ArticlePDF Available

Relationship between leptin level, body mass index and parathyroid hormone in chronic hemodialysis patients

Authors:

Abstract and Figures

Endocrine Abstracts (2019) 63 P70 | DOI: 10.1530/endoabs.63.P70 Relationship between leptin level, body mass index and parathyroid hormone in chronic hemodialysis patients Ivona Risovic1,2, Snjezana Popovic Pejicic1,2, Vlastimir Vlatkovic1,2 & Gabrijela Malesevic1,2 1 University Clinical Center of the Republic of Srpska, Banja Luka, Bosnia and Herzegovina, 2 University of Banja Luka, Faculty of Medicine, Banja Luka, Bosnia and Herzegovina ________________________________________ Bone metabolism disorders in hemodialysed patients (HD) involve several humoral factors, of which PTH plays the central role. Leptin is a protein hormon secreted by the adipocytes and related to malnutrition, anemia and bone metabolism disorders in chronic kidney disease patients. The aim of the study was to was to evaluate serum leptin levels and bone metabolism in chronic HD patients depending on body mass index (BMI). This cross section study included 93 HD patients distributed based on BMI in: underweight (n=7), normal weight (n=38), overweight (n=38) and obesity (n=10). Underweight patients had significantly significantly lower leptin level (2.02±1.7 vs 8.62±10.66 vs 32.99±34.52 vs 78.02±51.61, P<0.001), higher PTH level (686.42±1100.43 vs 271.60±321.47 vs 242.0±271.54 vs 254.20±280.68 P<0.001) and higher alkalne phosphatase (156.27±27.13 vs 81.92±44.69 vs 84.50±28.16 vs 66.70±19.27, P<0.001). There were no significant differance in calcium and phosphate level between groups. A significant direct correlation was observed in all groups between leptin level and BMI (P<0.001) and indirect correlation between leptin and PTH level in underweight and obesity group (P<0.05). Hypoleptinemia in chronic HD patients was associated with high PTH and undernutrition. Keywords: leptin, body mass index, parathyroid hormone, hemodialysis
Content may be subject to copyright.
Relationship Between Leptin Level, Inflammation, and
Volume Status in Maintenance Hemodialysis Patients
Ivona Risovi
c,
1,2
Vlastimir Vlatkovi
c,
2,3
Snježana Popovi
c-Peji
ci
c,
2,4
and
Jasna Trbojevi
c-Stankovi
c
5,6
1
International Dialysis Center,
2
Faculty of Medicine, University of Banja Luka, Departments of
3
Nephrology,
4
Endocrinology, University Clinical Center of the Republic of Srpska, Banja Luka, Republic of Srpska, Bosnia
and Herzegovina,
5
Clinic of Urology, Department of Hemodialysis, University Clinical Center Dr. Dragiša
Mišovi
cDedinjeand
6
School of Medicine, University of Belgrade, Belgrade, Serbia
Abstract: Maintenance hemodialysis (HD) patients often
experience fluctuations of volume status. Although hyper-
volemia possibly induces systemic inflammation, the rela-
tionship between volume status and leptin has not yet
been well defined. The aims of this study were to deter-
mine the levels of leptin, C-reactive protein (CRP), and
ferritin in relation to volume status and to assess the rela-
tionship between leptin and volume and inflammatory sta-
tus in chronic HD patients. This prospective study
included 93 HD patients divided, based on evaluation
using the body composition monitor, into normovolemic
and hypervolemic groups (overhydration/extracellular
water [OH/ECW] 15% and OH/ECW > 15%, respec-
tively). The levels of leptin and inflammatory markers
(CRP, ferritin) were determined during a mid-week dialy-
sis session in all patients. There were more hypervolemic
patients after 12 months of follow up than at baseline
(41% vs. 38%). Hypervolemic patients had significantly
lower leptin levels (11.42 19.24 ng/mL vs. 34.53
40.32 ng/mL at baseline and 13.41 22.04 ng/mL vs.
41.54 21.78 ng/mL at 12 months), longer time on dialy-
sis, and poorer nutritional status than normovolemic
patients. Inflammation was present regardless of the vol-
ume status, but hypervolemic patients had significantly
higher CRP and ferritin than normovolemic patients. A
statistically significant reverse correlation was found
between leptin level, hyperhydration index, and OH/ECW.
No significant correlation was found between leptin and
inflammatory markers CRP and ferritin. Key Words:
Hemodialysis, Inflammation, Leptin, Volume status.
Patients on chronic hemodialysis (HD) often
experience fluctuations of volume status, including
repetitive interdialytic weight gains. Achieving and
maintaining optimal dry weight and hydration
parameters in these patients represent a major clini-
cal challenge in the presence of multiple overlap-
ping comorbidities. Persistent volume overload is
associated with hypertension, arterial stiffness, and
left ventricular dysfunction and is strongly linked
with poor outcomes in this population (13).
In contrast, it is estimated that 3060% of HD
patients exhibit persistent inflammation, caused by
multiple factors, including vascular access infections,
malnutrition, and chronic infections, and further
aggravated by uremic immune dysfunction, inade-
quate renal removal of cytokines, and inflammatory
response to dialysis (46).
Hypervolemia is considered a stimulus for sys-
temic inflammation, even though the pathophysio-
logical mechanisms of this relationship are not yet
well defined. One possibility is the increased transi-
tion of endotoxins through the edematous intestinal
wall (7). It has been noted that hypervolemic
patientsnamely, those with heart failurehave
higher levels of endotoxins than euvolemic patients,
which tend to decrease following diuretic therapy
(7). These results suggest an important relationship
between hypervolemia and/or heart failure and
immunological reactions (7). The negative correla-
tion between hypervolemia and serum albumin level
in chronic HD patients is not solely a consequence
Received January 2018; revised August 2018; accepted
August 2018.
Address correspondence and reprint requests to Ivona Risovi
c,
Maksima Gorkog 15, 78000 Banja Luka, Bosnia and
Herzegovina. Email: ivona.risovic@gmail.com
59
Therapeutic Apheresis and Dialysis 2019; 23(1):5964
doi: 10.1111/1744-9987.12750
© 2018 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy
of dilution but also of diminished albumin synthesis
induced by endotoxins and cytokines (8,9). Inflam-
mation, body composition, and hypervolemia are
established risk factors for cardiovascular diseases,
and if they coexist, the risk multiplies (812).
Leptin is a 167-amino acid peptide hormone with a
four-helix bundle motif. It is predominantly synthe-
sized in the adipose tissue. Its name derives from the
Greek word leptos,meaning slim (13,14). Leptin is
involved in the regulation of appetite and might have
a role in the development of anorexia in uremia
through inflammation-related suppression of appetite.
A higher leptin level is linked with higher body mass
index (BMI) and a higher amount of adipose tissue.
Furthermore, a significant association between leptin
and nutritional parameters, such as serum albumin,
prealbumin, and total cholesterol, has been observed
(1517). However, to the best of our knowledge, the
relationship between leptin and volume status has not
yet been investigated in HD patients.
The aims of this study were to determine the
levels of leptin, C-reactive protein (CRP), and ferri-
tin in relation to volume status and to assess the
relationship between leptin and volume and inflam-
matory status in chronic HD patients.
PATIENTS AND METHODS
This prospective study included 93 patients on
maintenance HD in the International Dialysis Cen-
ter in Laktasi, Republic of Srpska. The follow-up
period was 12 months. All patients were divided
according to their volume status into two groups:
normovolemic with overhydration/extracellular
water (OH/ECW) ratio 15% and hypervolemic
with OH/ECW > 15%. Informed written consent
was obtained from all participants prior to enroll-
ment. The study was carried out according to the
principles of the Declaration of Helsinki and was
approved by the Ethical Board of the University
Clinical Center of the Republic of Srpska.
All biochemical analyses were performed in the
Konzilijumlaboratory. Venous blood samples were
drawn before the mid-week HD session. Analyses
were performed at baseline and after 12 months of
follow up. The following parameters were measured
in serum: leptin, hemoglobin, albumin, CRP, and fer-
ritin. Leptin was determined using the enzyme-linked
immunosorbent assay (ELISA), with a reference
range of 0.359.61 ng/mL for men and 2.4328 ng/mL
for women. Serum albumin, iron, CRP, and ferritin
were all determined using the AU 680 Olympus
machine by spectrophotometry, immunoturbidimetric,
and immunochemiluminescent assays, respectively.
Serum hemoglobin was determined on the Advia
2120 machine by cytometric peroxidase. The BMI
was calculated using the Quetelet formula: BMI =
body weight (kg)/height (m
2
). Systolic and dia-
stolic blood pressures (BP) were measured with
the Riester Sanaphon sphyngomanometer
(Ventura, CA, USA). Dialysis dose was calculated
based on mathematical models of single-pool
Kt/V. The severity of comorbidity was assessed
using the Charlson comorbidity index (CCI) with-
out an age component.
Overhydration (OH), extracellular water (ECW),
intracellular water (ICW), total body water (TBW),
OH/ECW ratio, lean tissue index (LTI), and fat tis-
sue index (FTI) were measured using multifre-
quency bioimpedance (Body Composition Monitor
[BCM], Fresenius Medical Care, Bad Homburg,
Germany). All measurements were taken before
the mid-week HD session, in the supine position,
after 2 min of rest.
All patients were on high-flux dialysis using the
polysulfone CorDiax membranes. The underlying
renal diseases were chronic pyelonephritis (27.9%),
diabetic nephropathy (22.6%), glomerulonephritis
(14%), cystic renal disease (11.8%), renovascular
disease (6.5%), and other renal diseases (17.2%).
Exclusion criteria were less than 3 months of dialy-
sis vintage, fewer than three HD weekly, corticoste-
roid therapy and thyroid dysfunction (4,13), acute
inflammation, malignancy, congestive heart failure,
ongoing immunosuppressive, and/or anti-
inflammatory therapy (statins, calcitriol). Eighty
patients (86%) had Brescia-Cimino arteriovenous
fistulas as vascular access, one (1%) had PTFE
graft, and four (4.3%) had permanent and eight
(8.7%) had temporary central venous catheters.
Dialysis adequacy was assessed using the single-pool
Kt/V and online clearance monitoring (OCM) mod-
ule. The burden of comorbidities was assessed using
the CCI. Patients used the following antihyperten-
sive medications: angiotensin-converting enzyme
inhibitors (35 patients, 12 normovolemic and
13 overhydrated, at baseline and 28 patients, 16 nor-
movolemic and 12 overhydrated, at 12 months),
angiotensin receptor blockers (16 patients, 9 normo-
volemic and 7 overhydrated, at baseline and
18 patients, 10 normovolemic and 8 overhydrated,
at 12 months), calcium channel blockers (28 patients,
12 normovolemic and 16 overhydrated, at baseline
and 20 patients, 12 normovolemic and 8 overhy-
drated, at 12 months), and diuretics (7 patients,
4 normovolemic and 3 overhydrated, at baseline
and 5 patients, 3 normovolemic and 2 overhydrated,
at 12 months).
© 2018 International Society for Apheresis,
Japanese Society for Apheresis, and Japanese Society for Dialysis TherapyTher Apher Dial, Vol. 23, No. 1, 2019
I Risovi
c et al.60
After 12 months of follow up, 83 patients were
alive, 9 were deceased, and 1 was transplanted. The
demographic data, biochemical parameters, and vol-
ume status profiles at baseline are summarized in
Table 1, stratified by hydration status.
Statistical analysis
Continuous variables were described by means
and standard deviations. Normality of distribution
of the datasets was assessed using the Kolmogorov
Smirnov test. To compare means of continuous
variables with normal distribution, we used the Stu-
dentst-test for independent samples or analysis of
variance (ANOVA) in cases of more than two inde-
pendent samples. The F-test was used to compare
variances of continuous variables in independent
samples. The MannWhitney or KruskallWallis
test was used for comparison of nonparametric data
as appropriate. Repeated measurements were ana-
lyzed by the Studentst-test for paired samples in
case of normal distribution, Wilcoxon test for vari-
ables with non-normal distribution, or Friedman test
for more than two data groups with non-normal dis-
tribution. Correlation between the observed vari-
ables was assessed using the Spearman
nonparametric rank-order test. Statistical signifi-
cance was defined at the 95% level (P< 0.05).
All analyses were carried out using the IBM SPSS
Statistics 21.0 (IBM Corp, Armonk, NY, USA).
RESULTS
As presented in Table 1, 57 patients (4 men and
23 women) were normovolemic and 36 patients
(21 men and 15 women) were overhydrated at base-
line. After 12 months of follow up, 49 patients were
normovolemic (27 men and 22 women), and
34 (21 men and 13 women) were overhydrated
(Table 2). No statistically significant difference was
found between leptin level at baseline and after
12 months of follow up (25.96 35.71 ng/mL
vs. 29.80 37.80 ng/mL; P> 0.05). Serum leptin
levels and volume indexes are presented in Figures 1
and 2, stratified by hydration status.
A significant direct correlation was observed in
all subjects between leptin level and BMI (r= 0.68,
P< 0.001 at baseline and r= 0.72, P< 0.001 at
12 months) and FTI (r= 0.71, P< 0.001 at baseline
and r= 0.74, P< 0.001 at 12 months). Statistically
significant reverse correlation was obeserved
between leptin level and LTI (r=0.30,
P< 0.005 at baseline and r=0.349, P< 0.05 at
12 months), OH (r=0.31, P< 0.05 at baseline and
r=0.36, P< 0.001 at 12 months), and OH/ECW
(r=0.32, P< 0.05 at baseline and r=0.38,
P< 0.001 at 12 months) (Table 3). No statistically
TABLE 1. Demographic data and laboratory and bioimpedance results stratified by overhydration status at baseline
Normovolemic (N= 57) Hypervolemic (N= 36) Entire cohort (N= 93) P
Age (years) 64.56 12.40 65.29 14.57 64.74 13.06 ns
Dialysis vintage (months) 75.10 64.94 97.89 55.84 84.74 62.66 <0.001
BMI (kg/m
2
) 26.20 4.34 22.12 2.73 24.70 4.27 <0.001
Leptin (ng/mL) 34.53 40.32 11.42 19.24 25.95 33.70 <0.001
Hemoglobin (g/L) 115.43 11.63 107.29 14.04 112.58 12.95 <0.05
Iron (μmol/L) 11.85 5.41 12.31 8.79 12.08 7.1 ns
EPO (IU/kg/month) 297 219 303 168 300 193.5 ns
Albumin (g/L) 41.53 3.25 39.84 3.11 40.85 3.31 ns
CRP (mg/L) 7.40 11.14 9.73 12.34 7.68 9.72 <0.05
Ferritin (ng/mL) 544.10 300.67 670.83 316.27 587.94 306.12 <0.05
OH (L) 1.33 1.78 3.44 1.83 2.24 1.93 <0.001
OH/ECW (%) 8.20 8.51 19.26 3.83 13.64 9.61 <0.001
TBW (L) 35.34 6.74 34.47 6.82 34.91 6.79 ns
ICW (L) 17.6 3.14 17.63 3.17 17.64 3.16 ns
ECW (L) 17.89 4.89 16.73 4.33 17.32 4.48 ns
LTI (kg/m
2
) 12.55 3.04 10.08 3.71 12.11 2.88 <0.05
FTI (kg/m
2
) 12.05 2.04 11.41 2.39 12.31 5.25 ns
BP sys (mm Hg) 145.17 17.87 146.89 19.87 145.80 18.77 ns
BP dia (mm Hg) 74.84 10.40 71.78 13.56 73.63 11.88 ns
Single-pool Kt/V 1.59 0.27 1.63 0.24 1.61 0.27 ns
RRF (mL/24 h) 290.65 187.79 108.14 65.21 398.79 253 <0.001
CCI 3.10 1.10 3.56 1.23 3.30 1.17 ns
Data are presented as mean SD. BMI, body mass index; BP, blood pressure; CCI, Charlson comorbidity index; CRP, C-reactive pro-
tein; dia, diastolic; ECW, extracellular water; EPO, erythropoietin; FTI, fat tissue index; ICW, intracellular water; LTI, lean tissue index;
NS, not significant; OH, overhydration; RRF, residual renal function; sys, systolic; TBW, total body water.
© 2018 International Society for Apheresis,
Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy Ther Apher Dial, Vol. 23, No. 1, 2019
Leptin, Inflammation, and Volume Status in HD 61
significant correlation was found between leptin
level and inflammatory parameters.
DISCUSSION
The association between leptin and nutritional
status in HD patients has been well established.
Several studies have shown decreased leptin levels
in severely malnourished dialysis patients (1517).
In constrast, research on the relationship between
leptin and inflammatory markers has yielded
conflicting results (15,17). Furthermore, the rela-
tionship between volume status and leptin level has
not yet been thoroughly investigated in HD
patients, even though hypervolemia is also a serious
and frequent issue in HD patients, in whom it con-
tributes to the development of numerous
complications.
In order to explore a possible association between
these entities, in this study, we distributed HD
patients in normovolemic and hypervolemic group.
The distribution pattern between groups differed at
baseline and at the end of follow up, with more
hypervolemic patients after 12 months. This shift
was mainly caused by patientscompliance with pre-
scribed nutritional regime and, to a much lesser
extent, by intradialytic complications. The ratio of
overhydrated HD patients in our study was some-
what higher than the European average of 20% but
was similar to those reported in studies by Antlan-
ger and Vega (2,9,13). Of the 10 patients who were
lost to follow up, 7 were hypervolemic, and 3 had
normal volume status, suggesting an association
between hypervolemia and poor outcome in HD
patients (2,3).
Normovolemic patients in our study cohort had a
shorter time on dialysis and better preserved resid-
ual renal function and nutritional status, as repre-
sented by higher BMI and FTI. Consistent with
TABLE 2. Demographic data and laboratory and bioimpedance results stratified by overhydration status after 12 months
of follow up
Normovolemic (N= 57) Hypervolemic (N= 36) Entire cohort (N= 83) P
Age (years) 64.88 13.33 63.54 13.31 63.2 13.19 ns
Dialysis vintage (months) 82.44 55.84 118.29 70.74 96.06 63.97 <0.001
BMI (kg/m
2
) 25.70 4.40 22.47 3.23 24.33 4.31 <0.001
Leptin (ng/mL) 41.54 21.78 13.41 22.04 29.80 37.80 <0.001
Hemoglobin (g/L) 117.02 9.78 115.39 9.83 116.20 9.80 ns
Iron (μmol/L) 13.21 4.69 13.41 0.89 13.17 2.79 ns
EPO (IU/kg/month) 307 247 303 156 305 201.5 ns
Albumin (g/L) 42.67 3.08 39.60 5.41 41.14 4.21 ns
CRP (mg/L) 7.59 9.67 11.60 27.89 9.14 17.15 <0.001
Ferritin (ng/mL) 521.06 282.56 670.42 433.61 584.03 360.92 <0.001
OH (L) 1.36 1.03 3.50 1.09 2.26 1.51 <0.001
OH/ECW (%) 8.02 5.69 20.09 4.21 13.00 7.95 <0.001
TBW (L) 34.45 8.65 33.58 7.12 34.29 7.75 ns
ICW (L) 17.20 3.20 17.29 3.28 17.22 3.22 ns
ECW (L) 18.18 4.50 16.54 3.71 17.60 4.24 <0.05
LTI(kg/m
2
) 12.06 3.05 12.09 2.35 12.2 2.77 ns
FTI (kg/m
2
) 13.60 5.59 10.46 4.21 12.19 5.29 <0.001
BP sys (mm Hg) 139.60 16.23 138.59 17.09 136.71 18.54 ns
BP dia (mm Hg) 70.6 9.78 68 12.62 69.61 11.15 ns
Single-pool Kt/V 1.59 0.24 1.60 0.21 1.59 0.23 ns
RRF (mL/24 h) 267.15 85.21 91.11 25.92 179.13 55.5 <0.001
CCI 3.28 1.03 3.62 1.38 3.40 1.23 ns
Data are presented as the mean SD. BMI, body mass index; BP, blood pressure; CCI, Charlson Comorbidity index; CRP, C-reactive
protein; dia, diastolic; ECW, extracellular water; EPO, erythropoietin; FTI, fat tissue index; ICW, intracellular water; LTI, lean tissue
index; NS, not significant; OH, overhydration; RRF, residual renal function; sys, systolic; TBW, total body water.
FIG. 1. Serum leptin levels and volume indexes at baseline.
© 2018 International Society for Apheresis,
Japanese Society for Apheresis, and Japanese Society for Dialysis TherapyTher Apher Dial, Vol. 23, No. 1, 2019
I Risovi
c et al.62
these findings, previous studies reported an associa-
tion between hypervolemia, longer time on dialysis,
lower BMI, serum albumin, and fat tissue index in
HD patients, as well as a positive correlation
between BMI and FTI (11,18,19).
Even though leptin levels were higher than the
reference range in both study groups during the
entire follow-up period, hypervolemic patients had
significantly lower leptin than the normovolemic
patients. One possible reason for this might be
poorer nutritional status as leptin is associated with
BMI and FTI. In contrast, variations in volume sta-
tus are accompanied by changes in body composi-
tion as hypervolemia is often associated with loss of
muscle and fat tissue (2,7).
Systolic BP was above the recommended level in
both study groups at baseline, regardless of the vol-
ume status. At the end of the follow up, however,
both groups had adequate systolic BP. Hypertension
is common among HD patients, and its positive cor-
relation with hypervolemia has been well estab-
lished in several previous studies (2,3,10,20).
Considering that hypertension is directly propor-
tional to cardiovascular morbidity and mortality in
HD population, it is of extreme importance to
achieve a normotensive state. Bioimpedance can be
a useful and easy method to define if hypertension
is a consequence of hypervolemia, which can be
resolved by adjusting HD parameters (3).
The inflammatory status in our study cohort was
evaluated by serum CRP and ferritin levels. Both
normohydrated and hyperhydrated patients had
CRP levels above the reference range during the
entire follow-up period. However, CRP concentra-
tion was higher and continued to rise during the fol-
low up in hyperhydrated patients, consistent with
previous reports (8). Ferritin levels were within the
reference range for HD patients during the entire
follow-up period in both study groups but was sig-
nificantly higher in hypervolemic than in normovo-
lemic patients. Previous studies also observed
ferritin levels within the reference range in HD
patients, regardless of the volume status (7). Consid-
ering the role of ferritin as a marker of anemia, no
significant differences were found in the levels of
serum iron, hemoglobin, and required erythropoie-
tin doses to maintain stable red blood cell counts
between the normovolemic and overhydrated
patients.
Previous studies have emphasized the possible
role of central venous catheters as a source of
chronic inflammation in HD patients (4,5). Hence,
one possible cause of inflammation in our patient
cohort may have been the relatively high prevalence
of central venous catheters. Furthermore, comorbid-
ities that are frequently present in HD patients are
often associated with malnutrition and inflamma-
tion. However, in our study cohort, no significant
difference was observed in the presence of comor-
bidities between normohydrated and overhydrated
patients. In addition, there was no difference in anti-
hypertensive therapy between the study groups dur-
ing the follow-up period. All patients included in
the study received an adequate dialysis dose, irre-
spective of their volume status.
A statistically significant reverse correlation was
confirmed between volume status and leptin level in
both study groups, as well as direct correlation
between leptin and BMI and FTI. Previous studies
reported a negative correlation between leptin level
and interdialytic weight gain (21). In line with sev-
eral other studies, we have not observed a signifi-
cant correlation between leptin level and the chosen
markers of inflammation in our study cohort
(17,22,23). However, some studies have observed a
significant relationship between leptin and inflam-
mation, namely, a direct correlation between levels
of leptin, tumor necrosis factor, and interleukins
6 and 10 (1,10,24).
FIG. 2. Serum leptin levels and volume indexes at 12 months.
TABLE 3. Correlation between leptin, anthropometric,
and hydration parameters
At baseline (N= 93) After 12 months (N= 83)
rP r P
BMI 0.68 <0.001 0.72 <0.001
FTI 0.71 <0.001 0.74 <0.001
LTI 0.30 <0.05 0.34 <0.05
OH 0.31 <0.05 0.36 <0.05
OH/ECW 0.32 <0.05 0.38 <0.05
BMI, body mass index; ECW, extracellular water; FTI, fat tis-
sue index; LTI, lean tissue index; OH, overhydration.
© 2018 International Society for Apheresis,
Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy Ther Apher Dial, Vol. 23, No. 1, 2019
Leptin, Inflammation, and Volume Status in HD 63
Traditional anthropometric methods and BCM
are inadequate or limited in patients with amputa-
tions or metal implants (e.g. pacemakers), and the
objective assessment of dry body weight in these
individuals represents quite a challenge in clinical
practice. Such patients are often excluded from
studies evaluating volume and nutritional status,
thus representing a somewhat neglected, and yet
quite numerous, population on HD. Based on the
observed relationships between leptin level, volume
status, and nutritional markers, leptin might be used
as a highly valuable alternative to assess volume sta-
tus in these particular cases.
CONCLUSIONS
Overhydrated patients had a lower leptin level
than normohydrated ones. Leptin was significantly
associated with indices of volume and nutritional
status but not with markers of inflammation in our
study population.
Conflict of Interest: There are no conflicts of inter-
est to declare.
REFERENCES
1. Mitsides N, Cornelis T, Broers NJH et al. Extracellular over-
hydration linked with endothelial dysfunction in the context
of inflammation in haemodialysis dependent chronic kidney
disease. PLoS One 2017;12:e0183281.
2. Antlanger M, Hecking M, Haldinger M et al. Fluid overload
in hemodialysis patients: a cross-sectional study to determine
its association with cardiac biomarkers and nutritional status.
BMC Nephrol 2013;2:266.
3. Yilmaz Z, Yildrim Y, Yilmaz Adin F et al. Evaluation of fluid
status related parameters in hemodialysis and peritoneal dial-
ysis patients: clinical usefulness of bioimpedance analysis.
Medicina (Kaunas) 2014;50:26974.
4. Yao Q, Axelsson J, Heimburger O, Stenvinkel P,
Lindholm B. Systemic inflammation in dialysis patients with
end-stage renal disease: causes and consequences. Minerva
Urol Nefrol 2004;56:23748.
5. Jofre R, Rodriguez-Bonitez P, Lopez-Gomez JM, Perez-
Garcia R. Inflammatory syndrome in patients on hemodialy-
sis. J Am Soc Nephrol 2006;17:S27480.
6. Jankowska M, Cobo G, Lindholm B, Stenvinkel P. Inflamma-
tion and protein-energy wasting in the uremic milieu. Contrib
Nephrol 2017;191:5871.
7. Vlatkovic V, Trbojevic-Stankovic J, Stojimirovic B. Relation-
ship between Malnutrition-inflammation complex syndrome
and fluid balance in maintenance hemodialysis patients. Urol
Nephrol Open Access J 2017;4:00144.
8. Garagarza C, Joao-Matias P, Sousa-Guerreiro C
et al. Nutritional status and overhydration: can bioimpedance
spectroscopy be useful in hemodialysis patients. Nefrologia
2013;33:66774.
9. Vega A, Quiroga B, Abad S, Ruiz C, Lopez-Gomez JM.
Study on overhydration in dialysis patients and its association
with inflammation. Nefrologia 2014;34:57983.
10. Dekker MJE, Marcelli D, Canaud BJ, Carioni P, Wang Y,
Grassmann A. Impact of fluid status and inflammation and
their interaction on survival: a study in an international
hemodialysis patients cohort. Kidney Int 2017;91:121423.
11. Wizemann V, Wabel P, Chamney P et al. The mortality risk
of overhydration in hemodialysis patients. Nephrol Dial
Transplant 2009;24:15749.
12. Kim EJ, Choi MJ, Lee JH, Oh JE, Seo JW, Lee YK. Extra-
cellular fluid/intracellular fluid voleume ration as a novel risk
indicator for all-cause mortality and cardiovascular disease in
hemodialysis patients. PLoS One 2017;12:114.
13. Kelesidis T, Kelesidis I, Chou S, Mantzoros C. Narrative
review: the role of leptin in human physiology: emerging clin-
ical applications. Ann Intern Med 2010;152:93100.
14. Friedman J. Leptin at 20: an overview. J Endocrinol
2014;223:18.
15. Dervisoglu E, Eraldemir C, Kalender B, Kir HM,
Caglayan C. Adipocytokines leptin and adiponectin, and
measures of malnutrition-inflammation in chronic renal fail-
ure: is there a relationship. J Ren Nutr 2008;18:3327.
16. Ahamadi F, Bososrgmehr R, Razeghi E. Relationship
between serum leptin level and laboratory and anthropomet-
ric indices of malnutrition in patients on hemodialysis. Indian
J Nephrol 2008;18:10511.
17. Montazerifar F, Karajibani M, Hassanpour Z,
Pourmofatteh M. Study of serum levels of leptin, C-reactive
protein and nutritional status in hemodialysis patients. Iran
Red Crescent Med J 2015;17:e26880.
18. Piratelli CM, Telarolli JR. Nutritional evaluation of stage
5 chronic kidney disease patients on dialysis. Sao Paulo Med
J2012;130:3927.
19. Jialin W, Yi Z, Weiji Y. Relationship between body mass
index and mortality in hemodialysis patients: a meta-analysis.
Nephron Clin Pract 2012;121:c10211.
20. Chen YC, Lin CJ, Wu CJ, Chen HH, Yeh JC. Comparison of
extracellular volume and blood pressure in hemodialysis and
peritoneal dialysis patients. Nephron Clin Pract 2009;113:
c1126.
21. Ahbap E, Sakaci T, Kara E et al. Relationship between rela-
tive interdialytic weight gain and serum leptin levels, nutri-
tion, and inflammation in chronic hemodialysis patients. Clin
Nephrol 2015;83:15460.
22. Markaki A, Gkouskou K, Stylianou K et al. Relationship
between adiposity, adipokines, inflammatory markers and
lipid profile in hemodyalisis patients. Eur Rev Med Pharma-
col Sci 2014;18:14968.
23. Dervisevic A, Subo A, Avdagic N et al. Elevated serum lep-
tin level is associated with body mass index but not with
serum C-reactive protein and erythrocyte sedimentation rate
values in hemodialysis patients. Mater Sociomed
2015;27:99103.
24. Dz P, Liu XW, Huang L, Zhu XF, Zheng YQ, Wang LX.
Relationship between leptin and chronic inflammatory state
in uremic patients. Eur Rev Med Pharmacol Sci
2014;18:28825.
25. Yao YH, Fu CH, Ho SJ et al. Peritoneal dialysis as compared
with hemodialysis is associated with higher overhydration but
non-inferior blood pressure control and heart function. Blood
Purif 2012;34:407.
© 2018 International Society for Apheresis,
Japanese Society for Apheresis, and Japanese Society for Dialysis TherapyTher Apher Dial, Vol. 23, No. 1, 2019
I Risovi
c et al.64
ResearchGate has not been able to resolve any citations for this publication.
Article
Full-text available
Background Haemodialysis (HD) patients are predisposed to dysregulated fluid balance leading to extracellular water (ECW) expansion. Fluid overload has been closely linked with outcome in these patients. This has mainly been attributed to cardiac volume overload, but the relation between abnormalities in fluid status with micro- and macrovascular dysfunction has not been studied in detail. We studied the interaction of macro- and microvascular factors in states of normal and over- hydration in HD-dependent CKD. Methods Fluid compartments [total body water (TBW) and ECW] and overhydration index (OH) were measured with Multifrequency bio-impedance (BCM). Overhydration was defined as OH/ECW>7%. Overhydration was also assessed using the ECW/TBW ratio. Macrocirculation was assessed by pulse-wave velocity (PWV) and mean arterial pressure (MAP) measurements while microcirculation through sublingual capillaroscopy assessment of the Perfused Boundary Region of the endothelial glycocalyx (PBR 5-25mcg). A panel of pro-inflammatory and vascular serum biomarkers and growth factors was analysed. Results Of 72 HD participants, 30 were in normohydration (N) range and 42 overhydrated according to the OH/ECW ratio. Average ECW/TBW was 0.48±0.03. Overhydrated patients had higher MAP (122.9±22.5 v 111.7±22.2mmHg, p = 0.04) and comorbidities (median Davies score 1.5 v 1.0, p = 0.03). PWV (p = 0.25) and PBR 5-25mcg (p = 0.97) did not differ between the 2 groups. However, Vascular Adhesion Molecule (VCAM)-1, Interleukin-6 and Thrombomodulin, and reduced Leptin were observed in the overhydrated group. Elevation in VCAM-1 levels (OR 1.03; 95% CI 1.01–1.06; p = 0.02) showed a strong independent association with OH/ECW>7% in an adjusted logistic regression analysis and exhibited a strong linear relationship with ECW/TBW (Bata = 0.210, p = 0.03) in an also adjusted model. Conclusion Extracellular fluid overload is significantly linked to microinflammation and markers of endothelial dysfunction. The study provides novel insight in the cardiovascular risk profile associated with overhydration in uraemia.
Article
Full-text available
In hemodialysis patients extracellular fluid overload is a predictor of all-cause and cardiovascular mortality, and a relation with inflammation has been reported in previous studies. The magnitude and nature of this interaction and the effects of moderate fluid overload and extracellular fluid depletion on survival are still unclear. We present the results of an international cohort study in 8883 hemodialysis patients from the European MONDO initiative database where, during a three-month baseline period, fluid status was assessed using bioimpedance and inflammation by C-reactive protein. All-cause mortality was recorded during 12 months of follow up. In a second analysis a three-month baseline period was added to the first baseline period, and changes in fluid and Inflammation status were related to all-cause mortality during six-month follow up. Both pre-dialysis estimated fluid overload and fluid depletion were associated with an increased mortality, already apparent at moderate levels of estimated predialysis fluid overload (1.1–2.5L); hazard ratio 1.64 (95% confidence interval 1.35–1.98). In contrast, post-dialysis estimated fluid depletion was associated with a survival benefit (0.74 [0.62–0.90]). The concurrent presence of fluid overload and inflammation was associated with the highest risk of death. Thus, while pre-dialysis fluid overload was associated with inflammation, even in the absence of inflammation, fluid overload remained a significant risk factor for short-term mortality, even following improvement of fluid status.
Article
Full-text available
Background In hemodialysis patients, fluid overload and malnutrition are accompanied by extracellular fluid (ECF) expansion and intracellular fluid (ICF) depletion, respectively. We investigated the relationship between ECF/ICF ratio (as an integrated marker reflecting both fluid overload and malnutrition) and survival and cardiovascular disease (CVD) in the context of malnutrition-inflammation-arteriosclerosis (MIA) complex. Methods Seventy-seven patients from a single hemodialysis unit were prospectively enrolled. The ECF/ICF volume was measured by segmental multi-frequency bioimpedance analysis. MIA and volume status were measured by serum albumin, C-reactive protein (CRP), pulse wave velocity (PWV) and plasma B-type natriuretic peptide (BNP), respectively. Results The mean ECF/ICF ratio was 0.56±0.06 and the cut-off value for maximum discrimination of survival was 0.57. Compared with the low ECF/ICF group, the high ECF/ICF group (ratio≥0.57, 42%) had higher all-cause mortality, CVD, CRP, PWV, and BNP, but lower serum albumin. During the 5-year follow-up, 24 all-cause mortality and 38 CVD occurred (18 and 24, respectively, in the high ECF/ICF group versus 6 and 14 respectively in the low ECF/ICF group, P<0.001). In the adjusted Cox analysis, the ECF/ICF ratio nullifies the effects of the MIA and volume status on survival and CVD and was an independent predictor of all-cause mortality and CVD: hazard ratio (95% confidence interval); 1.12 (1.01–1.25) and 1.09 (1.01–1.18) for a 0.01 increase in the ECF/ICF ratio. The degree of malnutrition (albumin), inflammation (CRP), arteriosclerosis (PWV), and fluid overload (BNP) were correlated well with the ECF/ICF ratio. Conclusions Hemodialysis patients with high ECF/ICF ratio are not only fluid overloaded, but malnourished and have stiff artery with more inflammation. The ECF/ICF ratio is highly related to the MIA complex, and is a major risk indicator for all-cause mortality and CVD.
Article
Full-text available
Background: Leptin is secreted by adipose tissue and decreases appetite. However, the role of leptin in the pathogenesis of hemodialysis (HD)-related malnutrition has not been fully evaluated. Objectives: The aim of study was to investigate the association between the serum leptin levels, serum C-reactive protein (CRP) levels, and nutritional status in hemodialysis patients. Patients and methods: This analytical descriptive study included 45 hemodialysis patients and 40 healthy subjects. Biochemical parameters and serum leptin levels were measured. The nutritional status was evaluated using a food frequency questionnaire (FFQ) and the calculation of the body mass index (BMI). Results: Serum leptin (P < 0.05) and albumin (P < 0.0001) levels and BMI (P < 0.001) of HD patients were significantly lower, while CRP levels were significantly higher than those of controls (P < 0.0001). HD patients consumed the lower daily servings of the food groups compared to the control subjects (P < 0.0001). A significant positive correlation between serum levels of leptin and albumin and BMI was demonstrated. No significant correlations were identified between leptin level, CRP level, and other variables. Conclusions: The findings suggest that low levels of leptin may be a contributory factor for malnutrition in HD patients. Further studies are required to ascertain the significance of leptin levels in relation to nutritional factors in hemodialysis patients.
Article
Full-text available
Aim of the present study was to investigate serum concentration of leptin and its association with values of body mass index (BMI), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) in hemodialysis (HD) patients. This cross-sectional study included 60 HD patients (34 male, 26 female) and 30 age- and sex-matched (4 males, 26 females) apparently healthy subjects. Serum leptin concentration was determined by an enzyme-linked immunosorbent assay (ELISA). Serum CRP concentration was measured by means of particle-enhanced immunonephelometry. ESR value was determined by Western Green method. BMI was calculated as weight (kg) divided by height squared (m(2)). Results have shown that median serum leptin concentration (30.65 ng/mL; 12.48-86.40 ng/mL) was statistically significantly higher in HD patients compared to median serum leptin concentration (15.75 ng/mL; 9.15-30.65 ng/mL) in the control group of healthy subjects (p<0.05). Likewise, median serum CRP concentration (5.5 mg/L; 1.93-8.9 mg/L) and median ESR value (57.5 mm/h; 40.5-77.0 mm/h) were significantly higher in HD patients compared to median serum CRP concentration (0.8 mg/L; 0.38-1.43 mg/L) (p<0.001) and median ESR value (10.0 mm/h; 6.5-14.0 mm/h) (p<0.001) determined in the control group. Statistically significant positive correlation was found between BMI values and serum leptin concentration in HD patients (rho=0.434; p<0.001). Positive, although not significant, correlation was observed between serum CRP and leptin levels in HD patients (rho=0.171; p>0.05). Negative correlation between ESR values and serum leptin concentrations in HD patients was determined but it was not statistically significant (rho= -0.029; p>0.05). Increased serum concentration of leptin as pro-inflammatory cytokine as well as elevated serum values of CRP and ESR indicate presence of systemic micro inflammation in HD patients. Results of the present study point to possible use of serum leptin concentration as an indicator of nutritional status in HD patients based on observed significant positive correlation between serum leptin concentrations and BMI values. However, absence of significant association between serum leptin and CRP levels as well as between serum leptin concentrations and ESR values in HD patients requires further investigation and clarification.
Article
Full-text available
Introduction: Excessive relative interdialytic weight gain (RIDWG, %) is an important risk factor for long-term adverse cardiovascular outcomes in chronic hemodialysis (HD) patients. On the other hand, it may also be an index of good appetite and nutritional status. We aimed to assess the relationship between RIDWG and appetite, nutrition, inflammation parameters of chronic HD patients. Methods: 100 chronic anuric HD patients were enrolled in this prospective study between January 2013 and January 2014. Patients with hospitalization, major surgery, obvious infectious/inflammatory disease, end-stage liver disease, malignancies, and malabsorption syndromes were excluded. Patients were divided into 3 groups according to their RIDWG levels; group 1 = RIDWG < 3%, group 2 = RIDWG: 3 - 5%, and group 3 = RIDWG > 5%. Results: Group 3 patients were younger (p = 0.011) and had a lower body mass index (BMI) (p = 0.014). Nutrition and inflammation parameters including malnutrition inflammation score (MIS), serum albumin, prealbumin, triceps skinfold thickness, hs-CRP, and TNF-α ere not significantly different between the groups. Leptin and leptin/BMI ratio were significantly lower in group 3 (p = 0.001). RIDWG was negatively correlated with age (p = 0.001, r = -0.371), BMI (p = 0.001, r = -0.372), leptin (p = 0.001, r = -0.369), leptin/BMI (p = 0.001, r = -0.369). After adjustment for BMI in linear regression analyis, leptin/BMI remained significantly correlated with RIDWG (p = 0.024). Conclusion: This study revealed that RIDWG was associated with younger age, lower BMI and dry weight, and lower serum leptin levels. More detailed studies are needed to validate and dissect the mechanisms of these findings.
Article
Full-text available
Historically, adipose tissue was considered to be a passive storage vessel discharging nutrients in times of famine and accumulating fat in times of surfeit. This view changed with the identification of leptin as an adipocyte hormone. Leptin functions as an afferent signal in a negative feedback loop that regulates food intake and metabolism to maintain homeostatic control of adipose tissue mass. Prior to this, the existence of a system maintaining homeostatic control of energy balance was unclear. The identification of leptin has thus uncovered a new endocrine system that also links changes in nutrition to adaptive responses in most if not all other physiologic systems. Further studies have revealed a set of clinical syndromes caused by leptin deficiency, including lipodystrophy and hypothalamic amenorrhea. This work has led to new therapeutic approaches for a number of human conditions and has also established a conceptual framework for studying the pathogenesis of obesity.
Article
Inflammation is normally a protective and physiological response to harmful stimuli, but typically becomes an uncontrolled, maladaptive, and persistent process in patients with end-stage renal disease (ESRD). Through a deleterious cascade of poorly controlled reactions mediated by biologically active molecules (also called middle molecular weight uremia retention solutes), inflammation associates with a range of complications including cardiovascular disease and protein-energy wasting (PEW). Persistent inflammation, which is central to the conceptual etiological models of PEW and the malnutrition, inflammation, and atherosclerosis syndrome, induces and reignites processes leading to PEW in a number of ways including stimulation of both direct and indirect mechanisms of muscle proteolysis. Similar to other chronic diseases, inflammation in the uremic milieu is the consequence of multiple factors including comorbidities, such as infections. In addition, inflammation is further aggravated in ESRD by uremic immune dysfunction, inadequate renal removal of cytokines, and inflammatory responses to dialysis. It is plausible that only by disrupting this vicious circle(s) by acting on several levels of the inflammatory cascade rather than targeting single causes of inflammation will it be possible to improve the prognosis in ESRD patients. Accordingly, treatment of uremic inflammation and PEW require an integrated approach. In addition to lifestyle modifications, nutritional supplements, and drugs with anti-inflammatory potential, improved dialysis therapy using high retention onset membranes has emerged recently. This novel dialysis technique, also called expanded hemodialysis (HDx), may provide a more efficient removal of middle molecules involved in the cascade of inflammatory mediators with selectivity against albumin losses. Plausibly, the implementation of HDx, integrated with strategies blocking an excessive secretion of inflammatory mediators, may offer a new therapeutic approach to chronic inflammation and PEW in ESRD.
Article
Objective: To explore the relation between high leptin and inflammation in uremic patients. Patients and methods: A group of 73 uremic patients in dialysis center of our Department were assigned as uremic group; a group of 30 healthy persons who were examined over the same period were regarded as control group. The level of body mass index (BMI), serum creatinine (SCr), blood urea nitrogen (BUN), leptin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-10, and the neutrophils phagocytosis function were compared in two groups. Results: BMI and IL-10 of uremic group were lower than the control group. The levels of SCr, BUN, leptin, TNF-α, IL-6 of uremic group were higher than the control group (p < 0.05). The neutrophils phagocytosis function in uremic group significantly decreases, compared to control group (p < 0.05). Using one-way ANOVA analysis, serum leptin was positively correlated with the level of TNF-α, IL-6 (r = 0.58, 1.00 respectively, p < 0.05), and was negatively correlated with the level of IL-10 (r = -0.45, p < 0.05). Conclusions: The high level of leptin and correlated inflammation were involved in the initiation and development of uremia; moreover, leptin was an important mediator.
Article
Background: Patients with chronic kidney disease receiving haemodialysis (HD) have permanent variations in hydration status that may affect their survival. Objectives: To analyse hydration status and body composition in patients on haemodialysis and its relation to inflammation. Methods: We included 128 prevalent clinically stable patients on haemodialysis. We analysed body composition using spectroscopic bioimpedance and inflammation using blood parameters. Results: Patients with higher lean tissue had less intracellular (p=0.02) and extracellular water (p = 0.001). We did not find association with fat tissue and hydration. Mean overhydration was 7.5 %. We found an association between overhydration adjusted to extracellular water (OH/ECW) higher than 15 % similar to 10 %. They were both associated with low prealbumin levels (p = 0.001 and p = 0.05 respectively) and low levels of fat tissue (p = 0.001 and p = 0.05 respectively). Conclusions: Overhydration defined as OH/ECW higher than 10 % and 15 % are related to low prealbumin levels and low fat tissue. We suggest decreasing the overhydration limit measured by bioimpedance to OH/ECW higher than 10 %.