1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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 TGF- β and angiogenic factors, such as VEGF.

10. 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 concentration- dependent 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.

11. 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.

12. 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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