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Hypoglycaemia is the most frequent complication of diabetes management,
affecting up to one quarter of all patients with type 2 diabetes,
at least once a year.1 Although permanent damage or mortality due
to hypoglycaemia is uncommon, even minor hypoglycaemic events
can have a major effect on diabetes management. Hypoglycaemia
(or a “hypo”) is cited as the most important (and feared) complication
of diabetes by patients themselves, more important than kidney failure
or heart disease. Hypoglycaemia is often the most important barrier to
good glucose control, as attempts to avoid it result in therapeutic inertia
and (reluctant) tolerance of higher glucose levels.2
Although the kidney is primarily regarded as an excretory organ, it
also plays an important role in glucose homoeostasis. Impaired kidney
function is associated with abnormal glucose metabolism, including
decreased sensitivity to insulin, inadequate insulin secretion, and altered
gluconeogenesis. Kidney disease also directly or indirectly alters
the pharmacokinetics and pharmacodynamics of all agents used to
treat type 2 diabetes.3 Combined, these contribute to an increased incidence
and severity of hypoglycaemic episodes (Figure 1). This chapter
will examine some of the reasons for this association, and the opportunities
to reduce the risk of hypoglycaemic events in patients with
chronic kidney disease (CKD).
affecting up to one quarter of all patients with type 2 diabetes,
at least once a year.1 Although permanent damage or mortality due
to hypoglycaemia is uncommon, even minor hypoglycaemic events
can have a major effect on diabetes management. Hypoglycaemia
(or a “hypo”) is cited as the most important (and feared) complication
of diabetes by patients themselves, more important than kidney failure
or heart disease. Hypoglycaemia is often the most important barrier to
good glucose control, as attempts to avoid it result in therapeutic inertia
and (reluctant) tolerance of higher glucose levels.2
Although the kidney is primarily regarded as an excretory organ, it
also plays an important role in glucose homoeostasis. Impaired kidney
function is associated with abnormal glucose metabolism, including
decreased sensitivity to insulin, inadequate insulin secretion, and altered
gluconeogenesis. Kidney disease also directly or indirectly alters
the pharmacokinetics and pharmacodynamics of all agents used to
treat type 2 diabetes.3 Combined, these contribute to an increased incidence
and severity of hypoglycaemic episodes (Figure 1). This chapter
will examine some of the reasons for this association, and the opportunities
to reduce the risk of hypoglycaemic events in patients with
chronic kidney disease (CKD).
Epidemiology and impact of hypoglycaemia in type 2
diabetes and CKD
In patients with advanced type 2 diabetes, such as those with CKD, the
incidence and severity of hypoglycaemia are high. Severe hypoglycaemia
(requiring medical attention) probably occurs at a rate of
about 50 episodes per 100 patient-years. These rates are at least 5-10
fold higher than observed in diabetic patients without CKD. Mild and/
or asymptomatic hypoglycaemic events are even more common, and
possibly ubiquitous. Data from small studies using continuous glucose
monitoring in diabetic patients on dialysis reveal a glimpse of the size of
the potential problem. For example, in a recent study of nine diabetic
patients undergoing haemodialysis, ten hypoglycaemic events were
seen in five subjects over a two-day monitoring period.4 Only three
episodes were associated with symptoms and confirmed by capillary
blood glucose tests.4
Individuals experiencing hypoglycaemia have an increased risk of adverse
outcomes. This is not simply severe symptomatic events or deaths
due to neuroglycopaenia. In fact, all-cause mortality is increased in
those with a higher incidence of hypoglycaemia.5 It is possible that
hypoglycaemia is simply a marker of vulnerability to such events. However,
some data suggest that hypoglycaemia may directly contribute to
adverse outcomes. For example, the surge of sympathetic activity and a
release of catecholamines associated with hypoglycaemia has been
associated with cardiovascular events, arrhythmia 6 and sudden death.7
diabetes and CKD
In patients with advanced type 2 diabetes, such as those with CKD, the
incidence and severity of hypoglycaemia are high. Severe hypoglycaemia
(requiring medical attention) probably occurs at a rate of
about 50 episodes per 100 patient-years. These rates are at least 5-10
fold higher than observed in diabetic patients without CKD. Mild and/
or asymptomatic hypoglycaemic events are even more common, and
possibly ubiquitous. Data from small studies using continuous glucose
monitoring in diabetic patients on dialysis reveal a glimpse of the size of
the potential problem. For example, in a recent study of nine diabetic
patients undergoing haemodialysis, ten hypoglycaemic events were
seen in five subjects over a two-day monitoring period.4 Only three
episodes were associated with symptoms and confirmed by capillary
blood glucose tests.4
Individuals experiencing hypoglycaemia have an increased risk of adverse
outcomes. This is not simply severe symptomatic events or deaths
due to neuroglycopaenia. In fact, all-cause mortality is increased in
those with a higher incidence of hypoglycaemia.5 It is possible that
hypoglycaemia is simply a marker of vulnerability to such events. However,
some data suggest that hypoglycaemia may directly contribute to
adverse outcomes. For example, the surge of sympathetic activity and a
release of catecholamines associated with hypoglycaemia has been
associated with cardiovascular events, arrhythmia 6 and sudden death.7
Renal gluconeogenesis
Although the liver is generally regarded as the seat of gluconeogenesis,
healthy kidneys also synthesise and release significant quantities
of glucose into the circulation 8, the loss of which also contributes to hypoglycaemia
in patients with CKD. Following overnight fasting, approximately
half of all glucose released comes from gluconeogenesis, with
the other half coming from hepatic glycogenolysis (Figure 2).8 The liver
and the kidney are the only two organs capable of gluconeogenesis in
the human body. The liver is the major contributor to gluconeogenesis
in healthy individuals (~60% of all gluconeogenesis following overnight
fasting). However, glucose levels are maintained even in the absence
of liver tissue (e.g. after removal of the liver in individuals undergoing
liver transplantation), with overall endogenous glucose release only
falling by less than 50%. It is now thought that hormonally regulated gluconeogenesis
in the renal cortex accounts for ~20% of all glucose produced
following overnight fasting (40% of all gluconeogenic sugar).9, 10
The kidneys also play an important role in the counter-regulatory response
to hypoglycaemia, with both increased renal gluconeogenesis
and, to a lesser extent, decreased glucose uptake, acting to maintain
glucose circulating levels.11 The contribution of renal gluconeogenesis
to total gluconeogenesis is also substantially greater in hypoglycaemia,
with up to a third of all glucose produced coming from the kidneys.12
Furthermore, in patients with type 2 diabetes, in whom hepatic glycogen
stores are depleted or glycogenolysis pharmacologically inhibited,
a renal counter-regulatory response may be even more pivotal.
Kidney function and insulin kinetics
The production of insulin by the pancreas in response to feeding facilitates
the uptake of glucose into the liver, fat and skeletal muscle to
maintain euglycaemia post-prandially in healthy individuals. During
fasting, insulin production is suppressed; triggering the release of glucose
to ensure the brain receives the constant supply of glucose that it
requires to function normally. A similar balance can be approximated
with pharmacotherapy in patients with type 2 diabetes using exogenous
insulin, sensitizers or secretogogues to achieve and sustain glucose
control.
to hypoglycaemia, with both increased renal gluconeogenesis
and, to a lesser extent, decreased glucose uptake, acting to maintain
glucose circulating levels.11 The contribution of renal gluconeogenesis
to total gluconeogenesis is also substantially greater in hypoglycaemia,
with up to a third of all glucose produced coming from the kidneys.12
Furthermore, in patients with type 2 diabetes, in whom hepatic glycogen
stores are depleted or glycogenolysis pharmacologically inhibited,
a renal counter-regulatory response may be even more pivotal.
Kidney function and insulin kinetics
The production of insulin by the pancreas in response to feeding facilitates
the uptake of glucose into the liver, fat and skeletal muscle to
maintain euglycaemia post-prandially in healthy individuals. During
fasting, insulin production is suppressed; triggering the release of glucose
to ensure the brain receives the constant supply of glucose that it
requires to function normally. A similar balance can be approximated
with pharmacotherapy in patients with type 2 diabetes using exogenous
insulin, sensitizers or secretogogues to achieve and sustain glucose
control.
Renal function significantly affects this balance. Degradation of insulin
by liver and skeletal muscle is reduced in patients with CKD.13 At the
same time, renal insulin handling is altered. Approximately 25% of the
insulin secreted by beta cells is removed by healthy kidneys, equating
to 6-8 units per day.13, 14 The kidneys, due to bypassing of the portal
circulation and first-pass clearance by the liver, clear a much larger
proportion of injected insulin - over half in some studies.13, 14 As a peptide
of ~6 kDA in size, insulin is freely filtered at the glomerulus. Some
insulin is also extracted from peri-tubular capillaries and secreted into
the urine, possibly via insulin receptor-dependent transport.15 In the
healthy kidney, >98% of filtered/secreted insulin is then reabsorbed and
degraded.16 While peri-tubular insulin uptake increases as renal function
declines to maintain renal insulin clearance, tubular injury in the
diabetic kidney combined with a falling estimated glomerular filtration
rate (eGFR) ultimately means that intact insulin is often found in the
urine and, ultimately, the urinary insulin clearance approaches that of
the (low) glomerular filtration rate. As a consequence, the circulating
half-life of insulin is significantly modified in patients with CKD, especially
when eGFR falls to below 30 ml/min/1.73m2.13 Indeed, the insulin halflife
has been proposed as a valid test of kidney function.17
This prolonged insulin half-life significantly increases the risk of hypoglycaemia
in patients with CKD as the glucose lowering effects of insulin
and secretogogues carryover beyond the immediate post-prandial
period. The effect of renal impairment on insulin kinetics appears similar
for both short- and long-acting insulin, as well as agents that stimulate
endogenous insulin production. As a result, some authors have recommended
avoiding long-acting insulin preparations in patients with advanced
renal failure to reduce the risk of hypoglycaemia.18 However,
other studies support the use of long-acting insulin in this setting.13 The
most important thing appears to be close monitoring and individualisation
of diabetes care and glucose control targets in patients with
CKD. This always involves reduced insulin doses. In general, those with an
eGFR 30-45 ml/min/1.73m2 need 10% less insulin, those 15-30 ml/min/1.73m2
need 25% less insulin, and those with <15 ml/min/1.73m2 need about
half their requirement when they have an eGFR >60 ml/min/1.73m2.
Although insulin sensitisers such as metformin and the glitazones are
not traditionally associated with hypoglycaemia, because of the prolonged
actions of insulin in CKD, the incidence and severity of hypoglycaemia
can also be increased by these drugs in this setting.
by liver and skeletal muscle is reduced in patients with CKD.13 At the
same time, renal insulin handling is altered. Approximately 25% of the
insulin secreted by beta cells is removed by healthy kidneys, equating
to 6-8 units per day.13, 14 The kidneys, due to bypassing of the portal
circulation and first-pass clearance by the liver, clear a much larger
proportion of injected insulin - over half in some studies.13, 14 As a peptide
of ~6 kDA in size, insulin is freely filtered at the glomerulus. Some
insulin is also extracted from peri-tubular capillaries and secreted into
the urine, possibly via insulin receptor-dependent transport.15 In the
healthy kidney, >98% of filtered/secreted insulin is then reabsorbed and
degraded.16 While peri-tubular insulin uptake increases as renal function
declines to maintain renal insulin clearance, tubular injury in the
diabetic kidney combined with a falling estimated glomerular filtration
rate (eGFR) ultimately means that intact insulin is often found in the
urine and, ultimately, the urinary insulin clearance approaches that of
the (low) glomerular filtration rate. As a consequence, the circulating
half-life of insulin is significantly modified in patients with CKD, especially
when eGFR falls to below 30 ml/min/1.73m2.13 Indeed, the insulin halflife
has been proposed as a valid test of kidney function.17
This prolonged insulin half-life significantly increases the risk of hypoglycaemia
in patients with CKD as the glucose lowering effects of insulin
and secretogogues carryover beyond the immediate post-prandial
period. The effect of renal impairment on insulin kinetics appears similar
for both short- and long-acting insulin, as well as agents that stimulate
endogenous insulin production. As a result, some authors have recommended
avoiding long-acting insulin preparations in patients with advanced
renal failure to reduce the risk of hypoglycaemia.18 However,
other studies support the use of long-acting insulin in this setting.13 The
most important thing appears to be close monitoring and individualisation
of diabetes care and glucose control targets in patients with
CKD. This always involves reduced insulin doses. In general, those with an
eGFR 30-45 ml/min/1.73m2 need 10% less insulin, those 15-30 ml/min/1.73m2
need 25% less insulin, and those with <15 ml/min/1.73m2 need about
half their requirement when they have an eGFR >60 ml/min/1.73m2.
Although insulin sensitisers such as metformin and the glitazones are
not traditionally associated with hypoglycaemia, because of the prolonged
actions of insulin in CKD, the incidence and severity of hypoglycaemia
can also be increased by these drugs in this setting.
The effect of kidney function on sulphonylurea (SU)
antidiabetics
Sulphonylurea (SU) agents are widely used in the management of patients
with type 2 diabetes, to directly stimulate the release of insulin
from the beta cells of the pancreas. Hypoglycaemia is the most common
complication of SU agents, occurring when insulin stimulation is
not matched with food intake in those with irregular eating habits or
medication compliance. Some SU agents are directly eliminated by
the kidneys, or are metabolised in the liver to a variety of active compounds,
which are then excreted by the kidneys. As a result, first generation
sulphonylurea drugs, including tolazamide, acetohexamide and
chlorpropamide 19, and glibenclamide (glyburide), a second-generation
sulphonylurea with an active metabolite 20, are more likely to cause
hypoglycaemia in individuals with renal impairment, and should not
be used in this setting. By contrast, SU drugs with inactive metabolites
including tolbutamide, glipizide, gliclazide and gliquidone are less likely
to cause hypoglycaemia, although, as noted above, in patients with
CKD, the half-life of endogenous insulin is prolonged. Consequently,
SU-induced hypoglycaemia is also more common in those with impaired
kidney function, regardless of the SU agent or formulation. All
SUs should be used cautiously and with a dose reduction in patients
with a reduced eGFR.3
Kidney Function and Metformin
One largely unheralded reason for an increased incidence of hypoglycaemia
in diabetic patients with CKD, is the fact that the most widely
used oral anti-diabetic agent, metformin, is often stopped and replaced
with agents including insulin and secretagogues that are more
likely to induce hypoglycaemia, weight gain and other side effects.
By contrast, hypoglycaemia is generally not observed with metformin
used as monotherapy, which acts as an insulin sensitiser to lower glucose
levels by reducing hepatic production of glucose and slowing
the absorption of glucose from a meal. The rationale for stopping metformin
and substituting drugs with a potentially worse side effect profile
is problematic.21, 22 Certainly, the excretion of biguanides such as
metformin and phenformin is largely dependent on renal clearance,
by both glomerular ultrafiltration and tubular secretion. Consequently,
in patients with renal impairment, plasma concentrations may be
significantly elevated and the drug may accumulate. This accumulation
of phenformin has been associated with an increased risk of lactic
acidosis, although data regarding the risk associated with metformin in
CKD are less clear and largely anecdotal. When taken in an overdose,
metformin can cause lactic acidosis, implying that significant drug ac
antidiabetics
Sulphonylurea (SU) agents are widely used in the management of patients
with type 2 diabetes, to directly stimulate the release of insulin
from the beta cells of the pancreas. Hypoglycaemia is the most common
complication of SU agents, occurring when insulin stimulation is
not matched with food intake in those with irregular eating habits or
medication compliance. Some SU agents are directly eliminated by
the kidneys, or are metabolised in the liver to a variety of active compounds,
which are then excreted by the kidneys. As a result, first generation
sulphonylurea drugs, including tolazamide, acetohexamide and
chlorpropamide 19, and glibenclamide (glyburide), a second-generation
sulphonylurea with an active metabolite 20, are more likely to cause
hypoglycaemia in individuals with renal impairment, and should not
be used in this setting. By contrast, SU drugs with inactive metabolites
including tolbutamide, glipizide, gliclazide and gliquidone are less likely
to cause hypoglycaemia, although, as noted above, in patients with
CKD, the half-life of endogenous insulin is prolonged. Consequently,
SU-induced hypoglycaemia is also more common in those with impaired
kidney function, regardless of the SU agent or formulation. All
SUs should be used cautiously and with a dose reduction in patients
with a reduced eGFR.3
Kidney Function and Metformin
One largely unheralded reason for an increased incidence of hypoglycaemia
in diabetic patients with CKD, is the fact that the most widely
used oral anti-diabetic agent, metformin, is often stopped and replaced
with agents including insulin and secretagogues that are more
likely to induce hypoglycaemia, weight gain and other side effects.
By contrast, hypoglycaemia is generally not observed with metformin
used as monotherapy, which acts as an insulin sensitiser to lower glucose
levels by reducing hepatic production of glucose and slowing
the absorption of glucose from a meal. The rationale for stopping metformin
and substituting drugs with a potentially worse side effect profile
is problematic.21, 22 Certainly, the excretion of biguanides such as
metformin and phenformin is largely dependent on renal clearance,
by both glomerular ultrafiltration and tubular secretion. Consequently,
in patients with renal impairment, plasma concentrations may be
significantly elevated and the drug may accumulate. This accumulation
of phenformin has been associated with an increased risk of lactic
acidosis, although data regarding the risk associated with metformin in
CKD are less clear and largely anecdotal. When taken in an overdose,
metformin can cause lactic acidosis, implying that significant drug ac
cumulation in renal disease, in theory, could cause the same phenomenon.
However, even in those with CKD, lactic acidosis is a very rare
event.21, 22 While stopping metformin in patients with CKD would eliminate
this risk, it seems more prudent to reduce metformin dosing by one
third in patients with eGFR between 30-45 ml/min/1.73m2.3 In some patients
with stable renal impairment and an eGFR of 15-30 ml/min/1.73m2
metformin can also be safely used, at approximately half the normal
dose. However, caution should be exercised in patients with unstable
renal function, and those with co-morbid heart failure, alcoholism or
liver disease, and the drug should be stopped 2–3 days prior to surgery
or any procedure using iodinated radiographic contrast media, as a
sudden decline in renal function can lead to drug accumulation in a
hypoxic setting where lactate production may be already increased.3
The effects of kidney function on counter-regulatory
response to hypoglycaemia
Falling blood glucose levels trigger the activation of a range of counter-
regulatory responses, that contribute to both the symptomatology
of the event as well as its reversal.23 The key regulators of this response
include increased secretion of glucagon, growth hormone and cortisol
as well as adrenergic activation. Each of these may be substantially
abnormal in patients with advanced diabetes, and especially those
with CKD.24 The effects of autonomic nervous system dysfunction associated
with advanced diabetes on catecholamine release in response
to hypoglycaemia are well known, contributing to both defective glucose
counter-regulation and hypoglycaemia unawareness. Many patients
also take sympathetic blocking medications, which impair counterregulatory
glycogenolysis by the liver, although the risk is lower with
selective beta-blockers than non-selective agents.25 Even in the absence
of autonomic neuropathy, many patients with type 2 diabetes
show attenuated glucagon, growth hormone, and cortisol responses
to hypoglycaemia. In particular, insulin-dependent patients with type
2 diabetes, who represent the majority of those with advanced CKD,
have extremely impaired glucagon response to hypoglycaemia when
compared to controls and those with type 2 diabetes treated with oral
hypoglycaemics, reflecting the more advanced pancreatic damage
observed in these patients. In addition, elevated insulin concentrations
in CKD, due to impaired renal clearance, inhibit glucagon release in
response to low blood glucose. Rather than prevent hypoglycaemia,
growth hormone and cortisol are “slow-acting” hormones that act to
limit its severity and duration. Again, both these pathways are abnormal
in patients with CKD, with dysfunction correlating with the severity
of renal impairment.
However, even in those with CKD, lactic acidosis is a very rare
event.21, 22 While stopping metformin in patients with CKD would eliminate
this risk, it seems more prudent to reduce metformin dosing by one
third in patients with eGFR between 30-45 ml/min/1.73m2.3 In some patients
with stable renal impairment and an eGFR of 15-30 ml/min/1.73m2
metformin can also be safely used, at approximately half the normal
dose. However, caution should be exercised in patients with unstable
renal function, and those with co-morbid heart failure, alcoholism or
liver disease, and the drug should be stopped 2–3 days prior to surgery
or any procedure using iodinated radiographic contrast media, as a
sudden decline in renal function can lead to drug accumulation in a
hypoxic setting where lactate production may be already increased.3
The effects of kidney function on counter-regulatory
response to hypoglycaemia
Falling blood glucose levels trigger the activation of a range of counter-
regulatory responses, that contribute to both the symptomatology
of the event as well as its reversal.23 The key regulators of this response
include increased secretion of glucagon, growth hormone and cortisol
as well as adrenergic activation. Each of these may be substantially
abnormal in patients with advanced diabetes, and especially those
with CKD.24 The effects of autonomic nervous system dysfunction associated
with advanced diabetes on catecholamine release in response
to hypoglycaemia are well known, contributing to both defective glucose
counter-regulation and hypoglycaemia unawareness. Many patients
also take sympathetic blocking medications, which impair counterregulatory
glycogenolysis by the liver, although the risk is lower with
selective beta-blockers than non-selective agents.25 Even in the absence
of autonomic neuropathy, many patients with type 2 diabetes
show attenuated glucagon, growth hormone, and cortisol responses
to hypoglycaemia. In particular, insulin-dependent patients with type
2 diabetes, who represent the majority of those with advanced CKD,
have extremely impaired glucagon response to hypoglycaemia when
compared to controls and those with type 2 diabetes treated with oral
hypoglycaemics, reflecting the more advanced pancreatic damage
observed in these patients. In addition, elevated insulin concentrations
in CKD, due to impaired renal clearance, inhibit glucagon release in
response to low blood glucose. Rather than prevent hypoglycaemia,
growth hormone and cortisol are “slow-acting” hormones that act to
limit its severity and duration. Again, both these pathways are abnormal
in patients with CKD, with dysfunction correlating with the severity
of renal impairment.
Parathyroid hormone (PTH) and glucose control
The metabolic actions of PTH extend beyond calcium homeostasis.
Parathyroid hormone-related protein is produced by the pancreatic
islet, where it acts to suppress insulin release from the beta cells. Secondary
hyperparathyroidism acts to suppress insulin release in patients
with CKD. Suppression of PTH levels with vitamin D supplementation or
surgical removal of the glands, results in significant improvement in insulin
release, and with it, an increased risk of hypoglycaemia in patients
with CKD following such interventions.26, 27
Specific situations: hypoglycaemia on haemodialysis
Haemodialysis is the most common modality for renal replacement
therapy in patients with type 2 diabetes and end stage renal disease
(ESRD). Haemodialysis clears the blood of toxins via diffusion across a
semi-permeable membrane and ultrafiltration, maintained by altering
the pressure in the dialysate compartment that allows free water and
some dissolved solutes to move across the membrane along a created
pressure gradient. This has the potential to alter glucose homeostasis in
a number of ways:
Firstly, insulin resistance associated with uraemic toxicity can be substantially
alleviated by dialysis.13 This means that when starting haemodialysis
in diabetic patients there can be a dramatic improvement in
peripheral insulin sensitivity, which alongside increased physical activity
and a persisting prolonged insulin half-life can lead to an increased
risk of hypoglycaemia in the days and weeks after starting dialysis. Insulin
requirement should therefore be closely monitored after starting
dialysis in patients with type 2 diabetes, as doses will need to be rapidly
adjusted, sometimes to less than half of what was previously needed.
Secondly, haemodialysis with a sodium bicarbonate buffer can lead to
a loss of serum glucose in the dialysate effluent. In order to get around
the problem of hypoglycaemia, it is common practice to add glucose
to the dialysate, especially for diabetic patients on insulin. Certainly,
less hypoglycaemia occurs when using a dialysate containing glucose
compared to a glucose-free dialysate.28 Hypoglycaemia is further reduced
when using 11 mM as opposed to 5.5 mmol/l of glucose.29 Blood
pressures may be modestly lower with glucose in the dialysate, possibly
due to suppression of counter-regulatory sympathetic drive.30 In addition,
inter-dialytic weight gain, hypertriglyceridaemia and increased
oxidative stress can also result from a high glucose dialysate. Some
authors also suggest that the risk of post-dialysis hypoglycaemia is increased
by a glucose-containing dialysate (by stimulating insulin then
withdrawing dialysate glucose). The long-term balance of benefits of
The metabolic actions of PTH extend beyond calcium homeostasis.
Parathyroid hormone-related protein is produced by the pancreatic
islet, where it acts to suppress insulin release from the beta cells. Secondary
hyperparathyroidism acts to suppress insulin release in patients
with CKD. Suppression of PTH levels with vitamin D supplementation or
surgical removal of the glands, results in significant improvement in insulin
release, and with it, an increased risk of hypoglycaemia in patients
with CKD following such interventions.26, 27
Specific situations: hypoglycaemia on haemodialysis
Haemodialysis is the most common modality for renal replacement
therapy in patients with type 2 diabetes and end stage renal disease
(ESRD). Haemodialysis clears the blood of toxins via diffusion across a
semi-permeable membrane and ultrafiltration, maintained by altering
the pressure in the dialysate compartment that allows free water and
some dissolved solutes to move across the membrane along a created
pressure gradient. This has the potential to alter glucose homeostasis in
a number of ways:
Firstly, insulin resistance associated with uraemic toxicity can be substantially
alleviated by dialysis.13 This means that when starting haemodialysis
in diabetic patients there can be a dramatic improvement in
peripheral insulin sensitivity, which alongside increased physical activity
and a persisting prolonged insulin half-life can lead to an increased
risk of hypoglycaemia in the days and weeks after starting dialysis. Insulin
requirement should therefore be closely monitored after starting
dialysis in patients with type 2 diabetes, as doses will need to be rapidly
adjusted, sometimes to less than half of what was previously needed.
Secondly, haemodialysis with a sodium bicarbonate buffer can lead to
a loss of serum glucose in the dialysate effluent. In order to get around
the problem of hypoglycaemia, it is common practice to add glucose
to the dialysate, especially for diabetic patients on insulin. Certainly,
less hypoglycaemia occurs when using a dialysate containing glucose
compared to a glucose-free dialysate.28 Hypoglycaemia is further reduced
when using 11 mM as opposed to 5.5 mmol/l of glucose.29 Blood
pressures may be modestly lower with glucose in the dialysate, possibly
due to suppression of counter-regulatory sympathetic drive.30 In addition,
inter-dialytic weight gain, hypertriglyceridaemia and increased
oxidative stress can also result from a high glucose dialysate. Some
authors also suggest that the risk of post-dialysis hypoglycaemia is increased
by a glucose-containing dialysate (by stimulating insulin then
withdrawing dialysate glucose). The long-term balance of benefits of
risk remains to be determined. However, given the short survival of patients
with diabetes on haemodialysis, such short-term gains appear to
have primacy.
ESRD is associated with an increased prevalence of protein-calorie
malnutrition, reflected in reduced serum albumin concentrations and
diminished hepatic glycogen stores. Institution of dialysis can have additional
effects on protein and energy balance, including the loss of
free amino acids, peptides and small proteins in the dialysate, especially
with high flux dialysers. The net result of this can be to attenuate
the counter-regulatory response to hypoglycaemia. Adding glucose to
the dialysate can also reduce this effect by suppressing gluconeogenesis
and catabolism.
Another technique widely used to avoid hypoglycaemia on dialysis is to
provide a meal to patients during the dialysis procedure. In theory, this
can provide the glucose reserve to balance losses during and subsequent
to dialysis. However, in practice, patients with advanced diabetes
have significant gastroparesis 31, meaning that the effect of the meal
is often manifested after dialysis. Moreover, dilation of the splanchnic
bed following a meal can drop the blood pressure during dialysis.32 This
has led some units to deliberately not feed during dialysis. However,
feeding afterwards may also be problematic when plasma volumes are
at their lowest and patients are attempting to mobilise to get home or
return to their ward. Moreover, glucose control during dialysis (achieved
by a glucose-containing dialysate that stimulates insulin release),
if unmatched by food intake, subsequently and in the setting of an impaired
counter-regulatory response, leads to a significant risk of hypoglycaemia
that is greatest 2-6 hours after dialysis. Indeed, this post-dialysis
period may be the most dangerous for patients with diabetes on dialysis.
Finally, changes in the cytoplasmic pH of erythrocytes when using high
bicarbonate dialysate, can result in the increased uptake of glucose
into red cells, as intracellular acidosis stimulates the consumption of glucose
by anaerobic metabolism.33
One of the major difficulties of hypoglycaemia on dialysis is that few patients
are aware of low glucose levels, due to blunting of the counterregulator
response in advanced disease (detailed above) and/or the
use of sympathetic blockade. Symptoms are often attributed to dialysis
disequilibrium or co-morbid disease. While hypoglycaemia should be
suspected in any diabetic patient with CKD who exhibits any change
in mental status, its prevention ultimately relies on frequent and careful
glucose determinations. It is also important to remember that testing
from an extracorporeal line is problematic because of recirculation.
with diabetes on haemodialysis, such short-term gains appear to
have primacy.
ESRD is associated with an increased prevalence of protein-calorie
malnutrition, reflected in reduced serum albumin concentrations and
diminished hepatic glycogen stores. Institution of dialysis can have additional
effects on protein and energy balance, including the loss of
free amino acids, peptides and small proteins in the dialysate, especially
with high flux dialysers. The net result of this can be to attenuate
the counter-regulatory response to hypoglycaemia. Adding glucose to
the dialysate can also reduce this effect by suppressing gluconeogenesis
and catabolism.
Another technique widely used to avoid hypoglycaemia on dialysis is to
provide a meal to patients during the dialysis procedure. In theory, this
can provide the glucose reserve to balance losses during and subsequent
to dialysis. However, in practice, patients with advanced diabetes
have significant gastroparesis 31, meaning that the effect of the meal
is often manifested after dialysis. Moreover, dilation of the splanchnic
bed following a meal can drop the blood pressure during dialysis.32 This
has led some units to deliberately not feed during dialysis. However,
feeding afterwards may also be problematic when plasma volumes are
at their lowest and patients are attempting to mobilise to get home or
return to their ward. Moreover, glucose control during dialysis (achieved
by a glucose-containing dialysate that stimulates insulin release),
if unmatched by food intake, subsequently and in the setting of an impaired
counter-regulatory response, leads to a significant risk of hypoglycaemia
that is greatest 2-6 hours after dialysis. Indeed, this post-dialysis
period may be the most dangerous for patients with diabetes on dialysis.
Finally, changes in the cytoplasmic pH of erythrocytes when using high
bicarbonate dialysate, can result in the increased uptake of glucose
into red cells, as intracellular acidosis stimulates the consumption of glucose
by anaerobic metabolism.33
One of the major difficulties of hypoglycaemia on dialysis is that few patients
are aware of low glucose levels, due to blunting of the counterregulator
response in advanced disease (detailed above) and/or the
use of sympathetic blockade. Symptoms are often attributed to dialysis
disequilibrium or co-morbid disease. While hypoglycaemia should be
suspected in any diabetic patient with CKD who exhibits any change
in mental status, its prevention ultimately relies on frequent and careful
glucose determinations. It is also important to remember that testing
from an extracorporeal line is problematic because of recirculation.
Specific situations: peritoneal dialysis
Peritoneal dialysis uses the patient’s peritoneal membrane to exchange
fluids and dissolved substances. The dialysis fluid typically contains
a high concentration of glucose to ensure hyper-osmolality and
hence continuous ultrafiltration. This potentially exposes patients to a
significant glucose load that can cause difficulties for some patients
with type 2 diabetes. Although the risk of hypoglycaemia might appear
to be diminished (as a result of continuous glucose availability),
in practice, attempts to match this glucose load with insulin, delivered
into the dialysate or subcutaneously, can sometimes lead to more brittle
control, especially initially. In general, patients on peritoneal dialysis
need 2-3 times the insulin they received before starting it, coordinated
with the strength of the bags as well as the dwell time. Intra-peritoneal
insulin has a number of advantages including a reduced frequency of
hypoglycaemic episodes.34 The recent development of glucose-free
dialysate fluids can modify the risk of hypoglycaemia in some patients
with diabetes. Although insulin requirements are much lower, and some
studies have suggested reduced glucose variability, monitoring of glucose
levels may be confounded by the icodextrin used in the place of
glucose as the primary osmotic agent, which may give false glucose
readings in some patients.35
Preventing hypoglycaemia in the clinic
In most cases, adjusting behaviours, the dose or timing of medications
and/or the targets of treatment can prevent recurrent hypoglycaemic
events. Selecting foods that meet individual glucose requirements
can also be useful. For example, low GI foods and products, such as
uncooked cornstarch, that ensure the slow delivery of glucose are
helpful to prevent lows during the night or after meals (post-prandial
hypoglycaemia). Sometimes having meals that provide more glucose
up front may be important, particularly after dialysis and in those who
are on fast-acting agents or insulin. Overeating or snacking to prevent
hypoglycaemia is never a sustainable solution, and should be discouraged.
Coordination of physical activity with medication doses and dialysis
is also important.
Because of the ever-present threat of hypoglycaemia, the rationale
for attempting even modest glycaemic control in patients with CKD is
somewhat precarious. It rests on the paradigm that maintaining glucose
levels as close as possible to physiological levels will result in improved
clinical outcomes. However, the evidence for this in diabetic
patients with CKD remains largely anecdotal and inconclusive. Certainly,
glycaemic control correlates closely with morbidity and mortality
Peritoneal dialysis uses the patient’s peritoneal membrane to exchange
fluids and dissolved substances. The dialysis fluid typically contains
a high concentration of glucose to ensure hyper-osmolality and
hence continuous ultrafiltration. This potentially exposes patients to a
significant glucose load that can cause difficulties for some patients
with type 2 diabetes. Although the risk of hypoglycaemia might appear
to be diminished (as a result of continuous glucose availability),
in practice, attempts to match this glucose load with insulin, delivered
into the dialysate or subcutaneously, can sometimes lead to more brittle
control, especially initially. In general, patients on peritoneal dialysis
need 2-3 times the insulin they received before starting it, coordinated
with the strength of the bags as well as the dwell time. Intra-peritoneal
insulin has a number of advantages including a reduced frequency of
hypoglycaemic episodes.34 The recent development of glucose-free
dialysate fluids can modify the risk of hypoglycaemia in some patients
with diabetes. Although insulin requirements are much lower, and some
studies have suggested reduced glucose variability, monitoring of glucose
levels may be confounded by the icodextrin used in the place of
glucose as the primary osmotic agent, which may give false glucose
readings in some patients.35
Preventing hypoglycaemia in the clinic
In most cases, adjusting behaviours, the dose or timing of medications
and/or the targets of treatment can prevent recurrent hypoglycaemic
events. Selecting foods that meet individual glucose requirements
can also be useful. For example, low GI foods and products, such as
uncooked cornstarch, that ensure the slow delivery of glucose are
helpful to prevent lows during the night or after meals (post-prandial
hypoglycaemia). Sometimes having meals that provide more glucose
up front may be important, particularly after dialysis and in those who
are on fast-acting agents or insulin. Overeating or snacking to prevent
hypoglycaemia is never a sustainable solution, and should be discouraged.
Coordination of physical activity with medication doses and dialysis
is also important.
Because of the ever-present threat of hypoglycaemia, the rationale
for attempting even modest glycaemic control in patients with CKD is
somewhat precarious. It rests on the paradigm that maintaining glucose
levels as close as possible to physiological levels will result in improved
clinical outcomes. However, the evidence for this in diabetic
patients with CKD remains largely anecdotal and inconclusive. Certainly,
glycaemic control correlates closely with morbidity and mortality
in diabetic patients with advanced CKD and those on dialysis.36 However,
such observational data cannot be used to prove that attempts
to improve glycaemic control through anti-diabetic agents or other
interventions will therefore result in better clinical outcomes. Indeed,
recent studies in diabetic patients without CKD have failed to demonstrate
mortality and cardiovascular benefits from better glycaemic
control, even though HbA1c remains closely correlated with adverse
outcomes in these cohorts.5 This does not mean that there is no point
in any glucose control. Rather, that the utility for aggressive glycaemic
control has probably passed and that other targets may be more appropriate
for intensification. Poor glycaemic control remains a potent
risk marker for those at increased absolute risk, in whom the absolute
gain from intervention may therefore also be enhanced. Nonetheless,
a modest degree of glucose control is probably still effective in reducing
the risk of infection and cataracts, while choosing an individual target
that reduces the risk of hypoglycaemia, especially in those with
advanced age, irregular compliance or lifestyles. Patients that hope to
maintain a driving license offer an additional challenge in balancing
risk and mobility. Ultimately, careful individualisation of glucose management
is the best recourse, which can never be reflected in guidelines
or performance indices aimed at generic utility. As Sir William Osler
once said, “If it were not for the great variability among individuals,
medicine might as well be a science and not an art!”
such observational data cannot be used to prove that attempts
to improve glycaemic control through anti-diabetic agents or other
interventions will therefore result in better clinical outcomes. Indeed,
recent studies in diabetic patients without CKD have failed to demonstrate
mortality and cardiovascular benefits from better glycaemic
control, even though HbA1c remains closely correlated with adverse
outcomes in these cohorts.5 This does not mean that there is no point
in any glucose control. Rather, that the utility for aggressive glycaemic
control has probably passed and that other targets may be more appropriate
for intensification. Poor glycaemic control remains a potent
risk marker for those at increased absolute risk, in whom the absolute
gain from intervention may therefore also be enhanced. Nonetheless,
a modest degree of glucose control is probably still effective in reducing
the risk of infection and cataracts, while choosing an individual target
that reduces the risk of hypoglycaemia, especially in those with
advanced age, irregular compliance or lifestyles. Patients that hope to
maintain a driving license offer an additional challenge in balancing
risk and mobility. Ultimately, careful individualisation of glucose management
is the best recourse, which can never be reflected in guidelines
or performance indices aimed at generic utility. As Sir William Osler
once said, “If it were not for the great variability among individuals,
medicine might as well be a science and not an art!”
References:
1. Amiel SA, Dixon T, Mann R, Jameson K. Hypoglycaemia in Type 2 diabetes. Diabet
Med 2008;25(3):245-54.
2. Leiter L, Yale, J-F, Chiasson, J-L, Harris, SB, Kleinstiver, P, Sauriol, L. Assessment of the
impact of fear of hypoglycemic episodes on glycemic and hypoglycemic management.
Can J Diabetes 2005;29:186-192.
3. Snyder RW, Berns JS. Use of insulin and oral hypoglycemic medications in patients
with diabetes mellitus and advanced kidney disease. Semin Dial 2004;17(5):365-70.
4. Jung HS, Kim HI, Kim MJ, Yoon JW, Ahn HY, Cho YM, et al. Analysis of hemodialysisassociated
hypoglycemia in patients with type 2 diabetes using a continuous
glucose monitoring system. Diabetes Technol Ther 2010;12(10):801-7.
5. Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe hypoglycemia
and risks of vascular events and death. N Engl J Med 2010;363(15):1410-8.
6. Nordin C. The case for hypoglycaemia as a proarrhythmic event: basic and clinical
evidence. Diabetologia 2010;53(8):1552-61.
7. Yakubovich N, Gerstein HC. Serious cardiovascular outcomes in diabetes: the role
of hypoglycemia. Circulation 2011;123(3):342-8.
8. Meyer C, Dostou JM, Gerich JE. Role of the human kidney in glucose counterregulation.
Diabetes 1999;48(5):943-8.
9. Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis: its importance
in human glucose homeostasis. Diabetes Care 2001;24(2):382-91.
10. Cersosimo E, Garlick P, Ferretti J. Renal glucose production during insulin-induced
hypoglycemia in humans. Diabetes 1999;48(2):261-6.
11. Cersosimo E, Garlick P, Ferretti J. Renal substrate metabolism and gluconeogenesis
during hypoglycemia in humans. Diabetes 2000;49(7):1186-93.
12. Woerle HJ, Meyer C, Popa EM, Cryer PE, Gerich JE. Renal compensation for
impaired hepatic glucose release during hypoglycemia in type 2 diabetes: further
evidence for hepatorenal reciprocity. Diabetes 2003;52(6):1386-92.
13. Mak RH. Impact of end-stage renal disease and dialysis on glycemic control. Semin
Dial 2000;13(1):4-8.
14. Rabkin R, Simon NM, Steiner S, Colwell JA. Effect of renal disease on renal uptake
and excretion of insulin in man. N Engl J Med 1970;282(4):182-7.
15. Petersen J, Kitaji J, Duckworth WC, Rabkin R. Fate of [125I]insulin removed from the
peritubular circulation of isolated perfused rat kidney. Am J Physiol 1982;243(2):
F126-32.
16. Rubenstein AH, Mako ME, Horwitz DL. Insulin and the kidney. Nephron 1975;15(3-5):
306-26.
17. Goll K, Lück, G. The insulin half-life as a kidney function test. Z Urol Nephrol 1975;68(12):
927-33.
18. Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood
glucose in diabetic patients with renal failure. Diabetes Metab 2000;26 Suppl 4:73-85.
19. Harrower AD. Pharmacokinetics of oral antihyperglycaemic agents in patients with
renal insufficiency. Clin Pharmacokinet 1996;31(2):111-9.
20. Rydberg T, Jonsson A, Roder M, Melander A. Hypoglycemic activity of glyburide
(glibenclamide) metabolites in humans. Diabetes Care 1994;17(9):1026-30.
21. Nye HJ, Herrington WG. Metformin: The Safest Hypoglycaemic Agent in Chronic
Kidney Disease? Nephron Clin Pract 2011;118(4):c380-c383.
22. Preiss DJ, Sattar N. Metformin and lactic acidosis. Metformin: framed again? BMJ
2009;339:b5570.
23. Tesfaye N, Seaquist ER. Neuroendocrine responses to hypoglycemia. Ann N Y Acad
Sci 2010;1212:12-28.
24. Arem R. Hypoglycemia associated with renal failure. Endocrinol Metab Clin North Am
1989;18(1):103-21.
25. Kerr D. Drugs and alcohol. In: Frier B, Fisher B, editors. Hypoglycaemia and Diabetes.
Clinical and Physiological Aspect. London: Edward Arnold; 1993:pp. 328–336.
26. Mak RH, Bettinelli A, Turner C, Haycock GB, Chantler C. The influence of hyperparathyroidism
on glucose metabolism in uremia. J Clin Endocrinol Metab 1985;60(2):229-33.
27. Mak RH, Turner C, Haycock GB, Chantler C. Secondary hyperparathyroidism and
glucose intolerance in children with uremia. Kidney Int Suppl 1983;16:S128-33.
1. Amiel SA, Dixon T, Mann R, Jameson K. Hypoglycaemia in Type 2 diabetes. Diabet
Med 2008;25(3):245-54.
2. Leiter L, Yale, J-F, Chiasson, J-L, Harris, SB, Kleinstiver, P, Sauriol, L. Assessment of the
impact of fear of hypoglycemic episodes on glycemic and hypoglycemic management.
Can J Diabetes 2005;29:186-192.
3. Snyder RW, Berns JS. Use of insulin and oral hypoglycemic medications in patients
with diabetes mellitus and advanced kidney disease. Semin Dial 2004;17(5):365-70.
4. Jung HS, Kim HI, Kim MJ, Yoon JW, Ahn HY, Cho YM, et al. Analysis of hemodialysisassociated
hypoglycemia in patients with type 2 diabetes using a continuous
glucose monitoring system. Diabetes Technol Ther 2010;12(10):801-7.
5. Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe hypoglycemia
and risks of vascular events and death. N Engl J Med 2010;363(15):1410-8.
6. Nordin C. The case for hypoglycaemia as a proarrhythmic event: basic and clinical
evidence. Diabetologia 2010;53(8):1552-61.
7. Yakubovich N, Gerstein HC. Serious cardiovascular outcomes in diabetes: the role
of hypoglycemia. Circulation 2011;123(3):342-8.
8. Meyer C, Dostou JM, Gerich JE. Role of the human kidney in glucose counterregulation.
Diabetes 1999;48(5):943-8.
9. Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis: its importance
in human glucose homeostasis. Diabetes Care 2001;24(2):382-91.
10. Cersosimo E, Garlick P, Ferretti J. Renal glucose production during insulin-induced
hypoglycemia in humans. Diabetes 1999;48(2):261-6.
11. Cersosimo E, Garlick P, Ferretti J. Renal substrate metabolism and gluconeogenesis
during hypoglycemia in humans. Diabetes 2000;49(7):1186-93.
12. Woerle HJ, Meyer C, Popa EM, Cryer PE, Gerich JE. Renal compensation for
impaired hepatic glucose release during hypoglycemia in type 2 diabetes: further
evidence for hepatorenal reciprocity. Diabetes 2003;52(6):1386-92.
13. Mak RH. Impact of end-stage renal disease and dialysis on glycemic control. Semin
Dial 2000;13(1):4-8.
14. Rabkin R, Simon NM, Steiner S, Colwell JA. Effect of renal disease on renal uptake
and excretion of insulin in man. N Engl J Med 1970;282(4):182-7.
15. Petersen J, Kitaji J, Duckworth WC, Rabkin R. Fate of [125I]insulin removed from the
peritubular circulation of isolated perfused rat kidney. Am J Physiol 1982;243(2):
F126-32.
16. Rubenstein AH, Mako ME, Horwitz DL. Insulin and the kidney. Nephron 1975;15(3-5):
306-26.
17. Goll K, Lück, G. The insulin half-life as a kidney function test. Z Urol Nephrol 1975;68(12):
927-33.
18. Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood
glucose in diabetic patients with renal failure. Diabetes Metab 2000;26 Suppl 4:73-85.
19. Harrower AD. Pharmacokinetics of oral antihyperglycaemic agents in patients with
renal insufficiency. Clin Pharmacokinet 1996;31(2):111-9.
20. Rydberg T, Jonsson A, Roder M, Melander A. Hypoglycemic activity of glyburide
(glibenclamide) metabolites in humans. Diabetes Care 1994;17(9):1026-30.
21. Nye HJ, Herrington WG. Metformin: The Safest Hypoglycaemic Agent in Chronic
Kidney Disease? Nephron Clin Pract 2011;118(4):c380-c383.
22. Preiss DJ, Sattar N. Metformin and lactic acidosis. Metformin: framed again? BMJ
2009;339:b5570.
23. Tesfaye N, Seaquist ER. Neuroendocrine responses to hypoglycemia. Ann N Y Acad
Sci 2010;1212:12-28.
24. Arem R. Hypoglycemia associated with renal failure. Endocrinol Metab Clin North Am
1989;18(1):103-21.
25. Kerr D. Drugs and alcohol. In: Frier B, Fisher B, editors. Hypoglycaemia and Diabetes.
Clinical and Physiological Aspect. London: Edward Arnold; 1993:pp. 328–336.
26. Mak RH, Bettinelli A, Turner C, Haycock GB, Chantler C. The influence of hyperparathyroidism
on glucose metabolism in uremia. J Clin Endocrinol Metab 1985;60(2):229-33.
27. Mak RH, Turner C, Haycock GB, Chantler C. Secondary hyperparathyroidism and
glucose intolerance in children with uremia. Kidney Int Suppl 1983;16:S128-33.
28. Jackson MA, Holland MR, Nicholas J, Lodwick R, Forster D, Macdonald IA. Hemodialysis-
induced hypoglycemia in diabetic patients. Clin Nephrol 2000;54(1):30-4.
29. Simic-Ogrizovic S, Backus G, Mayer A, Vienken J, Djukanovic L, Kleophas W. The
influence of different glucose concentrations in haemodialysis solutions on metabolism
and blood pressure stability in diabetic patients. Int J Artif Organs 2001;24(12):863-9.
30. Sangill M, Pedersen EB. The effect of glucose added to the dialysis fluid on blood
pressure, blood glucose, and quality of life in hemodialysis patients: a placebocontrolled
crossover study. Am J Kidney Dis 2006;47(4):636-43.
31. Eisenberg B, Murata GH, Tzamaloukas AH, Zager PG, Avasthi PS. Gastroparesis in
diabetics on chronic dialysis: clinical and laboratory associations and predictive
features. Nephron 1995;70(3):296-300.
32. Barakat MM, Nawab ZM, Yu AW, Lau AH, Ing TS, Daugirdas JT. Hemodynamic
effects of intradialytic food ingestion and the effects of caffeine. J Am Soc Nephrol
1993;3(11):1813-8.
33. Takahashi A, Kubota T, Shibahara N, Terasaki J, Kagitani M, Ueda H, et al. The
mechanism of hypoglycemia caused by hemodialysis. Clin Nephrol 2004;62(5):362-8.
34. Duckworth W, Saudek C, Henry R. Why intraperitoneal delivery of insulin with implantable
pump in NIDDM? Diabetes 1992;41:657-661.
35. Disse E, Thivolet, C. Hypoglycemic coma in a diabetic patient on peritoneal dialysis
due to interference of icodextrin metabolites with capillary blood glucose measurements.
Diabetes Care 2004;27(9):2279.
36. Oomichi T, Emoto M, Tabata T, Morioka T, Tsujimoto Y, Tahara H, et al. Impact of
glycemic control on survival of diabetic patients on chronic regular hemodialysis:
a 7-year observational study. Diabetes Care 2006;29(7):1496-500.
induced hypoglycemia in diabetic patients. Clin Nephrol 2000;54(1):30-4.
29. Simic-Ogrizovic S, Backus G, Mayer A, Vienken J, Djukanovic L, Kleophas W. The
influence of different glucose concentrations in haemodialysis solutions on metabolism
and blood pressure stability in diabetic patients. Int J Artif Organs 2001;24(12):863-9.
30. Sangill M, Pedersen EB. The effect of glucose added to the dialysis fluid on blood
pressure, blood glucose, and quality of life in hemodialysis patients: a placebocontrolled
crossover study. Am J Kidney Dis 2006;47(4):636-43.
31. Eisenberg B, Murata GH, Tzamaloukas AH, Zager PG, Avasthi PS. Gastroparesis in
diabetics on chronic dialysis: clinical and laboratory associations and predictive
features. Nephron 1995;70(3):296-300.
32. Barakat MM, Nawab ZM, Yu AW, Lau AH, Ing TS, Daugirdas JT. Hemodynamic
effects of intradialytic food ingestion and the effects of caffeine. J Am Soc Nephrol
1993;3(11):1813-8.
33. Takahashi A, Kubota T, Shibahara N, Terasaki J, Kagitani M, Ueda H, et al. The
mechanism of hypoglycemia caused by hemodialysis. Clin Nephrol 2004;62(5):362-8.
34. Duckworth W, Saudek C, Henry R. Why intraperitoneal delivery of insulin with implantable
pump in NIDDM? Diabetes 1992;41:657-661.
35. Disse E, Thivolet, C. Hypoglycemic coma in a diabetic patient on peritoneal dialysis
due to interference of icodextrin metabolites with capillary blood glucose measurements.
Diabetes Care 2004;27(9):2279.
36. Oomichi T, Emoto M, Tabata T, Morioka T, Tsujimoto Y, Tahara H, et al. Impact of
glycemic control on survival of diabetic patients on chronic regular hemodialysis:
a 7-year observational study. Diabetes Care 2006;29(7):1496-500.
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