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Anemia, Diabetes and Chronic Kidney Disease
Anemia, Diabetes and Chronic Kidney Disease
R E V I E W
D
iabetes is the leading cause of vanced stages of CKD and in those with
chronic kidney disease (CKD) and proteinuria (7,14,15) For example, in a tissue iron defined as a serum ferritin level
is associated with excessive cardio- 5-year prospective observational study ⱖ100 ng/ml and a reduction in iron sat-
vascular morbidity and mortality (1,2). conducted in a diabetes clinic in Austra- uration. The latter is more common and is
Anemia is common among those with di- lia, anemia was found in early kidney dis- strongly associated with upregulation of
abetes and CKD and greatly contributes to ease, and declining Hb levels were more inflammatory cytokines and impaired tis-
phrotic syndrome is complex and in- cer, hypertension, progression of kidney patients. Anemia prevalence is up to 10-
volves both inflammatory-mediated disease, and cardiovascular events (15). fold higher among diabetic patients with
mechanisms as discussed above as well as CKD and heart failure and is a modifiable
absolute iron deficiency. Iron excretion Progression of kidney disease risk factor among diabetic patients (36,
increases in early stages of kidney disease In general, kidney disease in diabetes is 37). Low Hb concentration is an indepen-
in patients with diabetes and albuminuria progressive, and it has been hypothesized dent risk factor for left-ventricular hyper-
and is exacerbated by development of ne- that anemia may contribute to progres- trophy, heart failure, and cardiovascular
phrotic-range proteinuria. In nephrotic sion of kidney disease (7,16,28,29). Pos- mortality (37– 44). Heart failure is com-
syndrome, many nonalbumin proteins sible mechanisms include renal ischemia mon in diabetic patients with nephropa-
are excreted in the urine, including trans- caused by reduced oxygen delivery due to thy and may result in reduced renal blood
ferrin and erythropoietin. Significant low Hb and underlying heart failure. For flow, thereby contributing to further re-
losses of transferrin and erythropoietin example, anemia may worsen renal med- duction in GFR and erythropoietin pro-
can occur in nephrotic syndrome, leading ullary hypoxia, leading to renal interstitial duction. Also, anemia may aggravate
to both iron- and erythropoietin- injury and fibrosis (30,31). Whole animal tissue hypoxia, and subsequently heart
deficiency– caused anemia in patients and in vitro studies indicate that renal failure, resulting in further renal sodium
with diabetes (23). Evidence for in- hypoxia upregulates hypoxia-inducible retention, volume expansion, increased
that treatment of anemia with an ESA to them for 19 months. The primary out-
No difference
Trial ongoing
reach a higher Hb level would slow de- come was the change in left-ventricular
Improved
Improved
Improved
Improved
QOL
cline in kidney function. Subjects were mass index, and secondary outcomes in-
targeted to one of two Hb levels (13–15 or cluded kidney function and QOL. There
11–12 g/dl) and followed for 12 months. were no significant differences in left-
Although the decline in GFR was numer- ventricular mass index in those random-
Results
No benefit
No benefit
Table 1—Randomized controlled cardiovascular outcome trials of anemia treatment with erythropoietin-stimulating agents in patients with chronic kidney disease
Still, those randomized to the high group higher Hb arm. There were no differences
showed improvement in QOL and vitality in kidney function decline and no signif-
(47). However, the two largest trials to icant differences in adverse events (48).
date to examine the effect of ESA on pro-
gression of kidney disease (as a secondary CARDIOVASCULAR
Primary outcome
outcome) did not show any renal benefit EVENTS — Singh et al. (11) tested the
of raising Hb to a higher level. (See hypothesis that a higher Hb level would
below.) reduce risk for the composite cardiovas-
⌬LVMI
LVMI
LVH
ducted a prospective, randomized, open- with various causes of CKD including di-
label trial in 155 anemic CKD patients abetes (⬃46%). In this trial, the Correc-
(stage 3– 4), testing the hypothesis that tion of Hb and Outcomes in Renal
Follow-up
(months)
24–48
ESA treatment could prevent develop- Insufficiency (CHOIR) trial, 1,432 pa-
22.6
24
16
36
18
ment or progression of left-ventricular tients with anemia and stage 3– 4 CKD
hypertrophy. Study subjects were ran- were randomized to an Hb target of 11.5
domized to receive subcutaneous dosing or 13–13.5 g/dl and followed for an aver-
13–15/10.5–11.5
with erythropoietin-␣ to achieve and age of 16 months (11). During the trial,
11–11.5/13–13.5
HCT/Hb target
13.0/⬍11.0
9–10/12–13
9–10.5/12–14
11–11.5/13–15
maintain Hb in the range of 9 –10 or Hb levels were significantly higher in
11–13 g/dl and followed for 2 years with those randomized to the higher Hb arm.
repeated measures of left-ventricular The composite event rate was higher in
structure and function. They found no those assigned to the higher Hb arm;
HCT, hematocrit; HD, hemodialysis; LVH, left ventricular hypertrophy; LVMI, left-ventricular mass index.
difference in the primary outcome of left- however, there was no difference in the
ventricular wall thickness; however, rate of development of ESRD. Also, in
Stage of study
those assigned to the higher Hb arm of the contrast to the results of other studies,
population
Stage 1–3
study experienced improvement in QOL. there was no improvement in QOL in
3–5
2–5
4–5
4–5
3–4
Levin et al. (8) conducted a randomized those randomized to the higher target.
clinical trial to test the hypothesis that The authors concluded that use of a target
prevention or correction of anemia, by Hb level of 13.5 g/dl (compared with 11.3
the change in left-ventricular mass index. Hb arm had prior coronary events, hyper-
They randomized 176 CKD patients who tension, and dropout prior to an event or
had experienced a decrease of 1 g/dl Hb in completion of the study. In the Cardio-
the prior year and a baseline Hb level of vascular risk Reduction by Early Anemia
11–13.5 g/dl to treatment with epoetin-␣ Treatment with Epoetin beta (CREATE),
Open label
Open label
Open label
Open label
Open label
to maintain Hb in the range of 12–14 g/dl Drueke et al. (6) randomized 603 patients
or to maintain a target Hb range of 9 –10.5 with stage 3– 4 CKD, from various causes
g/dl; the subjects were followed for 24 including diabetes (⬃25%), to early ver-
months with repeated measures of left- sus late treatment with epoetin-␣ to test
Diabetes
ventricular structure and function. De- the hypothesis that a higher Hb level
24–33
35–41
48
25
100
100
(%)
603
176
4,000
Those assigned to higher Hb experienced 11.5 or 13–15 g/dl and followed for an
N
Singh et al.
tients with type 1 or type 2 diabetes and posite outcome, but there was a trend
Levin et al.
Ritz et al.
Mix et al.
stage 1–3 CKD to treatment with epo- toward a higher event rate in the higher
etin-␣ and a target Hb level of either Hb arm. In addition, multiple QOL mea-
13–15 or 10.5–11.5 g/dl and followed sures were significantly improved in those
randomized to the higher Hb arm. In con- uation of anemia (13,51). Additional tests g/dl. Manufacturers of ESA accordingly
trast to the CHOIR study, the time to to evaluate anemia should be guided by added black box warnings noting these
ESRD, a secondary outcome, was shorter this initial evaluation (e.g., serum folic recommendations (53).
in the higher Hb arm. Post hoc analysis acid, vitamin B12 level, Coombs test, In summary, the NKF and FDA rec-
demonstrated that the study was under- etc.). Despite the high prevalence of ane- ommendations are in conflict. Whereas
powered to detect a difference in the pri- mia in the CKD population, treatment there is agreement that ESAs are valuable
mary outcome variable as a result of the with erythropoietin or iron often is not for treating anemia, they differ with re-
lower-than-expected overall event rate in used in the predialysis period. For exam- gard to the level of Hb at which to initiate
both arms of the study. ple, nearly 70% of patients initiated on ESA and the upper limit of the Hb target.
The increased risk for adverse out- dialysis are anemic by the NKF definition The NKF supports the safety of ESA use
comes during ESA treatment of anemia but are not treated with erythropoietin, and recognizes the importance of individ-
in clinical trials of patients with CKD is and ⬎50% of these patients have severe ualizing anemia treatment. Further stud-
not completely understood. One possi- anemia (hematocrit ⬍30%). ies on the safety of ESA use in the diabetes
bility is that higher Hb increases risk for population, as well as efforts to better un-
thrombosis. Another possibility is that RECOMMENDATIONS FOR derstand the explanation for the associa-
those who experience adverse cardio- TREATMENT OF ANEMIA tion of higher Hb with worse cardiovascular
versus oral iron in patients with CKD not Adverse side effects of therapy 12 g/dl? Another area of uncertainty con-
on dialysis (56). In clinical trials, up to 25% of patients cerns the diagnosis and management of
An initial dose of 10,000 units epoetin- experience an increase in blood pressure erythropoietin hyporesponsiveness, for
␣ once weekly or 0.75 g/kg darbepoetin-␣ or develop overt hypertension (blood which there is no widely accepted, stan-
every other week subcutaneously are effec- pressure ⬎140/90 mmHg) (8,27,47,61– dardized definition. This confounds the
tive for increasing Hb concentration by 63). Thus, ESA should not be used to treat analysis of clinical trials in which higher
1–2 g/dl over 4 – 8 week periods (27). anemia in patients with uncontrolled doses of ESA and higher Hb occur in
Darbepoetin can be administered subcu- blood pressure. Moreover, increases in those randomized to higher Hb targets.
taneously every other week at outset and blood pressure should be looked for in Additional studies are needed to under-
then administered once monthly to main- any anemic CKD patient treated with an stand the nature and extent of hypo-
tain Hb target. Ling et al. (57) demon- ESA, and dose adjustments in ESA, iron, responsiveness to erythropoietin in
strated efficacy of maintaining Hb in the or antihypertension medications should
patients with CKD—an area of high pri-
range of 10 –12 g/dl (total dose of 88 g) be undertaken as needed. Common side
ority for future research. However, it is
after extending the dosing interval from effects include local pain or tissue reac-
tion to subcutaneous injection and devel- not established whether the benefits of
every other week to once every 4 weeks. improved QOL measures outweigh the
opment of flu-like symptoms within
ciency of renal anaemia therapy in hae- 25. Marathias KP, Agroyannis B, Mavro-
Acknowledgments — This work was sup- modialysis patients receiving intravenous moustakos T, Matsoukas J, Vlahakos DV.
ported in part by National Institutes of Health epoetin. Nephrol Dial Transplant 2005; Hematocrit-lowering effect following in-
Grant 5-K24-DK002818-05. 20(Suppl. 3):iii25–iii32 activation of renin-angiotensin system
R.D.T. serves as an investigator in TREAT, 11. Singh AK, Szczech L, Tang KL, Barnhart with angiotensin converting enzyme in-
an Amgen-sponsored clinical trial seeking to H, Sapp S, Wolfson M, Reddan D, the hibitors and angiotensin receptor block-
reduce end points with Aranesp therapy. No CHOIR Investigators. Correction of ane- ers. Curr Top Med Chem 2004;4:
other potential conflicts of interest relevant to mia with epoetin alfa in chronic kidney 483– 486
this article were reported. disease. N Engl J Med 2006;355:2085– 26. Mohanram A, Zhang Z, Shahinfar S, Lyle
2098 PA, Toto RD. The effect of losartan on Hb
12. Fishbane S, Nissenson AR. The new FDA concentration and renal outcome in dia-
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