**3. The relationship between benign prostatic hyperplasia and chronic kidney disease – A consequence of urinary outflow obstruction?**

Although the exact etiology of BPH is not known it seems (from recent studies and daily clinical practice) that the natural history and evolution of benign prostatic enlargement ends up in urinary obstruction causing degradation of renal function over time.

Both diseases are extremely common among aging male, leading some to suggest that it is a natural concomitant of aging (Wu, Li et al. 2006).

In his 1989 retrospective study of 19 patients who were admitted to renal dialysis units for end-stage renal disease caused by BPH, authors (Sacks, Aparicio et al. 1989) raised awareness of BPH as a cause for CKD and suggested a more adequate screening of renal function in men with untreated LUTS. More recently a cross-sectional survey in Spain of 2,000 randomly sampled men who were 50 years or older showed a 2.4% prevalence of self-reported renal failure related to a prostate condition (9% reported renal failure from any cause) (Hunter, Berra-Unamuno et al. 1996; Rule, Lieber et al. 2005). The main limitation of this study was that it relied on the self report of CKD, and no distinction between Acute Renal Failure (ARF) or CKD was made. Nonetheless it remains one largest studies that reveals a connection between CKD and BPH (Hunter, Berra-Unamuno et al. 1996). Another study (Hill, Philpott et al. 1993) showed that men presenting for prostate

Benign Prostate Hyperplasia and Chronic Kidney Disease 351

As we take all this data into account, one should bear in mind that BPH is an almost ubiquitous condition in the old man. The low occurrence of CKD in BPH clinical trials should not be used to infer a weak association between the two disease processes. However it is clear that not all expressions of BPH are associated with CKD: Prostate volume, PSA (Prostate Specific Antigen) and even LUTS do not share a strong association with CKD

Bladder outlet obstruction signs and symptoms (QMax, PVR, Obstructive LUTS) are significant predictors of CKD (Rule, Jacobson et al. 2005; Yamasaki 2010), bladder outlet obstruction probably makes the bridge between CKD and BPH (Hong, Lee et al. 2010). This

We should also never forget that CKD is a multifactorial process, and it becomes difficult to separate the contribution of BHP from all the other renal insults. This also takes its toll on the design of the studies as many men with concomitant disease are excluded, and thus making it harder for investigators to take into account the true influence of BPH on

The exact etiology of BPH is unknown, however the similarity between BPH and the embryonic morphogenesis of the prostate has led to hypothesis that BPH may result from a reawakening of embryonic induction process in adulthood (Oesterling 1996; McVary 2006). The most common renal pathology finding in men with obstructive nephropathy due to BPH is chronic interstitial nephritis (Coroneos, Assouad et al. 1997; Rule, Lieber et al. 2005)

Late or end stage renal failure secondary to prostatic or bladder outflow obstruction should be amenable to prevention if cases are recognised early, however it still difficult to recognise which men with BPH are at risk of renal failure and need close investigation. For this reason we truly believe that is important to recognize factors that can be measured and are

To assess BPH as risk factor for chronic kidney disease or renal failure it is important to understand the surrogate measures often used to diagnose BPH. These factors are

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

(Rule, Jacobson et al. 2005; Ponholzer, Temml et al. 2006; Hallan, Kwong et al. 2010).

is probably a reflection of the etiology of CKD secondary to BPH.

and 30% of cases have been attributed to obstructive uropathy.

essentially clinical, anatomical and physiological.

**4.1 Benign prostate enlargement**

ultrasound).

important bases or risk factors for the evaluation and treatment of BPH.

**4. BPH physiopathology, disease progression and renal failure** 

CKD.

surgery had a 7,7% prevalence of renal failure compared to a 3,7% prevalence in age matched men presenting for nonprostate surgery. This proves that renal failure in men with advanced BPH does not only reflect older age. Other statistical study revealed that men presented to urologist for BPH treatment showed an average of 13,6% of renal failure(McConnell, Barry et al. 1994).

The Rochester Epidemiology Project found a significant association between signs and symptoms of BPH and CKD in their population-based sample of 476 white men (Rule, Jacobson et al. 2005; Rule, Lieber et al. 2005). There was a significant association between CKD and moderate/ severe LUTS and peak flow rate of <15 mL/s. In conclusion there was a cross-sectional association between signs and symptoms of bladder outlet obstruction and chronic kidney disease in community-dwelling men (Rule, Lieber et al. 2005).

In contrast, a population-based study from Austria did not find LUTS to be an independent risk factor for impaired kidney function in men. A total of 2.469 men entered the crosssectional study and 439 with CKD were assessed in longitudinal analysis. LUTS was assessed using the IPSS (International Prostate Symptom Score) questionnaire. There was no significant association between degree of LUTS and GFR after adjusting for age in this crosssectional study (Ponholzer, Temml et al. 2006).

Furthermore a 30,466 men study from the HUNT II (Second Health Study in Nord-Trøndelag; 1995-1997) failed to show a connection between LUTS and CKD (Hallan, Kwong et al. 2010). Results have shown that men with moderate to severe LUTS, indicating BPH, did not have increased risk of future kidney failure after adjusting for age, and inclusion of men with such symptoms did not improve the effectiveness of a CKD screening strategy using kidney failure as the main outcome (Hallan, Kwong et al. 2010; Hallan and Orth 2010).

Nonetheless quite recently evidence of association between BPH and CKD has arisen in two different studies. In a recent study by Yamasaki *et* al, the Post-Void Residue (PVR) of the patients with CKD was significantly greater than that of the patients without CKD and the presence of post-void residual urine was independently associated with CKD, indicating a close association between CKD and residual urine. In this study the PVR is used as a surrogate measure of Bladder Outlet Obstruction (BOO) and thus of urodinamically relevant BPH (Yamasaki 2010). Authors reported a higher prevalence (31,8%) of CKD among BPH patients (Yamasaki 2010). In another study by Hong et al (Hong, Lee et al. 2010), the results showed that a decreased Qmax (Peak flow rate), with a history of hypertension and/or diabetes, were significantly associated with CKD in men seeking management for LUTS caused by BPH of various severity. Although the prevalence of CKD can be considered relatively low among men with BPH, the possibility of CKD should be considered in those who have a low Qmax, obstructive urinary symptoms, or have comorbidities such as hypertension and DM (Hong, Lee et al. 2010). In this study the authors report 494 patients from a group of 2741 BPH patients that were classified as having CKD (eGFR < 60 mL/min/1,73 m2).

The 1994 Agency for Health Care Policy and Research created BPH clinical guidelines that recommended serum creatinine screening in men presenting with lower urinary tract symptoms, however a 2003 update discontinued the serum creatinine measurements (Rule, Lieber et al. 2005). These different approaches to BPH patients may lead to a significant amount of patients underdiagnosed for CKD.

surgery had a 7,7% prevalence of renal failure compared to a 3,7% prevalence in age matched men presenting for nonprostate surgery. This proves that renal failure in men with advanced BPH does not only reflect older age. Other statistical study revealed that men presented to urologist for BPH treatment showed an average of 13,6% of renal

The Rochester Epidemiology Project found a significant association between signs and symptoms of BPH and CKD in their population-based sample of 476 white men (Rule, Jacobson et al. 2005; Rule, Lieber et al. 2005). There was a significant association between CKD and moderate/ severe LUTS and peak flow rate of <15 mL/s. In conclusion there was a cross-sectional association between signs and symptoms of bladder outlet obstruction and

In contrast, a population-based study from Austria did not find LUTS to be an independent risk factor for impaired kidney function in men. A total of 2.469 men entered the crosssectional study and 439 with CKD were assessed in longitudinal analysis. LUTS was assessed using the IPSS (International Prostate Symptom Score) questionnaire. There was no significant association between degree of LUTS and GFR after adjusting for age in this cross-

Furthermore a 30,466 men study from the HUNT II (Second Health Study in Nord-Trøndelag; 1995-1997) failed to show a connection between LUTS and CKD (Hallan, Kwong et al. 2010). Results have shown that men with moderate to severe LUTS, indicating BPH, did not have increased risk of future kidney failure after adjusting for age, and inclusion of men with such symptoms did not improve the effectiveness of a CKD screening strategy using kidney failure as the main outcome (Hallan, Kwong et al. 2010; Hallan and Orth 2010). Nonetheless quite recently evidence of association between BPH and CKD has arisen in two different studies. In a recent study by Yamasaki *et* al, the Post-Void Residue (PVR) of the patients with CKD was significantly greater than that of the patients without CKD and the presence of post-void residual urine was independently associated with CKD, indicating a close association between CKD and residual urine. In this study the PVR is used as a surrogate measure of Bladder Outlet Obstruction (BOO) and thus of urodinamically relevant BPH (Yamasaki 2010). Authors reported a higher prevalence (31,8%) of CKD among BPH patients (Yamasaki 2010). In another study by Hong et al (Hong, Lee et al. 2010), the results showed that a decreased Qmax (Peak flow rate), with a history of hypertension and/or diabetes, were significantly associated with CKD in men seeking management for LUTS caused by BPH of various severity. Although the prevalence of CKD can be considered relatively low among men with BPH, the possibility of CKD should be considered in those who have a low Qmax, obstructive urinary symptoms, or have comorbidities such as hypertension and DM (Hong, Lee et al. 2010). In this study the authors report 494 patients from a group of 2741 BPH patients that were classified as having

The 1994 Agency for Health Care Policy and Research created BPH clinical guidelines that recommended serum creatinine screening in men presenting with lower urinary tract symptoms, however a 2003 update discontinued the serum creatinine measurements (Rule, Lieber et al. 2005). These different approaches to BPH patients may lead to a significant

chronic kidney disease in community-dwelling men (Rule, Lieber et al. 2005).

failure(McConnell, Barry et al. 1994).

sectional study (Ponholzer, Temml et al. 2006).

CKD (eGFR < 60 mL/min/1,73 m2).

amount of patients underdiagnosed for CKD.

As we take all this data into account, one should bear in mind that BPH is an almost ubiquitous condition in the old man. The low occurrence of CKD in BPH clinical trials should not be used to infer a weak association between the two disease processes. However it is clear that not all expressions of BPH are associated with CKD: Prostate volume, PSA (Prostate Specific Antigen) and even LUTS do not share a strong association with CKD (Rule, Jacobson et al. 2005; Ponholzer, Temml et al. 2006; Hallan, Kwong et al. 2010).

Bladder outlet obstruction signs and symptoms (QMax, PVR, Obstructive LUTS) are significant predictors of CKD (Rule, Jacobson et al. 2005; Yamasaki 2010), bladder outlet obstruction probably makes the bridge between CKD and BPH (Hong, Lee et al. 2010). This is probably a reflection of the etiology of CKD secondary to BPH.

We should also never forget that CKD is a multifactorial process, and it becomes difficult to separate the contribution of BHP from all the other renal insults. This also takes its toll on the design of the studies as many men with concomitant disease are excluded, and thus making it harder for investigators to take into account the true influence of BPH on CKD.
