peritoneal dialysis ( pd ) is a therapy used to replace kidney function in end - stage renal disease patients . the therapy is based on the ability of the peritoneal membrane to function as a dialysing membrane , allowing exchange of solutes and waste products between the pd fluids ( pdfs ) and the circulation . pdfs contain an osmotic agent , mostly glucose , which facilitates fluid movement from the bloodstream to the peritoneal cavity leading to removal of metabolic waste products and water . continuous removal of waste products achieved using pds , results in improved well - being of patients . furthermore , patients on pd have increased mobility compared to haemodialysis since pd can be done at home , and moreover , pd is less expensive . however , drawbacks of pd include the risk of peritonitis and peritoneal membrane damage upon exposure to pdf . the latter induces inflammation , angiogenesis , and fibrotic changes . in this paper , we describe the usefulness of a rat pd exposure model in defining the impact of pdf components in this process . finally , we will discuss interventions in this model and the possible clinical implications for long - term pd . the efficacy of pd depends on the structural and functional integrity of the peritoneum , that is , the inner surface of the abdominal wall ( parietal peritoneum ) , omentum , and mesentery ( visceral peritoneum ) . the peritoneum consists of a mesothelial cell ( mc ) monolayer and underlying connective tissue interstitium comprising extracellular matrix ( ecm ) , blood vessels , fibroblasts , and innate immune cells .   in our rat pd - exposure model , we use normal renal function , no omentomectomy , and no addition of heparins during pd - exposure or addition of antibiotics . we have shown that several weeks of pd results in a loss of mcs and denuded areas in the mesothelial layer . liver imprints of rats show increased mesothelial cell density , indicating mesothelial regeneration [ 3 , 4 ] . among the mesothelial cells , vimentin - positive , spindle - like - shaped cells are found indicating the process of epithelial to mesenchymal transition ( emt ; ) . changes also take place in the submesothelial interstitium , and ecm thickness is significantly increased upon pd [ 68 ] . significantly higher numbers of leukocytes are found in the effluents of pd - treated animals compared to nontreated animals . although the percentage of macrophages and lymphocytes does not change , an exchange of mast cells and eosinophils for neutrophils is seen after pd treatment [ 7 , 9 ] . increased numbers of activated macrophages are seen in mesentery and omentum upon pd , including accumulations around vessel networks in the omentum , known as milky spots [ 7 , 10 ] . in a steady state , milky spots occupy a small percentage of the total surface area of the omentum , whereas after pdf exposure , this increases dramatically [ 3 , 11 ] . throughout the peritoneal tissues , new blood vessels and lymphatics furthermore , the thickened submesothelial fibrotic layer counteracts osmotic pressure further , reducing efficacy of exchange . in summary , loss of mesothelium and induction of inflammation and angiogenesis are typical morphologic features seen in long - term pd which in part contribute to fibrotic changes , ultimately leading to technique failure .   in this paper , we discuss the changes that occur upon pd in our rat pd - exposure model . this model , as described above , shows similar changes upon long - term exposure to pdf fluid as patients on capd . for example , thickening of the submesothelial compact zone , degeneration of the mc layer , loss of microvilli on residual mc , and increased vessel numbers are also observed in biopsies from patients on long - term pd , as in detail described by williams et al . . in addition , devuyst et al . recently reviewed the similarities between mice , rats , and humans regarding a.o . several factors can contribute to pd - related changes , including the presence of the catheter , uraemia , peritonitis , and instillation of the volume loading of pdf itself . moreover , different components of the pdf , including the used buffer ( low ph ) , glucose concentration , and glucose degradation products ( gdps ) generated during heat sterilisation , influence peritoneal inflammation ( as reviewed by schilte et al .   and summarized in table 1 ) . the presence of only the catheter itself already induces pd - related morphological changes such as increase in angiogenesis and thickness of ecm , as well as slight effect on total effluent cell numbers [ 9 , 16 ] . morphologic and inflammatory parameters of rats treated with pdf via a peritoneal catheter are significantly increased compared to rats treated via intraperitoneal needle injections ( blood vessels , ecm thickness , and total cell count ) . showed that instillation of lactate buffer without glucose or gdps already resulted in increased cell influx , mesothelial regeneration , angiogenesis , and increased number of milky spots although it not significantly enhanced fibrosis [ 7 , 9 ] . moreover , they showed that the addition of glucose to the buffer - induced angiogenesis and mesothelial regeneration , and induced fibrosis as well as cell influx even further . finally , the presence of gdps enhanced all mentioned peritoneal changes , apart from cell influx and mesothelial regeneration , even further . besides , gdps , advanced glycation end products ( ages ) formed by heating of glucose , contribute to the toxicity of pdf . it has become increasingly clear that more biocompatible pdfs ( bicarbonate / lactate buffer , reduced concentration of glucose and gdps ) induce less damage and decrease impaired ultrafiltration when compared with conventional pdf [ 2 , 6 , 8 , 17 ] . in addition , supplementing pdf with aminoguanidine , which scavenges gdps and prevents age formation , resulted in less mesothelial denudation , reduced fibrosis , and less angiogenesis in omentum and parietal peritoneum , but not in mesentery   as shown in our own rat pd - exposure model . apart from intrinsic factors as pdf composition , other factors have been suggested to contribute to pd - related tissue remodelling ( table 1 ) . animal studies have shown the increase in vascular network as a result of uraemia in non - pd - treated animals . although differences between uremic and nonuremic rats were found in control animals ( no pd ) , there is no longer a prominent effect of uraemia during pd therapy [ 4 , 20 ] . in contrast , peritonitis episodes always significantly contribute to peritoneal changes by inducing mesothelial damage , a massive inflammatory response , and increased vascularisation of peritoneal tissue leading to impaired membrane function [ 12 , 21 , 22 ] . activation of peritoneal cells , mediators , and pathways , results in functional and structural changes of peritoneal membranes in long - term pd . some of these changes can be reversed by peritoneal rest . the reversibility of both morphological and functional alterations in the peritoneal membrane by peritoneal rest has been shown in animal studies [ 23 , 24 ] . peritoneal rest of more than 4 weeks restored ultrafiltration capacity as well as peritoneal permeability for glucose and total protein [ 23 , 24 ] . moreover , the thickness of the parietal peritoneum was reduced , and omental and mesenterial vessel density was restored [ 23 , 24 ] . furthermore , peritoneal rest reversed the increased mast cell density and milky spot response and recovered pd - induced mesothelial damage . these data suggest that pd - induced changes in the peritoneal membrane are reversible after peritoneal rest , at least in the rat model . we therefore foresee future therapies focusing on the prevention and reversibility of these changes as shown below . moreover , this may have major implications for therapeutic clinical interventions in preventing the pd - induced changes in long - term pd . recent reviews of our group have shown that the rat pd model is also ideally to test anti - inflammatory therapeutic interventions [ 2 , 25 ] . heparin has been mentioned as a regulator in inflammation , but the addition of unfractionated or low - molecular weight heparin was not able to counteract the pd - fluid - induced changes in our rat pd model , but in an editorial , the usefulness was highlighted . recently , we could show that sunitinib inhibits angiogenesis in our rat pd model , and so the usefulness of inhibitors in the field of angiogenesis can have important functional implications . moreover , the usefulness of celecoxib as inhibitor of cox-2 and the inflammation cascade has been discussed   and indeed in our rat pd model , we could demonstrate an effect on angiogenesis and functional ultrafiltration , but not on clear inflammation markers . these two interventions so in part show some positive results , but future experiments should determine if no side effects of celecoxib are seen , when used in a clinical setting ( as presently is investigated in our institute ) and whether the reduction of angiogenesis by sunitinib really results in better ultrafiltration . it must be mentioned that macrophages are thought to play a key role in the inflammatory process , as earlier discussed . more recently , it was shown that the discrete balance between the so - called proinflammatory m1 macrophages and alternatively activated m2 macrophages might determine the outcome in inflammation in pd   as has also been shown for macrophages in wound healing   and oncology [ 32 , 33 ] . finally , molecules as bone morphogenetic protein-7 ( bmp-7 ) and the vitamin d analogue paricalcitol have been shown to be important in inhibiting peritoneal and renal fibrosis [ 34 , 35 ] . bmp-7 also was shown to prevent peritoneal damage in our pd - exposure model , and preliminary data on paricalcitol also show a clear effect in our pd rat model . these observations should be investigated more deeply and mechanistically in the in vivo animal model , since they offer opportunities for therapeutic clinical interventions in the near future . in long - term pd , the catheter , uraemia , peritonitis , and permanent exposure to pdf ( volume loading , glucose , and gdp 's ) result in morphological and functional changes of the peritoneal membranes . in part , the ultrafiltration loss seen in pd patients is caused by the bioincompatibility of pdf . novel pdfs offer an improvement in biocompatibility , and further development of biocompatible fluids will lead to better preservation of the peritoneal membrane . especially therapeutic interventions on angiogenesis , fibrosis , and inflammation we therefore foresee a combination therapy using more biocompatible fluids along with specific inhibitors involved in peritoneal inflammation / angiogenesis / fibrosis to be the most effective approach in future pd to prevent pd - induced changes and which will be beneficial for pd patients .
peritoneal dialysis ( pd ) is associated with functional and structural changes of the peritoneal membrane . in this paper , we describe the impact of different factors contributing to peritoneal incompatibility of pd fluid installation including presence of a catheter , volume loading , and the pd fluid components itself . 
 these factors initiate recruitment and activation of peritoneal immune cells such as macrophages and mast cells , as well as activation of peritoneal cells as mesothelial cells in situ . 
 we provide an overview of pd - associated changes as seen in our rat pd - exposure model . 
 since these changes are partly reversible , we finally discuss therapeutic strategies in the rat pd model with possible consequences of long - term pd in the relevant human setting .