Last year, the International Diabetes Federation released new figures showing that
the number of people living with diabetes worldwide is expected to rise from 366 million
in 2011 to 552 million by 2030. This equates to approximately three new cases every
10 s, and one adult in 10 will have diabetes by 2030
1
. Unexpected rapid increases of diabetic patients in developing and developed countries,
and the global burden of chronic kidney disease (CKD) is expected to increase dramatically
within coming decades.
Diabetes mellitus is the major cause of end‐stage renal disease (ESRD) throughout
the world, in both developed and underdeveloped countries. Diabetic nephropathy is
the primary diagnosis causing CKD in 40–50% of newly developed ESRD patients worldwide.
These patients experience a low quality of life, and a high hospitalization and mortality
rate. Approximately two‐thirds of ESRD patients with dialysis die within 5 years of
initiation of dialysis treatment, and 5‐year survival is worse than that expected
in the majority of patients with cancer
2
.
Diabetic nephropathy does not develop in all diabetic patients and it is believed
to be a progressive disease from microalbuminuria to macroalbuminuria and ESRD. The
diagnosis of diabetic nephropathy can be made in diabetic patients by the persistent
presence of albumin in the urine, or continuous rise in serum creatinine, or a reduction
in the glomerular filtration rate. However, many diabetic patients will not show microalbuminuria
before experiencing a decline in their renal function
3
. The progression to advanced CKD and ESRD usually occurs over years, although not
all patients follow this course. Therefore, a strategy to detect diabetic kidney disease
earlier by screening for albuminuria and reduced glomerular filtration rate is important
to prevent progression of diabetic nephropathy.
Fortunately, there is evidence that early therapeutic intervention in diabetic patients
with CKD can delay the onset of complications and improve outcomes. Several studies
suggest that the incidence and progression of diabetic neuropathy is consistently
reduced in diabetic patients with tight glycemic control (glycated hemoglobin [HbA1c]
<7% or lower). Action in Diabetes and Vascular disease: PreterAx and DiamicroN‐MR
Controlled Evaluation (ADVANCE), Action to Control Cardiovascular Risk in Diabetes
(ACCORD) and Veterans Affairs Diabetes Trial (VADT) have shown a significant reduction
in new or worsening nephropathy, and progression to macroalbuminuria in high‐risk
patients with type 2 diabetes assigned to an intensive glucose‐control strategy. Combined
data from these three trials have shown similar hazard ratios with 95% confidence
intervals in a similar range (relative risk ratio: 0.64–0.79). Although previous studies
have suggested that the effect of glycemic control on morbidity and mortality in patients
with normal kidney function and with early stages of diabetic nephropathy is effective,
recent clinical trials have provided conflicting results on tight glycemic control
outcomes in patients with advanced CKD or ESRD. In VADT, despite the reduced progression
of albuminuria, the intensive glycemic control had no significant effect on the doubling
of serum creatinine level or glomerular filtration rate <15 mL/min for 5.6 years of
median follow up. Similarly, in a follow‐up study of the ACCORD trial, the outcome
of ESRD was not significantly different between the intensive and standard glucose
control groups.
Shurraw et al.
4
determined whether HbA1c level is independently associated with important clinical
outcomes, such as all‐cause mortality, cardiovascular events, hospitalizations and
kidney failure, in people with diabetes mellitus and stage 3–4 CKD. They reported
that a higher HbA1c (>9%) in diabetic CKD patients was associated with markedly worse
clinical outcomes, and lower HbA1c (<6.5%) was associated with excess mortality. They
emphasized the importance of a high HbA1c level as a risk factor for renal outcomes
and that prudent practice was required for moderately intensive risk factor management
while minimizing the potential for serious adverse effects of the treatment regimens.
In conclusion, they suggested that appropriate and timely control of fasting and postprandial
glucose, and HbA1c level in people with diabetes mellitus and CKD might be more important
than previously realized. Oh et al.
5
retrospectively assessed the appropriate HbA1c level for diabetics to minimize the
incidence of ESRD and all cause mortality. They reported that HbA1c <6.5% was associated
with reduced development of ESRD in all patients and later stages of CKD compared
with HbA1c≥6.5%, regardless of glomerular filtration rate. However, HbA1c <6.5% showed
no benefit on ESRD development in patients older than 80 years and in patients with
diabetic duration >10 years.
As a result of these studies, a HbA1c target of 7.0% is appropriate for the majority
of patients with diabetic nephropathy (Table 1). A lower target will increase their
risk of hypoglycemia and might increase their risk of mortality, whereas a higher
target might accelerate the rate at which renal failure and other diabetes complications
develop. The selection of the optimal HbA1c needs to be individualized for each patient
by considering the variables, such as patient characteristics, treatment modalities,
and relative risks and benefits of different levels of glycemia.
Table 1
Target glycated hemoglobin in chronic kidney disease by National Kidney Foundation/Kidney
Disease Outcomes Quality Initiative classification in diabetic patients
Stage
Description
GFR (mL/min/1.73 m2) for ≥3 months
Target HbA1c
1
Normal or ↑ GFR
>90
≤7%
2
Mild ↓ GFR
60–89
≤7%
3
Moderate ↓ GFR
30–59
≤7%
4
Severe ↓ GFR
15–29
≤7%
5
Kidney failure
<15 or dialysis
>7% (?)
GFR, glomerular filtration rate; HbA1c, glycated hemoglobin.
It is unclear, however, what therapeutic target level marker has to be used for glycemic
control in advanced CKD and ESRD patients, and in what stages of CKD its application
has to replace or supplement HbA1c, which could be confounded in the uremic milieu.
To avoid of the drawbacks of HbA1c, the use of fructosamine and glycated albumin in
long‐term glycemic control in advanced CKD patients has been proposed, but they are
not superior to HbA1c in ESRD patients
2
. Therefore, we have to use other adequate methods, such as a continuous glucose monitoring
system, to measure glycemic variability.
Until now, the optimal glycemic control in patients with advanced CKD had not been
determined. The American Diabetes Association and National Kidney Foundation both
recommend achieving a HbA1c level of 7.0% in most patients with diabetes, regardless
of the presence of CKD. The issue of long‐term outcomes as a function of diabetes
control is especially complicated in patients with advanced CKD and ESRD in whom there
are complex changes affecting glucose homeostasis
2
. The gradual decline in renal function in itself causes significant changes that
alter glucose homeostasis in patients with diabetic kidney disease. The reasons for
these alterations in glucose homeostasis are multifactorial and involve various mechanisms
related to both decreased renal function. Once glomerular filtration rate declines
below 15–20 mL/min, the renal and hepatic clearance of insulin decreases significantly.
Counterbalancing diminished insulin clearance is lower insulin production and increased
insulin resistance. It is also unclear what the ideal target HbA1c level has to be
for glycemic control in diabetic ESRD patients. The advantages of a normal blood sugar
level in advanced CKD and ESRD likely take a very long time to manifest, and in the
short‐term these patients might in fact be more prone to developing clinically relevant
hypoglycemic episodes. Observational studies in ESRD patients indeed suggest that
patients with the lowest HbA1c levels suffer significantly higher mortality rates.
Recent studies in patients with normal kidney function, but advanced diabetes, showed
that attempts to improve blood glucose control toward levels resembling normoglycemia
can become deleterious, possibly because of the consequences of hypoglycemic events.
The effect of optimal blood glucose control on outcomes in patients with advanced
CKD and ESRD is less well‐studied, with a limited number of published studies showing
somewhat inconsistent results. Therefore, larger clinical trials are required to show
that that better glycemic control is beneficial in patients with advanced CKD and
ESRD, and most importantly to establish what an ideal blood glucose level is in these
patients. Hyperglycemic patients with advanced CKD and ESRD are usually treated in
clinical practice based on guidelines established for patients with normal kidney
function. Although this is probably better than not treating them at all, more practical
efforts are required to ensure that the undesirable complications of overenthusiastic
therapy are avoided and to find suitable criteria for advanced CKD and ESRD patients.
In conclusion, recently, diabetes prevalence has increased in developed and underdeveloped
countries. The number of diabetic kidney disease patients has increased very rapidly,
and their economic burden for management of advanced CKD and ESRD has become a significant
problem for individual patients and society. Therefore, earlier detection of diabetic
nephropathy patients is essential for preventing the progression to advanced CKD and
ESRD; and, optimal glycemic control for early diabetic nephropathy patients is required
as an effective strategy in preventing and delaying the development of CKD. Up to
the present, we do not have an optimal glucose control level and HbA1c level for advanced
CKD and ESRD patients in clinical practice guidelines. In addition, we don’t have
adequate therapeutic target markers for monitoring glycemic control in diabetic dialysis
patients. Therefore, we must carry out large clinical trials to determine the proper
glucose level and HbA1c for advanced CKD and ESRD patients to decrease the hospitalization
rate, increase survival time and improve the quality of life.