Diabetes Care Volume 44, July 2021 1647

Hemodialysis-Related Glycemic Akinori Hayashi,1,2 Naoya Shimizu,2

Agena Suzuki,2 Kenta Matoba,2
Disarray Proven by Continuous Akari Momozono,2 Tsuguto Masaki,2
Akifumi Ogawa,2 Ibuki Moriguchi,3
Glucose Monitoring; Glycemic Koji Takano,2 Naoyuki Kobayashi,3
and Masayoshi Shichiri2

Downloaded from http://diabetesjournals.org/care/article-pdf/44/7/1647/633009/dc210269.pdf by Tanzania, United Republic of Institution user on 29 March 2024
Markers and Hypoglycemia
Diabetes Care 2021;44:1647–1656 | https://doi.org/10.2337/dc21-0269

OBJECTIVE
There is a high risk of asymptomatic hypoglycemia associated with hemodialysis
(HD) using glucose-free dialysate; therefore, the inclusion of glucose in the dialy-
sate is believed to prevent intradialytic hypoglycemia. However, the exact glyce-
mic fluctuation profiles and frequency of asymptomatic hypoglycemia using
dialysates containing >100 mg/dL glucose have not been determined.

PATHOPHYSIOLOGY/COMPLICATIONS
RESEARCH DESIGN AND METHODS
We evaluated the glycemic profiles of 98 patients, 68 of whom were men, with
type 2 diabetes undergoing HD (HbA1c 6.4 ± 1.2%; glycated albumin 20.8 ± 6.8%)
with a dialysate containing 100, 125, or 150 mg/dL glucose using continuous glu-
cose monitoring.

RESULTS
Sensor glucose level (SGL) showed a sustained decrease during HD, irrespective
of the dialysate glucose concentration, and reached a nadir that was lower than
the dialysate glucose concentration in 49 participants (50%). Twenty-one partici-
pants (21%) presented with HD-related hypoglycemia, defined by an SGL <70
mg/dL during HD and/or between the end of HD and their next meal. All these
hypoglycemic episodes were asymptomatic. Measures of glycemic variability cal-
culated using the SGL data (SD, coefficient of variation, and range of SGL) were 1
Department of Laboratory Medicine, Kitasato
higher and time below range (<70 mg/dL) was lower in participants who experi- University School of Medicine, Kanagawa,
enced HD-related hypoglycemia than in those who did not, whereas time in range Japan
2
between 70 and 180 mg/dL, time above range (>180 mg/dL), HbA1c, and glycated Department of Endocrinology, Diabetes and
Metabolism, Kitasato University School of
albumin of the two groups were similar.
Medicine, Kanagawa, Japan
3
Sohbudai Nieren Clinic, Kanagawa, Japan
CONCLUSIONS
Corresponding author: Akinori Hayashi,
Despite the use of dialysate containing 100–150 mg/dL glucose, patients with dia- ahayashi@kitasato-u.ac.jp.
betes undergoing HD experienced HD-related hypoglycemia unawareness fre- Received 1 February 2021 and accepted 3 April
quently. SGL may fall well below the dialysate glucose concentration toward the 2021
end of HD. This article contains supplementary material online
at https://doi.org/10.2337/figshare.14372123.
© 2021 by the American Diabetes Association.
Diabetes is a major cause of end-stage kidney disease and cardiovascular disease Readers may use this article as long as the
work is properly cited, the use is educational
(1,2). The prognosis of patients with diabetes undergoing maintenance hemodialy-
and not for profit, and the work is not altered.
sis (HD) is worse than that of patients without diabetes undergoing HD (3), but it More information is available at https://
remains unclear whether differences in glycemic profile affect the high mortality www.diabetesjournals.org/content/license.
1648 Hemodialysis-Related Glycemic Disarray
and morbidity of these patients (4,5).
Appropriate glycemic control slows the
progression of micro- and macrovascu-
lar complications (6). However, in addi-
tion to high hemoglobin A1c (HbA1c)
levels (4,7), low levels are also associated
with higher mortality and comorbidity
in patients with diabetes undergoing
HD (4,8–11). Furthermore, strict glyce-
mic control increases the incidence of
hypoglycemia, of which patients are
often unaware, increases glycemic
variability, and sometimes induces fa-
tal complications in those with diabe-
tes undergoing HD. High glycemic
variability and hypoglycemia are asso-
ciated with higher incidences of car-
diovascular events and other fatal
complications (12), and HD-related hy-
poglycemia develops more frequently
in patients with diabetes than in those
without (13–15). Although the glyce-
mic profile of each patient should be
monitored and properly controlled,
conventional glycemic markers, such as
HbA1c and glycated albumin (GA), do
not provide sufficient information with
which to predict large glycemic fluctua-
tions or hypoglycemia in those with
type 2 diabetes undergoing HD (16).
Asymptomatic hypoglycemia is com-
monly associated with HD when
glucose-free or glucose-poor dialysate
solution is used, and glucose-supple-
mented dialysate is believed to prevent
these episodes (14,15,17,18). However,
most previous studies included a small
number of patients and monitored
blood glucose concentrations intermit-
tently. In contrast, continuous glucose
monitoring (CGM) has become estab-
lished as an ideal method of obtaining
well-defined glucose profiles (19). Re-
cent studies using CGM have revealed
the frequency of all-cause hypoglycemia
in patients with diabetes undergoing HD
to be 16.7–23.5% (20–22) and shown
that patients have distinct glycemic pro-
files on consecutive days on and off HD
(21–24). The use of dialysate containing
100 mg/dL glucose has been reported
to prevent hypoglycemia during HD, on
the basis of CGM recordings, although
the glycemic patterns obtained are un-
predictable, often including sporadic ep-
isodes of asymptomatic hypoglycemia
during HD (20,25,26). However, the ex-
act glucose fluctuation pattern and the
incidence of hypoglycemia related to
HD have not been well characterized us-
ing CGM (27).
To evaluate HD-related hypoglycemia
and HD-induced glucose variability, we
assessed the glucose profiles of patients
with type 2 diabetes undergoing HD us-
ing CGM on consecutive days on and
off HD. Close assessment of the CGM
data prompted us to focus on the glu-
cose profiles during and immediately
after the completion of HD performed
using dialysates containing glucose con-
centrations $100 mg/dL.
RESEARCH DESIGN AND METHODS
Study Design and Population
We enrolled 98 consecutive patients
with type 2 diabetes who were under-
going maintenance HD at either Kitasa-
to University Hospital or Sohbudai
Nieren Clinic, up to June 2017. This
study was approved by the ethics com-
mittees of Kitasato University Hospital
(B17–147) and Sohbudai Nieren Clinic
(20170905). All study methods were
performed in accordance with the rele-
vant guidelines and regulations of Kita-
sato University Hospital as well as the
Ethical Guidelines for Medical and
Health Research Involving Human Sub-
jects in Japan and under the Code of
Ethics of the Helsinki Declaration. Type
2 diabetes was defined using the Ameri-
can Diabetes Association criteria. Pa-
tients with malignancy, liver cirrhosis,
hematologic disease, thyroid dysfunc-
tion, pregnancy, or hemoglobinopathy
were excluded from the study. Partici-
pants were confirmed to have stable
glycemic control during at least the
preceding 3 months, while taking the
same dose of erythropoietin-stimulating
agent, and not to have undergone
blood transfusion during this period.
CGM
We performed CGM using CGMS Sys-
tem Gold (Medtronic Minimed, North-
ridge, CA) in 40 patients and Medtronic
iPro2 CGM (Medtronic Minimed) in 58
for 2 consecutive days, both when on
and off HD. The complete sensor glu-
cose level (SGL) data were analyzed in
CGM records obtained between 0000
and 2400 h of the 2-day period. Hypo-
glycemia was defined as SGL <70 mg/dL
(3.9 mmol/L) for >20 min (28,29). Hypo-
glycemia during HD and post-HD hypo-
glycemia were defined as hypoglycemia
Diabetes Care Volume 44, July 2021
that occurred during HD therapy and
during the period between the comple-
tion of HD and the meal following,
respectively. We defined HD-related
hypoglycemia as hypoglycemia during
HD and/or post-HD hypoglycemia. The
following markers of glycemic variability
were calculated using SGL data for the
entire 48-h recording period: range
(maximum to minimum SGL), SD, and
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coefficient of variation (CV). Further-
more, the glucose management indicator
(GMI) was calculated from the 48-h
mean SGL, and the percentages of time
of SGL between 70 and 180 mg/dL (time
in range; TIR), <70 mg/dL (time below
range; TBR70), <54 mg/dL (TBR54), and
>180 mg/dL (time above range; TAR)
for 2 consecutive days, an HD day and
non-HD day, were calculated (29).
Biochemical Measurements
The following tests were performed to
assess the eligibility of potential partici-
pants for the study: HbA1c, GA, plasma
glucose, C-peptide immunoreactivity,
complete blood count, serum albumin,
and serum creatinine. GA was mea-
sured by an enzymatic synthesis meth-
od using a glycated albumin-L assay kit
(Lucica; Asahi Kasei Pharma, Tokyo,
Japan) (CV <0.3%).
Statistical Analysis
Statistical analyses were performed
using GraphPad Prism (version 5.02;
GraphPad Software Inc., San Diego, CA)
and JMP (version 14; SAS Institute, Cary,
NC). Data are presented as means ±
SDs, unless otherwise indicated. Un-
paired Student t or Mann-Whitney tests
were used to compare data from two
groups, and ANOVA was used for the
evaluation of the glucose profiles in
groups using three different dialysate
glucose concentrations. x2 or Fisher
exact tests were used to evaluate cat-
egorical data. Correlations between
the CGM data and other clinical gly-
cemic parameters were performed
using linear regression analysis and
multiple regression analysis. P < 0.05
was considered to indicate statistical
significance.
RESULTS
Participants Characteristics
Nighty-eight participants were included
in this study, of whom 68 (69%) were
care.diabetesjournals.org Hayashi and Associates 1649

men; the average age was 62 ± 12

Table 1—Demographics of enrolled participants (n 5 98)
years, HbA1c was 6.4 ± 1.2% (45.9 ±
Demographic Value
12.7 mmol/mol), and GA was 20.8 ±
6.8% (Table 1). Sixty-five patients (66%) Male sex 68 (69.4)
were treated with insulin therapy, and Age, years 62 ± 12
six (6%) were treated with diet therapy Dry weight, kg 63.7 ± 14.5
only. The participants underwent 4-h BMI, kg/m2 23.8 ± 4.5
maintenance HD three times per week Duration of diabetes, years 20.5 (1–58)
and ate the next meal within 0.5–1 h Duration of hemodialysis, months 2.0 (0.5–171.0)
after the completion of HD. Eighty-two

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Dialysate glucose concentration, mg/dL
patients started their HD in the morning
100 65 (66.3)
(between 0800 and 1000 h), 11 in the 125 24 (24.5)
afternoon (between 1300 and 1500 h), 150 9 (9.2)
and five in the evening (between 1500 HD time
and 1700 h). Morning 82 (83.7)
Afternoon 11 (11.2)
Glycemic Profiles on HD and Non-HD Evening 5 (5.1)
Days Blood flow, mL/min 198.9 ± 20.1
The complete glycemic profiles for HD Dialysis fluid flow, mL/min 453.1 ± 88.8
and non-HD days are shown in Fig. 1. Dialysis membrane area, m2 1.78 ± 0.29
The mean SGL did not significantly differ Mode of hemodialysis
between the 2 days (150.5 ± 32.9 mg/ HD 93 (94.9)
dL on HD day vs. 151.0 ± 35.9 mg/dL on HDF 5 (5.1)
non-HD day; P 5 0.7881). Although the Red blood cell count,  104/mL) 353.4 ± 57.6
maximum SGL did not significantly differ Hemoglobin concentration, g/dL 10.6 ± 1.6
(249 ± 58 mg/dL on HD day vs. 241 ± Hematocrit, % 33.0 ± 5.2
57 mg/dL on non-HD day; P 5 0.0822), Serum albumin, g/dL 3.6 ± 0.5
the minimum SGL was significantly HbA1c
lower on the HD day than on the non- % 6.4 ± 1.2
HD day (86 ± 26 mg/dL on HD day vs. mmol/mol 45.9 ± 12.7
92 ± 31 mg/dL on non-HD day; P 5 GA, % 20.8 ± 6.8
0.0068). The SD and CV were significantly GA-to-HbA1c ratio, % 3.27 ± 0.82
higher on the HD day than on the non- Casual plasma glucose, mg/dL 141.0 ± 59.8
HD day (42.0 ± 17.3 mg/dL and 27.9 ±
Casual CPR, ng/mL 4.34 (#0.03–32.30)
9.3% on HD day vs. 38.1 ± 14.2 mg/dL
CPR index 3.96 (0.01–34.80)
and 25.4 ± 8.1% on non-HD day; P 5
0.0042 and P 5 0.0020, respectively), Diet therapy, kcal/IBWkg 32.6 ± 3.1
and the range of SGL was significantly ESA dosage, units/week 5500 (0–30000)
higher on the HD day than on the non- Treatment
HD day (163.3 ± 57.7 vs. 149.4 ± 52.5 Diet 6 (6.1)
mg/dL; P 5 0.0045). TIR, TBR70, and OHA 20 (20.4)
Insulin ± OHA 56 (57.1)
TAR did not significantly differ between
Insulin 1 GLP-1A 9 (9.2)
the 2 days (77.4% [1.4–100%], 0% GLP-1A 7 (7.1)
[0–28.0%], and 18.2% [0–98.6%] on HD Retinopathy
day vs. 79.9% [0–100%], 0% [0–23.2%], None 14 (14.3)
and 17.8% [0–100%] on non-HD day; Simple 17 (17.3)
P 5 0.6901, P 5 0.1471, and P 5 Preproliferative 4 (4.1)
0.7907, respectively), but TBR54 was sig- Proliferative 60 (62.1)
nificantly higher on the HD day than on Unknown 3 (3.1)
the non-HD day (0% [0–16.6%] vs. 0% Neuropathy 89 (90.8)
[0–2.4%]; P 5 0.0299). 48-h SGL
The univariate linear regression analy- Mean, mg/dL 150.9 ± 36.9
sis showed that the mean 48-h SGL was SD, mg/dL 40.1 ± 15.6
CV, % 26.7 ± 8.2
significantly correlated with the dura-
Maximum, mg/dL 271 ± 54
tion of diabetes, HbA1c, GA, and GA-to- Minimum, mg/dL 77 ± 23
HbA1c ratio (r 5 0.23, P 5 0.0235; r 5 Range, mg/dL 193.9 ± 52.7
0.69, P < 0.0001; r 5 0.53, P < 0.0001; GMI, % 6.9 ± 0.8
and r 5 0.20, P 5 0.0435, respectively), TIR, % 78.7 (3.6–100)
whereas multiple linear regression anal- TBR70, % 0 (0–22.5)
Continued on p. 1650
yses of these items revealed that the
1650 Hemodialysis-Related Glycemic Disarray Diabetes Care Volume 44, July 2021

Table 1—Continued non-HD days (r 5 0.43, P < 0.0001 and

Demographic Value
r 5 0.48, P < 0.0001, respectively), but
TBR54, % 0 (0–9.5)
not with CV of HD and non-HD days
TAR, % 19.5 (0–96.4) (r 5 0.10, P 5 0.3278 and r 5 0.05,
HD day, CGM data P 5 0.6590, respectively). GA signifi-
Mean, mg/dL 150.5 ± 32.9 cantly correlated with the mean SGL of
SD, mg/dL 42.0 ± 17.3 HD and non-HD days (r 5 0.53, P <
CV, % 27.9 ± 9.3 0.0001 and r 5 0.48, P < 0.0001, re-
Maximum, mg/dL 249 ± 58 spectively), with SD of HD and non-HD
Minimum, mg/dL 86 ± 26
days (r 5 0.54, P < 0.0001 and r 5

Range, mg/dL
Start of HD, mg/dL
End of HD, mg/dL
Change during HD, mg/dL
TIR, %
TBR70, %
TBR54, %
TAR, %
Non-HD day, CGM data
Mean, mg/dL
SD, mg/dL
CV, %
Maximum, mg/dL
Minimum, mg/dL
Range, mg/dL
TIR, %
TBR70, %
TBR54, %
TAR, %
All-cause hypoglycemia
HD-related hypoglycemia
Post-HD hypoglycemia
Hypoglycemia during HD
Data are presented as n (%), mean ± SD, or median (minimum to maximum). CPR, C-pep-
tide immunoreactivity; CPR index, CPR-to–plasma glucose ratio (CPR/plasma glucose  100);
ESA, erythropoietin-stimulating agent; GLP-1A, glucagon-like peptide 1 agonist; HDF, hemo-
diafiltration; IBW, ideal body weight (height [m]2  22); OHA, oral hypoglycemic agent.
mean 48-h SGL significantly correlated
with HbA1c, GA, and GA-to-HbA1c ratio
(r2 5 0.48, b 5 1.49, F 5 30.26, P <
0.0001; r2 5 0.57, b 5 1.37, F 5
9.11, P 5 0.0033; and r2 5 0.53, b 5
1.34, F 5 12.61, P 5 0.0006, respec-
tively) (Supplementary Table 1). The uni-
variate analysis showed that 48-h SD
was significantly correlated with HbA1c,
GA, and GA-to-HbA1c ratio (r 5 0.51,
P < 0.0001; r 5 0.53, P < 0.0001; and
r 5 0.29, P 5 0.0035, respectively), and
multivariate analysis of these items re-
vealed that 48-h SD significantly corre-
lated with HbA1c and GA (r2 5 0.35,
b 5 0.37, F 5 9.15, P 5 0.0032 and
r2 5 0.29, b 5 0.24, F 5 13.41, P <
0.0001, respectively) (Supplementary
Table 1). The univariate analysis showed
that 48-h CV significantly correlated
with GA and GA-to-HbA1c ratio (r 5
0.23, P 5 0.207 and r 5 0.20, P 5
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163.3 ± 57.7
177.6 ± 53.8 0.42, P < 0.0001, respectively), and
119.2 ± 44.0 with CV of the HD day (r 5 0.23, P 5
61 ( 225 to 164) 0.0207), but not with CV of the non-HD
77.4 (1.4–100) day (r 5 0.19, P 5 0.0594).
0 (0–28.0)
0 (0–16.6)
18.2 (0–98.6)
Prevalence of Hypoglycemia and SGL
Nadir During Dialysis
Thirty-four (35%) of the 98 participants
151.0 ± 35.9
38.1 ± 14.2 exhibited all-cause hypoglycemia during
25.4 ± 8.1 their 48-h CGM periods. In addition, 14
241 ± 57 (14%) of the 98 showed hypoglycemia
92 ± 31 during HD, and 20 (20%) showed post-
149.4 ± 52.5 HD hypoglycemia. In total, 21 partici-
79.9 (0–100)
0 (0–23.2)
pants (21%) had HD-related hypo-
0 (0–2.4) glycemia. All HD-related hypoglycemic
17.8 (0–100) episodes were asymptomatic. Further-
34 (34.7) more, 18 participants (18%) showed
21 (21.4) nocturnal hypoglycemia, and four of
20 (20.4) these episodes (22% of the nocturnal
14 (14.3) hypoglycemic episodes) were symptom-
atic. In 14 patients who experienced hy-
poglycemia during HD, the SGL nadir
during HD was 61.1 ± 10.2 mg/dL, and
the SGL at the end of HD was 80.0 ±
40.3 mg/dL, which increased thereafter
in five participants, and was not below
the hypoglycemic threshold (<70 mg/
0487, respectively), and multivariate dL) at end of HD in eight participants. In
analysis revealed that 48-h CV signifi- 20 participants who showed post-HD
cantly correlated with GA only (r2 5 hypoglycemia, the SGL at end of HD
0.05, b 5 0.21, F 5 5.54, P 5 0.0207) was 86.6 ± 34.5 mg/dL, and the SGL
(Supplementary Table 1). In addition, was not below the hypoglycemic
HbA1c significantly correlated with GMI threshold in 12 of these. The SGL de-
(r 5 0.69, P < 0.0001), TIR (r 5 0.61, clined after the end of HD in 17 partici-
P < 0.0001), and TAR (r 5 0.69, P < pants, and the SGL nadir after HD was
0.0001), but not with TBR70 (r 5 0.14, 57.8 ± 9.2 mg/dL.
P 5 0.1629) or TBR56 (r 5 0.14, P 5 The SGL nadir was below the dialy-
0.1742). Similarly, GA significantly corre- sate glucose concentration in 49 par-
lated with GMI (r 5 0.55, P < 0.0001), ticipants (50%), and this occurred
TIR (r 5 0.48, P < 0.0001), and TAR irrespective of the dialysate glucose
(r 5 0.50, P < 0.0001), but not with concentration; it occurred in 31 (48%)
TBR70 or TBR54, and GA-to-HbA1c ratio of 65 participants treated with dialy-
correlated with GMI (r 5 0.20, P 5 sate containing 100 mg/dL glucose, in
0.0298) and TAR (r 5 0.21, P 5 14 (58%) of 24 treated with 125
0.0426). Furthermore, HbA1c signifi- mg/dL, and in four (44%) of nine
cantly correlated with the mean SGL of treated with 150 mg/dL. The mean SGL
HD and non-HD days (r 5 0.66, P < profile during HD and during the post-
0.0001 and r 5 0.64, P < 0.0001, re- HD period did not differ between
spectively) and with SD of HD and the groups of participants using
care.diabetesjournals.org
Figure 1—Continuous glucose monitoring of participants over 24 h. Mean ± SD SGL on HD day (A) and non-HD day (B).
different dialysate glucose concentra-
tions (Supplementary Fig. 1).
Differences Between Participants
Who Did and Did Not Experience
HD-Related Hypoglycemia,
Post-HD Hypoglycemia, and
Hypoglycemia During HD
In comparing the groups of patients
with type 2 diabetes undergoing HD
who did or did not experience HD-
related hypoglycemia and post-HD hy-
poglycemia, there were no significant
differences in sex, age, dry weight, BMI,
duration of diabetes, duration of HD,
red blood cell count, hemoglobin con-
centration, or hematocrit (Table 2). Fur-
thermore, there were no significant
differences in markers of glucose status
(HbA1c, GA, and GA-to-HbA1c ratio) or
HD conditions (dialysate glucose con-
centration, HD time, blood flow, dialysis
fluid flow, dialysis membrane area, and
HD mode) (Table 2). However, in com-
paring the groups of participants who
did or did not experience hypoglycemia
during HD, red blood cell count, hemo-
globin concentration, and hematocrit
were significantly higher and serum al-
bumin was significantly lower in the
group with hypoglycemia during HD ver-
sus the group without (P 5 0.0116, P 5
0.0032, P 5 0.0078, and P 5 0.0121,
respectively) (Table 2).
In the 48-h CGM data, the mean SGL
and GMI were significantly lower and
the SD, CV, and range of SGL were
significantly higher in participants who
experienced HD-related hypoglycemia
than in those who did not. The results
were similar for groups with and with-
out post-HD hypoglycemia and with and
without hypoglycemia after HD, but the
range of SGL was not significantly differ-
ent between patients with and without
post-HD hypoglycemia, and the mean
SGL, GMI, and range of SGL were not
significantly different between patients
with and without hypoglycemia during
HD. Although TIR and TAR did not differ
between the groups with and without
each type of hypoglycemia related to
HD, TBR70 and TBR54 were significantly
higher in participants who experienced
each type of hypoglycemia related to
HD than in those who did not (Table 2).
On the HD day, the mean SD, CV, and
range of SGL significantly differed be-
tween the groups who did and did not
experience HD-related hypoglycemia
and post-HD hypoglycemia, and the SD,
CV, and range of SGL significantly dif-
fered between the groups who did and
did not experience hypoglycemia during
HD. The SGL at the start of HD did not
significantly differ between the two
groups with and without each type of
hypoglycemia related to HD, but the
SGL at the end of HD was significantly
lower in those who experienced each
type of hypoglycemia related to HD
than in those who did not. Further-
more, there were significant differences
in TBR70 and TBR54, but not in TIR or
TAR, on the HD day between the groups
who did and did not experience each
type of hypoglycemia related to HD
(Table 2). On the non-HD day, the SD,
Hayashi and Associates 1651
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CV, and TBR70 were significantly higher
in participants who experienced each
type of hypoglycemia related to HD
than in those who did not. The range of
SGL and TBR54 on the non-HD day were
significantly different only between the
groups who did and did not experience
HD-related hypoglycemia and post-HD
hypoglycemia (Table 2).
When examined with regard to dia-
betes treatment details, 14 (19.7%)
of 71 patients treated with insulin, sul-
fonylureas, and/or glinides and seven
(25.9%) of 27 patients treated with diet
and medications that do not cause
hypoglycemia experienced HD-related
hypoglycemia, with no significant differ-
ence in the frequency of hypoglycemia
(P 5 0.5034). Only patients receiving in-
sulin therapy were analyzed for differ-
ences in insulin doses between HD and
non-HD days; four (10.5%) of 38 pa-
tients receiving the same doses of
insulin, two (16.7%) of 12 treated with
higher insulin doses on the HD day, and
five (25.0%) of 20 treated with higher
insulin doses on the non-HD day experi-
enced HD-related hypoglycemia, and
there was no difference in the hypogly-
cemia frequency (P 5 0.3530). In addi-
tion, regarding basal, bolus, and total
daily insulin dosages on the HD day,
there was no significant difference be-
tween patients with and without HD-re-
lated hypoglycemia.
Glycemic profiles on the HD day were
shown in participants undergoing HD in
the morning, afternoon, and night
(Supplementary Fig. 2). In a comparison
 1652

Table 2—Characteristics of participants who did or did not experience each type of hypoglycemia related to HD
HD-related hypoglycemia Post-HD hypoglycemia Hypoglycemia during HD
No Yes P No Yes P No Yes P
N of patients 77 21 78 20 84 14
Sex, male/female 52/25 16/5 0.4454* 53/25 15/5 0.5416* 57/27 11/3 0.4206*
Age, years 61 ± 12 65 ± 12 0.2511 61 ± 12 64 ± 13 0.3399 62 ± 12 64 ± 13 0.5632
Dry weight, kg 64.4 ± 15.3 61.3 ± 11.0 0.3950 64.2 ± 15.3 61.7 ± 11.2 0.4887 63.7 ± 14.9 63.6 ± 12.2 0.9681
BMI, kg/m2 24.0 ± 4.7 22.9 ± 3.8 0.3186 24.0 ± 4.7 22.9 ± 3.9 0.3526 23.8 ± 4.6 23.6 ± 4.4 0.8982
Duration of diabetes, years 20 (4–58) 24 (1–46) 0.9620† 20 (4–58) 25 (1–46) 0.9683† 21 (1–58) 21 (6–45) 0.6257†
Duration of hemodialysis, months 1.0 (0.5–171.0) 5.0 (0.5–143.0) 0.5795 1.5 (0.5–171.0) 5.0 (0.5–143.0) 0.4360† 2.5 (0.5–171.0) 1.0 (0.5–27.0) 0.1920†
Hemodialysis-Related Glycemic Disarray

Red blood cell count,  104/mL 350 ± 54 364 ± 71 0.3226 351 ± 53 364 ± 73 0.3521 347 ± 53 389 ± 70 0.0116
Hemoglobin, g/dL 10.4 ± 1.5 11.2 ± 1.7 0.0587 10.5 ± 1.5 11.2 ± 1.7 0.0723 10.4 ± 1.5 11.7 ± 1.7 0.0032
Hematocrit, % 32.6 ± 4.9 34.7 ± 5.8 0.0929 32.6 ± 4.9 34.7 ± 6.0 0.1131 32.5 ± 4.8 36.4 ± 6.0 0.0078
Albumin, g/dL 3.6 ± 0.5 3.5 ± 0.5 0.1198 3.6 ± 0.5 3.4 ± 0.6 0.0910 3.7 ± 0.4 3.3 ± 0.6 0.0121
HbA1c 0.5342 0.5346 0.5999
% 6.4 ± 1.1 6.2 ± 1.2 6.4 ± 1.1 6.2 ± 1.3 6.3 ± 1.1 6.5 ± 1.4
mmol/mol 46.4 ± 12.6 44.4 ± 13.4 46.3 ± 12.5 44.4 ± 13.8 45.7 ± 12.3 47.6 ± 15.3
GA, % 20.9 ± 5.8 20.5 ± 9.6 0.8194 20.8 ± 5.8 20.6 ± 9.9 0.9253 20.7 ± 5.8 21.1 ± 11.2 0.8627
GA-to-HbA1c ratio 3.3 ± 0.7 3.3 ± 1.1 0.8988 3.3 ± 0.7 3.3 ± 1.1 0.9641 3.3 ± 0.8 3.2 ± 1.2 0.6626
Casual plasma glucose, mg/dL 139.7 ± 48.2 145.4 ± 90.7 0.7023 139.4 ± 48.0 147.0 ± 92.7 0.6156 139.5 ± 48.6 149.5 ± 105.3 0.5670
Casual CPR, ng/mL 4.28 (#0.03–32.20) 4.52 (0.07–26.10) 0.4208† 4.58 (#0.03–32.20) 4.34 (0.07–26.10) 0.7089† 4.87 (#0.03–32.20) 4.34 (0.07–26.10) 0.6398†
CPR index 3.45 (0.01–26.83) 4.65 (0.02–34.80) 0.1148† 3.58 (0.01–26.83) 4.65 (0.02–34.80) 0.2628† 3.71 (0.01–26.80) 4.64 (1.25–34.80) 0.3454†
Dietary energy, kcal/IBWkg 32.3 ± 3.2 33.5 ± 2.2 0.1148 32.3 ± 3.2 33.7 ± 2.0 0.0707 32.4 ± 3.2 33.7 ± 1.9 0.1435
ESA dosage, units/week 6,000 (0–30,000) 4,500 (0–24,000) 0.6295† 6,000 (0–30,000) 4,500 (0–24,000) 0.9040† 5,500 (0–30,000) 5,250 (0–24,000) 0.8896†
Treatment, n
Diet/OHA/insulin ± OHA/ 3/15/46/8/5 3/5/10/1/2 0.3712* 3/16/46/8/5 3/4/10/1/2 0.4574* 5/16/49/8/6 1/4/7/1/1 0.9410*
insulin 1 GLP-1A/GLP-1A
Neuropathy 70 (91) 19 (90) 0.9514* 71 (91) 18 (90) 0.8873* 75 (91) 14 (100) 0.1987*
Retinopathy, n
None/simple/prepro/pro/ 11/12/4/47/3 3/5/0/13/0 0.6349* 12/12/4/ 47/3 2/5/0/13/0 0.5537* 13/12/4/ 52/3 1/5/0/8/0 0.2903*
unknown
HD time, n
Morning/afternoon/evening 68/5/4 14/6/1 0.0175* 69/5/4 13/6/1 0.0114* 71/8/5 11/3/0 0.3013*
Dialysate glucose concentration, n
100/125/150 mg/dL 50/19/8 15/5/1 0.7121* 50/20/8 15/4/1 0.6155* 57/19/8 8/5/1 0.5706*
Blood flow, mL/min 199 ± 18 197 ± 26 0.5732 199 ± 19 199 ± 24 0.9759 199 ± 19 199 ± 28 0.9514
Dialysis fluid flow, mL/min 455 ± 90 448 ± 87 0.7530 454 ± 89 450 ± 89 0.8638 460 ± 92 414 ± 53 0.0773
2
Dialysis membrane area, m 1.77 ± 0.28 1.82 ± 0.34 0.5094 1.77 ± 0.28 1.84 ± 0.34 0.3610 1.77 ± 0.28 1.85 ± 0.34 0.3454
Mode of hemodialysis, n
Continued on p. 1653
Diabetes Care Volume 44, July 2021

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Table 2—Continued
HD-related hypoglycemia Post-HD hypoglycemia Hypoglycemia during HD
No Yes P No Yes P No Yes P
HD/HDF 72/5 21/0 0.2306 73/5 21/0 0.2451 79/5 14/0 0.3487
48-h SGL data
Mean, mg/dL 154.3 ± 37.8 136.8 ± 29.9 0.0458 154.7 ± 37.6 136.5 ± 30.6 0.0482 153.0 ± 38.6 138.6 ± 20.4 0.1762
SD, mg/dL 38.1 ± 15.5 47.7 ± 14.0 0.0119 38.3 ± 15.6 47.1 ± 14.2 0.0240 38.4 ± 15.2 50.6 ± 14.8 0.0064
care.diabetesjournals.org

CV, % 24.4 ± 7.0 34.9 ± 7.3 <0.0001 24.6 ± 7.2 34.6 ± 7.4 <0.0001 25.1 ± 7.4 36.1 ± 6.9 <0.0001
Maximum, mg/dL 247.7 ± 60.1 253.6 ± 49.7 0.6811 271.2 ± 51.3 271.0 ± 65.6 0.9885 273.0 ± 53.1 259.9 ± 60.6 0.4028
Minimum, mg/dL 94.0 ± 22.0 54.8 ± 8.6 <0.0001 81.7 ± 22.2 59.9 ± 14.7 <0.0001 79.8 ± 22.8 62.1 ± 14.4 0.0062
Range, mg/dL 153.7 ± 55.6 198.8 ± 52.3 0.0012 189.5 ± 47.6 211.1 ± 67.7 0.1017 193.3 ± 51.9 197.8 ± 59.1 0.7668
GMI, % 7.0 ± 0.8 6.6 ± 0.6 0.0388 7.0 ± 0.8 6.6 ± 0.6 0.0413 7.0 ± 0.8 6.7 ± 0.5 0.2773
TIR, % 79.0 (3.6–100) 76.1 (41.9–97.2) 0.3565 79.0 (3.6–100) 76.3 (41.9–97.2) 0.4098 79.0 (3.6–100) 76.3 (54.2–90.1) 0.3881
TBR70, % 0 (0–9.7) 3.8 (0.3–22.5) <0.0001 0 (0–9.7) 3.7 (0.3–22.5) <0.0001 0 (0–22.5) 3.7 (0.3–17.9) <0.0001
TBR54, % 0 (0–0.5) 0 (0–9.5) <0.0001 0 (0–4.2) 0 (0–9.5) <0.0001 0 (0–2.3) 0 (0–9.5) <0.0001
TAR, % 20.3 (0–96.4) 15.4 (0–57.2) 0.5077 20.4 (0–96.4) 14.9 (0–57.2) 0.4643 19.5 (0–96.4) 20.3 (0–40.7) 0.9232
SGL data for HD day
Mean, mg/dL 152.7 ± 34.2 131.4 ± 17.7 0.0070 152.7 ± 33.9 130.4 ± 17.6 0.0057 150.1 ± 34.0 136.5 ± 18.3 0.1500
SD, mg/dL 40.2 ± 18.3 51.1 ± 14.5 0.0134 40.6 ± 18.6 49.9 ± 13.8 0.0399 40.6 ± 17.9 53.8 ± 15.3 0.0111
CV, % 26.0 ± 9.2 38.6 ± 7.7 <0.0001 26.3 ± 9.5 38.0 ± 7.5 <0.0001 27.0 ± 9.5 39.1 ± 8.3 <0.0001
Maximum, mg/dL 247.7 ± 60.1 253.6 ± 49.7 0.6811 249.2 ± 61.1 248.2 ± 44.3 0.9596 246.7 ± 58.1 262.7 ± 56.3 0.3396
Minimum, mg/dL 94.0 ± 22.0 54.8 ± 8.6 <0.0001 93.3 ± 22.7 55.5 ± 8.1 <0.0001 90.9 ± 23.5 53.7 ± 9.2 <0.0001
Range, mg/dL 153.7 ± 55.6 198.8 ± 52.3 0.0012 155.8 ± 58.4 192.7 ± 45.4 0.0101 155.7 ± 54.4 209.0 ± 58.2 0.0011
Start of HD, mg/dL 179.9 ± 53.4 169.1 ± 55.8 0.4175 179.9 ± 53.0 168.5 ± 57.1 0.4001 178.1 ± 53.3 174.3 ± 58.3 0.8095
End of HD, mg/dL 128.7 ± 41.4 84.4 ± 35.1 <0.0001 127.6 ± 42.4 86.6 ± 34.5 0.0001 125.7 ± 41.3 80.0 ± 40.3 0.0002
Change during HD, mg/dL 57 ( 225 to 164) 71 ( 205 to 49) 0.0568† 59 ( 225 to 164) 70 ( 205 to 49) 0.1096† 60 ( 225 to 164) 87 ( 205 to 16) 0.0570†
TIR, % 78.9 (1.4–100) 73.0 (42.2–94.5) 0.1880 78.9 (1.4–100) 74.4 (42.2–94.5) 0.2356 78.9 (1.4–100) 72.5 (42.2–88.2) 0.1408
TBR70, % 0 (0–16.6) 6.6 (0.7–28.0) <0.0001 0 (0–16.6) 6.6 (0.7–28.0) <0.0001 0 (0–21.8) 7.1 (0.7–28.0) <0.0001
TBR54, % 0 (0–2.8) 0 (0–16.6) 0.0201 0 (0–2.8) 0 (0–16.6) 0.0143 0 (0–8.3) 0 (0–16.6) 0.1292
TAR, % 21.1 (0–98.6) 16.6 (0–56.4) 0.6001 21.1 (0–98.6) 16.3 (0–56.4) 0.5604 17.8 (0–98.6) 18.9 (0–56.4) 0.8310
SGL data for non-HD day
Mean, mg/dL 156.9 ± 44.3 142.1 ± 51.3 0.1924 156.6 ± 44.1 142.5 ± 52.6 0.2221 155.9 ± 47.8 140.6 ± 31.9 0.2507
SD, mg/dL 36.0 ± 16.5 44.3 ± 16.8 0.0448 36.1 ± 16.4 44.4 ± 17.2 0.0475 36.2 ± 16.3 47.4 ± 17.1 0.0202
CV, % 22.9 ± 7.2 32.2 ± 10.2 <0.0001 23.0 ± 7.2 32.2 ± 10.5 <0.0001 23.4 ± 8.0 33.6 ± 8.4 <0.0001
Maximum, mg/dL 239.7 ± 53.4 245.2 ± 70.0 0.6967 239.4 ± 53.1 246.4 ± 71.6 0.6287 240.1 ± 55.9 245.4 ± 65.5 0.7500
Minimum, mg/dL 97.6 ± 31.1 69.2 ± 16.4 0.0001 97.3 ± 31.0 68.9 ± 16.7 0.0002 95.0 ± 31.4 70.7 ± 15.5 0.0057
Range, mg/dL 142.1 ± 45.2 176.0 ± 68.3 0.0080 142.1 ± 44.9 177.5 ± 69.7 0.0066 145.1 ± 49.6 174.7 ± 63.6 0.0507
TIR, % 82.0 (0–100) 78.9 (25.6–100) 0.7160 81.9 (0–100) 78.0 (25.6–100) 0.7309 81.4 (0–100) 77.2 (42.9–95.2) 0.8430
TBR70, % 0 (0–8.0) 0.3 (0–23.2) <0.0001 0 (0–8.0) 0.5 (0–23.2) <0.0001 0 (0–23.2) 0.2 (0–11.1) 0.0066
TBR54, % 0 (0–1.0) 0 (0–2.4) 0.0011 0 (0–1.0) 0 (0–2.4) 0.0007 0 (0–1.7) 0 (0–2.4) 0.0961
TAR, % 17.6 (0–100) 20.1 (0–74.4) 0.4056 17.8 (0–100) 16.5 (0–74.4) 0.3730 17.5 (0–100) 21.8 (0–56.7) 0.8390
Data are presented as n (%), mean ± SD, or median (minimum to maximum), unless indicated otherwise. Data were analyzed using unpaired Student t test, unless indicated otherwise. Bold font indi-
cates significance. CPR, C-peptide immunoreactivity; CPR index, CPR-to–plasma glucose ratio (CPR/plasma glucose  100); ESA, erythropoietin-stimulating agent; GLP-1A, glucagon-like peptide 1 agonist;
HDF, hemodiafiltration; IBW, ideal body weight (height [m]2  22); OHA, oral hypoglycemic agent; prepro, preproliferative; pro, proliferative. *Fisher exact test. †Mann-Whitney U test.
Hayashi and Associates
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1654 Hemodialysis-Related Glycemic Disarray
Figure 2—Comparison of time courses of changes in SGL during and after HD between patients
who did and did not experience HD-related hypoglycemia. Mean ± SD SGL during 5 h from start
of HD in 21 patients who showed HD-related hypoglycemia (A) and 77 who did not (B). All pa-
tients underwent HD for 4 h and ate within 0.5–1 h of end of HD.
of the mean SGL on the HD day be-
tween patients undergoing HD in the
morning who did or did not experience
HD-related hypoglycemia, the nocturnal
SGL did not significantly differ between
the two groups. However, the mean
SGL in participants who experienced
HD-related hypoglycemia was signifi-
cantly lower than that in those who did
not during the period between 1135
and 1405 h (P < 0.05) (i.e., from the
middle of dialysis to after the end of
HD). In a comparison of the mean SGL
on the HD day between patients under-
going HD in the afternoon who did or
did not experience HD-related hypogly-
cemia, the mean SGL in participants
who experienced HD-related hypoglyce-
mia was significantly lower than that in
those who did not during the period be-
tween 0235 and 0350 h (P < 0.05) and
between 1545 and 1920 h (P < 0.05 for
1545 to 1750 h, P < 0.01 for 1755 to
1840 h, and P < 0.05 for 1845 to 1920
h), (i.e., natural and from the middle of
dialysis to after the end of HD). Com-
parison of the mean SGL in participants
undergoing night HD was impossible be-
cause of the small number of cases.
In the comparison of the mean SGL
profile on the non-HD day between par-
ticipants with and without HD-related
hypoglycemia (Supplementary Fig. 3),
the mean SGL in participants with
HD-related hypoglycemia was signifi-
cantly lower than that in those without
during the night, between 0135 and
0350 h (P < 0.05 for 0135 to 0205 h,
P < 0.01 for 0210 to 0250 h, P < 0.005
for 0255 to 0335 h, P < 0.01 for 0340
to 0410 h, and P < 0.05 for 0415 to
0430 h), and between 2305 and 2400 h
(P < 0.05). A comparison of the mean
SGL profile during the 5-h period after
starting HD between participants who
did and did not experience HD-related
hypoglycemia is shown in Fig. 2. The
mean SGL in participants who did expe-
rience HD-related hypoglycemia was sig-
nificantly lower between 1 h 20 min
and 5 h after the start of HD than that
in those who did not experience HD-re-
lated hypoglycemia.
CONCLUSIONS
In the current study, we investigated
glucose variability and hypoglycemia us-
ing CGM in 98 patients with type 2 dia-
betes undergoing HD. First, the mean
glucose level did not differ between HD
and non-HD days, but the glycemic vari-
ability was greater on the HD day than
on the non-HD day. Previous studies
provided no consensus on mean glu-
cose levels or glycemic variability on HD
and non-HD days (16,22–24). One rea-
son is the small number of cases in
these studies; we were able to evaluate
the difference in glycemic dynamics in
more patients.
Second, mean glucose level correlat-
ed with both HbA1c and GA, but glyce-
mic variability correlated with GA only.
Similarly, we previously reported that
HbA1c correlated with the mean SGL,
Diabetes Care Volume 44, July 2021
more closely than GA did. In contrast,
although GA itself reflected the mean
SGL without correction, it did so less ac-
curately than HbA1c, but it could serve
as an indicator of glycemic variability
(16). We also demonstrated previously
that the GA-to-HbA1c ratio reliably re-
flects glycemic fluctuation in patients
with diabetes without end-stage kidney
disease (30). A recent study showed
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that HbA1c is no more variable and less
biased than GA in patients with type 2
diabetes and mild renal dysfunction not
undergoing HD (31). Our results support
that HbA1c reflects mean glucose level
and GA reflects glycemic fluctuations in
the population of patients with type 2
diabetes undergoing HD. Additionally,
the current study is the first to examine
the relationship between existing glyce-
mic markers and the new standardized
CGM metrics in participants with diabe-
tes undergoing HD. It was shown that
HbA1c and GA were correlated with
GMI, TIR, and TAR, but not with TBR, in
these patients.
Third, the most important finding in
this study was that >20% of the partici-
pants experienced HD-related hypogly-
cemia, and all of them were
asymptomatic. Many factors have been
suggested to be associated with the de-
velopment of hypoglycemia, such as
caloric intake loss (32), diabetic auto-
nomic neuropathy (33), diabetes treat-
ment, and chronic inflammation (34,35);
however, it is still unclear which factors
play an important role in HD-related hy-
poglycemia. Previous studies showed
that HD-related hypoglycemia and HD-
associated hyperglycemia were detected
by CGM in these patients, but the
characteristics of those who experience
this glucose disarray remain unclear
(22,27,36). In this study, there was no
difference in the clinical characteristics
of patients who did or did not experi-
ence hypoglycemia. In particular, there
was no difference in the frequency of
HD-related hypoglycemia with regard to
diabetes treatment, insulin regimen, or
insulin dosage. Furthermore, HD-related
hypoglycemia was seen even in patients
with diabetes undergoing HD who were
treated with diet and medications that
do not cause hypoglycemia. This sug-
gests that patients with diabetes under-
going HD are at risk for HD-related
hypoglycemia, regardless of diabetic
treatments. Additionally, conventional
care.diabetesjournals.org
glycemic markers, such as HbA1c, GA,
and GA-to-HbA1c ratio, could not satis-
factorily detect hypoglycemia. Markers
of glycemic variabilities obtained from
CGM, such as SD, CV, and range of SGL
data calculated during a 48-h period in-
cluding HD and non-HD days, showed
higher values in patients who experi-
enced HD-related hypoglycemia than in
those who did not. Additionally, al-
though there was no significant differ-
ence in the SGL at the start of HD
between the two groups, the SGL at the
end of HD was significantly lower in pa-
tients who experienced HD-related hy-
poglycemia than that in those who did
not. Treatment to suppress daily glyce-
mic fluctuation may help patients avoid
this type of hypoglycemia. Therefore,
further investigation should be under-
taken to identify appropriate interven-
tions to reduce glycemic variability and
HD-related hypoglycemia. However, our
results reveal that hypoglycemia during
HD may be associated with higher red
blood cell counts and a lower serum al-
bumin level. A previous study suggested
that glucose diffuses from the plasma
into the erythrocytes (37); our results
may support this phenomenon. A lower
serum albumin level may reflect chronic
inflammation in patients undergoing HD
(38), but whether chronic inflammation
is associated with HD-related hypoglyce-
mia remains unclear. In addition, our
study showed a sustained decrease in
the mean SGL during HD, irrespective of
the dialysate glucose concentration. In
particular, the SGL decreased toward the
end of HD, and its nadir was well below
the dialysate glucose concentration in
49 participants (50%).
One strength of our results is that the
sample size was the largest compared
with previous CGM studies in dialysis
patients. However, our study has some
limitations as well. Because this was an
observational study, we could not inves-
tigate the relationship between diabetic
biomarkers and CGM data and mortality
or progression of complications. We in-
vestigated the effects of differences in
dialysate glucose concentration on gly-
cemic profiles and HD-related hypogly-
cemia, but the ratio of patients using
the dialysate high glucose concentration
was small. In addition, we analyzed the
CGM data from 2 consecutive days,
both when on and off HD, to equalize
the effects of both days, but the
consensus guideline recommends >10
days of analyzable CGM data (39). Fur-
thermore, the duration of HD in our
participants was short. It is possible
that many patients had a residual renal
function, and GA may decrease as a re-
sult of the effect of proteinuria or other
conditions. Therefore, GA is recom-
mended as an indicator for long-term
follow-up for patients undergoing main-
tenance HD in the Japanese guideline
(40).
In conclusion, HD-related hypoglyce-
mia unawareness is far more common
in patients with type 2 diabetes under-
going HD than currently recognized,
potentially putting them at risk for car-
diovascular disease and mortality. Physi-
cians should be aware of the high risk
of asymptomatic hypoglycemia in those
with diabetes undergoing HD, irrespec-
tive of the use of glucose-containing
dialysate.
Acknowledgments. The authors thank Mark
Cleasby from Edanz Group for editing a draft
of this manuscript.
Funding. This work was supported in part by
a Grant-in-Aid for Young Scientists (B) from
the Japan Society for the Promotion of Sci-
ence to A.H. (17K18081) and by Kitasato Uni-
versity Shogaku-Kifu research support to M.S.
The funders had no role in the study de-
sign, data collection or analysis, decision to
publish, or preparation of the manuscript.
Duality of Interest. A.H. reports speaker
honoraria from Medtronic, Abbott, Terumo,
and Roche and grants from Abbott outside
the submitted work. N.S. reports speaker
honoraria from Medtronic outside the submit-
ted work. A.O. reports speaker honoraria
from Abbott and Terumo outside the submit-
ted work. No other potential conflicts of in-
terest relevant to this article were reported.
Author Contributions. A.H., K.T., N.K., and
M.S. were responsible for the conception and
design of the study. A.H., N.S, A.S, K.M., A.O.,
and I.M. identified eligible patients for the
study and collected and evaluated the CGM
data and clinical information. A.H., A.M., and
T.M. undertook the statistical analysis of the
data. A.H., N.K., and M.S. reviewed the data
and were responsible for the drafting and ed-
iting of the manuscript. A.H. is the guarantor
of this work and, as such, had full access to
all the data in the study and takes responsi-
bility for the integrity of the data and the ac-
curacy of the data analysis.
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