series of men with symptomatic BPH, 78% of

(Hunter, Berra-Unamuno et al. 1996).

disease.

lesions.

patients with low bladder compliance had renal failure (Comiter, Sullivan et al. 1997). Low bladder compliance and detrusor instability may be causal mechanisms for renal failure in men in chronic urinary retention (Rule, Lieber et al. 2005).

In other studies (animal experimental studies) in addition to obstruction-induced changes in the smooth muscle cell and collagen of the bladder wall, there was clear evidence that obstruction may modulate neural-detrusor responses, causing reduced bladder contractility and altered sensation (Chai, Andersson et al. 2000)

Bladder remodelling is a response to continued bladder obstruction, and detrusor smooth muscle cell is a key contributor to the complex symptoms associated with prostatic obstruction (Christ and Liebert 2005), namely in BPH/BPE (benign prostatic enlargement).
