CME

EARN CATEGORY I CME CREDIT by reading this article and ttie article beginning on page 54 and successfully
completing ttie posttest on page 60. Successful completion Is defined as a cumulative score of at least 70%
correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME
credit by the AAPA. The term of approval is for 1 year from the publication date of November 2012.

LEARNING OBJECTIVES
Relate the pathophysiology ot deteriorating renal function to the challenges of maintaining
glycennic control
Formulate a plan to monitor renal function and glycmie control tor patients with CKD and diabetes
Incorporate the latest clinical eyidence for sloy\/ing the progression of CKD in patients with diabetes

Management of diabetes in patients

with end-stage kidney disease
Physiologic changes in diabetic patients with deteriorating kidney function reguire close
monitoring and dose adjustments in their antihyperglycemic medications.

Kim Zuber, PAC, DFAAPA

hronic kidney disease (CKD) is a silent epidemic in the United States.' According to the
National Kidney Foundation Kidney Disease
Outcome Quality Initiative (KDOQI), the
five stages of CKD are defined by the estimated glomerular filtration rate (eGFR) (Table 1) and
dependent on the serum creatinine, gender, age, and race
of the patient.2 The rate of stage 4 CKD has increased by
67% over the past 20 years. Many patients with stage 4
CKD will eventually develop kidney failurestage 5 disease (eGFR <15 mL/min/1.73m^).' In patients older than
65 years, the rate of CKD has increased 4.6 times since
1995.^ Thus, PAs in every specialty will see more and
more patients with kidney failure as the aging of America
continues (Figure 1).
Diabetes meUitus, which has been the main cause of kidney failure in the United States, is now the most common
cause of kidney failure worldwide, with more than 50 milHon cases reported in 2010* (Figure 2). The rate of diabetes
is growing exponentially hoth globally and in the United
States.'^ Thirty percent of patients with type 1 diabetes melHtus (TIDM) and 10% to 40% percent of patients with type
2 diabetes meUitus (T2DM) will eventually suffer kidney
failure." Prior to the wide-scale acceptance of the need for
cardiac, glycmie, and dietary changes, the patient with
diabetes and stage 4 CKD (eGFR 15-30 mL/minyi.73 m^)
was more likely to die of cardiac disease than to progress to
end-stage renal disease (ESRD) and dialysis. Now, because
of the identification and aggressive treatment of this population by primary care practitioners, the opposite is true:
Patients with diabetes and CKD are more likely to progress
26 JAAPA NOVEMBER 2012 25(11) www.jaapa.com

z:

50

Counts

40

2,000

1,500

.2

1,000

Rates

500

04 08
FIGURE 1. Incident counts and adjusted rates of end-stage renal
disease by age'

to ESRD and hemodialysis than they are to die of cardiovascular disease.'

Because the number of padents with diabetes and ESRD
is expected to explode in the next 20 years, we need to define
glycmie control in this populadonwith the understanding
that glycmie goals can be a moving target in the changing
world of kidney disease because ofthe confounding physiology of kidney fauure.
PATHOPHYSIOLOGY

Physiologic changes occur as the kidney fails to flmcdon.^

Because insulin is degraded by the kidney, the degradadon
process is slowed as the kidney is failing and insulin is available
in the bloodstream for longer periods.^"' Although this change
in insulin availability may be propordonal to the decrease in
the mass ofthe kidney, it does not foUow a longitudinal curve.
Thus, a reducdon in insulin dose is necessary, and as Utde
as one-third the amount of the padcnt's usual dose may be
required." In padents with TIDM whose kidney fbncdon is
declining, the number of severe hypoglycmie events is esdmated to befivedmes greater than it was prior to the loss of
kidney funcdon.'^ As GKD develops, the padent wiU progress
through a stage of kidney failure that does not yet require dialysis, usually at an eGFR of 8 to 15mL/min/1.73m^, at which
point mabutridon occurs due to the loss of taste and appedte
in the uremic padent. At this stage, another significant dose
adjustment of the diabetes medicadon is required.

TABLE 1. Stages of chronic kidney disease^

Description

eGFR
mL/min/1.73 m^

Kidney damage with normal

or increased GFR

>90

Kidney damage with

mild decrease in GFR

60-89

Moderate decrease in GFR

30-59

Severe decrease in GFR

15-29

Kidney failure
Key: eGFR, estimated glomerular filtration rate.

and fluid removal. PD fluid comes in differing glucose concentradons: commonly 1.5%, 2.5%, and 4.25%.''' Because
patient-specific factorssuch as uptake by the peritoneal
lining, number and concentration of glucose baths, use of
a nocturnal PD cycler, and use of large molecular weight
PD fluid (icodextrin)'''-determine the glycmie parameters,
this article does not discuss patients with diabetes receiving
PD. This group of renal failure padents is followed closely
by endocrine and nephrology specialists and does not lend
itself easily to generalized statements of glycmie control.
Thus, all discussion from this point on applies only to the
patient with diabetes receiving HD.

DIALYSIS

LABORATORY STUDIES

In the United States, padents undergoing dialysis are

treated with one of two main modalities : hemodialysis
(HD) or peritoneal dialysis (PD). Patients usually undergo
HD three times a weekon a MondayAVednesday/Friday
or Tuesday/Thursday/Saturday schedule, for an average
of 4 hours per dialysis session. Nocturnal dialysis (8 hours
per session), with the patient sleeping at the dialysis unit,
is becoming more common foUowing publication of studies showing the physiologic advantage of longer dialysis."
Patients can also utilize hemodialysis at home on a daily
or thrice-weekly basis.
Peritoneal dialysis uses glucose-based solutions that are
introduced into the peritoneal cavity as a method of urea

Glycosylated hemoglobin (AlG) is the standard measurement

for diabetes management in the general poptiladon. Most
padents with renal failure take an erythopoietin-sdmulatbg
agent (ESA), such as epoetin alfa (Epogen, Procrit) or darbepoedn (Aranesp), for treatment of their renal failure-induced
anemia. ESAs wl cause rapid RBG turnover, which wl
confound the AlG, causing it to be falsely low and negating its
validity."''* The chromatography and agar gel electrophoresis
used to calculate AlG can be affected by urea and metabolic
addosis, both prominent in the hemodialysis populadon.'"
Thrice-weekly HD, the HD diet, and muldplc medicadons can
affect normalizadon of AlG values.^" Some authors have suggested that the serumfiiictosaminelevel is a better indicator

KEY POINTS
Because patients witti diabetes and chronic kidney disease (CKD) are now treated aggressively by primary care practitioners, these
patients are more likely to progress to end-stage renal disease and hemodialysis than they are to die of cardiovascular disease.
Most patients with CKD take an erythopoietin-stimulating agent (ESA) for treatment of anemia. ESAs will cause rapid RBC turnover,
which will confound the A1C, causing it to be falsely low and negating its validity.
Insulins, including the long-acting insulin analogs, allow the most flexible dosing for patients receiving hemodialysis. The long-acting
insulins have the advantage of once-daily day dosing while allowing adjustment for diet and hemodialysis schedule.
Authors of a 2006 study involving 24,875 patients found no statistical correlation between good glycmie control and survival in the
US hemodialysis population.
Another study found that a patient with an AlC greater than 8% had a higher statistical likelihood of dying but so did a patient with
an AlC of 6.5% or less.

www.jaapa.com NOVEMBER 2012 25(11) JAAPA

27

CME CKD and diabetes

of glycmie control in the hemodialysis population; however,
few HD patients are followed with this laboratory value.^'
Cost is the main reason for using the AlC rather than the
fioictosamine level, because a portion of the Medicare payment
made to dialysis units for each hemodialysis session includes
reimbursement for laboratory determinations. AlC is the only
Medicare-sanctioned laboratory value for glycmie monitoring
of the HD population.^^
MEDICATION DOSING

As the eGFR drops with progressive decreases in kidney

function, the oral sulfonylurea compounds, a standard in
diabetes management, are less useful for glycmie eontrol
because oral medications must be metabolized by the failing/
failed kidney. Moreover, the chance of lactic acidosis in
CKD has prompted a black-box warning for metformin,
which must be discontinued as kidney function deteriorates past CKD stage 3.^^ Thiazolidinediones can cause
or increase edema and heart failure, and no long-term
data are available for these agents in the hemodialysis
population.*
Insulins, including the long-acting insulin analogs, allow
the most fiexible dosing for the hemodialysis population.^**
The patient who was frightened of the insulin needle
prior to the start of hemodialysis is often less resistant to
the small 30-gauge needle used for insulin administration
after facing 14-gauge needles three times a week for HD
(K. Kalantar-Zadeh, oral communication. May 2012).
However, the dosing of insulin must take into account
both the burnt-out kidney and the three- to six-times-aweek hemodialysis regimen.'" The long-acting insulins
glargine, ultralente, and levemirhave the advantage of
once-daily day dosing while allowing adjustment for diet
and hemodialysis schedule.^''
KDOQI GUIDELINES

In an attempt to standardize treatment of patients with

diabetes and CKD, the National Kidney Foundation published guidelines for glycmie control in 2005 and 2007."-^^
According to the 2007 KDOQI guidefines.
The patient on long-term dialysis therapy no longer needs to
achieve good glyceniic control to prevent deterioration of kidney
function. However, good control may still prevent or slow the progression of retinopatliy, neuropathy, and possihly macrovascular
disease. Survival improves with better glycmie control in patients
on peritoneal dialysis and hemodialysis therapy.^'

However, no attempt was made to define "good" or

"better" control in either the 2005 or 2007 guidelines.
RESEARCH UPDATE

In the past 7 years, multiple studies have tried to define

the "goal" for glycmie control in the hemodialysis patient.
Since AlC is not a "true" measurement for patients using
hemodialysis," morbidity and mortality measures are the
28 JAAPA NOVEMBER 2012 25(11) www.jaapa.com

50
o
10

Counts

Diabetes
40 ~ " Hypertension
Glomerulonephijifis
30 Cystic kidney^

.1
4-
ID

20

Q.

10

160

Rates

80 84 88 92 96

00 04 08

FIGURE Z. Incident counts and adjusted rates of end-stage

renal disease by primary diagnosis'

end points identified and followed in trials of glycmie control

in this population. While hemodialysis patients are not often
included in clinical trials, two large dialysis organizations
with computerized records and the United States Renal Data
System (LJSRDS) have collected demographic, comorbidity,
and mortality data on every dialysis patient in the United
States since the 1970s as per federal regulations.'-^" This
allows inclusion of multiple studies, but they are all observational and thus susceptible to the inherent biases and mthodologie problems of such studies.
A large retrospective, observational study was published in
2006.'"'-" With an enrollment of 24,875 patients and analysis by researchers at theJosHn Diabetes Center of Harvard
Medical School, it continues to be the seminal study for the
US population. Using multiple statistical models to control
for comorbidities and case-mbc adjustments, investigators
found no statistical correlation between good glycmie control
and survival in the US hemodialysis population. In 2012,

a group from the University of California at Los Angeles

published mortality data gathered over 6 years from 54,757
diabetic patients who were receiving hemodialysis and found

that a padent with an AlC greater than 8% had a higher stadsdcal UkeHhood of dying but so did a padent with an AlC
of6.5%orless.''^
While the large clinical trials of diabetes patients (Action
to Control Cardiovascular Risk in Diabetes [ACCORD],
Action in Diabetes and Vascular Disease [ADVANCE],
Diabetes Control and Complications Trial [DCCT], and
Veterans Affairs Cooperative Study on Glycmie Control
and Complications [VADT]) included patients with
stage 4 and 5 CKD, they did not include hemodialysis
patients.3"-' ADVANCE, ACCORD, DCCT, and VADT
showed increasing mortality risk for those who are susceptible to hypoglycemia, including hemodialysis patients.
Thus, treatment of the hemodialysis patient with diabetes
is not that much different from the treatment for the elderly diabedc patient without kidney disease: go low, go slow,
and monitor closely.
ACCEPTED GOALS FOR GLYCEMIC CONTROL
IN KIDNEY FAILURE

Using the 2005 and 2007 KDOQI guidelines, die goals

presendy accepted by the nephrology community for glycmie control of the padent with kidney failure are as follows:
AlC measurement 2 to 4 times a year
AlC goal above 7%
Insulin as the medication of choice.
In November 2012, the new KDO(2 guidelines for glycemic control of the renal padent will be published. They
promise to clear up some of the current confusion for practitioners who care for these fragile patients, JAAPA
Kim Zuber practices nephrology at Metropolitan Nephrology in Alexandria,
Virginia. She is a past chair of the National Kidney Foundation Council of
Advanced Practitioners.
No reiationships to disciose.

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