Transcript Role of Renin-Angiotensin Aldosterone System in Peritoneal

Role of Renin-Angiotensin
Aldosterone System in Peritoneal
Membrane Damage
Source: Nessim SJ, Perl J, Bargman JM. The
renin–angiotensin–aldosterone system in
peritoneal dialysis:
Is what is good for the kidney also good for the
peritoneum? Kid Int. 2010;78:23–28.
Overview
• The renin-angiotensin aldosterone system (RAAS) is anticipated to
have a role in fibrosis and neoangiogenesis of the peritoneal
membrane, which was observed during peritoneal dialysis (PD).
• Elevated levels of glucose concentration, reduced pH and the glucose
degradation products (GDPs) present in the PD solutions have been
thought to be responsible for the inflection of peritoneal RAAS.
• Apart from the activation of the RAAS, the downstream production
of the transforming growth factor-β, leads to the transformation of
mesothelial cellsfrom epithelial-to-mesenchymal, thereby giving rise
tofibrosis of the peritoneal membrane.The progression results in the
elevated production ofthe vascular endothelial growth factor, which
advancesthe neoangiogenesis of the peritoneal membrane.
• These alterations decrease the peritoneal membrane’s
ultrafiltration(UF) ability, which is a vital cause behind the
techniquefailure in patients on long-term PD.
Peritoneal Membrane Changes in
Patients on PD
Peritoneal Membrane
– The peritoneal membrane consists of a mesothelial
monolayer, below which lies the submesothelial
compact zone, which is formed of the connective
tissue with interspersed fibroblasts, macrophages and
mast cells.
– Through these stratums, the processes of diffusion
and UF occur.
– Any morphological changes that usually happen with
the prolongation of PD are observed primarily within
the parietal peritoneal membrane.
Effect on the Peritoneal Membrane
• Submesothelial Compact Zone’s Median
Thickness:
– Studies have shown that uremic patients compared to
controls demonstrated reactive changes in the
mesothelial cell and an increase in the thickness of
submesothelial compact zone.
– Based on the biopsy results, it was seen that PD
patients had more pronounced mesothelial cell
changes, ranging from a reactive appearance to
mesothelial cell loss, as compared to uremic patients
not on dialysis.
Effect on the Peritoneal Membrane
• Vascular Changes:
– Significant vascular changes were observed in
patients on PD. Peritoneal neoangiogenesis as well
as progressive subendothelial hyalinization with
luminal narrowing or obliteration was observed.
– About 89% of patients on PD for no less than 6
years had an indication of vasculopathy.
Peritoneal Membrane Destruction
Causes
Solute Transportation
• An increased solute transportation has been attributed
to peritoneal neoangiogenesis, which results in the
increase in effective peritoneal surface area, whereas
the reduction in UF is likely multifactorial.
Ultrafiltration Failure
• Ultrafiltration failure is a vital cause behind the
technique failure in patients on long-term PD.
Therefore, it is important to understand the
mechanism of the peritoneal membrane changes and
prolongation of the duration of PD.
Peritoneal Membrane Destruction
Causes
RAAS Activation
• Various tissues, including the kidney tissues have been
observed to be able to locally synthesize all RAAS
components.
• The renal tubular cells have been seen to express renin and
angiotensin, which behaves in an autocrine or paracrine
manner, leading to an upregulation of the transforming
growth factor-􀁅 (TGF-β), and factors like aldosterone that
stimulates interstitial fibrosis.
• It has been observed that mesothelial cells constitutively
express angiotensin-converting enzyme (ACE),
angiotensinogen, the angiotensin II type 1 and type 2
receptors and fibronectin and TGF-β.
• The activation of RAAS could be due to one or more
components of the bioincompatible solutions like
elevated glucose and lactate concentration, low pH,
hyperosmolality and the presence of GDPs.
• Exposure of the peritoneal membrane to glucose gives
rise to the upregulation of angiotensinogen, ACE and
angiotensin II receptor type 1 expression.
• Glucose has also been shown to augment the
angiotensin II production and secretion, which further
upregulates TGF-β and fibronectin expression, as well
as vascular endothelial growth factor (VEGF)
stimulation and procollagen secretion.
• The RAAS can also get activated by the acute
inflammatory stimuli like peritonitis, which
causes a significant upregulation of
angiotensin II expression in human peritoneal
mesothelial cells, resulting in increased
expression of fibronectin.
• The inflammatory stimuli also activate the
pregulation of profibrotic factors, such as TGFβ and angiogenic factors, such as VEGF.
Strategies for Preservation of
Peritoneal Membrane
Systemic RAAS Blockade
• Several studies have shown that ACE inhibitors, ARBs, direct renin
inhibitors and aldosterone antagonists could have a potential role.
• Losartan and captopril, in vitro, has demonstrated the inhibition of
glucose-induced TGF-􀁅 and fibronectin expression.
• Moreover, the addition of captopril leads to a concentrationdependent reduction in VEGF synthesis.
• Data from the human trial have been limited.
• In a latest retrospective analysis it was shown that there is a
powerful survival benefit in PD patients who were treated with an
ARB or ACE inhibitor.
• Till date there have been no studies that have evaluated the
longitudinal effect of RAAS blockade on the histology of the
peritoneal membrane.
Strategies for Preservation of
Peritoneal Membrane
Attenuation of Local RAAS Activation
• The use of a glucose-sparing regimen substituting icodextrin or
amino acid-based PD solutions could reduce the glucose-induced
effects.
• Vitamin D is also thought to transform RAAS activation in kidney
tissues.
• The vitamin D deficiency is related to the upregulation of RAAS
activity, whereas supplementation with vitamin D has been shown
to decrease RAAS activation.
• However, the supplementation with active and/or inactive forms of
vitamin D in justifying the peritoneal RAAS activation needs to be
studied further, considering that most PD patients are deficient in
25- hydroxyvitamin D and 1,25-dihydroxyvitamin D.
Conclusion
• Long-term PD is linked with functional and
morphological changes within the peritoneal
membrane.
• Even though the etiology of these changes is
multifactorial, there are in vitro, animal and human
data that indicates the role of RAAS in the
pathogenesis of the peritoneal membrane fibrosis and
neoangiogenesis, which occurs during prolonged PD.
• The use of ACE inhibitors and ARBs in RAAS inhibition
needs to be studied further, although these agents
have demonstrated peritoneoprotection.
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