Tag Archive for: physiological

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Infographic: The origins of urinary stone disease: upstream mineral formations initiate downstream Randall’s plaque

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Figure 1 The medullo-papillary complex. A total of 8–12 paraboloid complexes are contained within each human kidney. Each complex can be separated into three zones (Zones 1–3) distinguished by distinct segments of the loop of Henle. There are short- and long-looped nephrons and vessels. Owing to the paraboloid geometry of the medullo-papillary complex, shorter looped nephrons and vessels are contained in the periphery, and the longest looped nephrons and vessels are located centrally. Non-fenestrated descending vasa recta are surrounded by layers of smooth muscle, in contrast to the ascending vasa recta comprised of fenestrated endothelium. Within Zone 3, a transition occurs where pericytes replace smooth muscle.

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Figure 2 Spatial relationships and size distributions of the tubules and vessels within the medullo-papillary complex. From Zone 1 to Zone 2, the ascending and descending vasa recta become organised into vascular bundles (dotted line) and interbundle regions. In Zone 3, the descending thin limbs join the vascular bundles (light dotted line), and these are separate from collecting duct clusters. Collecting ducts grow larger in diameter towards Zone 3 and coalesce to form the 6–12 ducts of Bellini. These anatomically specific compartments contribute to radial and axial concentration gradients along the course of the complex.

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Figure 3 Medullo-papillary function is characterised by pressure and chemical gradients. Pressure gradients are present from Zone 1 to Zone 3. Due to the paraboloid form of the complex, larger diameter vasa recta are located centrally within the vascular bundles and have higher pressure gradients and flow rates than in the peripherally located vasa recta. Poiseuille’s law relates flow rate as proportional to pressure and radius to the fourth power, and inversely proportional to fluid viscosity and tube length. Within each tube, velocity of fluid is highest at the centerline, but decreases near the wall due to resistance. Over time, within a concentrated fluid, solutes are expected to accumulate along the walls. From Zone 1 to Zone 3, an increasing osmolarity gradient, contributed by primarily sodium salts and urea, generates the urine concentrating ability through countercurrent exchange. Areas vulnerable to hypoxic injury include the tip of the Zone 3, and Zone 2 because of the metabolically active thick ascending limbs and their relative physical separation from the descending vasa recta.

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Figure 4 Biomineralisation of the medullo-papillary complex leading to Randall’s plaque. Over time, lower pressure gradients in the peripheral tubules relative to the centrally located tubules lead to intratubular mineralisation within Zones 1 and 2. The functional volume of the complex gradually decreases, and at a certain threshold, the change in pressure gradient drives a mechanoresponsive switch that leads to interstitial mineralisation in Zone 3. The accumulation of biominerals in the interstitial space eventually becomes endoscopically visible as Randall’s plaque, the foundation for a future urinary tract stone.

 

Abstract

Objectives

To describe a new hypothesis for the initial events leading to urinary stones. A biomechanical perspective on Randall’s plaque formation through form and function relationships is applied to functional units within the kidney, we have termed the ‘medullo-papillary complex’ – a dynamic relationship between intratubular and interstitial mineral aggregates.

Methods

A complete MEDLINE search was performed to examine the existing literature on the anatomical and physiological relationships in the renal medulla and papilla. Sectioned human renal medulla with papilla from radical nephrectomy specimens were imaged using a high resolution micro X-ray computed tomography. The location, distribution, and density of mineral aggregates within the medullo-papillary complex were identified.

Results

Mineral aggregates were seen proximally in all specimens within the outer medulla of the medullary complex and were intratubular. Distal interstitial mineralisation at the papillary tip corresponding to Randall’s plaque was not seen until a threshold of proximal mineralisation was observed. Mineral density measurements suggest varied chemical compositions between the proximal intratubular (330 mg/cm3) and distal interstitial (270 mg/cm3) deposits. A review of the literature revealed distinct anatomical compartments and gradients across the medullo-papillary complex that supports the empirical observations that proximal mineralisation triggers distal Randall’s plaque formation.

Conclusion

The early stone event is initiated by intratubular mineralisation of the renal medullary tissue leading to the interstitial mineralisation that is observed as Randall’s plaque. We base this novel hypothesis on a multiscale biomechanics perspective involving form and function relationships, and empirical observations. Additional studies are needed to validate this hypothesis.

Ryan S. Hsi*, Krishna Ramaswamy*, Sunita P. Ho† and Marshall L. Stoller*

 

*Department of Urology, and Division of Biomaterials and Bioengineering, Department of Preventive and Restorative Dental Sciences, School of Dentistry, University of California San Francisco, San Francisco, CA, USA

 

Article of the Week: NSAID use and ED risk

Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Mr. Darshan Patel, discussing his paper.

If you only have time to read one article this week, it should be this one.

Non-steroidal anti-inflammatory drug (NSAID) use is not associated with erectile dysfunction risk: results from the Prostate Cancer Prevention Trial

 

Darshan P. Patel, Jeannette M. Schenk*, Amy Darke, Jeremy B. Myers, William O. Brant and James M. Hotaling

 

Division of Urology, University of Utah, Salt Lake City, UT, *Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, and SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

 

Read the full article

Objective

To evaluate the associations of non-steroidal anti-inflammatory drug (NSAID) use with risk of erectile dysfunction (ED), considering the indications for NSAID use.

Patients and Methods

We analysed data from 4 726 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) without evidence of ED at baseline. Incident ED was defined as mild/moderate (decrease in normal function) or severe (absence of function). Proportional hazards models were used to estimate the covariate-adjusted associations of NSAID-related medical conditions and time-dependent NSAID use with ED risk.

AOTWMar3

Results

Arthritis (hazard ratio [HR] 1.56), chronic musculoskeletal pain (HR 1.35), general musculoskeletal complaints (HR 1.36), headaches (HR 1.44), sciatica (HR 1.50) and atherosclerotic disease (HR 1.60) were all significantly associated with an increased risk of mild/moderate ED, while only general musculoskeletal complaints (HR 1.22), headaches (HR 1.47) and atherosclerotic disease (HR 1.60) were associated with an increased risk of severe ED. Non-aspirin NSAID use was associated with an increased risk of mild/moderate ED (HR 1.16; P = 0.02) and aspirin use was associated with an increased risk of severe ED (HR 1.16; P = 0.03, respectively). The associations of NSAID use with ED risk were attenuated after controlling for indications for NSAID use.

Conclusions

The modest associations of NSAID use with ED risk in the present cohort were probably attributable to confounding indications for NSAID use. NSAID use was not associated with ED risk.

Read more articles of the week

Editorial: PCPT May Exculpate COX Blockers in Erectile Dysfunction

NSAIDs are one of the most commonly used medications classes in the USA. Despite their ubiquity, they remain controversial. The withdrawal of the selective cyclooxygenase (COX)-2 inhibitor Rofecoxib in 2004 was a low point, culminating in a >$4.85 billion dollar (American dollars) settlement by Merck Pharmaceuticals. More recently, in July 2015 the USA Food and Drug Administration (FDA) strengthened a ‘black box warning’ (warning that appears on the package insert) on all NSAIDs for increased risks of heart attack, stroke, and heart failure (www.fda.gov/drugs/drugsafety). Given common vascular pathways in erectile dysfunction (ED) and heart disease, detrimental effects on sexual health have long been suspected as well. This month’s issue of BJUI provides a new perspective on this relationship and may help exculpate these common drugs [1].

It is thought that the cardiovascular risk of NSAIDs arises from inhibition of the COX-arachidonic acid synthesis pathway, which produces important mediators (e.g. eicosanoids like prostacyclin and various prostaglandin subtypes) for inflammation, vascular tone, and vascular permeability [2]. Given that many of the same chemical mediators affect erectile physiology, it is not surprising that a previous study of 80 966 men showed an association between NSAID use and ED after accounting for age, race, and comorbidities [3].

In ‘Non-steroidal anti-inflammatory drug use not associated with erectile dysfunction risk …’, Patel et al. [1] show that this risk may not be what it once seemed. They assess the risk of developing ED for men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) after first reported NSAID use. There is a small but statistically significant and consistent relationship between initiation of NSAID use and ED. Curiously, the association of NSAIDs with ED disappeared once they controlled for the indications for NSAID use such as arthritis, chronic pain, headaches, and cardiovascular disease. This finding makes sense: common indications for NSAIDs, like arthritis, headaches, and chronic musculoskeletal pain, may indicate an underlying sedentary lifestyle or chronic inflammatory conditions, both imputed in ED [4]. As such, this study design provides key epidemiological inference on the causal links between inflammation, lifestyle, and ED. It may be these factors, not NSAIDs themselves, which account for the previously shown association with ED.

With that said, epidemiological assessment of eicosanoid-mediated effects on ED may require further study. For example, NSAID-mediated downregulation of endothelial signalling molecules could produce a short-lived, but clinically significant effect on cavernosal blood supply. Alternatively, ED may only arise in the setting of chronic downregulation of affected pathways. Epidemiological studies characterising the relationship between NSAID use and ED should therefore assess the amount and duration of NSAIDs use, as well as the quality and timing of erections relative to use. Basic research may also help elucidate this relationship. Earlier studies have assessed cavernosal endothelial concentrations of these same vascular mediators in diabetic animal models [5]. In a similar fashion in vivo assessment of COX-derived mediators using animal models could further characterise the vascular pathways involved in erection and the effects of NSAID use.

Patel et al. [1] add a valuable contribution to the study of NSAIDs and ED. Their finding that NSAID-induced effects on ED disappear when controlling for the indications of NSAID, may support the inflammatory hypothesis of ED. But as others have noted, there is an intrinsic difficulty in retrospectively assessing the complex, multifactorial causes of sexual dysfunction [6]. Future studies on the amount and timing of NSAID use, paired with biochemical studies of vascular mediators in the cavernosal endothelium in NSAID users, may allow for even more nuanced characterisation of the effects of COX inhibition on erectile function. While logistically challenging, such studies could provide the key evidence for assessing the vascular pathways underlying ED and their relationship with NSAIDs.

Read the full article
Alexander P. Cole, Jeffrey J. Leow, and Quoc-Dien Trinh
Center for Surgery and Public Health, Division of Urology, Brigham and Womens Hospital, Harvard Medical School, Boston, MA, USA

 

References

 

1 Patel DP, Schenk JM, Darke A, Myers JB, Brant WO, Hotaling JMNon-steroidal anti-inammatory drug use not associated with erectile dysfunction risk: results from the Prostate Cancer Prevention Trial. BJU Int 2016; 117: 5006

 

2 Antman EM, DeMets D, Loscalzo J. Cyclooxygenase inhibition and cardiovascular risk. Circulation 2005; 112: 75970

 

3 Gleason JM, Slezak JM, Jung H et al. Regular nonsteroidal anti- inammatory drug use and erectile dysfunction. J Urol 2011; 185: 138893

 

4 Vlachopoulos C, Rokkas K, Ioakeimidis N, Stefanadis C.Inammation, metabolic syndrome, erectile dysfunction, and coronary artery disease: common links. Eur Urol 2007; 52: 1590600

 

5 Sullivan M, Thompson CS, Mikhailidis DP, Morgan RJ, Angelini GDJeremy JY. Differential alterations of prostacyclin, cyclic AMP and cyclic GMP formation in the corpus cavernosum of the diabetic rabbit. Br Urol 1998; 82: 57884

 

6 Lombardi G, Musco S, Kessler TM, Li Marzi V, Lanciotti MDel Popolo G. Management of sexual dysfunction due to central nervous system disorders: a systematic review. BJU Int 2015; 115(Suppl.6): 4756

 

Video: NSAID use is not associated with erectile dysfunction risk

Non-steroidal anti-inflammatory drug (NSAID) use is not associated with erectile dysfunction risk: results from the Prostate Cancer Prevention Trial

Darshan P. Patel, Jeannette M. Schenk*, Amy Darke, Jeremy B. Myers, William O. Brant and James M. Hotaling

 

Division of Urology, University of Utah, Salt Lake City, UT, *Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, and SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

 

Read the full article

Objective

To evaluate the associations of non-steroidal anti-inflammatory drug (NSAID) use with risk of erectile dysfunction (ED), considering the indications for NSAID use.

Patients and Methods

We analysed data from 4 726 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) without evidence of ED at baseline. Incident ED was defined as mild/moderate (decrease in normal function) or severe (absence of function). Proportional hazards models were used to estimate the covariate-adjusted associations of NSAID-related medical conditions and time-dependent NSAID use with ED risk.

AOTWMar3

Results

Arthritis (hazard ratio [HR] 1.56), chronic musculoskeletal pain (HR 1.35), general musculoskeletal complaints (HR 1.36), headaches (HR 1.44), sciatica (HR 1.50) and atherosclerotic disease (HR 1.60) were all significantly associated with an increased risk of mild/moderate ED, while only general musculoskeletal complaints (HR 1.22), headaches (HR 1.47) and atherosclerotic disease (HR 1.60) were associated with an increased risk of severe ED. Non-aspirin NSAID use was associated with an increased risk of mild/moderate ED (HR 1.16; P = 0.02) and aspirin use was associated with an increased risk of severe ED (HR 1.16; P = 0.03, respectively). The associations of NSAID use with ED risk were attenuated after controlling for indications for NSAID use.

Conclusions

The modest associations of NSAID use with ED risk in the present cohort were probably attributable to confounding indications for NSAID use. NSAID use was not associated with ED risk.

Read more articles of the week
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