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Hypoglycemia in chronic kidney disease

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Hypoglycemia in chronic kidney disease
Abstract
Hypoglycemia is a significant issue among chronic kidney disease population.
Management requires early identification and judicious use of drugs. This review narrates
various aspects of uremic hypoglycemia by focusing on individually tailored therapy.
Keywords: hypoglycemia; chronic kidney disease; diabetes; diabetic nephropathy; uremic
hypoglycemia
Introduction
Prevalence of chronic kidney disease among diabetic population is alarmingly high [1, 2].
Chronic kidney disease (CKD) is a major micro vascular complication of diabetes and the
inherent risk of hypoglycemia among diabetes get amplified in CKD [3]. Though achieving an
optimum glycemic status is the prime concern of health professionals, it’s still a mirage due to
the peculiar micro environment of a diabetic - CKD duo. Managing this clinical chaos is often a
“balancing game” for many clinicians. This review article discusses the various aspects of
uremic hypoglycemia.
Epidemiology
Despite the escalating rates of diabetic kidney disease, a precise statistics of
hypoglycemia among diabetic CKD especially in India is lacking. Because mild fluctuations may
not be clinically evident and also hypoglycemic unawareness - reduced ability or failure to
recognize hypoglycemia at the physiological plasma glucose concentration at which warning
symptoms normally occur- impairs prompt identification of a hypoglycemic episode [4, 5].
Moreover a complete analysis of glycemic status cannot be made by the conventional blood
glucose measures. Only continuous glucose monitoring facilitates absolute detection of
hypoglycemia over stipulated periods [6].
A retrospective cohort study by Moen et al has reported greater risk of cardiovascular
mortality among CKD patients from recurrent hypoglycemia and hypoglycemic unawareness.
1
They found that the adjusted rate of hypoglycemia was higher in patients with CKD than those
without CKD. Similarly regardless of severity, the rate of hypoglycemia among patients with
diabetes was higher than in patients without diabetes. And finally higher rates of hypoglycemia
were observed among patients who had both diabetes and CKD than either disease state alone.
So it is evident that both diabetes and CKD are independent risk factors for hypoglycemia [7].
Findings from the famous ACCORD study also revealed that detected and undetected
hypoglycemia was more common in the intensively treated group than in the standard group. A
statistically significant relationship also established between the number of hypoglycemic
episodes and the risk of death among participants [8]. The major UK Hypoglycemia Study
Group reported that incidence of severe hypoglycemia is more among type 1 diabetes than type 2
[9].
Findings from the systematic review by the department of veteran’s affairs, Washington
DC revealed that the incidence of severe hypoglycemia ranges between 0 - 3% per year for
adults with type 2 diabetes on anti-diabetic drugs. The rate is highest in trials of people on
insulin, sulfonylureas and regimens targeting intensive control of hemoglobin A1C (HbA1c)
levels. For patients those who are on metformin, GLP-1 analogs, DPP-4 inhibitors, glinides and
TZDs, the risk is negligible [10].
Often CKD is associated with a multitude of metabolic risk factors like hyperlipidemia,
hypertension and diabetes. So the exact role of hypoglycemia in CKD mortality cannot be
ascertained [4]. But many experimental studies have shown that clinical hypoglycemia can cause
abnormal cardiac repolarization and an attendant risk of cardiac arrhythmia [11-13]. A
prospective, randomized study from Asia investigated the relationships of hypoglycemia with
total mortality and cardiovascular events and found that symptomatic hypoglycemia, whether
clinically mild or severe, is associated with an increased risk of cardiovascular events, all-cause
hospitalization, and all-cause mortality [14].
Hypoglycemia
Hypoglycemia is a clinical scenario where the plasma glucose levels will be abnormally
low [15]. Because of wide individual variations a fixed cut off value is lacking. A diagnosis of
hypoglycemia can be made with the help of a framework – Whipple’s triad. (1) Symptoms
consistent with hypoglycemia, (2) a low plasma glucose concentrations, (3) relief of symptoms
after the plasma glucose level is raised [15].
2
The American Diabetes Association and Endocrine Society workgroup on hypoglycemia
(2012) has put forwarded a clear definition on iatrogenic hypoglycemia. i.e. all episodes of an
abnormally low plasma glucose concentration that expose the patient to potential harm. The
group suggested the following classification system for hypoglycemia [16].
Table 1. Classification of hypoglycemia [5] [The American Diabetes Association and
Endocrine Society workgroup on hypoglycemia (2012)]
Category
Severe hypoglycemia
Description
An event requiring assistance of another person to actively administer
carbohydrates.
Documented
An event during which typical symptoms of hypoglycemia are
symptomatic
accompanied by a measured plasma glucose concentration ≤70 mg/dL
hypoglycemia
(≤3.9 mmol/L).
Asymptomatic
An event not accompanied by typical symptoms of hypoglycemia but
hypoglycemia
with a measured plasma glucose concentration ≤70 mg/dL
Probable
symptomatic
hypoglycemia.
Pseudohypoglycemia.
An event during which symptoms typical of hypoglycemia are not
accompanied by a plasma glucose determination but that was
presumably caused by a plasma glucose concentration ≤70 mg/dL (≤3.9
mmol/L)
An event during which the person with diabetes reports any of the
typical symptoms of hypoglycemia with a measured plasma glucose
concentration >70 mg/dL (>3.9 mmol/L) but approaching that level.
Counter regulatory scenario in Hypoglycemia
Irrespective of the substantial variations in food intake and activity, plasma glucose levels
are maintaining a relatively narrow therapeutic range ie, 60-150 mg/dL. Rigorous endocrinal
feedback axis or counter regulatory mechanisms are the key players in this. This counter
regulatory mechanism primarily constitutes break down of glycogen stores and gluconeogenesis.
Response of catecholamines also critical as it stimulates glycogenolysis and gluconeogenesis and
limits the tissue glucose utilization. In the event of a sustained hypoglycemic attack, growth
3
hormones and cortisol also limits glucose utilization and enhances its production. The glucose
threshold for these counter regulatory responses is dynamic and depends on various metabolic
factors [15].
Etiology
Major causes of Hypoglycemia includes intake of drugs - especially insulin and
sulfonylureas, sepsis, hyperinsulinism, congenital metabolic disorders, ethanol, starvation and
factitious factors [15]. Of the anti-diabetic drugs, sulfonylureas are the agents which most likely
to increase the risk of hypoglycemia. A major systematic review by Health Services Research
wing, USA found out that the incidence of severe hypoglycemia in patients treated with
sulfonylureas was 1.2% (95% CI 0.9 to 1.5%) over a an average follow-up period of 2.4 years.
Specific factors that might increase the risk of hypoglycemia include use of insulin
secretagogues, missed meals, advanced age, duration of diabetes, and unawareness of
hypoglycemia [10].
Clinical manifestations
Generally hypoglycemic features fall into two domains i.e., neuroglycopenic and
autonomic. Brain is highly sensitive to glucose deprivations so the neuroglycopenic symptoms of
hypoglycemia range from behavioral changes, confusion, fatigue, seizure, loss of consciousness
and finally death in prolonged severe hypoglycemic situations (glucose levels of less than 40
mg/dL). Palpitation, tremor, anxiety, sweating, parasthesia and hunger are the common
adrenergic symptoms [15, 16]. The hypoglycemic manifestations often can be quite
uncomfortable and perplexing. Patient may experience a variety of subjective feelings like aura,
flashes, headache and generalized weakness. These complex experiences may lead to
anticipatory fear, a phenomenon known as fear of hypoglycemia (FOH) [17].
Significance of Hypoglycemia in CKD.
Glycemic management in CKD is complex because of a variety of factors like impaired
peripheral insulin degradation, reduced insulin requirements, impaired glucose counter
regulatory mechanisms and malnutrition. As renal function deteriorates over time, prolonged
4
half-life of antidiabetic drugs also aggravates the glycemic status. Constellation of these all
factors may exaggerate the implied risk of hypoglycemia in diabetic CKD patients [7, 18].
Chronic kidney disease
According to ‘National Kidney Foundation - Kidney Disease Outcome Quality Initiative’
(NKF KDOQI), Chronic Kidney Disease can be defined as kidney damage for three or more
months, as defined by structural or functional abnormalities of the kidney, with or without
decreased glomerular filtration rate (GFR), manifested by pathologic abnormalities or markers of
kidney damage, including abnormalities in the composition of the blood or urine or abnormalities
in imaging tests (GFR<60mL/minute/1.73 m2 for three months or more, with or without kidney
damage) [19].
Classification of CKD is based on the Estimation of glomerular filtration rate (GFR).
Estimation equations are derived based on the ser. creatinine value. Though validation in Indian
setting is lacking, Modification of Diet in Renal Disease (MDRD) equation and the more recent
CKD – EPI (Chronic Kidney Disease Epidemiology Collaboration) formula are commonly used
[19, 20].
Table 2. Classification of CKD based on GFR (KDIGO 2012 guidelines) [21]
CATEGORY
DESCRIPTION
GFR
G1
Normal or high
≥90
G2
Mildly decreased
60–89
G3a
Mildly to moderately decreased
45–59
G3b
Moderately to severely decreased
30–44
G4
Severely decreased
15–29
G5
Kidney failure
<15
Diabetic management strategies in CKD
Glycemic management in CKD is a complex issue. Many factors like presence of
comorbidities, poly pharmacy, fear of hypoglycemia and deterioration in quality of life, personal,
economic and social factors may make the situation more intricate [4].
5

Optimization of glycemic control: Optimum glycemic control is the prime consideration
among the therapeutic management of diabetic CKD. Goals need to be readjusted as per the
renal status [24]. The worsening of kidney function in diabetes can be slowed through
intensive glycemic control [25].

Judicious drug use: Many clinical trials are underway in this regard. Of the available anti
diabetic agents, an intelligent selection and good prescribing practice should be followed [4,
19, 21, 23]. Till now, any particular agent cannot be preferred over another for renoprotective
effect [25]. Apart from standardized treatment, individually tailored treatment is the current
strategy [24, 29].

Glucose monitoring: Continuous glucose monitoring (CGM) lowers A1C by ~0.26%
compared with SMBG. CGM may be a supplemental tool to SMBG in those with
hypoglycemia unawareness and/or frequent hypoglycemic episodes [25]. Diffuse glycemic
fluctuations in CKD can only be elicited through a CGM [26, 27, 28].

Patient education: Self-management education is vital in patients with diabetic kidney
disease. And it should address psychosocial issues, since emotional well-being is associated
with positive outcomes [24, 29].

Reevaluation: As hypoglycemia unawareness is a common phenomenon in CKD, one or
more episodes of severe hypoglycemia should trigger re-evaluation of the treatment regimen.
Glycemic targets should be reevaluated to strictly avoid further hypoglycemia for at least
several weeks, to partially reverse hypoglycemia unawareness and reduce risk of future
episodes [14, 23, 24].
Conclusions
Hypoglycemia is a common clinical entity among diabetic patients and the risk is highest
in patients with CKD and diabetes. It is an unintended consequence of therapy to treat. As it is an
iatrogenic independent risk factor for mortality, individually tailored pharmacologic therapy is
vital.
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