However, some studies suggest that other factors i. The mechanism of anemia in nephrotic syndrome is complex and involves both inflammatory-mediated mechanisms as discussed above as well as absolute iron deficiency. Iron excretion increases in early stages of kidney disease in patients with diabetes and albuminuria and is exacerbated by development of nephrotic-range proteinuria.
In nephrotic syndrome, many nonalbumin proteins are excreted in the urine, including transferrin and erythropoietin. Significant losses of transferrin and erythropoietin can occur in nephrotic syndrome, leading to both iron- and erythropoietin-deficiency—caused anemia in patients with diabetes Evidence for increased transferrin catabolism in nephrotic syndrome may contribute to iron deficiency—caused anemia Decreased erythropoietin production, secretion, and hyporesponsiveness can contribute to anemia in nephrotic patients.
See above. Both of these drug classes may cause a reversible decrease in Hb concentration in patients with diabetes and CKD The mechanisms by which ACE inhibitors and angiotensin receptor blockers lower Hb include a direct blockade of the proerythropoietic effects of angiotensin II on red cell precursors, degradation of physiological inhibitors of hematopoiesis, and suppression of IGF-I. Importantly, this effect does not diminish the renoprotective effect of losartan.
It should be recognized that these classes of agents may induce or worsen symptomatic anemia in nephropathy patients Anemia is an important cause of physical and mental impairments in diabetic CKD patients including malaise, fatigue, weakness, dyspnea, impaired cognition, and other symptoms. Clinical trials indicate that improving anemia improves cognitive function, sexual function, general well-being, and exercise capacity and reduces the need for blood transfusions 6 , 8 — 10 , 27 There is renewed evidence of anemia in diabetes contributing to retinopathy, neuropathy, diabetic foot ulcer, hypertension, progression of kidney disease, and cardiovascular events In general, kidney disease in diabetes is progressive, and it has been hypothesized that anemia may contribute to progression of kidney disease 7 , 16 , 28 , Possible mechanisms include renal ischemia caused by reduced oxygen delivery due to low Hb and underlying heart failure.
For example, anemia may worsen renal medullary hypoxia, leading to renal interstitial injury and fibrosis 30 , It is upregulated by renal hypoxia and induces collagen gene expression in renal fibroblasts, thereby increasing interstitial fibrosis. Anemia may also increase renal sympathetic nerve activity, resulting in increased glomerular pressure and proteinuria which in turn may accelerate progression of kidney disease , and contribute to worsening kidney function by exacerbating underlying heart failure—a common complication in patients with diabetes and kidney disease, Early animal model studies in renal ablation, hypertension, and diabetes demonstrated that treatment of anemia worsened systemic and glomerular hypertension and renal structural and functional damage, suggesting that anemia may actually be renoprotective 32 , Recently, Nakamura et al.
However, in clinical trials, erythropoietin has not yet been proven to slow kidney disease progression in patients with diabetes and nephropathy. Observational studies indicate that death is five times more likely than progression to end-stage kidney disease in patients with CKD Moreover, cardiovascular disease is the most common cause of death in patients with diabetes and CKD; and anemia appears to be a risk multiplier for all-cause mortality among those same patients.
Anemia prevalence is up to fold higher among diabetic patients with CKD and heart failure and is a modifiable risk factor among diabetic patients 36 , Low Hb concentration is an independent risk factor for left-ventricular hypertrophy, heart failure, and cardiovascular mortality 37 — Heart failure is common in diabetic patients with nephropathy and may result in reduced renal blood flow, thereby contributing to further reduction in GFR and erythropoietin production.
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Also, anemia may aggravate tissue hypoxia, and subsequently heart failure, resulting in further renal sodium retention, volume expansion, increased venous return, and increased venomotor. For these reasons, treatment of anemia in patients with diabetes and CKD is a proposed strategy to reduce excessive cardiovascular morbidity and mortality.
It is important to note that none of the published trials examining the safety and efficacy of ESA for anemia treatment included a placebo control group. With one exception 45 , all study subjects with varying Hb levels were treated with an ESA. Several small trials in patients with CKD, including those with diabetes, demonstrated a beneficial effect on kidney disease progression.
Kuriyama et al. Those with anemia were randomized to ESA treatment or no treatment. The time to a doubling of serum creatinine from baseline was the study's primary end point. They found that time to doubling of serum creatinine was significantly longer in the treated group than in the nontreated group and similar to that in the nonanemic control subjects Gouva et al.
They found that early correction of anemia was associated with improved renal and patient survival compared with delayed treatment of anemia. Rossert et al. Although the decline in GFR was numerically less in the high-Hb group, this difference was not statistically significant. Still, those randomized to the high group showed improvement in QOL and vitality However, the two largest trials to date to examine the effect of ESA on progression of kidney disease as a secondary outcome did not show any renal benefit of raising Hb to a higher level.
Roger et al. They found no difference in the primary outcome of left-ventricular wall thickness; however, those assigned to the higher Hb arm of the study experienced improvement in QOL. Levin et al. The primary outcome was the change in left-ventricular mass index. Despite significant difference in Hb level between groups, they found no significant difference in left-ventricular mass index.
Randomized controlled cardiovascular outcome trials of anemia treatment with erythropoietin-stimulating agents in patients with chronic kidney disease. Ritz et al.
The primary outcome was the change in left-ventricular mass index, and secondary outcomes included kidney function and QOL. There were no significant differences in left-ventricular mass index in those randomized to the higher target; however, QOL measures were significantly better in the higher Hb arm. There were no differences in kidney function decline and no significant differences in adverse events Singh et al. During the trial, Hb levels were significantly higher in those randomized to the higher Hb arm.
The composite event rate was higher in those assigned to the higher Hb arm; however, there was no difference in the rate of development of ESRD. Also, in contrast to the results of other studies, there was no improvement in QOL in those randomized to the higher target. The authors concluded that use of a target Hb level of Post hoc analysis demonstrated that a higher fraction of patients in the higher Hb arm had prior coronary events, hypertension, and dropout prior to an event or completion of the study. Subjects were randomized to an Hb target range of 11— They found no significant differences in the primary composite outcome, but there was a trend toward a higher event rate in the higher Hb arm.see
In addition, multiple QOL measures were significantly improved in those randomized to the higher Hb arm. Post hoc analysis demonstrated that the study was underpowered to detect a difference in the primary outcome variable as a result of the lower-than-expected overall event rate in both arms of the study. The increased risk for adverse outcomes during ESA treatment of anemia in clinical trials of patients with CKD is not completely understood.
One possibility is that higher Hb increases risk for thrombosis. Another possibility is that those who experience adverse cardiovascular events have higher comorbidity, are relatively resistant to erythropoietin, and require higher doses of ESA to achieve higher Hb and that the higher doses of ESA are vasculotoxic Further studies are needed to determine whether higher doses versus resistance to action of ESA cause harm in anemic patients with CKD. The primary outcome is a composite of all-cause mortality and cardiovascular morbidity.
This ongoing trial is unique in many respects, including the double-blind, placebo-controlled design; the population of exclusively anemic patients with type 2 diabetes and CKD; and a large sample size. This study will add important new information concerning benefits and risks of ESA treatment of anemia in patients with diabetes and CKD.
Results are expected in In summary, two clear messages emerge from the anemia treatment trials.
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The NKF clinical practice guidelines for diagnosis and management of anemia in patients with CKD recommend a routine history and physical examination, a complete blood count, a reticulocyte count, evaluation of serum iron and total iron binding capacity and serum ferritin level, and a fecal test for occult blood for evaluation of anemia 13 , Additional tests to evaluate anemia should be guided by this initial evaluation e. Despite the high prevalence of anemia in the CKD population, treatment with erythropoietin or iron often is not used in the predialysis period.
In addition, the NKF recommends that treatment should be individualized, taking into account patient characteristics including symptoms, Hb level, and evaluation for other causes of anemia. If the initial evaluation indicates absolute iron deficiency as the cause, treatment with supplemental iron and a search for the cause of iron loss should be undertaken. Importantly, ESA-treated patients should, in general, receive iron to ensure that adequate stores are available for erythropoietic response Manufacturers of ESA accordingly added black box warnings noting these recommendations Whereas there is agreement that ESAs are valuable for treating anemia, they differ with regard to the level of Hb at which to initiate ESA and the upper limit of the Hb target.
Further studies on the safety of ESA use in the diabetes population, as well as efforts to better understand the explanation for the association of higher Hb with worse cardiovascular outcomes reported in clinical trials, are needed. The first step in the management of anemia is evaluating the underlying cause.
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See above on diagnosis and evaluation. If absolute iron deficiency is present, the patient should be put on oral or intravenous iron therapy. Several oral iron preparations are available for treatment including ferrous gluconate, fumarate, and sulfate. Doses of — mg of one of these agents three times daily can increase the Hb level significantly in such patients.
Notably, significant gastrointestinal side effects may lead to poor adherence and compliance with oral iron. An alternative is to administer intravenous iron on a periodic basis. Several studies indicate that these preparations are effective and safe in predialysis populations 11 , 54 , Dahdah et al. Significant increases in Hb occurred within 2 weeks; all patients tolerated infusions without serious adverse reactions. Intravenous iron preparations including ferric sodium gluconate, iron sucrose, and iron dextran are available and can be administered safely.
Among these agents, iron dextran has been associated with the highest incidence of adverse reactions, although the incidence of such reactions is low with all three preparations. Although some studies indicate that intravenous iron is in general more efficacious than oral iron for achieving increases in Hb in patients with CKD, oral iron is also effective Moreover, no definite advantages have been shown with intravenous versus oral iron in patients with CKD not on dialysis Darbepoetin can be administered subcutaneously every other week at outset and then administered once monthly to maintain Hb target.
Ling et al.
Provenzano et al. Extended dosing of short- and long-acting ESA, including the hematopoietic and adverse effects, has recently been reviewed In clinical practice, darbepoetin is often administered every other week initially, until the Hb target is achieved, before extending dosing to every 4 weeks. Extended dosing may require an increase in dose 27 , Patients should be evaluated for improvement in symptoms including fatigue, vitality, physical functioning, and cognitive function.
Initially, Hb level should be measured every other week to monitor the hematopoietic response and monthly thereafter. In most patients, increases or decreases in ESA dose should not be made more frequently than monthly. Functional iron deficiency should be suspected in any patient not responding to ESA treatment, and patient compliance with iron therapy should be investigated.
CAUSES OF ANEMIA
Routine measurement of iron stores including serum iron, iron binding capacity, and ferritin should be monitored monthly for 3 months then quarterly once Hb target is achieved 56 , The gene for erythropoietin is located on chromosome 7 and is regulated by HIF. HIF molecules are composed of an alpha subunit, which is unstable at high Po 2 , and a beta subunit, constitutively present in the nucleus.
In hypoxic conditions, the HIF dimer is transcriptionally active and binds to specific DNA recognition sequences called hypoxia-response elements. Gene transcription is upregulated, leading to increased production of erythropoietin. Under normal oxygen tension, on the other hand, the proline residue of the HIF alpha subunit is hydroxylated. The hydroxylated HIF alpha subunit is then degraded by proteasomal ubiquitylation, which is mediated by the von Hippel-Lindau tumor-suppressor gene pVHL.
HIF therefore cannot bind to the hypoxia-response elements, and erythropoietin gene transcription does not occur. Thus, in states of hypoxia, erythropoietin production is upregulated, whereas with normal oxygen tension, production is downregulated.