Blockage of the renin-angiotensin system in peritoneal dialysis

EDITORIAL

Blockage of the renin-angiotensin system in peritoneal dialysis

Hugo Abensur

University Hospital, School of Medicine of the University of São Paulo

^{Correspondence to}

Blockade of the renin-angiotensin system (RAS) in patients on peritoneal dialysis offers three potential benefits: reduced cardiovascular mortality, preservation of residual renal function, and maintenance of peritoneal membrane integrity.

No studies have examined the specific effects of RAS blockade on the mortality of patients on peritoneal dialysis. But evidence suggests patients with chronic kidney disease on hemodialysis may benefit from RAS blockade.^1,2 However, Wong et al.³ reported a correlation between angiotensin converting enzyme activity, macroangiopathy, and death in 49 diabetic patients on peritoneal dialysis.

Residual renal function preservation is a determining factor in the survival of patients undergoing peritoneal dialysis.⁴ RAS blockade is an important therapeutic tool to prevent the progression of chronic kidney disease.^4-6 A large observational study enrolling over 1000 patients on peritoneal dialysis showed that patients on angiotensin converting enzyme inhibitors had delayed development of anuria.⁷ Li et al.⁸ reported that ramipril protected residual renal function of patients on peritoneal dialysis. The 2006 American guidelines for peritoneal dialysis recommend the use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers to preserve residual renal function in patients on peritoneal dialysis.⁹ However, some authors have failed to demonstrate the benefits of RAS blockade in preserving residual renal function of patients on peritoneal dialysis.^10,11

Over the course of peritoneal dialysis the peritoneal membrane thickens, loses its mesothelial layer, undergoes neoangiogenesis, and develops fibrosis. These changes are caused by uremia, insults resulting from episodes of peritonitis, lack of bio-compatibility with the dialysis solution, and presence of a peritoneal dialysis catheter. The high concentration of glucose in the dialysis solution has been identified as the main causal agent of damages to the peritoneal membrane. These insults stimulate the production of inflammatory cytokines such as interleukin-6, transforming growth factor-β (TGF-β), and vascular endothelium growth factor (VEGF), among others.¹² Mesothelial cells are believed to turn into mesenchymal cells, which then infiltrate the submesothelial layer and produce various cytokines that promote vascular proliferation and fibrosis.¹³ These histopathological changes have been correlated with fast transport patterns characterized by rapid absorption of glucose from the dialysate intraperitoneally, early dissipation of the osmotic gradient, and reduced ultrafiltration. The final pathway of this inflammatory process is sclerosing peritonitis, which in its most severe form has been associated with intestinal obstruction in what is called sclerosing encapsulating peritonitis.¹⁴

Various measures have been studied in the areas of prophylactic care and treatment of peritoneal injuries, such as the use of more biocompatible dialysis solutions, antioxidants such as N-acetylcysteine,¹⁵ antifibrotic agents such as tamoxifen,¹⁶ immunosuppressants,¹⁶ corticosteroids, and others. RAS activation has been correlated with fibrosis, mainly due to increases in the production of TGF-β. Experimental evidence indicates RAS blockade on peritoneal dialysis patients can protect the peritoneal membrane.^17-21 In humans, the results of RAS blockade are controversial, with some authors suggesting it offers protective properties^22-25 while others not.^26-28

In this issue of the Brazilian Journal of Nephrology, Schuinski et al.²⁹ looked into this matter and administered captopril by gavage to Wistar rats given intravenous hypertonic glucose solution. The authors could not clearly demonstrate protection against peritoneal histological changes with captopril, but they observed a non-statistical trend toward protection. Perhaps a larger number of animals or a longer observation period could help improve our understanding of this matter.

Although its role on peritoneal dialysis has not been fully elucidated, RAS blockade is recommended for the possibilities it offers in cardiovascular protection, reduction of the rate of loss of residual renal function, and peritoneal membrane protection.

REFERENCES

1. McCullough PA, Sandberg KR, Yee J, Hudson MP. Mortality benefit of angiotensin-converting enzyme inhibitors after cardiac events in patients with end-stage renal disease. J Renin Angiotensin Aldosterone Syst 2002;3:188-91. DOI: http://dx.doi.org/10.3317/jraas.2002.040

2. Efrati S, Zaidenstein R, Dishy V, Beberashvili I, Sharist M, Averbukh Z, et al. ACE inhibitors and survival of hemodialysis patients. Am J Kidney Dis 2002;40:1023-9. PMID: 12407648 DOI: http://dx.doi.org/10.1053/ajkd.2002.36340

3. Wong TY, Szeto CC, Chow KM, Chan JC, Li PK. Prognostic role of serum ACE activity on outcome of type 2 diabetic patients on chronic ambulatory peritoneal dialysis. Am J Kidney Dis 2002;39:1054-60. DOI: http://dx.doi.org/10.1053/ajkd.2002.32789

4. Bargman JM, Thorpe KE, Churchill DN; CANUSA Peritoneal Dialysis Study Group. Relative contribution of residual renal function and peritoneal clearance to adequacy of dialysis: a reanalysis of the CANUSA study. J Am Soc Nephrol 2001;12:2158-62.

5. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993;329:1456-62. DOI: http://dx.doi.org/10.1056/NEJM199311113292004

6. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, at al.; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-9.

7. Moist LM, Port FK, Orzol SM, Young EW, Ostbye T, Wolfe RA. Predictors of loss of residual renal function among new dialysis patients. J Am Soc Nephrol 2000;11:556-64.

8. Li PK, Chow KM, Wong TY, Leung CB, Szeto CC. Effects of an angiotensin-converting enzyme inhibitor on residual renal function in patients receiving peritoneal dialysis. A randomized, controlled study. Ann Intern Med 2003;139:105-12. PMID: 12859160 DOI: http://dx.doi.org/10.7326/0003-4819-139-2-200307150-00010

9. National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for 2006 Updates: Hemodialysis Adequacy, Peritoneal Dialysis Adequacy and Vascular Access. Am J Kidney Dis 2006;48:S1-S322.

10. Johnson DW, Mudge DW, Sturtevant JM, Hawley CM, Campbell SB, Isbel NM, et al. Predictors of decline of residual renal function in new peritoneal dialysis patients. Perit Dial Int 2003;23:276-83. PMID: 12938830

11. Margetts PJ, Bonniaud P, Liu L, Hoff CM, Holmes CJ, West-Mays JA, et al. Transient overexpression of TGF-{beta}1 induces epithelial mesenchymal transition in the rodent peritoneum. J Am Soc Nephrol 2005;16:425-36. DOI: http://dx.doi.org/10.1681/ASN.2004060436

12. Pecoits-Filho R, Araújo MR, Lindholm B, Stenvinkel P, Abensur H, Romão JE Jr, at al. Plasma and dialysate IL-6 and VEGF concentrations are associated with high peritoneal solute transport rate. Nephrol Dial Transplant 2002;17:1480-6. DOI: http://dx.doi.org/10.1093/ndt/17.8.1480

13. Selgas R, Bajo A, Jiménez-Heffernan JA, Sánchez-Tomero JA, Del Peso G, Aguilera A, et al. Epithelial-to-mesenchymal transition of the mesothelial cell--its role in the response of the peritoneum to dialysis. Nephrol Dial Transplant 2006;21:ii2-7.

14. Cestari AT, Conti ML, Prats JA, Sato Junior H, Abensur H. Sclerosing encapsulating peritonitis after peritoneal dialysis. J Bras Nefrol 2013;35:65-8. DOI: http://dx.doi.org/10.5935/01012800.20130010

15. Bui DS, Seguro AC, Shimitzu MH, Schliemann I, Martini D, Romão JE Jr, et al. N-Acetylcysteine protects the peritoneum from the injury induced by hypertonic dialysis solution. J Nephrol 2012;25:90-5.

16. Huddam B, Azak A, Koçak G, Başaran M, Voyvoda N, Duranay M. Additive effectiveness of everolimus plus tamoxifen therapy in treatment of encapsulating peritoneal sclerosis. Ren Fail 2012;34:387-9. DOI: http://dx.doi.org/10.3109/0886022X.2011.647338

17. Duman S, Günal AI, Sen S, Asçi G, Ozkahya M, Terzioglu E, et al. Does enalapril prevent peritoneal fibrosis induced by hypertonic (3.86%) peritoneal dialysis solution? Perit Dial Int 2001;21:219-24.

18. Duman S, Wieczorowska-Tobis K, Styszynski A, Kwiatkowska B, Breborowicz A, Oreopoulos DG. Intraperitoneal enalapril ameliorates morphologic changes induced by hypertonic peritoneal dialysis solutions in rat peritoneum. Adv Perit Dial 2004;20:31-6.

19. van Westrhenen R, Dragt CAM, Kunne C, Zweers MM, Krediet RT. Lisinopril protects against the development of fibrosis during chronic peritoneal exposure to dialysis fluid. Perit Dial Int 2004:24:S10.

20. Duman S, Sen S, Duman C, Oreopoulos DG. Effect of valsartan versus lisinopril on peritoneal sclerosis in rats. Int J Artif Organs 2005;28:156-63.

21. Jing S, Kezhou Y, Hong Z, Qun W, Rong W. Effect of renin-angiotensin system inhibitors on prevention of peritoneal fibrosis in peritoneal dialysis patients. Nephrology (Carlton) 2010;15:27-32. DOI: http://dx.doi.org/10.1111/j.1440-1797.2009.01162.x

22. Coronel F, Hortal L, Naranjo P, Cruceyra A, Barrientos A. Captopril, proteinuria and peritoneal protein leakage in diabetic patients. Nephron 1989;51:443. PMID: 2645536 DOI: http://dx.doi.org/10.1159/000185350

23. Coronel F, Berni A, Cigarrán S, Calvo N, Herrero JA. Effects of angiotensin II receptor blocker (irbesartan) on peritoneal membrane functions. Adv Perit Dial 2004;20:27-30.

24. Kolesnyk I, Dekker FW, Noordzij M, le Cessie S, Struijk DG, Krediet RT. Impact of ACE inhibitors and AII receptor blockers on peritoneal membrane transport characteristics in long-term peritoneal dialysis patients. Perit Dial Int 2007;27:446-53.

25. Kolesnyk I, Noordzij M, Dekker FW, Boeschoten EW, Krediet RT. A positive effect of AII inhibitors on peritoneal membrane function in long-term PD patients. Nephrol Dial Transplant 2009;24:272-7. DOI: http://dx.doi.org/10.1093/ndt/gfn421

26. Favazza A, Motanaro D, Messa P, Antonucci F, Gropuzzo M, Mioni G. Peritoneal clearances in hypertensive CAPD patients after oral administration of clonidine, enalapril, and nifedipine. Perit Dial Int 1992;12:287-91.

27. Ripley EB, Gehr TW, Kish CW, Sica DA. Hormonal, blood pressure, and peritoneal transport response to short-term ACE inhibition. Perit Dial Int 1994;14:378-83.

28. Rojas-Campos E, Cortés-Sanabria L, Martínez-Ramírez HR, González L, Martín-del-Campo F, González-Ortiz M, et al. Effect of oral administration of losartan, prazosin, and verapamil on peritoneal solute transport in continuous ambulatory peritoneal dialysis patients. Perit Dial Int 2005;25:576-82.

29. Schuinski AFM, Baroni G, Pecoits Filho RF, Meyer F, Cerqueira MLW, Alexandre da Silva MA, Carvalho V. Avaliação do uso do captopril na fibrose peritoneal induzida em ratos pelo uso de solução de glicose a 4,25%. J Bras Nefrol. 2013;35:273-278.

Submitted on: 10/07/2013.

Approved on: 10/08/2013.

Publication Dates

• Publication in this collection
  19 Dec 2013
• Date of issue
  Dec 2013