Perit Dial Int
29(Supplement_2):
123-127
2009
© 2009 International Society for Peritoneal Dialysis
Part 3: Clinical Experiences |
UPDATE ON MECHANISMS OF ULTRAFILTRATION FAILURE
Yong-Lim Kim
Division of Nephrology, Kyungpook National University Hospital School of
Medicine, Daegu, Korea
Correspondence to: Y.L. Kim, Division of Nephrology and Department of Internal
Medicine, Kyungpook National University Hospital, 50, Samduk-dong 2Ga,
Jung-gu, Daegu 700-721 Korea.
ylkim{at}knu.ac.kr
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ABSTRACT
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Ultrafiltration failure (UFF) continues to be a major complication of
peritoneal dialysis (PD), particularly long-term PD. Continuous exposure to
bioincompatible PD solutions causes inflammation of the peritoneal membrane,
which progressively undergoes fibrosis and angiogenesis and, ultimately, UFF.
There is emerging evidence that epithelial–mesenchymal transition (EMT)
of peritoneal mesothelial cells (MCs) may play an important role in the
failure of peritoneal membrane function. Submesothelial myofibroblasts
originating from MCs through EMT and from activated resident fibroblasts
participate in inflammatory responses, extracellular matrix accumulation, and
angiogenesis. High glucose and glucose degradation products from PD solutions
are responsible for production of transforming growth factor β
(TGFβ) and vascular endothelial growth factor (VEGF) by MCs, which induce
EMT. Leptin and receptor for advanced glycation end-products (AGEs) augment
myofibroblastic conversion through the TGFβ signaling system.
A reduction in osmotic conductance in addition to increased solute
transport causes UFF. This situation may be caused by loss of aquaporin (AQP)
function and formation of the submesothelial fibrotic layer. During PD, AQP1
plays an essential role in water permeability and ultrafiltration (UF),
modulating processes such as endothelial permeability and angiogenesis. During
a hypertonic dwell, AQP1 mediates 50% of UF. Insufficient AQP1 function may be
causative for inadequate UFF. A significant amount of evidence from animal
studies now exists to show that mast cells communicate with fibroblasts and
are implicated in fibrogenesis, angiogenesis, and UFF. However, it is not
confirmed in human studies that mast cells contribute to the fibrosis seen in
the peritoneum of PD patients.
The patterns of UFF in PD patients depend on duration of treatment.
Inherently high small-solute transport status is associated with
hypoalbuminemia and a greater comorbidity index. However, most of the
variability in peritoneal transport remains unexplained, pointing to the
potential role of genetic factors. Gene polymorphisms associated with
peritoneal membrane transport have been identified. Recent studies have shown
that VEGF, interleukin-6, endothelial NO synthase, AGE receptor, and
RAS gene polymorphisms are associated with transport properties in PD
patients. Current insights into the mechanisms of UFF will provide rationales
for new therapeutic strategies.
KEY WORDS: Ultrafiltration failure; epithelial-to-mesenchymal transition; aquaporin.
Ultrafiltration failure (UFF) is a major complication of peritoneal
dialysis (PD), particularly long-term PD. Continuous exposure to
bioincompatible PD solutions and peritonitis cause inflammation of the
peritoneal membrane, which progressively undergoes fibrosis and angiogenesis
and, ultimately, UFF.
In a Japanese study of biopsy specimens from 80 PD patients, patients with
a history of peritonitis were excluded. The study found that duration of PD
was positively correlated with peritoneal thickness and vasculopathy.
Peritoneal thickness was correlated with vasculopathy. In the group with
impaired ultrafiltration (UF) capacity, the peritoneum was thicker than in the
group with maintained UF capacity. These results clearly showed that PD
treatment itself had a strong impact on peritoneal fibrosis
(1). On the other hand, in an
animal study, PD solution with low glucose degradation products (GDPs)
effectively attenuated the peritoneal vascularization and fibrosis related to
conventional PD solutions
(2).
The PD catheter also has a significant effect on the peritoneum. The PD
catheter itself increases the inflammatory response in the peritoneal membrane
and induces fibrosis, angiogenesis, and increased peritoneal transport
(3).
Recently, research progress has been made regarding several aspects of
peritoneal pathophysiology: epithelial–mesenchymal transition (EMT) of
mesothelial cells; aquaporin in peritoneum, interstitium, and lymphatics; mast
cells in peritoneum; pattern or factors of UFF according to time on PD; and
genetic variation such as studies of single nucleotide polymorphisms.
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EMT AND SENESCENCE OF MESOTHELIAL CELLS
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Recent findings suggest that mesothelial cells are able to switch cell
phenotype depending on the local environment. The mesothelial cells can
transform into myofibroblasts or endothelial cells and smooth muscle cells.
During organogenesis, serosal mesothelial cells differentiate into smooth
muscle cells surrounding the blood vessels
(4). The EMT of mesothelial
cells is one important mechanism of peritoneal fibrosis
(5).
Transforming growth factor β1 (TGFβ1) is a key regulator of EMT
in the peritoneal membrane. Margetts and colleagues showed that TGFβ1
overexpression with gene therapy induced EMT
(6). The GDPs in PD solution
and the reactive carbonyl compounds in uremia induce formation of advanced
glycation end-products (AGEs). Activation of receptor for AGEs (RAGE) plays an
important role in TGFβ-induced fibrosis through EMT and vascular
endothelial growth factor (VEGF)–induced angiogenesis through capillary
tube formation
(7,8).
This process has been confirmed in human tissue. In uremia, RAGE and
expression of 
smooth muscle actin (-SMA) are increased in human
tissue and aggravated with time on PD
(9). On the other hand,
apoptosis in human peritoneal mesothelial cells (HPMCs) is induced by
3,4-dideoxyglocosone-3-ene at a concentration similar to or slightly higher
than that found in 4.25% conventional PD solution. Pancaspase inhibitor
reduced this apoptosis
(10).
Recently a couple of papers have been published concerning leptin and
peritoneal fibrosis
(11,12).
Leptin induces TGFβ synthesis through functional leptin receptor
expressed in HPMCs. Leptin augments EMT and fibrogenic activity. In an ex
vivo study, human non-epithelioid cells that undergo EMT were observed to
produce a great amount of collagen I and IV, fibronectin, and VEGF as compared
with epithelial-like (non-EMT) cells. These molecules are related to high
solute transport (13). It has
been shown that EMT may occur early during PD. A Spanish group studied 35
stable PD patients for less than 2 years. Cytokeratin staining confirmed EMT
in tissues from those patients. In multivariate analysis, the mass transport
area coefficient of creatinine was found to be an independent factor (odds
ratio: 12.47) predicting the presence of EMT
(14).
Bone morphogenetic protein 7 (BMP-7) has been known to reverse EMT in
kidney. In an ex vivo study, treatment with BMP-7 reversed EMT
morphology in HPMCs, showing -SMA as a marker of myofibroblasts
(15). The BMP-7 may improve or
reduce the peritoneal solute transport rate (PSTR). By contrast, in a human
clinical study, BMP-7 in dialysate effluent was positively correlated with
small-solute transport. The role of exogenous BMP-7 on peritoneal transport
requires further study
(16).
Looking at all current evidence, EMT of mesothelial cells is induced by
multiple stimuli, which include a PD fluid component and inflammatory
cytokines. Mesothelial cells that undergo EMT promote angiogenesis through
VEGF and fibrosis through the formation of extracellular matrix.
Another change of HPMCs is accelerated senescence, whose key regulator is
TGFβ1. Exposure to high glucose induces increased expression of
senescence-associated β-galactosidase (SA-β-Gal). The addition of
anti-TGFβ1 neutralizing antibody partially reduced the activation of
SA-β-Gal activity. This result suggests that exposure to high glucose
results in autocrine TGFβ-mediated accelerated senescence. Senescent
HPMCs increase production of VEGF and extracellular matrix
(17,18).
The senescence of HPMCs in human peritoneal specimens is observed during
aging. Aging is accompanied by the presence of an inflammatory state in HPMCs.
Culture of HPMCs isolated from non-septic abdominal surgery showed a
significant correlation between the age of the donor and the levels of basal
cytokine or nuclear factor 
B mRNA production
(19).
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AQUAPORIN IN PERITONEUM
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On the other hand, overexpression of SMAD7 induced by an
ultrasound microbubble–mediated gene delivery system inhibited
TGFβ–Smad2/3 pathway and improved fibrosis. Overexpression of
SMAD7 improved fibrosis and vascularization in uremic rats with PD.
Smad2/3 was inhibited, and solute transport was improved
(20). By contrast,
TGFβ-induced gene product, which is the downstream protein of TGFβ,
improved the wound healing process after scratch injury. The TGFβ plays a
role in both fibrosis and the wound healing process
(21).
Studies in aquaporin (AQP) knockout mice showed that AQP1 plays an
essential role in water permeability and UF during PD. A strong signal for
AQP1 was observed in plasma membranes and plasma membrane in-folding of
capillary endothelial cells. Compared with AQP1+/+ mice, mice lacking in AQP1
showed a complete loss of sodium sieving, but unchanged end
dialysate–to–initial dialysate (D/D0) glucose. In
addition, AQP1–/–mice showed significantly lower volume curves and
initial UF rates. During a hypertonic dwell, AQP1 mediates 50% of UF.
Insufficient AQP1 function may be causative for inadequate UF
(22).
Aquaporin 1 plays a important role in angiogenesis and endothelial cell
migration. Increased vasculature was observed in AQP1+ mice as compared with
AQP1-null mice. In endothelial cell cultures, endothelial cell proliferation
is more prominent in AQP1+ cells than in AQP1-deficient cells. In AQP1-null
mice, wound healing or cell migration is impaired
(23). Verkman
(24) proposed one mechanism of
AQP1-dependent cell migration: Water influx at the tip of a lamellipodium
results in membrane protrusion in the direction of cell migration. Not only
does AQP1 modulate endothelium permeability, but also angiogenesis.
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MAST CELLS IN PERITONEAL CAVITY
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A significant amount of evidence from animal studies suggests that mast
cells contribute to fibrosis, angiogenesis, and UFF. During experimental PD,
mast cells accumulate in the omentum and make a typical milky spot with a
unique vascular network. Mast-cell-deficient and cromoglycate groups
(cromoglycate being a mast cell stabilizer) show reduced milky spots and
associated vascular networks
(25). However, confirmation
that mast cells contribute to fibrosis has not yet been obtained in human
studies. The number of mast cells is reduced in a PD group as compared with a
control or uremic group. That finding differs from the results of the animal
study (26). However, in
another human study, mast-cell expression was upregulated in a PD group, but
not in a group with encapsulating peritoneal sclerosis (EPS). The authors
speculated that loss of control functions of mast cells may contribute to the
ill-understood disease entity of EPS
(27).
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PATTERN OR FACTORS OF UFF ACCORDING TO TIME ON PD
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One recent review article divided fast transporters into early inherent and
late acquired phenotypes. According to that paper, early inherent fast
transporters can be categorized into two types. One type is associated with
vasculopathy and endothelial dysfunction caused by inflammation or
comorbidity. Surrogate markers are C-reactive protein and interleukin 6 (IL-6)
in serum and PD effluent. The prognosis is usually poor in this group. The
second group is associated with a large peritoneal surface area. Increased
cancer antigen 125 in PD effluent may indicate this type, whose prognosis is
usually good (28).
In the literature, the clinical determinants of inherent PSTR are variable
(Table 1). In the CANUSA study,
the determinants were old age, diabetes, and hypoalbuminemia
(29). In the Davies study, it
was male sex and high residual urine volume
(30). In the
Australia–New Zealand registry data, the genetic component was important
(31). In studies by Gillerot
et al. and Clerbaux et al., the use of angiotensin
converting-enzyme inhibitor or angiotensin II receptor blocker may affect
peritoneal transport
(32,33).
One study from Korea showed that inherent PSTR is not associated with systemic
inflammation, but with serum albumin
(34). In a one longitudinal
observational study from Spain, inherent PSTRs were found to be associated
with plasma albumin and comorbidity index
(35). A study from Portugal
showed that local inflammation, as demonstrated by effluent IL-6 is associated
with PSTR (36).
The UFF pattern may be different according to PD duration. A total of 50
UFF patients were divided into three groups according to PD duration. In UFF
patients on PD for more than 60 months ("long-term PD"), free
water UF, UF coefficient, and osmotic conductance were decreased as compared
with the same parameters in short- or mid-term patients with UFF
(37).
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SUMMARY
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Having reviewed the mechanisms of UFF, it still must be noted that most of
the variability in peritoneal transport remains unexplained, pointing to the
potential role of genetic factors. Gene polymorphisms associated with
peritoneal membrane transport have been identified, including VEGF, IL-6,
RAGE, endothelial NO synthase, plasminogen activator inhibitor 1
(38).
In mesothelial cells, EMT and senescence have been studied intensively.
Mast cells and genetic factors may play an important role in UFF. Dysfunction
with regard to AQP1 in peritoneal endothelial cells is a major cause of UFF.
Peritoneal dialysis fluid is closely associated with these changes.
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ACKNOWLEDGMENTS
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This study was supported by a grant from the Korea Healthcare Technology
R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of
Korea (A084001).
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ABSTRACT
EMT AND SENESCENCE OF...
