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Nephrol Dial Transplant (2007) 22 [Suppl 3]: iii20iii26 doi:10.


OPTA: Optimal treatment of anaemia in patients with chronic kidney disease (CKD)
W. H. Ho rl, Y. Vanrenterghem, P. Aljama, P. Brunet, R. Brunkhorst, L. Gesualdo, I. Macdougall, C. Wanner and B. Wikstro m Introduction
Anaemia is an early complication of chronic kidney disease (CKD). The optimal treatment of anaemia in patients with CKD is of increasing importance, since early and adequate treatment of anaemia may have a positive impact or morbidity and mortality in this patient population. A timely start of anaemia treatment is only partly realized due to different reasons:  In the early stages of CKD, anaemia is nonsymptomatic. Patients adapt to a certain level and to further declining haemoglobin (Hb) levels.  The fact that modest decrements in renal function already lead to a decrease in Hb levels is underestimated, especially outside the nephrology field, e.g. patients with diabetes [1].  In many European countries, patients with CKD are managed by non-nephrologists who are not treating or are not allowed to treat mild anaemia. The referral to nephrologists is late, often too late.  Even under the care of nephrologists, many patients start anaemia treatment too late. Patients are categorized according to their underlying disease, comorbidity and the stage of CKD. Guidelines (EBPG) (5). The Hb levels at which therapy with erythropoiesis-stimulating agents (ESAs) should be initiated, as well as its target Hb level, remain controversial [6]. The EBPG recommend Hb values >11 g/dl, while the K/DOQI clinical practice guidelines and clinical practice recommendations suggest Hb levels between 11 and 13 g/dl [7]. Recent trials recommend a target Hb level between 11 and 12 g/dl in CKD patients [8,9].

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Impact of anaemia in CKD patients

(a) Anaemia in CKD patients is associated with cardiovascular complications. Anaemia has been independently associated with the development of left ventricular hypertrophy (LVH) [1012]. LVH, present in up to 74% of patients at the initiation of renal replacement therapy, is an independent predictor of subsequent cardiac morbidity and mortality [1012]. (b) The presence of anaemia early in end-stage renal disease (ESRD) is also associated with a greater rate of subsequent hospitalizations and mortality [13,14]. (c) The effect of anaemia correction on the progression of CKD is controversial, with some studies showing a positive impact [15], and other studies showing no change in disease progression [16,17]. (d) CKD patients suffering from anaemia have an impaired quality of life, exercise capacity, cognitive and sexual function [18]. (e) Anaemia in CKD patients may increase blood transfusion requirements, and epoetin treatment decreases the number of transfusions [19].

Epidemiology and definitions

In the general population, the mean Hb concentration of healthy individuals is a function of age, gender and iron status. In men, free testosterone levels decrease with advanced age and this may lead to a decrease in Hb. In women, Hb concentrations are lower as compared with men, probably due to lower testosterone levels but not iron deficiency, since transferrin saturation increases with advanced age in both men and women [2]. Anaemia is an early complication of CKD [3]. In the NHANES III study, a statistically significant decrease in Hb was already apparent among men starting at creatinine clearance (CrCl) below 70 ml/min and among women starting at CrCl below 50 ml/min [4]. Anaemia should be investigated and treated as recommended by the European Best Practice

Patient categorization within stages of CKD

Development of anaemia is influenced by inflammation and comorbid conditions. It may be appropriate to distinguish different patient categories that nephrologists usually see during daily practice.

The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email:

OPTA in patients with CKD


Rationale for recommendations 1. Patients with diabetes mellitus display a higher incidence of anaemia in the earlier stages of CKD [2022]. Anaemia development is a continuous process and the overall risk in these patients is two to three times higher as compared with CKD patients with comparable kidney function and similar iron levels but no diabetes mellitus. Lower Hb levels are linked with development or worsening of diabetic complications such as retinopathy [23] and progression of diabetic nephropathy to ESRD [24]. Reduced Hb levels independently identify diabetic patients with an increased risk of microvascular complications, cardiovascular disease and mortality [25]. 2. Anaemia is correlated with symptoms of congestive heart failure, even in patients with preserved renal function and normal ejection fraction [26]. 3. Systemic diseases are characterized by inflammation and elevated serum concentrations of C-reactive protein (CRP). Therefore, patients with systemic vasculitis such as Wegeners granulomatosis or microscopic polyarteritis, as well as patients with systemic lupus erythematosus, display lower Hb levels than other patients with chronic glomerulonephritis but without systemic disease. 4. Elderly patients with CKD are more prone to anaemia. Anaemia magnifies the risk of death in elderly patients with CKD and congestive heart failure [27]. Furthermore, it was shown that elderly patients with CKD and consistent treatment with ESA before dialysis treatment was started, had a lower risk for death in the first year of dialysis [28]. 5. Post-transplant anaemia is common and occurs either early or late after post-transplantatation. Its causation includes mainly impaired kidney function, immunosuppression and iron deficiency [29]. Its prevalence ranges from 20 to 40%, and is related to between-study differences in the definition of anaemia. The use of ESA is low in this patient population (10% of all patients). More than 50% of patients after renal transplantation are in stage 3 of CKD. There is a negative correlation between Hb level and glomerular filtration rate (GFR) also in this patient population. 6. Among the immunosuppressive drugs, mycophenolate mofetil and tacrolimus are associated with a lower haematocrit [30]. The highest prevalence of post-transplant anaemia (57%) has recently been described in sirolimus treated patients [31]. Gene expression of proteins related to erythropoiesis is reduced in transplant recipients during rejection episodes [32]. ESRD patients with a failed kidney transplant exhibit worse anaemia and ESA resistance index [33]. Anaemia may be a risk factor for cardiovascular complications and graft loss in kidney transplant recipients. Incidence, risk factors for, and interrelationships between de novo congestive heart failure, de novo

ischaemic heart disease, and mortality were analysed in 638 consecutive adult renal transplant recipients who were free of cardiac disease at 1 year post-transplant. Age, diabetes, gender, blood pressures and anaemia were identified as independent risk factors for de novo congestive heart failure. Anaemia was not a risk factor for ischaemic heart disease in this patient population [34]. On the other hand, anaemia (Hb <10 g/dl) was neither associated with failure of kidney transplants nor all-cause mortality in 438 kidney transplant recipients 7.8 years after transplantation [35]. Prospective, multicentre trials are needed to clarify this issue. Other patient segments that require specific attention are those with severe cardiovascular disease, as well as those with advanced CKD considered inappropriate for dialysis and treated with palliative care. Even patients with polycystic kidney disease may develop renal anaemia. Treatment of anaemia in CKD patients (a) Status Quo of treatment The Predialysis Survey on Anemia Management (PRESAM) has evaluated anaemia treatment in CKD patients. Although the majority of patients (57%) had been under the care of a nephrologist for more than 12 months before the start of dialysis therapy, most CKD patients were anaemic prior to dialysis (mean Hb concentration 9.5 1.7 g/dl). Only 27% of patients had started ESA treatment before dialysis therapy [36]. Similarly, TRESAM (Transplant European Survey on Anaemia Management) demonstrated that only a minority (10.8%) of anaemic transplant recipients received ESA treatment for their anaemia [37]. In patients with diabetic nephropathy, anaemia associated with erythropoietin deficiency can occur early before the onset of advanced renal failure and does not normally occur in non-diabetic CKD of similar severity. In a study by Bosman et al. (2q0), 13 of 27 diabetic patients were anaemic (Hb 10.6 0.9 g/dl) in contrast to none of the 26 patients with chronic glomerulonephritis (Hb 13.7 1.4 g/dl, P < 0.005) at a similar level of kidney function. (b) Effect of anaemia treatment on progression of CKD and overall outcome Numerous studies have demonstrated that GFR is correlated directly to Hb in both groups of CKD patients. One early study [38] investigated the effect of ESA on different endpoint rates, including cumulative renal survival within untreated anaemic (Hb <10 g/dl), treated anaemic (Hb <10 g/dl) and untreated nonanaemic (Hb >10 g/dl) groups of CKD patients. Partial correction of anaemia improved renal survival rate and reduced renal replacement therapy and allcause mortality [38]. In contrast, Roger et al. [16] found no significant difference in decline of GFR


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maintaining Hb levels at either between 9 and 10 g/dl or between 12 and 13 g/dl in 155 CKD patients with CrCl 1550 ml/min. It should, however, be noted that the rate of progression was very small in both groups of CKD patients. Rossert et al. [17] assessed the effect of early and complete correction of anaemia on the progression of CKD. Patients in the high Hb group (13.0 to 15.0 g/dl) had a lower GFR decrease (0.058 vs 0.081 ml/min/1.73 m2/mo) than the low Hb group (11.0 to 12.0 g/dl) but this difference was not significant. Strippoli et al. [39] performed a systematic review in order to summarize the benefits and harms of lower vs higher Hb targets in the treatment of the anaemia of CKD using existing randomized, controlled trial data. Nineteen relevant trials were indentified. Twelve trials (638 patients) compared use of ESA versus no ESA treatment, and seven trials (2058 patients) compared higher vs lower Hb targets. In the CKD population with cardiovascular disease, Hb values <12.0 g/dl were associated with lower all-cause mortality as compared with Hb values >13.0 g/dl. Hb values of 10.0 g/dl or less reduced the risk of hypertension, but surprisingly increased the risk of seizures. Data from a recent Cochrane Systematic Review demonstrated an improvement in quality of life and exercise capacity in predialysis CKD patients receiving ESA therapy [40]. Volkova and Arab [41] undertook a systematic review to investigate, anaemia and mortality in dialysis patients and confirmed a consist trend toward increased mortality with decreasing Hb levels. The Cardiovascular Reduction Early Anemia Treatment Epoetin Beta (CREATE) trial tested the hypothesis that early correction of anaemia may provide cardiovascular protection. In CKD patients with an estimated GFR of 15.035.0 ml/min, a target Hb value in a range between 13.0 and 15.0 g/dl did not decrease the incidence of cardiovascular events as compared with CKD patients with a target Hb value in a range between 10.5 and 11.5 g/dl [8]. In the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial, a target Hb value of 13.5 g/dl in CKD patients was associated with a significant higher incidence of composite endpoint cardiovascular events and mortality, without improvement in the quality of life as compared with a target Hb value of 11.3 g/dl. Therefore, a target Hb value of 11.0 to 12.0 g/dl in patients with CKD was recommended [9]. A number of clinical trials were design to test whether correcting anaemia can reverse LVH. Data obtained from mainly small and uncontrolled studies suggestd that correcting anaemia led to partial LVH regression but larger randomized trials failed to confirm that higher Hb levels (>13 g/dl) result in significant positive effects [14,42,43]. Parfrey et al. [44] carried out a randomized, double-blind trial to compare lower and higher Hb targets (9.511.5 g/dl vs 13.414.5 g/dl) in 596 incident haemodialysis patients without symptomatic cardiac desease or LV dilation. After a 74 week follow-up period, the change in LV index was not different between the two groups.

Mortality was also not different but the patients in the higher target group experienced a higher number of cerobrvascular disorders [44]. Furuland et al. [45] were unable to demonstrate a significant reduction in mortality after Hb normalization in pre-dialysis and dialysis patients. No cardiovascular benefit was found in a study by Rossert and coworkers [17] that compared treatments with a higher target Hb level [13.015.0 g/dl] to a lower target level [11.012.0 g/dl].

Parameters and conditions that need to be monitored in anaemic CKD patients CKD patients are prone to develop anaemia also because of other conditions and deficiencies that should be monitored and corrrected. Table 1 lists parameters and suggested intervals for monitoring. However, a number of drawbacks and uncertainties need to be discussed: 1. Proteinuria is an important marker in the progression of CKD but a link to anaemia has not been demonstrated so far. 2. Hsu et al. [46] studied the percentage of iron deficiency in a group of CKD patients. When criteria were used that are valid in dialysis patients, only a minority of CKD patients fulfilled these criteria. 3. PTH is related to anaemia in haemodialysis patients, but whether PTH plays a similar role in predialysis CKD patients has not been investigated so far. 4. Malnutrition may be a factor of anaemia, and nutritional supplementation in CKD patients improves the response to ESA therapy [47].
Table 1. Parameters and conditions that need to be monitored in CKD patients, in relation to their anaemia management Major factors  Kidney function by estimation of GFR  Proteinuriaa  Haemoglobinb  Iron statusc  C-reactive protein (CRP)d Minor factors  Parathyroid hormone (PTH)e  BMI and nutrition status (SGA)f  Screen for blood loss or haemolysisg  Serum B12 and folate levels  Haemoglobinopathies 24 h or spot urine protein/creatinine. Monitor at every visit, including white cell and platelet count. Ferritin and transferrin saturation; distinguish absolute or functional iron deficiency at 3-monthly intervals or according to stages of CKD. d Monitor at every visit, preferably high sensitivity CRP. e Monitor PTH twice a year (under specific conditions and stages of CKD every 3 months). f Determine BMI (body mass index) and SGA (subjective global assessment). g Order a Coombs test for diagnosis of autoimmune haemolysis if appropriate.
b c a

OPTA in patients with CKD


5. Haemoglobinopathy needs to be excluded in certain ethnic groups, for example Mediterranean populations (Southern Italian and Greek populations) or African-Americans. Major and minor treatment-influencing factors Oral iron is often not well-tolerated, although a certain proportion of patients may respond to it. The choice of intravenous iron administration might be based on the quantity of iron needs to obtain or maintain adequate Hb levels [48]. With respect to specific aspects in inflammation and infection, the workgroup refers to the OPTA Influence of Inflammation/Infection on Anaemia in Haemodialysis Patients recommendations (Table 2). Management of major treatment-influencing factors Iron. In PRESAM, the majority of predialysis CKD patients (60%; n 1997) had either absolute or functional iron deficiency (as determined by ferritin level and transferrin saturation), including those starting ESA treatment (59%; n 1652) [36]. The survey also showed that mean Hb values of 11.0 g/dl or less (<11 g/dl) at the start of dialysis therapy were observed regardless of whether patients were treated with ESA or not. In patients requiring iron treatment, the majority of studies showed that intravenous iron supplementation is more effective than oral iron therapy. If the ferritin is very low, iron should be administered intravenously [48]. Inflammation and infection. If the CRP level is significantly elevated, then potential sources of infection or inflammation (e.g. diabetic foot ulcers, connective tissue disease, chronic allograft
Table 2. Anaemia treatment-influencing factors according to impact Major  Iron deficiency and treatment with iron  Inflammation and overt infectiona  Underlying disease and co-morbidityb  Chronic allograft nephropathy (CAN) immunosuppression Minor  Age and gender  BMI and nutrition  Concomitant medicationc  Malignancies (recurrent and de novo)  Occult blood loss and haemolytic anaemiad  Hyperparathyroidism  Vitamin B12 and folate deficiency  Hypothyroidism  Haemoglobinopathy i.e. diabetic ulcers or cyst infection in patients with polycystic kidney disease. b i.e. vasculitis, chronic inflammatory conditions, congestive heart failure or fluid overload. c Angiotensin-converting enzyme inhibitors angiotensin-II receptor blockers, and non-steroidal anti-inflammatory drugs (NSAIDs). d Order a Coombs test.

nephropathy) should be investigated. Inflammation and infection may cause hyporesponsiveness to ESA therapy, and these conditions should be corrected whenever possible. In summary, anaemia is underestimated and undertreated in CKD patients. The development of anaemia differs among patients with various underlying diseases, comorbidity or stages of CKD. The effect of anaemia treatment on survival or progression of CKD remains controversial. Currently it seems wisest to refrain from complete correction of anaemia in patients with CKD [6]. Effects of ESA therapy at a cellular level Early data showed that ESA increases vascular resistance and resistance to the vasodilatory action of nitric oxide via impact on calcium influx in vascular smooth muscle cells. ESA also has autocrine or paracrine actions, for example on the brain [49]. It increases the number of circulating erythrocytes primarily by preventing apoptosis of erythroid progenitors. In vitro, ESA prevents neuronal apoptosis. Results of recent studies show that systemically administered ESA is neuroprotective in vivo [50]. ESA stimulates angiogenesis. The number of circulating stem cells (CD34 cells) increased with low doses of ESA treatment in haemodialysis patients. Endothelial progenitor cell proliferation and differentiation is also regulated by ESA [51,52]. In vivo pleiotropic renoprotective actions of ESA. Several in vivo investigations have shown that ESA can reduce the renal dysfunction and injury caused by oxidative stress, hypoxia and haemorrhagic shock, generally by reducing caspase activation and apoptotic cell death [5260]. Bahlmann et al. [51] investigated whether low-dose subcutaneous ESA could protect against renal dysfunction and injury in rats with induced chronic renal failure (5/6 nephrectomy). Given once weekly, the drug improved renal function and reduced histological evidence of renal injury. Treated rats also had greater weight gain than controls, with no change in systemic blood pressure. The drug did not increase packed-cell volume and it improved survival (mortality 63% vs 33%). ESA persistently activated the prosurvival Akt (protein kinase B) pathway in endothelial and glomerular cells throughout the experimental period, which was accompanied by reduced apoptotic death of cells. The study suggests that epoetin can ameliorate chronic as well as acute renal failure. Clinical trials will be needed to confirm these renoprotective effects in man. However a phase II trial with ESA in patients with acute ischaemic stroke yielded promising results [61]. Potential areas for renoprotection are donor kidneys before transplantation or clamping of the renal arteries during surgery for aortic aneurysms [53,57]. The discovery of ESA receptors in the renal





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tubule, suggesting non-haemopoietic roles for ESA in the kidney, such as mitogenesis, supports that idea [62]. The reduction of oxidative stress in acute model of ischaemia by ESA, as well as its proangiogenic actions could probably reduce oxidative stress and ameliorate vascular dysfunction with chronic renal failure. All these pleiotropic actions, seen at subtherapeutical ESA doses, must be separated from the haemopoietic properties occurring at clinical doses [63]. An all-purpose tissue-protective effect of epoetin has recently been discussed by Savino and Ciliberto [64]. Other erythropoietin analogues Increasing the plasma levels of ESA will facilitate their haemopoietic actions and, possibly, unwanted effects. Novel analogues of ESA that are devoid of haemopoietic activity but are still renoprotective have been developed [65]. Asialoerythropoietin has neuroprotective properties and reduces tissue injury in models of cerebral ischaemia, spinal-cord compression, and sciatic nerve crush-injury [66]. Asialoerythropoietin is as neuroprotective as an equivalent dose of ESA in 7-day-old neonatal rats when given 4 h before hypoxiaischaemia [67]. This protection was obtained without increasing packed-cell volumes in mice and rats, possibly due to the shorter half-life in plasma of asialoerythropoietin than that of ESA [65]. Carbamylated ESA analogues are even more interesting because they do not bind to the classical ESA receptor yet protect against stroke, spinal-cord injury, and diabetic neuropathy as well as ESA but without haemopoietic activity [61]. The ability of such ESA analogues to reduce ischaemic injury of other organs and to ameliorate renal failure awaits investigation. So far, the renoprotection induced by ESA and its analogues remains experimental.

CKD patient categories with (a) (b) (c) (d) (e) diabetes mellitus congestive heart failure diseases e.g. vasculitis, lupus erythematosus advanced age kidney transplantation

are at high risk for anaemia development and should receive a greater level of attention.

1. If Hb level is <11 g/dl, other factors that may contribute to anaemia should be excluded before initiating ESA therapy. 2. Iron status should be measured and any deficiency corected before ESA is given. Pending further evidence, the EBPG for dialysis patients should be applied to pre-dialysis CKD patients. 3. Patients with absolute iron deficiency should be treated with intravenous iron administration, at least at the start of ESA therapy. 4. ESA therapy should be started when the Hb level is below 11 g/dl [5].

The pleiotropic effects of ESA observed in low doses, not relevant for the haemopoetic activity, and evaluated so far at cellular levels, offer probably new areas of renoprotection in acute and chronic renal failure and also during renal ischaemia.

References Recommendation
Because anaemia is an early complication of CKD, patients with a GFR <60 ml/min/1.73 m2 should have their Hb level checked, and if found to be low then their anaemia should be further investigated and treated, as recommended by international guidelines [5,7]. Recent trials suggest a target Hb level between 11 and 12 g/dl in CKD patients [8,9].
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1. Anaemia should be treated CKD patients in order to achieve the benefits of increased exercise capacity, quality of life, cognitive and sexual function, as well as a reduction in transfusion requirements and hospitalizations. 2. Whenever possible, blood transfusions should be avoided in order to minimize the risk of HLA sensitization.

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