Hypoalbuminemia in Peritoneal Dialysis Patients

Advances in Peritoneal Dialysis, Vol. 29, 2013
Steven Guest
Clinicians caring for patients on peritoneal dialysis
(PD) have relied on a variety of laboratory measures
to assess the health of patients and their response to
treatment. Traditionally, serum albumin has been an
indicator of nutrition status and has therefore been
included in monthly blood testing in most centers.
The development of hypoalbuminemia in dialysis
patients has been associated with increased mortality and often leads to interventions such as trials of
nutritional supplements. In PD, hypoalbuminemia
combined with ongoing losses of protein into effluent
raise particular concerns with clinicians.
Serum albumin may be affected by a variety of
non-nutrition factors such as inflammation, volume
status, and comorbidities. Albumin synthesis in the
liver exceeds, in most cases, albumin losses in urine
or effluent. Interpreting the medical implications of
declining serum albumin in PD patients can therefore
be a challenge.
This paper reviews protein balance in PD. The
nutritional and non-nutritional factors affecting serum
albumin are discussed, with specific emphasis on how
membrane physiology contributes to dialysate protein
losses. A general clinical approach to the PD patient
developing hypoalbuminemia is discussed.
Key words
Hypoalbuminemia, albumin, protein balance, protein
losses, nutrition, inflammation
Introduction
Uremic patients initiating peritoneal dialysis (PD)
would be expected to experience clinical improvement, with an increase in appetite and nutritional intake. This increase in dietary intake would be expected
to favorably affect any underlying nutritional deficits
that may have developed in the pre-dialysis interval.
And yet, despite the improvement in uremia, some patients develop a progressive decline in serum albumin
From: Baxter Healthcare Corporation, Deerfield, Illinois,
U.S.A.
Hypoalbuminemia in
Peritoneal Dialysis Patients
concentration. The development of hypoalbuminemia
in PD patients may represent a complicated interplay
of nutrition, non-nutrition, and modality-specific factors such as protein loss into PD effluent.
To further complicate matters, clinicians may now
be uncertain about the implications of hypoalbuminemia. Is hypoalbuminemia a marker of nutrition?
Is hypoalbuminemia a marker of active comorbid
disease, separate from true protein intake? Is hypoalbuminemia purely a marker of volume status and
indicative of dilution of the serum albumin concentration? These questions are valid, and clinicians caring
for hypoalbuminemic patients may benefit from a
clinical algorithm for the assessment and treatment
of those patients.
This paper reviews the role of serum albumin as a
true marker of nutrition, reviews other processes that
may affect serum albumin concentration, discusses
protein balance in PD patients, and reviews a clinical
approach and treatment strategy for the PD patient
developing hypoalbuminemia.
Discussion
Utility of serum albumin as a marker of nutrition
As eloquently reviewed by Friedman and Fadem,
serum albumin may not adequately reflect the true
nutritional status of patients (1). Perhaps most illustrative of this fact is an examination of the patient with
analbuminemia—a congenital absence of measureable
serum albumin (2). This autosomal recessive disorder
presents with an absence or marked reduction in serum
albumin and is the result of several described mutations in the albumin gene (3). The mutations are felt
to disrupt intracellular transport of albumin and to
lead to early degradation. Serum oncotic pressure is
maintained by increased production of non-albumin
proteins such as alpha-2-globulin, beta globulin, and
apolipoproteins. Despite unmeasurable serum albumin
levels, these patients may have a normal nutritional
status and have not been felt to demonstrate serious
clinical complications of analbuminemia itself.
56
Another example of the limited use of serum albumin as an indicator of nutritional status is the condition
of marasmus. This condition occurs after longer-term
deprivation of adequate nutritional intake, as is seen in
starvation. Patients are markedly thin, weak, and listless, and yet may demonstrate a normal serum albumin
concentration. Similar observations have been made
in patients with anorexia nervosa: despite intentional
limitations in nutritional intake, patients may maintain
a near-normal serum albumin concentration until the
terminal end of the process (4).
Serum albumin is not a sensitive measure of dietary protein intake. For example, protein-restricted
diets have been recommended in patients with chronic
kidney disease (CKD) to slow disease progression. In
the United States, the Modification of Diet in Renal
Disease study, published in 1997, studied the impact
of dietary protein restriction on the progression of
CKD (5). In that study, patients with CKD stages 3
and 4 were randomized to a usual-protein diet of 1.3 g/
kg daily or a low-protein or very-low-protein diet of
0.58 g/kg daily. Mean duration of follow-up was 2.2
years. In the low- and very-low-protein groups, serum
albumin rose. A French study prescribed supplemented
protein-restricted diets that reduced protein intake to
0.43 g/kg from 0.85 g/kg daily. During the study period, serum albumin concentrations were unchanged
(6). Those studies demonstrate that, within a range
of lower protein intakes, patients with kidney disease
have been able to maintain a traditional indicator of
nutrition (serum albumin), suggesting that this measure alone is an insensitive marker of true protein
intake or requirements.
Serum albumin might therefore not be indicative
of nutritional status and might be inferior to other classical measures such as subjective global assessment,
mid-arm circumference, and careful dietary histories.
Non-nutrition factors affecting serum albumin
concentration
A variety of clinical conditions may affect serum
albumin (Table I). Those conditions may be wholly
separate and distinct from nutritional intake and may
independently alter the serum albumin concentration.
States of overhydration have classically been
described as causing hypoalbuminemia because of
dilution. Dilutional hypoalbuminemia can be seen
in a variety of overhydration states such as congestive heart failure or CKD. Volume depletion has the
Hypoalbuminemia in Peritoneal Dialysis Patients
opposite effect, causing elevated albumin because
of plasma volume contraction. Volume status may
therefore independently affect serum albumin.
Albumin is a negative acute-phase reactant, meaning that, in states of inflammation, serum albumin is
depressed. Inflammatory states can affect the levels
of a variety of plasma constituents, increasing them
(acute-phase reactants) or lowing them (negative
acute-phase reactants) (8). The putative role of the
negative acute-phase response is to reduce production
of some proteins to conserve amino acids, shifting
those substrates to the production of other hepatic
proteins that can augment the immune system during
infection or inflammation. This negative acute-phase
response of albumin is, therefore, generally independent of nutritional intake.
These non-nutritional factors affecting serum
albumin concentration may explain the unpredictable response in patients on dialysis to nutritional
supplements administered in an attempt to increase
this laboratory value (9).
Protein balance in PD
Albumin and protein stores in the PD patient are
determined by dietary protein intake, rates of hepatic
synthesis of albumin and other proteins, protein losses
into effluent, and urinary losses in patients with residual kidney function (Table II). In the stable PD
patient, recommendations for dietary protein intake are
1.2 – 1.3 g/kg daily (10). Protein losses into effluent
are typically 5 – 15 g daily (11). Urinary protein losses
are also a possibility. To offset those losses, the rate
of albumin synthesis in the liver is 12 – 15 g daily. In
PD patients, Kaysen (7) demonstrated an increase in
the albumin synthesis rate proportional to external albumin losses. This compensatory increase in albumin
synthesis typically maintains normal plasma albumin
concentrations during PD therapy and explains why
peritoneal albumin and protein losses into dialysate
are, themselves, not predictive of outcome (13).
Further investigations in PD patients determined
that states of inflammation directly suppress hepatic
albumin synthesis, preventing compensatory increases
in albumin production (12). The development of hypoalbuminemia in most PD patients therefore appears
to be characterized by a combination of the acutephase response, with a reduction in serum albumin,
combined with a true decrease in albumin synthesis
to compensate for protein losses into effluent.
Guest
table i
57
Evidence suggesting that serum albumin is not a pure marker of nutrition
Evidence
Reference
Congenital analbuminemia has been described, and many patients appear to develop normally and to have a normal nutrition status.
1,2
Albumin can shift from the plasma space to the interstitial space in sepsis or burns.
1
Severe anorexia nervosa is often accompanied by normal serum albumin.
4
Patients with marasmus may maintain normal serum albumin.
1
The Modification of Diet in Renal Disease study examined reduction in protein intake as low as 0.3 g/kg daily and noted no
decline in levels of serum albumin.
5
Serum albumin may be affected by volume status (dilutional hypoalbuminemia)
7
Albumin is a negative acute-phase reactant; lower serum levels are seen in the setting of systemic inflammation
8
table ii
Protein balance in peritoneal dialysis (PD)
Contributor to protein balance
Reference
Recommended daily dietary protein intake in PD is 1.2–1.3 g/kg
10
Daily protein losses in dialysate are typically 5–15 g
11
Daily albumin losses in dialysate are 3–6 g/1.73 m2
12
In patients with residual kidney function, protein may be lost in urine
The daily albumin synthesis rate is 12–15 g
7
The albumin catabolic rate is depressed in dialysis patients
7
Determinants of protein losses into peritoneal effluent
Protein loss into peritoneal effluent has been noted
to vary widely from patient to patient and from day
to day in a single patient (14). The main determinant
of effluent protein loss is the large-pore flux across
the peritoneal capillary lumen (15). In the 3-pore
model of peritoneal permeability, the large pores
allow for the flux of proteins into dialysate, with
some loss of smaller proteins across the small pores
(16). As mentioned earlier, daily protein losses into
effluent are typically 5 – 15 g, with the variation
reflecting differences in the capillary density of the
peritoneal membrane.
Capillary density and surface area are the main
determinants of the peritoneal membrane transport
category, as described in the classical peritoneal
equilibration test [PET (17)]. Peritoneal membrane
transport categories—originally described as low,
low-average, high-average, and high—actually
reflect the capillary surface area of the peritoneal
membrane. Low-transport membranes are less vascular, and high-transport membranes typically reflect
increased vascular density because of the individual’s
underlying baseline anatomy or as a consequence of
neovascularization during longer-term exposure to
dialysate (18,19). The migration of PET results toward
higher transport characteristics over time is presumed
to be a result, in part, of the elaboration of vascular
endothelial growth factor, which induces capillary
neovascularization (20). Additionally, patients may
transiently demonstrate increased vascular permeability during peritoneal inflammation—as in peritonitis,
for example. Episodes of peritonitis are associated
with increased small-solute clearance across the
membrane and increased protein losses into effluent
because of vasodilation of the capillary bed, which
58
Hypoalbuminemia in Peritoneal Dialysis Patients
increases pore diameter and flux (21). Increased capillary vessel numbers implies an increased number of
large pores and increased peritoneal losses of protein
across those large pores. Peritoneal protein losses into
effluent are therefore a function of the vascularity of
the peritoneal membrane. However, that theory remains somewhat controversial, because not all studies
have demonstrated this association (22).
Clinical utility of serum albumin in the care of the
PD patient
Figure 1 shows a proposed algorithm, adapted from
the work of Heaf and associates (15), for interpreting
serum albumin concentration in PD patients.
In the patient approaching end-stage renal disease,
serum albumin may decline into the lower ranges of
normal, possibly reflecting the onset of anorexia and
diminished nutritional intake. The concentration may
be further depressed because of dilution from worsening kidney function and edema. With the initiation
of PD, the concentration of serum albumin can be
followed for one of three responses:
•
•
•
Serum albumin may be noted to improve because
of improvement in uremic symptoms and appetite, and reduction in edema with dialysis.
Other patients have been noted to demonstrate
stable serum albumin.
The third response is a further precipitous fall
in serum albumin after the initiation of PD. This
third presentation is most concerning and places
the patient in a group that may be at highest risk
of morbidity and technique failure.
With those possibilities in mind, serum albumin
can be used in the care of PD patients as a screening
tool so that the clinical team can triage their patients
and identify those who are potentially at highest risk
and in need of interventions.
In the PD patient demonstrating significant hypoalbuminemia, a variety of clinical interventions
may be indicated. The dietician can evaluate dietary
history to determine if any component of the hypoalbuminemia may be a result of inadequate protein
intake. A trial of supplements can be considered. The
care team should recognize that the hypoalbuminemia
may be largely attributable to systemic inflammation
and the negative acute-phase response. A focused
examination of the patient should attempt to identify
figure 1 Algorithm for addressing hypoalbuminemia in peritoneal
dialysis (PD). Alb = albumin; PVD = peripheral vascular disease.
any source of inflammation that could be addressed.
Examples include periodontal disease, foot ulcers,
active peripheral vascular disease, colonic bacterial
overgrowth with constipation, active comorbidities,
or inflammation because of a PD-related process such
as exit-site or tunnel infection or indolent peritonitis.
In addition to considering a trial of dietary supplements and treatment of any source of inflammation
that may be suppressing compensatory hepatic albumin synthesis, the clinical team can assess peritoneal
protein losses. In patients demonstrating higher transport properties, the team should consider the possibility of higher peritoneal protein losses. Protein losses
in higher transporters may be lessened by a change
in the PD prescription to automated PD. Elimination
of the longer day dwell in higher transporters may
allow for a temporary reduction in peritoneal protein
losses without significant compromise in small-solute
clearance (23). Conversion to a dry day with ongoing monitoring of total solute clearance to maintain
adequacy parameters can be considered in an attempt
to improve hypoalbuminemia.
Patients on PD who demonstrate worsening
hypoalbuminemia despite attempts at interventions
in nutrition, in detecting and addressing sources of
inflammation, and in changing the therapy prescription to minimize peritoneal protein losses will be at
higher risk of morbidity and mortality. The underlying
Guest
comorbidities contributing to inflammation may not
be improved by a change in modality, but the clinical
team should discuss whether a conversion to hemodialysis (HD) may be indicated. Conversion eliminates
the contribution of peritoneal protein losses to refractory hypoalbuminemia and might be attempted in this
high-risk population. However, the patient remaining
hypoalbuminemic on HD remains at significant risk
of higher mortality. In an extensive review of hypoalbuminemia as a predictor of mortality, Mehrotra and
colleagues (24) determined that, at any level of serum
albumin reduction, mortality was higher on HD than
PD, documenting the increased risk of hypoalbuminemia across these dialysis modalities.
Summary
Hypoalbuminemia in PD patients can be multifactorial and might reflect increased systemic inflammation, untreated volume excess with dilution, ongoing
peritoneal and urinary losses of protein, and impaired
compensatory hepatic synthesis of albumin. Nutritional supplementation can be attempted on the
understanding that hypoalbuminemia is not simply
reflective of decreased dietary protein intake. Caregivers should attempt to identify and treat any source
of inflammation and to assess peritoneal membrane
function to determine whether a prescription change
might be indicated to reduce peritoneal protein losses
while maintaining adequate total solute clearance
targets. The PD patient developing hypoalbuminemia
during PD therapy should be evaluated with the clinical algorithm proposed here.
Disclosures
SG is an employee of Baxter Healthcare Corporation.
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Corresponding author:
Steven Guest, md, Baxter Healthcare Corporation,
1 Baxter Parkway, Mailstop DF5 2-W, Deerfield,
IL, U.S.A.
E-mail:
steven_guest@baxter.com