Evaluating the relationship between haemodialysis and glucose control in insulin-treated diabetic patients - a pilot study

Diabetes mellitus is a common chronic disease due to insufficiency of insulin
secretion and/or increased insulin resistance. Short term complications are
hypoglycaemia and hyperglycemia with or without keto-acidosis. Long-term
complications can be divided into microvascular (e.g. retinopathy, nephropathy
and neuropathy) and macrovascular (e.g. myocardial infarction, cerebrovascular
event, peripheral arterial disease) complications. The risk of developing these
acute and chronic complications is significantly reduced by optimal glycaemic
control. Diabetes is a major cause of chronic renal failure, and is the
underlying disease in about 15% of patients on renal replacement therapy
(haemodialysis or peritoneal dialysis). The prognosis of diabetic patients on
haemodialysis is extremely poor, with 3-year survival rates of less than 30%.
It has been demonstrated that better glycaemic control in diabetic patients on
haemodialysis is associated with improved survival rates. However, randomised
controlled trials on the impact of intensive glucose control in these patients
are very limited.
Little is known about the potential influence of haemodialysis on the glycaemic
control in diabetic patients, and available data are inconclusive. It has been
suggested that plasma insulin is eliminated by the haemodialysis procedure,
resulting in postdialysis hyperglycaemia. In contrast, mean glucose levels were
found to be decreased on days with haemodialysis in two recent studies. The
risk of postdialysis hypoglycaemia was even increased in one of these studies.
Glucose levels in these two studies were measured with a continuous glucose
monitoring (CGM) system during 2 or 4 days. CGM is a registered technique for
frequent glucose measurements in the subcutaneous interstitial fluid and has
the advantage of providing glucose measurements at intervals as short as 1
minute during several days.
The mechanisms behind the reported variations in glucose levels on days with
and without a haemodialysis session remain to be elucidated. It is conceivable
that haemodialysis may affect glycaemic control either directly (e.g. by
eliminating glucose and insulin or changing insulin sensitivity) and/or
indirectly (e.g. by interfering with the patients* mobility and food intake).
No significant dietary changes were found in the only study examining food
intake. Mobility was not monitored in any of these studies. Moreover, the
patients studied were heterogeneous with respect to their diabetes treatment,
which varied from diet only to oral medication or insulin therapy. Therefore,
it is possible that these results are confounded by the heterogeneity of the
patient groups studied.
The aim of the present study is to monitor glucose levels by CGM together with
food intake and physical activity in insulin treated diabetic patients who are
on regular hemodialysis treatment. Glucose monitoring will be performed both on
days with and without a haemodialysis session. In addition, insulin
pharmacokinetics during haemodialysis will be evaluated in a subgroup of
patients. It is expected that the results of this study will contribute to
optimizing metabolic control in insulin treated diabetic subjects who are on
regular haemodialysis treatment.

Primary objective: to compare glucose profiles collected by CGM on days with
and without haemodialysis in a group of insulin treated diabetic patients who
are on regular hemodialysis treatment.

Secondary objectives:
o assessment of frequency and severity of hypoglycaemic episodes on days with
and without haemodialysis
o describing the relationship between glucose profiles and food intake
o describing the relationship between glucose profiles and physical activity
o examining whether insulin and/or glucose is eliminated by haemodialysis

Observational invasive study.

Participants undergo regular haemodialysis treatment (usually 3 times a week
for 3-4 hours). The usual schedule is either Monday-Wednesday-Friday, or
Tuesday-Thursday-Saturday.

The following study procedures and tests take place.

Week 1:
o instructions on how to use a pedometer and to keep a structured diary on
physical activities by a motion researcher. Pedometer is worn from 7 days
before connection of the CGM device until after completion of the 5-day CGM
period. The reason for starting the pedometer registration 7 days before the
CGM period is to compensate for the novelty effect. New users tend to increase
their walking activities during the first days of wearing the pedometer. In
general, walking pattern has normalized to baseline values after one week of
continued use. The pedometer and diary on physical activities are not
applicable to patients who are more or less immobilised as a result of e.g.
previous leg amputation or paralysis. In these patients, variations in physical
activity are not expected have a significant influence on the recorded glucose
profile.
o HbA1c measurement: a limited amount of blood (4 ml) is drawn. This
measurement may coincide with the monthly routine laboratory measurements in
these patients. In those instances, no additional blood volume is required. In
all other cases, a limited amount of blood needs to be drawn. All blood samples
are drawn from the fistula, and therefore, venipunctures are not required.
o instruction by dietician on how to keep a structured diary on food intake
during the CGM period
o instruction by diabetic nurse on how to record hypoglycaemic events during
CGM period
o instruction by diabetic nurse on how to use the Freestyle Navigator®

Week 2:
o connection of the Freestyle Navigator® on day 1 by the diabetic nurse (i.e.
Monday or Tuesday).The CGM device is disconnected by the patient 120 hours
later ( i.e. on Saturday or Sunday, respectively). Connection of the Freestyle
Navigator® takes place prior to a haemodialysis session. Consequently, the
patient who usually receives haemodialysis in the afternoon needs to perform
one finger stick blood glucose measurement at nighttime for calibration of the
CGM device (vide infra). Alternatively, the haemodialysis session on day 1
could be rescheduled to be performed in the morning. The choice between these
two options will be left to the patient.
o calibration of CGM device with finger stick blood glucose measurements tests
after 1, 2, 10, 24 and 72 h
o daily recording of insulin dose and time of administration (patient diary)
o daily recording of food intake (patient diary)
o daily recording of physical activities (patient diary) and registration of
daily number of steps as counted by pedometer
o recording of hypoglycaemic events (patient diary)
o a subgroup of 10 diabetic patients participates in the pharmacokinetics
study. Patients are asked in order of inclusion to participate in this
pharmacokinetics study, until the required number of 10 patients has been
achieved. Blood samples for determination of glucose and insulin will be drawn
before, during (at one hour intervals) and directly after one haemodialysis
session (4-5 blood samples of 7 ml each simultaneously from the arterial and
venous side of the haemodialysis unit = 56 -70 ml in total). Dialysate will be
sampled at corresponding time intervals for measurement of glucose
concentration (insulin can not be measured as its concentration is below the
limit of detection of the insulin immunoassay).

We consider the burden associated with this study limited. No extra study
visits are required as instructions and tests are planned during regular
hemodialysis sessions. Moreover, the study duration is only 12 days. A maximum
of one blood sample (4 ml) is drawn for determination of HbAc. Among the 10
participants of the pharmacokinetics study, blood samples are drawn with a
maximal total volume of 70 ml. All blood samples are drawn from the fistula,
and therefore, venipunctures are not required. We use a CE approved CGM device.
Risks associated with the Freestyle Navigator® are low and include adhesive
reaction (2%) and pain or bleeding on sensor insertion (2%). The several
diaries are assembled into a single, user-friendly booklet.