The Solution to Better Preservation of the Peritoneal Membrane Still Lies Hidden in the Solution

Long-term peritoneal dialysis (PD) may lead to peritoneal membrane failure. Functionally, this is characterized by ultrafiltration failure. The prevalence of ultrafiltration failure is reported to be more than 30% in long-term PD patients (1). In addition, morphologic abnormalities develop in the peritoneal membrane. The ultrafiltration failure is likely to be caused by the rapid dissipating osmotic gradient due to an increased number of vessels (2), which is most striking in patients with ultrafiltration failure (3). These vessels also show extensive abnormalities, such as subendothelial hyalinosis, especially of the venules and small veins, but sometimes also of arterioles (3,4). At the ultrastructural level, extensive lamellation of the capillary and mesothelial basement membranes is present, similar to that observed in diabetic microangiopathy (5). The increase in the number of peritoneal vessels is also accompanied by an increase in the severity of the fibrotic alterations (2).

Unfortunately, the causes of these changes in the peritoneal membrane are still not known. Yet, continuous exposure to glucose-based dialysis solutions is likely the most important factor in the development of these peritoneal membrane alterations. In high concentrations, glucose was found to be toxic to the mesothelium in both in vitro and animal studies (6,7). Deposition of advanced glycosylation end-products (AGEs) in peritoneal tissues has been described (8). Glucose is also likely to be involved in the development of peritoneal neoangiogenesis. That hypothesis is supported by the diabetiform alterations of microvessels that can be seen in patients (5) and induced in animal models (9). Vascular endothelial growth factor (VEGF) is locally produced in the peritoneum (10) and the effluent VEGF concentration increases with the duration of PD (11), underlining the similarity with diabetic retinopathy. The clinical importance of this diabetiform peritoneal neoangiogenesis, which leads to an enlargement of the peritoneal vascular surface area, is emphasized by the results of Davies et al. (12), who, in a prospective cohort study of continuous ambulatory peritoneal dialysis (CAPD) patients, found a relationship between cumulative glucose exposure and development of ultrafiltration failure. A greater cumulative glucose exposure was also present in patients with peritoneal sclerosis as compared with controls matched for duration of PD (13). To further increase the complexity of the potential role of glucose in the peritoneal morphological abnormalities, glucose degradation products (GDPs) formed during heat sterilization of the dialysate are toxic to peritoneal cells (14), and they induce the formation of AGEs much faster than does glucose itself (14). Glucose degradation products upregulate production of the profibrotic cytokine transforming growth factor (TGF) β and stimulate VEGF synthesis in peritoneal mesothelial cells (15,16). In an animal model, filter-sterilized dialysate resulted in less vessel formation and less fibrosis (17).

In the 1990s, PD solutions containing icodextrin or amino acids as osmotic agent were developed. Icodextrin is an isoosmolar mixture of glucose polymers, which makes it especially suited for long dwells as it results in a prolonged ultrafiltration due to the slow absorption of the oncotic agent (18). This solution does not contain glucose and has a low GDP content. Icodextrin improves ultrafiltration compared with glucose-based solutions, resulting in a better control of the patient’s fluid balance (19–21). Amino acids were developed to improve nutrition in malnourished patients (22) but can also be used once daily as an alternative to glucose-containing dialysate.

Later, “biocompatible” solutions with a more physiological pH, different buffers, and mostly reduced content of GDPs became available. The clinical benefits of the newer solutions have been recently reviewed (23–25). To summarize their findings, they concluded that although the newer PD solutions seem to improve at least some aspects of peritoneal membrane health and viability, no significant effects on peritonitis, technique survival, or patient survival were identified with their use. However, the use of neutral-pH, low-GDP PD solution led to greater urine output and higher residual renal function (RRF) after use exceeded 12 months.

As the use of the more “biocompatible” solutions by itself seems not to result in significant clinical improvement of outcomes of PD patients, one may wonder if a strategy of reducing the peritoneal glucose exposure in addition to using the newer solutions that are low in GDPs might lead to better results. Currently, various dialysis strategies are available to reduce the glucose load of the peritoneal membrane. The use of amino acid solution once daily is an option but has never been studied specifically for this purpose. Also the use of icodextrin once, or even twice, daily (26,27) reduces the glucose load. The most extensive strategy, combining the use of icodextrin, amino acids, and glucose-based solutions containing low glucose concentrations, has been advised early this century (28). Until now, only a few studies have been published using this regime, but the patient numbers were low and/or the duration of the study too short to draw firm conclusions (29–31).

In the current issue of Peritoneal Dialysis International, Yung et al. present a 6-month extension of their earlier study (32). In their first study, 150 patients were randomized between a low-glucose, low-GDP regime or a conventional glucose-based solution and followed for 1 year (33). The primary outcome of this study was change in RRF and daily urine volume. Secondary outcomes were peritoneal transport and inflammation markers. In the low-glucose group, daily urine volume was better preserved. The biocompatible PD fluids also lead to a modest increase in small-solute transport and an increase in the biomarkers dialysate cancer antigen 125 (CA125), interleukin-6 (IL-6), and adiponectin. In the present study, after 12 months, the low-glucose group changed to conventional glucose-based solutions while the control group continued with conventional glucose-based solutions, and both were followed for another 6 months. The same clinical and peritoneal transport parameters were followed, but more biomarkers were measured at 12 and 18 months. At the end of 12 months, effluent dialysate levels of CA125, decorin, hepatocyte growth factor, IL-6, adiponectin, and adhesion molecules were significantly higher in the low-glucose group compared with controls, but all decreased after patients switched to glucose-based dialysate. Macrophage migration inhibitory factor level was lower in the low-glucose group but increased after changing to glucose-based dialysate and was similar to controls at 18 months. Serum adiponectin levels were higher in the low-glucose group at 12 months, but similar in the 2 groups at 18 months. Of the other parameters, only the modest increase in peritoneal solute transport remained higher in the low-glucose group after 18 months.

What do we learn from this study, which is at the moment the largest and longest study using low-glucose, low-GDP solutions? Its results are similar to earlier studies, as its major findings are changes in biomarkers, suggesting a better preservation of the peritoneal membrane integrity and reduced systemic vascular endothelial injury when more biocompatible solutions are used. Unfortunately, the clinical relevance of biomarkers, either in evaluating clinical trials or as predictors of morphological changes of the peritoneal membrane, is currently still unclear (34). Finally, as clinically relevant changes usually occur after many years of treatment, a randomized-controlled clinical trial of at least 3 to 4 years is needed to solve this issue. In the meantime, the jury is still out on whether long-term use of the newer solutions in combination with a restrictive policy of glucose exposure will result in better preservation of the peritoneal membrane as well as patient survival.

Disclosures

The author has no financial conflicts of interest to declare.