The incidence of ultrafiltration failure (defined by the 3 × 4 rule as net ultrafiltration <400 ml at the end of a 4-hour dwell with a 3.86%/4.25% [215 mmol/L] glucose-based dialysis solution1) increases with the duration of peritoneal dialysis (PD).2 In the absence of adequate urine production, ultrafiltration failure easily causes overhydration, which is also a strong predictor of death in patients without heart failure.3 The problem has been reported as occurring in 38% of patients after 3 years of PD,2 making it a nontrivial issue in long-term PD. Ultrafiltration failure has traditionally been attributed to four possible causes: (1) fast transport of small solutes, leading to a rapid disappearance of the crystalloid osmotic gradient; (2) the presence of a low osmotic conductance to glucose; (3) a high lymphatic fluid loss from the peritoneal cavity; and (4) the presence of an extremely small peritoneal surface area.4 However, it has become evident that the latter is not a cause, that high peritoneal lymphatic fluid loss is rare, and that, if it does occur, it is usually already present at the start of PD.
The aim of this review is to discuss the contributions of the peritoneal microvasculature and interstitial tissues to the development of ultrafiltration failure in patients on long-term PD, including a hypothesis on how interstitial alterations may be causative in reducing free water transport.
Pathways for Peritoneal Fluid Transport and Their Assessment
According to the three-pore theory of peritoneal transport, fluid egresses from the microcirculation through pores in the endothelial lining.5 Intercellular small pores with radii of 40–45 Å constitute about 90% of all pores and contribute to 60% of fluid filtration, as estimated in mathematic models, and are also found in patients on PD during their first year of treatment.6 In addition, these pores allow diffusion of small solutes like urea, creatinine, electrolytes—and diffusion of glucose in the opposite direction—because all of these solutes have radii of 2–3 Å. Transcapillary ultrafiltration through the small pores is mainly determined by the hydrostatic pressure gradient, which decreases from the arteriolar to the venous part of the capillary network and has a mean value of 30 mm Hg.7 As a consequence of the size difference between the radius of a small pore and that of a glucose molecule, the contribution of crystalloid osmosis in fluid removal is limited and probably present only in the initial 2 hours of a dialysis dwell.
Water is also removed from the circulation by aquaporin-1 (AQP-1), which is an intraendothelial water channel, with a radius <5 Å, through which only water can traverse.8 AQP-1 is present in endothelial cells of peritoneal capillaries and venules.9 Its function—free water transport by crystalloid osmotic pressure—is not influenced by the hydrostatic pressure gradient. During the first hour of a 3.86%/4.25% glucose dwell, free water transport causes a decrease of the dialysate sodium concentration, also called sodium sieving,10 and can be used for semiquantitative assessment of free water transport.
The hydrostatic and crystalloid osmotic-filtered fluid first arrives in loose peritoneal tissue; the interstitium, composed of a substance consisting of hyaluronan and glycosaminoglycans; and a fibrous collagen network that constitutes a skeleton for the embedded structures. In addition to fibroblasts, adipose cells may be present. Because the mesothelium is not a barrier for solute transport, the composition of the interstitial fluid in patients on PD differs from that of healthy individuals, which is partly determined by the microvascular filtrate and by constituents of the PD fluid, the most important of which is glucose.11 Therefore, the mesothelial barrier only separates the peritoneal cavity and the interstitial matrix, cytoskeleton, and embedded cells.
The interstitial pressure is likely to be similar to the intraperitoneal pressure experienced by patients on PD with a dialysate-filled peritoneal cavity. This pressure averages 8 mm Hg in the recumbent position,12 and increases to 13 mm Hg when the patient stands.12 It is also dependent on the instilled dialysate volume, which averages 10 cm H2O (13.6 mm Hg) with a volume of 0.5 L, and increases linearly to 15 cm H2O (20.4 mm Hg) with a volume of 3 L.13 The extent of subsequent increases in interstitial pressure depend on the interstitial compliance.14
The quantitative contribution of the mechanisms mentioned above refers to PD in the early stage of treatment. Chronic exposure to dialysis solutions causes alterations in peritoneal morphology that influence fluid transport. The discussion below argues that specific alterations have different effects on fluid transport parameters.
Acquired Ultrafiltration Failure
Almost all studies on PD have been done with conventional dialysis solutions, which have a low pH and contain glucose degradation products. The first longitudinal follow-up studies, dating from the mid-1990s,15,16 showed a reduction in net ultrafiltration that started after 4 years of treatment, whereas small solute transport increased more or less in parallel. This suggests the development of an increased vascular surface area, allowing faster diffusion of glucose. However, vascular density was mainly reported as unaltered1718–19 or increased only in immature capillaries19; this suggests mainly increased perfusion, as has been established in mesothelial-to-mesenchymal transition,20 probably mediated by vascular endothelial growth factor (VEGF).21 A careful analysis of the relationship between net ultrafiltration and the dialysate/plasma ratio of creatinine (D/P creatinine) showed a difference after 4 years: ultrafiltration was less than expected on the basis of D/P creatinine.22 This has been interpreted as impaired conductance to glucose—that is, glucose being less effective as an osmotic agent, not because the osmotic gradient disappears at a faster rate, but rather because of peritoneal alterations affecting crystalloid osmosis. A similar finding was reported in a cross-sectional analysis in patients who underwent PD for at least 4 years.23 This was reinforced 2 years later, in a prospective longitudinal study from Italy, in which a multivariate analysis showed that a decreased D/P sodium ratio was the most important determinant of long-term ultrafiltration failure.2 A further analysis of long-term patients with ultrafiltration failure showed that the osmotic conductance to glucose was related to free water transport, and also that both free water transport and small pore fluid transport were lower than in patients with early ultrafiltration failure.6 A subsequent prospective, longitudinal analysis in incident patients confirmed the decrease in time for both free water transport and small pore fluid transport in long-term PD.24
The dependence of small pore fluid transport on the crystalloid osmotic gradient is limited to the first few hours of a dialysis dwell, emphasizing the importance of the hydrostatic pressure gradient for filtration. Long-term PD is associated with the presence of subendothelial hyalinosis, also called vasculopathy, which leads to a reduction in the lumen/wall ratio and, ultimately, obstruction of the vascular lumen.25 My colleagues and I have argued that this microvasculopathy is caused by the deposition of advanced glycosylation end products, reducing the filtration pressure and, thus, small pore fluid transport.26 In contrast, free water transport is totally dependent on the crystalloid osmotic pressure gradient, suggesting absence or dysfunction of AQP-1. However, patients with encapsulating peritoneal sclerosis have severely impaired free water transport27 but normal AQP-1 expression,28 pointing to the importance of interstitial fibrosis/sclerosis in the volume of free water transport. An analysis using mathematic modeling suggested that alterations in both capillary and interstitial transport contribute to acquired ultrafiltration failure, with the capillary wall component being mainly due to increased transport rates of small solutes and the interstitial component characterized by a faster disappearance of glucose that leads to a reduction of the hydraulic conductance by >50%.29
How Can Interstitial Fibrosis Modify Free Water Transport?
The presence of an enlarged submesothelial extracellular matrix with collagen fibers, in combination with angiogenesis in deeper layers of the peritoneum, has been proposed as resulting in diminished ultrafiltration.30 The passage of dialysate glucose through this avascular layer would be enhanced, leading to a rapid disappearance of the osmotic gradient at the increased capillary area. The presence of water-binding collagen fibers has been argued to be especially important in this situation. Indeed, in a serial barrier model, mathematic modeling, using capillary and fiber transport, has suggested that an increase of interstitial fiber density from 0.5%–3% boosted interstitial glucose transport but had no effect on the peritoneal Kf.31 A more recent kinetic modeling study, in a limited number of patients, found that those with ultrafiltration failure exhibited marginally increased tissue diffusivity for glucose in combination with a decreased penetration depth of fluid and solutes into the tissue.29 Neither of these two studies provided a pathophysiologic basis for decreased fluid transport by interstitial collagen fibers and the uncoupling of small solute and fluid transport. The relevance of a pathophysiologic explanation is illustrated by an in vitro study on a native collagen membrane that showed excellent water permeability and low reflection coefficients for electrolytes.32 In addition, studies in patients on PD have shown that the absorption of glucose from the dialysate during a dwell increases during follow-up, similar to the change in the mass transfer area coefficient of creatinine, the latter representing the effective vascular surface area.33 Moreover, my colleagues and I reported a similar parallelism between the creatinine and glucose alterations in patients undergoing PD who developed encapsulating peritoneal sclerosis.34 These findings suggest it is improbable that collagen fibers and extracellular matrix components leading to enhanced glucose absorption play a causative role in acquired ultrafiltration failure. Because an increased number of interstitial fibroblasts is the main hallmark of encapsulating peritoneal sclerosis, this review will focus on recent cytologic data from basic science studies.
During PD, damage to peritoneal interstitial tissue occurs. In encapsulating peritoneal sclerosis, peritoneal interstitial fibroblasts express α-smooth muscle actin, defining them as collagen-1–producing myofibroblasts.35 These cells probably originate from submesothelial fibroblasts.36 In addition, adipocytes that are abundant in the beginning of PD can transdifferentiate into myofibroblasts.37 Tissue hypoxia is an important stimulus for tissue repair and fibrosis in various organs, such as skin, kidney, heart, liver, and lung.38 Hypoxia’s effects can either be direct or via hypoxia inducible factor-1, a transcription factor for many genes, including plasminogen activator inhibitor type 1, VEGF, TGF-β, and glucose transporter-1 (GLUT-1).
Intracellular hypoxia affects the cell redox status, characterized by the ratio between reduced and oxidized NAD, the NADH/NAD+ ratio. A high cellular glucose load causes an increase in the cytosolic NADH/NAD+ ratio, and this has been referred to as pseudohypoxia.39,40 Intracellular glucose is degraded in the cytosol by the glycolysis and the sorbitol pathways. In both of these pathways, NADH is formed from NAD+, increasing the ratio. Pyruvate is the end product of glycolysis and can either be converted to lactate (by which NAD+ is generated from NADH) or enter the mitochondria to be taken up in the citric acid cycle. Because mitochondrial dysfunction is present in CKD, especially diabetic nephropathy,41 pyruvate uptake may be impaired, making conversion of pyruvate to lactate (catalyzed by lactate dehydrogenase) relatively more important. We postulated that the high lactate concentrations in PD solutions could inhibit this reaction,42 or even reverse it, as occurs in the Cori cycle in the liver. As a result, the glucose-induced pseudohypoxia is likely augmented.
Intracellular metabolism of glucose requires its transport from the extracellular compartment. Because a glucose molecule is too large to pass through the cell membrane by diffusion, intracellular uptake requires specific membrane proteins, so-called glucose transporters: facilitative glucose transporters (GLUTs) and sodium-glucose transporters (SGLTs), which also transport sodium into cells.43 GLUTs facilitate glucose diffusion through the cell membrane, and glucose uptake by SGLTs is driven by uptake of sodium. Because most cells require glucose for their metabolic functions, these transporters are present in many cells, either alone or in combination. GLUT-1 is distributed ubiquitously and is particularly abundant in erythrocytes and cardiac and small muscle cells.44 GLUT-1 expression is increased in various types of cancer45 and, during hypoxia, it has been found in many cell types, including in cultured murine fibroblasts,46 in 3T3-L1 fibroblasts,47 and in human dermal fibroblasts in systemic sclerosis.48 Hypoxia also induces GLUT-1 mRNA and protein expression in human adipocytes.49 Researchers have reported that, during exposure to low oxygen concentrations, hypoxia inducible factor-1α decreased the expression of SGLT-1 and SGLT-2 in renal epithelial tubular cells, whereas GLUT-1 expression was increased.50 This contrasts with results obtained in whole renal tissue from individuals with or without type 2 diabetes, in whom GLUT-1 and SGLT-1 were coupled and their overall expression was slightly lower in those with diabetes compared with controls.51
Published research on glucose transporters in PD is limited to the mesothelium. Cultured human mesothelial cells express GLUT-1, GLUT-3, and SGLT-1 mRNA.52 In one study, the researchers reported weak constitutive expression of GLUT-3 and SGLT-1 by mesothelial cells, suggesting a low pathophysiologic significance. GLUT-1 and GLUT-3 could be upregulated by exposure to concentrations of glucose at levels that are more than ten times the physiologic range of normal plasma levels, but still two to three times lower than the glucose concentrations of PD solutions.53 Similar concentrations of mannitol had no effect on GLUT or SGLT expression, making it unlikely that the effects were due to hyperosmolality. In contrast, studies in rats found that mesothelial cells expressed not only GLUT-1 and SGLT-1, but also GLUT-2 and SGLT-2.54 Exposure to a 2.5% glucose-based dialysis solution (approximately 125 mmol/L) upregulated the expression of the SGLTs, but had no effect on GLUT-1 and GLUT-2 expression. Recent experimental studies confirmed the presence of SGLT-1 and SGLT-2 in human55,56 and murine mesothelial cells.56 In one of these studies, exposure to 60 mmol/L glucose had no effect on SGLT-1 and SGLT-2 expression of cultured human mesothelial cells obtained from effluent of patients on PD.55 Curiously, administration of the SGLT-2 inhibitor empagliflozin increased SGLT-2 expression in rat mesothelial tissue and in cultured human mesothelial cells.55 In the second study, in a murine model, 5 weeks of peritoneal exposure to a 4.25% glucose-based dialysis solution showed the presence of GLUT-1, GLUT-3, GLUT-4, SGLT-1, and SGLT-2 in the mesothelium of animals given saline.56 Exposure to the dialysis solution upregulated the mesothelial expression of SGLT-2, GLUT-1, and GLUT-3, but not that of SGLT-1 and GLUT-4. The authors also reported similar results for a child on PD treatment with low-glucose degradation products/normal pH solution for 1 year and a child with normal renal function. Dapagliflozin inhibited only the expression of SGLT-2, but not expression of the other glucose transporters.56 A sound physiologic explanation for why mesothelial cells would have a high influx of sodium, which is the driving force for glucose uptake by SGLTs, is absent in all discussed studies.
The Glucose/Hypoxia/GLUT-1 Hypothesis
All of the studies on glucose transporters in PD discussed above focused on the mesothelium, which has no direct role in fluid transport, whereas long-term PD, characterized by loss of mesothelium and by interstitial fibrosis with myofibroblasts, has not been investigated at all. A hypothesis on why interstitial fibrosis is associated with reduced free water transport can be developed from findings of the discussed clinical and basic research. This hypothesis consists of two parts. First, reduced free water transport by AQP-1, leading to acquired ultrafiltration failure in long-term PD, is caused by a reduced crystalloid osmotic pressure gradient resulting from intracellular glucose uptake and metabolism in peritoneal interstitial tissue. This part of the hypothesis is illustrated in Figure 1. Second, the degradation of the ingested glucose changes the intracellular NADH/NAD+ ratio, similarly to hypoxia. This pseudohypoxia has downstream fibrotic effects through stimulating the formation of mediators, such as TGF-β and plasminogen activator inhibitor-1, and also by provoking GLUT-1 expression. The latter leads to further enhancement of intracellular glucose uptake and thereby stimulates the loop between dialysate glucose exposure, peritoneal fibrosis, and ultrafiltration failure, leading to a vicious circle. This part of the hypothesis is illustrated in Figure 2.
;)
Figure 1.: The crystalloid osmotic gradient beteen the peritoneal cavity and the microcirculation. Schematic representation of the crystalloid osmotic gradient across the peritoneal interstitium in the first few years of PD, when only a small amount of fibroblasts is present (top panel), and the situation in long-term PD, where the gradient decreases in the interstitium due to cellular uptake of glucose (bottom panel). The peritoneal cavity lumen is covered with the mesothelial cell layer, the vascular lumen with endothelial cells, separated by small pores and resting on a basement membrane. AQP-1 is present in some endothelial cells. The lines show the estimated time course of the crystalloid osmotic pressure gradient between the dialysate-filled peritoneal cavity and the blood. Note the pressure gradient remains almost stable during the passage of fluid through the interstitium in patients at the start of PD, resulting in a high gradient for AQP-1 (top panel), but decreases in patients on long-term PD due to uptake of glucose by interstitial myofibroblasts, leading to a lower crystalloid osmotic pressure gradient (bottom panel). ECM, extracellular matrix.
Figure 2.: The vicious circle between glucose-induced pseudohypoxia, increased GLUT-1 expression, and the consequent augmented glucose uptake by interstitial cells. The black ovals represent GLUT-1; the vertical oval symbolizes constitutive GLUT-1, the GLUT-1 induced by intracellular pseudohypoxia. The broken line symbolizes the vicious circle that can develop between glucose uptake, metabolism, pseudohypoxia, and increased GLUT-1 expression in the continuous presence of extremely high extracellular glucose concentrations.
Whether or not the quantity of glucose uptake by interstitial myofibroblasts can be sufficient to explain the decrease of the crystalloid osmotic gradient is open to debate. Although many factors are unknown, a comparison with glucose uptake in renal proximal tubular cells suggests that the proposed mechanism is quantitatively possible (as shown in Supplemental Appendixes 1http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2021010080/-/DCSupplemental–3). Depending on estimations of the volume of distribution of glucose, it could be calculated that the number of interstitial cells is large enough to ingest the required amount of glucose to induce a reduction of the osmotic gradient. The strength of the hypothesis lies in known findings from studies of fibroblast physiology and hypoxia, partly from basic cancer research. Kinetic modeling, indicating a reduced interstitial penetration depth of glucose in ultrafiltration failure, supports the glucose/hypoxia/GLUT-1 hypothesis.29 Furthermore, the progressive time course of the functional and morphologic peritoneal abnormalities adds support for the presence of a vicious circle. An obvious weakness in the hypothesis is the lack of data regarding the expression of glucose transporters on peritoneal interstitial fibroblasts in patients on long-term PD.
Some clinical studies not specifically designed to address this issue support the glucose/hypoxia/GLUT-1 hypothesis. Switching four patients on PD after at least 7 years of treatment with conventional glucose-based PD solutions to a nonglucose regimen (consisting of glycerol, amino acids, and icodextrin) caused a decrease of effluent concentrations of the hypoxia-induced growth factor VEGF, which had increased before this switch.57 An experimental study in a long-term peritoneal exposure model in rats with chronic kidney failure found better sodium sieving, less interstitial fibrosis, and a lower vessel density in animals receiving, for 16 weeks, a daily intraperitoneal administration of a hypertonic dialysis solution consisting of a mixture of 1.4% glycerol, 0.5% amino acids, and 1.1% glucose (approximately 55 mmol/L) versus a standard 3.86% glucose (215 mmol/L) solution.58 These results were in line with those obtained in ten long-term patients with severe ultrafiltration failure.59 Treatment for 6–12 weeks with dialysis solutions that contained glycerol, amino acids, and icodextrin, but no glucose, improved ultrafiltration, sodium sieving, and decreased glucose disappearance from the dialysate; this was statistically significant in the six patients without encapsulating peritoneal sclerosis. Similar results were obtained in a small clinical trial in stable patients on PD, in whom partial replacement of glucose with a mixture of amino acids/glycerol and icodextrin for 3 months resulted in an increase in net ultrafiltration that was not statistically significant, without a change in D/P creatinine.60
Concluding Remarks
Ultrafiltration capacity in patients on PD is dependent on two peritoneal components: the microcirculation and the interstitial tissue. The microvascular component consists of small interendothelial pores and the water channel AQP-1. Small pore fluid transport is mainly determined by the hydrostatic pressure gradient; free water transport through AQP-1 is only possible in the presence of a crystalloid osmotic pressure gradient. Ultrafiltration in the initial few years of PD is almost entirely determined by the microcirculatory contribution, meaning that a large, effective vascular surface area causes high diffusion rates of small solutes, leading to a rapid disappearance of the crystalloid osmotic gradient. Long-term PD causes peritoneal vasculopathy and interstitial fibrosis, consisting of myofibroblasts and augmentation of collagen fibers. The mechanisms of acquired ultrafiltration failure still include the effects of a large effective vascular surface area, but they also include vasculopathy, leading to a reduction in small pore fluid transport (resulting from narrowing of microvascular lumina) and to interstitial fibrosis that especially affects free water transport. The latter may be caused by glucose-induced pseudohypoxia, which stimulates GLUT-1 expression by interstitial myofibroblasts and thereby increases their glucose uptake, which will decrease the crystalloid osmotic pressure gradient for AQP-1.
It can be concluded that peritoneal glucose exposure is a key factor in all mechanisms of acquired ultrafiltration failure in long-term PD. High-quality, long-term PD requires a marked reduction of this exposure or the use of inhibitors of glucose transporters. SGLT-2 inhibitors are available, but, so far, the only accessible study of SGLT-2 inhibition on possible effects on peritoneal ultrafiltration has been done in a rat model and showed no effect, which is in line with the absence of sodium absorption by peritoneal cells.61 A number of GLUT-1 inhibitors have been developed, but none have been applied in humans to date.62 Developments in oncology research make it likely that results concerning clinical use of GLUT-1 inhibitors in patients with cancer will be forthcoming.
Disclosures
R. Krediet reports serving as an editorial board member of Peritoneal Dialysis International.
Funding
None.
Supplemental Material
This article contains the following supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2021010080/-/DCSupplemental.
Supplemental Appendix 1. Assumptions from basic science.
Supplemental Appendix 2. Comparison of renal proximal tubular cells with peritoneal interstitial fibroblasts.
Supplemental Appendix 3. Additional calculations.
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