Cancer Antigen 125 as a Biomarker in Peritoneal Dialysis: Mesothelial Cell Health or Death?

Abstract

The concentration or appearance rate of cancer antigen 125 (CA125) in peritoneal dialysis (PD) effluent has been used for many years as a biomarker for mesothelial cell mass in patients on PD. However, this marker has limitations, and emerging evidence has raised doubts as to its significance. This review explores our current understanding of CA125, its prominent role in studies of “biocompatible” PD solutions, and the ongoing uncertainty concerning its interpretation as a measure of mesothelial cell health.

Over time, changes in the peritoneal membrane can lead to alterations in solute transport and loss of ultrafiltration (1). Those changes may necessitate discontinuation of peritoneal dialysis (PD) and transition of patients to hemodialysis.

Identifying measurable biomarkers in peritoneal dialysis effluent (PDE) that have the potential to predict the development of membrane damage or failure has been an area of interest for some time. One such marker, cancer antigen 125 (CA125), has been used as a putative measure of the collective mass and health of the mesothelial cells lining the peritoneal cavity.

A high molecular weight glycoprotein, CA125 is produced in ovarian cancer cells and is used in monitoring ovarian cancer (2). Human peritoneal mesothelial cells also express CA125, and Zeimet et al. (3) reported that mesothelial cells are actually more potent than ovarian cancer cells in producing it. Visser et al. (4) were the first to suggest that dialysate CA125, measured as an appearance rate at the end of a 4-hour peritoneal equilibration test, could be used as marker of mesothelial cell mass in stable PD patients [reviewed by Krediet (5)]. This theory stood relatively unchallenged for the subsequent decade, and CA125 appearance was used as an outcome biomarker in many studies. It is well accepted that levels of CA125 tend to decline in parallel with the duration of PD (6). Studies of new PD solutions reported effluent CA125 levels as a surrogate outcome of membrane preservation on the assumption that an increase reflects a greater mass of preserved mesothelial cells (7-13).

Lai et al. (14) were the first to report the lack of correlation between CA125 levels and the number of mesothelial cells in PDE. Their study differed from others in the way that the PDE was analyzed. They noted a higher percentage of dead cells among the mesothelial cells than among the other cell populations. As a result, they postulated that mesothelial cells in the PDE may partly reflect detachment of damaged cells from the peritoneal membrane rather than surrogacy for mesothelial cell mass as others had speculated.

That study was followed with another by Breborowicz et al. (15), who also concluded that CA125 is not a reflection of mesothelial cell mass. Using in vitro cultures of human peritoneal mesothelial cells, those authors measured the CA125 level in PDE and found that it was not correlated with the number of cells in the monolayer of mesothelial cultures. Factors such as the age of the patient and a history of exposure to high glucose content, rather than just the number of mesothelial cells, were found to influence the level of CA125.

Interestingly, effluent CA125 can be elevated during episodes of peritonitis (16), certainly not a time typical of optimal mesothelial cell functioning. That observation leads to the question of whether elevated CA125 might reflect mesothelial cell damage or even cell death and slough into the effluent, rather than mesothelial cell health.

Taken together, the foregoing observations have resulted in uncertainty about the biologic and diagnostic significance of effluent CA125 (17). Despite considerable research, our current understanding of this biomarker is limited, and the clinical significance of an elevated CA125 level in PDE is unknown.

Peritoneal dialysis is challenged by the fact that the very solutions that are used to perform dialysis might actually be causing long-term damage to the peritoneal membrane. It is widely accepted that conventional glucose-based PD solutions contribute to changes in peritoneal membrane structure and function (18). The glucose in conventional solutions is thought to be responsible for deleterious cardiovascular and metabolic effects (19). In addition, the glucose degradation products that are present in heat-sterilized dialysis fluids are known to be responsible for retarding the endogenous process of mesothelial cell repair in vitro (20). That knowledge has led to an emphasis on the development of new solutions that are more “biocompatible” with the peritoneal membrane. A “biocompatible solution” is a heterogeneous term that encompasses various combinations of bicarbonate buffer, neutral pH, and low GDP concentrations, and osmolytes other than glucose.

Recent studies of patients treated with various biocompatible solutions have consistently shown that levels of CA125 increase in PDE after exposure—in some cases, in as little as 3 months (7-11). The interpretation is that these solutions may offer an environment that promotes mesothelial cell proliferation and health, with subsequent preservation of the peritoneal membrane. Other studies have also suggested that, compared with traditional solutions, biocompatible solutions may preserve residual renal function (6,11).

Any intervention that might prolong the life of the peritoneal membrane and improve patient outcomes would obviously be welcomed by the PD community, and so the excitement surrounding the widespread use of biocompatible solutions around the world is understandable. However, a closer look at the relevant studies also shows that, although effluent CA125 is increased with the use of these solutions, so too is the dialysate-to-plasma (D/P) ratio of creatinine (6) in these patients (Table 1). In other words, almost every study that has examined transport status and ultrafiltration with biocompatible solutions has noted increased transport and diminished ultrafiltration (6,21-23). That kind of change in transport is usually ascribed to increased effective peritoneal surface area as a result of vasodilatation of the submesothelial blood vessels and is interpreted as a consequence of inflammation. Indeed, other studies have shown that biocompatible solutions are associated with increases in established dialysate markers of inflammation such as interleukin 6 (24).

TABLE 1.

Effect of Various Solutions on Level of Cancer Antigen 125 (CA125) and Dialysate-to-Plasma (D/P) Ratio of Creatinine

It has been almost 30 years since the initial studies investigating CA125 as a potential biomarker for mesothelial cell mass. Unfortunately, a solid understanding of the biologic significance of CA125 is still lacking, and many questions remain unanswered. Might it be possible that these solutions cause subclinical inflammation of the peritoneal membrane, leading to the increase in transport status? What if CA125 in PDE actually represents a surrogate marker of inflammation or, as in the case of peritonitis, cell death?

The introduction of new biocompatible solutions has also brought new hope for the potential prolongation of the life of the peritoneal membrane, and yet the solutions themselves are surrounded by many unanswered questions. Little is known about their long-term effects. Do they preserve residual renal function? Do they increase mesothelial cell mass? Or are they in fact causing peritoneal inflammation as evidenced by increased transport status? Those important questions need to be answered in future studies before these expensive new solutions are readily adopted. Until then, we must accept the related uncertainty and continue the search for the coveted biomarker of membrane integrity.

Disclosures

HC has no financial conflicts to disclose. JMB has been a consultant or has served on advisory boards for Takeda Pharmaceuticals, Amgen, and Baxter Healthcare. She is a member of the speakers’ bureau for DaVita Healthcare Partners and for Amgen.