**4.1 Benign prostate enlargement**

BPH/BPE first develops in the periurethral *transition zone* of the prostate. The transition zone consists of two separate glands immediately external to the preprostatic sphincter. Prostate enlargement also involves an increase in the number of glands, particularly the periuretheral glands, and increase in smooth muscle and connective tissue in the periuretheral region of the prostate (McNeal 1978; Rule, Lieber et al. 2005; Wein 2007). Prostate size can be estimated by digital rectal examination (DRE) (underestimate true prostate size) but reliability across observers is in general considered poor (Wein 2007), for these reasons in all cross-sectional studies prostate volume is assessed by TRUS (trans-rectal ultrasound).

Benign Prostate Hyperplasia and Chronic Kidney Disease 353

tract symptoms. In our opinion under reported symptoms can induce a significant bias in

Although many patients who do not value their symptoms, mainly the older ones, the frequency of symptoms and its interference with quality of live (QoL) is the principal factor

Patient perceptions are receiving greater emphasis as part of clinical decision-making (Jacobsen, Guess et al. 1993; Roberts, Rhodes et al. 1994). The variability of relationships between symptom severity and the likelihood that the symptoms relate with CKD requires further investigations. However one must take into account that the absence of lower urinary tract symptoms in older man does not necessarily exclude BPH with urinary outlet obstruction. Moreover, whether symptoms can be graded according to severity (International Prostate Symtpoms Score – IPSS) this does not predict the degree of obstruction to urinary flow. However, when men with complete chronic urinary retention and severe symptoms needing surgical intervention were evaluated, the authors found as

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,

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

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

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,

are in line more severe cases of renal function deterioration (Yamasaki 2010).

medications, medical examination and urinary tract infections (mainly prostatitis).

that drive men to consult a physician (Hong, Rayford et al. 2005).

much as 30% of men with renal insufficiency (Sacks, Aparicio et al. 1989).

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

Neal et al. 1988; Rule, Lieber et al. 2005; Yamasaki 2010).

PVR influence renal function remains unknown.

**4.3.1 Acute urinary retention** 

most of studies already done.

In the physiological point of view, as the prostate enlarges, it compresses the urethra, preventing the outflow of urine and contributing to the common lower urinary tract symptoms.

Previous studies which examined the association between prostate size and renal function gave conflicting results (Rule, Lieber et al. 2005), some showing a strict relation between prostate size and GFR (Olbrich, Woodford-Williams et al. 1957) but other studies did not (Terris, Afzal et al. 1998)

Other authors, like Shapiro *et* al. emphasize the role of prostatic smooth muscle in pathophysiology of BPH (Shapiro, Hartanto et al. 1992). These authors advocated that the amount of muscle in prostate size and its contractile properties are an important factor in BPH. Smooth muscle cells in are not optimal for force generation. They present a downregulation of smooth muscle myosin heavy chain and a significant upregulation of nonmuscle myosin heavy chain, suggesting either proliferation or loss of normal modulation pathways (Lin, Robertson et al. 2000). Factors that determine passive tone in prostate remain to be elucidated (Wein 2007). However it is known that active muscle tone in human prostate is regulated by adrenergic nervous system (Schwinn 1994). Adrenergic neurotransmitters have been involved in prostate smooth muscle regulation as well as contraction, and α-adrenergic blockade leads to a significant downregulation of normal protein gene expression, specifically smooth muscle myosin heavy chain (Boesch, Dobler et al. 2000; Wein 2007).

Recent studies were made to relate prostate size and LUTS in BPH. Hassanzadeh *et.* al, found a significant correlation between urgency and prostate size (Hassanzadeh, Yavari-kia et al. 2010), which can be considered as predictive factor for the disease and probably a strong link between BPE and CKD.

So, prostate and its enlargement can contribute for outflow obstruction not only by is static component (periurehral compression caused by stromal component) but also dynamic component (smooth muscle cells and adrenergic pathway). Prostate growth is only one of the components of LUTS in aging men.

### **4.2 Lower Urinary Tract Symptoms (LUTS)**

Lower urinary tract symptoms (LUTS) are clinical criteria to define a man with urinary problems. Most of the men with BPH have voiding dysfunction, complaining with nocturia, urgency, week urinary stream, increased urinary frequency and sense of incomplete bladder emptying after micturition.

Many studies were done to achieve a scientific relation between LUTS and CKD, however until recent years there was no palpable evidence connecting these two entities. Hill et al. in a retrospective study did not find any relation between duration of symptoms and serum creatinine levels (Hill, Philpott et al. 1993). Likewise Gerber *et* al. did not achieve any success in linking serum creatinine levels and LUTS (Gerber, Goldfischer et al. 1997). Hong *et* al., reported that although there was no significant association between overall symptoms (IPSS score) with CKD, individual obstructive symptoms such as hesitancy and/or weak stream was significantly associated with CKD status (Hong, Lee et al. 2010)

Our clinical practice shows us that many men with LUTS do not value their symptoms, and do not seek medical care. Those older men often tolerate and disregard their lower urinary

In the physiological point of view, as the prostate enlarges, it compresses the urethra, preventing the outflow of urine and contributing to the common lower urinary tract

Previous studies which examined the association between prostate size and renal function gave conflicting results (Rule, Lieber et al. 2005), some showing a strict relation between prostate size and GFR (Olbrich, Woodford-Williams et al. 1957) but other studies did not

Other authors, like Shapiro *et* al. emphasize the role of prostatic smooth muscle in pathophysiology of BPH (Shapiro, Hartanto et al. 1992). These authors advocated that the amount of muscle in prostate size and its contractile properties are an important factor in BPH. Smooth muscle cells in are not optimal for force generation. They present a downregulation of smooth muscle myosin heavy chain and a significant upregulation of nonmuscle myosin heavy chain, suggesting either proliferation or loss of normal modulation pathways (Lin, Robertson et al. 2000). Factors that determine passive tone in prostate remain to be elucidated (Wein 2007). However it is known that active muscle tone in human prostate is regulated by adrenergic nervous system (Schwinn 1994). Adrenergic neurotransmitters have been involved in prostate smooth muscle regulation as well as contraction, and α-adrenergic blockade leads to a significant downregulation of normal protein gene expression, specifically smooth muscle

Recent studies were made to relate prostate size and LUTS in BPH. Hassanzadeh *et.* al, found a significant correlation between urgency and prostate size (Hassanzadeh, Yavari-kia et al. 2010), which can be considered as predictive factor for the disease and probably a

So, prostate and its enlargement can contribute for outflow obstruction not only by is static component (periurehral compression caused by stromal component) but also dynamic component (smooth muscle cells and adrenergic pathway). Prostate growth is only one of

Lower urinary tract symptoms (LUTS) are clinical criteria to define a man with urinary problems. Most of the men with BPH have voiding dysfunction, complaining with nocturia, urgency, week urinary stream, increased urinary frequency and sense of incomplete bladder

Many studies were done to achieve a scientific relation between LUTS and CKD, however until recent years there was no palpable evidence connecting these two entities. Hill et al. in a retrospective study did not find any relation between duration of symptoms and serum creatinine levels (Hill, Philpott et al. 1993). Likewise Gerber *et* al. did not achieve any success in linking serum creatinine levels and LUTS (Gerber, Goldfischer et al. 1997). Hong *et* al., reported that although there was no significant association between overall symptoms (IPSS score) with CKD, individual obstructive symptoms such as hesitancy and/or weak stream

Our clinical practice shows us that many men with LUTS do not value their symptoms, and do not seek medical care. Those older men often tolerate and disregard their lower urinary

was significantly associated with CKD status (Hong, Lee et al. 2010)

myosin heavy chain (Boesch, Dobler et al. 2000; Wein 2007).

strong link between BPE and CKD.

the components of LUTS in aging men.

emptying after micturition.

**4.2 Lower Urinary Tract Symptoms (LUTS)** 

symptoms.

(Terris, Afzal et al. 1998)

tract symptoms. In our opinion under reported symptoms can induce a significant bias in most of studies already done.

Although many patients who do not value their symptoms, mainly the older ones, the frequency of symptoms and its interference with quality of live (QoL) is the principal factor that drive men to consult a physician (Hong, Rayford et al. 2005).

Patient perceptions are receiving greater emphasis as part of clinical decision-making (Jacobsen, Guess et al. 1993; Roberts, Rhodes et al. 1994). The variability of relationships between symptom severity and the likelihood that the symptoms relate with CKD requires further investigations. However one must take into account that the absence of lower urinary tract symptoms in older man does not necessarily exclude BPH with urinary outlet obstruction. Moreover, whether symptoms can be graded according to severity (International Prostate Symtpoms Score – IPSS) this does not predict the degree of obstruction to urinary flow. However, when men with complete chronic urinary retention and severe symptoms needing surgical intervention were evaluated, the authors found as much as 30% of men with renal insufficiency (Sacks, Aparicio et al. 1989).
