AJKD
VOL 48, NO 4, OCTOBER 2006
American Journal of Kidney Diseases
REVIEW
Anemia After Renal Transplantation Behdad Afzali, MRCP, Salam Al-Khoury, MD, Nilesh Shah, MD, Ashraf Mikhail, MRCP, Adrian Covic, MD, PhD, and David Goldsmith, FRCP ● Anemia in the setting of chronic kidney disease is a well-recognized phenomenon that is associated with decreasing renal function and deficiency of or resistance to erythropoietin. However, anemia in the post–renal transplantation setting has received comparatively less attention in the literature. In this review, we aim critically to appraise the available literature regarding posttransplantation anemia, concentrating in particular on the prevalence of posttransplantation anemia, its etiopathogenesis, potential effects on morbidity and mortality, and the rationale for intervention and treatment. Despite deficiencies in the literature, we conclude that posttransplantation anemia is a common phenomenon that can occur either early or late posttransplantation, and its causation is usually multifactorial and includes contributions notably from poor or decreasing renal function, immunosuppression, and iron deficiency. Conversely, there is a shortage of well-conducted prospective studies looking at the morbidity attributable to posttransplantation anemia and a lack of trial evidence to determine whether intervention improves patient morbidity and outcome. Am J Kidney Dis 48:519-536. © 2006 by the National Kidney Foundation, Inc. INDEX WORDS: Anemia; renal transplant; renal function; immunosuppression; erythropoiesis-stimulating agents.
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HE KIDNEY DISEASE OUTCOMES Quality Initiative (KDOQI) classified chronic kidney disease (CKD) into stages 1 to 5 based on estimated glomerular filtration rate (eGFR). CKD stage 1 is defined as normal GFR (⬎90 mL/min [⬎1.5 mL/s]) with urine findings, structural abnormality, or a genetic trait pointing to kidney disease. CKD stages 2, 3, 4, and 5 are defined on the basis of decreasing GFR (69 to 89, 30 to 59, 15 to 29, and ⬍15 mL/min [1 to 1.48, 0.5 to 0.98, 0.25 to 0.48, and ⬍0.25 mL/s], respectively). Anemia in the context of CKD is a wellrecognized phenomenon associated with worsening renal function.1 The presence of anemia contributes to many of the symptoms concomitant with uremia, and its treatment is a central part of the management of patients with CKD.2-4 Anemia in this setting usually is a result of erythropoietin (EPO) deficiency, resistance to EPO, iron deficiency (either absolute or functional), and/or blood loss. The development and persistence of anemia in patients with CKD is associ-
ated with poorer quality of life; decreased exercise tolerance, mental agility, and renal and cardiac function; increased hospitalization; and decreased survival on dialysis therapy.5-7 Consequently, since the advent of erythropoiesisstimulating agents and parenteral iron formula-
From the Department of Nephrology and Transplantation, Guy’s Hospital, London; Renal Unit, Morriston Hospital, Swansea, Wales, UK; and Parhon Hospital, Iasi, Romania. Received February 7, 2006; accepted in revised form July 6, 2006. Originally published online as doi:10.1053/j.ajkd.2006.07.006 on September 4, 2006. Support: None. Potential conflicts of interest: B.A. and D.G. have received educational funding from Roche, and D.G. has given remunerated lectures on behalf of Roche. Address reprint requests to David Goldsmith, FRCP, Consultant Nephrologist, Renal Unit, 6th Floor, New Guy’s House, Guy’s Hospital, London SE1 9RT, UK. E-mail:
[email protected] © 2006 by the National Kidney Foundation, Inc. 0272-6386/06/4804-0001$32.00/0 doi:10.1053/j.ajkd.2006.07.006
American Journal of Kidney Diseases, Vol 48, No 4 (October), 2006: pp 519-536
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tions, by the time patients start renal replacement therapy, the use of iron supplementation8 coupled with erythropoiesis-stimulating agents is very common.6 Nevertheless, despite demonstrable benefits derived from correcting anemia9-12 and the advocacy of widely available and respected best practice guidelines,6 the prevalence of anemia in dialysis patients is not as low as one would expect. This phenomenon can be explained in part by the cost of erythropoiesisstimulating agents, delayed start of therapy (eg, through late recognition of CKD), and resistance to erythropoiesis-stimulating agents (eg, hyperparathyroidism, hematinic deficiency, and chronic inflammation). The development of anemia in the setting of renal transplantation (posttransplantation anemia), in contrast to that in the CKD and dialysis populations, has received far less attention in the literature. Before the widespread use of erythropoiesis-stimulating agents, most renal transplant recipients were anemic in the early postengraftment period because of preexisting anemia exacerbated by perioperative blood loss. With restoration of endogenous EPO secretion by the allograft, which occurs hours after successful engraftment, there was at least partial correction of anemia during the next 6 months. However, posttransplantation anemia has not disappeared after widespread use of erythropoiesis-stimulating agents. To some extent, this issue has been “overlooked” by the transplant community (as, it also may be argued, have been other sequelae of transplantation, such as dyslipidemia and hypertension), whose focus historically has been prevention of rejection and achievement of good renal function. However, continuing improvements in 1-year allograft and patient survival rates and allograft “half-life” have brought about a shift in emphasis, with greater importance on control of various cardiovascular risk factors relevant to survival of renal transplant recipients.13 This new emphasis is supported strongly by the fact that the most common cause of allograft loss is death (mostly cardiovascular) of patients with functioning allografts, and also the realization that “cardiovascular” risk factors are very relevant to the second most common cause of allograft loss, chronic allograft nephropathy (CAN).14
AFZALI ET AL
The purpose of this review is critically to appraise the literature regarding posttransplantation anemia by using recently published reports to focus on causation, potential morbidity, and the rationale for intervention to correct anemia in this clinical context. For this purpose, a thorough search of PubMed was conducted, and all relevant articles were obtained and read. HOW COMMON IS POSTTRANSPLANTATION ANEMIA?
Before discussing prevalence, it is necessary to state the obvious; the prevalence of anemia depends critically on its definition. It is surprisingly diverse in the literature. The World Health Organization (WHO) defines anemia as a hemoglobin level less than 13 g/dL (⬍130 g/L) in men and less than 12 g/dL (⬍120 g/L) in women (ie, any hemoglobin values less than sex-determined normal ranges, irrespective of age and menopausal status).15 This definition is disparate to the KDOQI16 and United Kingdom Renal Association17 criteria of hemoglobin level less than 12 g/dL (⬍120 g/L) in men and postmenopausal women and less than 11 g/dL (⬍11 g/L) in menstruating women. To add a layer of complexity, the Revised European Best Practice Guidelines define anemia as a hemoglobin level 2 SDs less than the population mean, ie, less than 11.5 g/dL (⬍115 g/L) in adult women, less than 13.5 g/dL (⬍135 g/L) in adult men, and less than 12.0 g/dL (⬍120 g/L) in adult men older than 70 years. With the evident heterogeneity in defining anemia, it is no surprise that there is great discrepancy in the literature with regard to the actual prevalence of posttransplantation anemia. In a sense, what you measure is how you measure it. One additional level of complexity that leads to disagreement between studies aimed at quantifying posttransplantation anemia is the time at which measurements of hemoglobin are obtained; as already mentioned, anemia in the period shortly after engraftment tends to be fairly universal (this concept of “early” [compared with “late”] posttransplantation anemia is elaborated on later). That is, what you measure is not only how you measure it, but also when you measure it. Nevertheless, a number of epidemiological studies attempted to quantify the prevalence of post-
ANEMIA AFTER RENAL TRANSPLANTATION
transplantation anemia (Table 1). Among these, the TRansplant European Study on Anemia Management (TRESAM) Study was a cross-sectional survey using a questionnaire-based analysis from 72 transplant centers in 16 countries involving 4,263 patients who had received a transplant 6 months or 1, 3, or 5 years earlier. Information was gathered in 2000 and 2001.18 Defining anemia as a hemoglobin level less than 13 g/dL (⬍130 g/L) for men and less than 12 g/dL (⬍120 g/L) for women, the investigators reported a prevalence of anemia of 38.6% at enrollment. Although 8.5% of subjects were severely anemic (defined as hemoglobin ⬍ 11 g/dL [⬍110 g/L] for men and ⬍10 g/dL [⬍100 g/L] for women), only 17.8% were treated with an erythropoiesisstimulating agent. Mean hemoglobin level in patients administered an erythropoiesis-stimulating agent was 11.1 ⫾ 2.0 g/dL (111 ⫾ 20 g/L) compared with patients not administered an erythropoiesis-stimulating agent (13.1 ⫾ 2.1 g/dL [131 ⫾ 21 g/L]; P ⬍ 0.05). Severely anemic patients administered EPO had a better (WHO) performance score than those not treated.18,19 Other studies also confirmed the high prevalence of anemia reported by TRESAM, although there are expected differences in the actual figures dependent on the definition of anemia used and the time observations were made. In a prospective study, Moore et al20 found anemia (defined as hematocrit ⬍ 38% in men and ⬍ 35% in women) in 80% of their subjects 2 weeks after transplantation. At 1 year of follow-up, this figure decreased to 29%. Using different thresholds for defining anemia (hemoglobin ⬍ 11 g/dL [⬍110 g/L] for women and ⬍ 12 g/dL [⬍120 g/L] for men), Shibagaki and Shetty21 reported a 20% prevalence of severe anemia in a series of 192 transplant recipients. Similarly, Mix et al22 studied 240 renal transplant recipients and found hematocrits less than 36% (corresponding to hemoglobin level of about ⬍12 g/dL [⬍120 g/L]) in 76% of patients at the time of transplantation and 21% and 36% at 1 and 4 years postengraftment, respectively. In addition, they reported a surprising lack of investigation and intervention; even in subjects with a hematocrit less than 30%, only 46% had undergone any investigation for iron repletion status and only 40% had been prescribed an erythropoiesisstimulating agent.22 The magnitude of the prob-
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lem is confirmed by the publication of Lorenz et al,23 primarily a study of iron status post–renal transplantation. They reported a figure as high as 39.7% for anemia in their cohort of 438 engrafted individuals by using WHO criteria,23 similar to the 34% in the recent report of Molnar et al24 (again using WHO criteria). In children, anemia after renal transplantation also appears to be more common than might have been imagined (for a comprehensive review, see25). For example, a cross-sectional analysis26 of 50 pediatric transplant recipients observed a mean hemoglobin level of 11.0 g/dL (110 g/L) and anemia prevalence of 60% (defined as hemoglobin ⬍ 11 g/dL [⬍110 g/L] for children aged 2 to 6 years, ⬍11.5 g/dL [⬍115 g/L] for those aged 6 to 12 years, and ⬍ 12 g/dL [⬍120 g/L] for children ⬎ 12 years). The study of Yorgin et al27 suggested an even greater prevalence of 64% to 82% in pediatric subjects from 1 to 5 years posttransplantation. Taking all these (and many other) studies together and allowing for the caveats invoked earlier, it is likely that approximately one third of transplant recipients are anemic at any one time. Taking the transplant recipients’ clinical journey, it is likely that up to two thirds of transplant recipients are anemic at some stage. It also appears that investigation and intervention are not (yet) the norm. CAUSE OF POSTTRANSPLANTATION ANEMIA
A useful construct for considering anemia in the posttransplantation setting is to divide it into anemia that develops early (in the first 6 months) and that which develops late (after the first 6 months) postengraftment. Although considerable overlap occurs, this distinction is important when considering causes for posttransplantation anemia because certain risk factors are more likely to have a part at some times than at others. Table 2 lists the many potential causes of posttransplantation anemia by cause. As can be seen, some factors are shared with patients with CKD who did not undergo transplantation (such as impaired kidney function, iron and nutrient deficiency, infection, inflammation, blood loss, and medications [eg, angiotensin-converting enzyme (ACE) inhibitors]), whereas others are unique to transplant recipients (eg, rejection episodes, immunosuppressive drugs, antivirals, antibiot-
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Table 1. Prevalence and Predictors of Posttransplantation Anemia No. of Patients
Author
Publication
Vanrenterghem et al
Am J Transplant 3:834845, 2003
4,263
Shibagaki et al
Nephrol Dial Transplant 19:2368-2373, 2004
Mix et al
Mean Hemoglobin (g/dL)
Summary of Findings
Commentary
13.2 ⫾ 1.9 at 5 y
Cross-sectional survey; 38.6% anemia prevalence at enrollment; 9% with severe anemia. Strong negative association between hemoglobin level and poor graft function. Treatment with ACE inhibitors/ARBs, MMF, and AZA also associated with higher likelihood of anemia. Very low prevalence of erythropoiesis-stimulating agent use.
192
13.0 ⫾ 0.1 at 1 y
Am J Transplant 3:1426-1433, 2003
240
Mean hematocrit, 38% at 60 mo
Kausman et al
Pediatr Nephrol 19:526-530, 2004
50
Shah et al
Transplantation 81:1112-1118, 2006
Karthikeyan et al
Am J Transplant 4:262269, 2004
20% of patients had severe anemia at 6 mo and 1 y. Multivariate analysis showed serum creatinine as strong independent risk factor for anemia. AfricanAmerican race was a risk factor at 6 mo, and female sex, at 1 y. Only 36% of anemic patients had iron indices checked in the first year posttransplantation. 76%, 21%, and 36% prevalence of anemia (hematocrit ⬍ 36%) at transplantation and 1 and 4 y posttransplantation. Female sex was a risk factor, but diabetes was not. Only 36% had iron studies; 46% administered iron supplement, and 40%, erythropoiesis-stimulating agent. 60% overall prevalence of anemia; 30% severe anemia. High prevalence of iron deficiency (34%). Tacrolimus therapy and serum creatinine were significant independent predictors of anemia. ACE inhibitors were not associated with anemia. 45% prevalence of anemia, but only 145 administered erythropoiesis-stimulating agents. Age, female sex, renal function, serum ferritin, and ACE-inhibitor therapy were independent predictors of anemia. Renal function was the greatest predictor of anemia. CKD present in 412 subjects. Prevalence of anemia increased from 0% in stage 1 to 33% in stage 5. Low ferritin (⬍100 ng/mL) in 50% of patients in CKD stages 3-5, but 0% in stage 1.
TRESAM Study of prevalence of posttransplantation anemia; largest study of its kind; 5-y follow-up data; showed very low erythropoiesis-stimulating agent use despite high prevalence of anemia; lacking data pertaining to iron status Single-center study, 1-y follow-up data
1,151
459
11.0 (range, 62-154)
12.9 ⫾ 1.6
14.2 ⫾ 1.6 at stage 1 to 11.7 ⫾ 1.1 at stage 5
Retrospective cohort study with 4-y follow-up data; showed poor investigation and treatment of posttransplantation anemia Pediatric study; cross-sectional design; age-specific definitions of anemia
3 Centers; cross-sectional design
NOTE. Hemoglobin expressed as mean ⫾ SD unless otherwise stated. Key publications studying the prevalence and predictors of anemia after renal transplantation are presented. To convert hemoglobin in g/dL to g/L, multiply by 10.
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Predominantly CKD study in transplantation; cross-sectional design; only 60% of patients with anemia had iron indices measured
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Table 2. Causes of Posttransplantation Anemia Early Generalized bone marrow suppression Immunosuppressants: AZA, MMF, sirolimus Antibacterials/antivirals: chloramphenicol, ganciclovir, trimethoprim-sulfamethoxazole Viral infections: CMV, Epstein-Barr virus, human immunodeficiency virus, human parvovirus B19 PRCA Drug related: AZA, MMF, tacrolimus, ACE inhibitors Infection related: parvovirus B19 Hemolytic uremic syndrome/hemolytic anemia Drug related: cyclosporine, tacrolimus, sirolimus Hematologic: ABO incompatibility, sickle cell disease, glucose 6 phosphate dehydrogenase deficiency Acute renal failure Acute tubular necrosis Acute rejection Iron deficiency Absolute: perioperative blood loss, stress-induced gastrointestinal hemorrhage, depleted iron stores Functional: chronic inflammation, uremia Folate and vitamin B12 deficiency Late Generalized bone marrow suppression Immunosuppressants: AZA, MMF, sirolimus PRCA Drug related: AZA, MMF, tacrolimus, ACE inhibitors Hemolytic uremic syndrome/hemolytic anemia Drug related: cyclosporine, tacrolimus, sirolimus Hematologic: ABO incompatibility, sickle cell disease, glucose 6 phosphate dehydrogenase deficiency Acute renal failure Acute tubular necrosis Acute rejection Chronic renal failure EPO deficiency EPO resistance: eg, chronic inflammation, hyperparathyroidism Iron deficiency Absolute: perioperative blood loss, stress-induced gastrointestinal hemorrhage, depleted iron stores Functional: Uremia, chronic inflammation Malignancy Folate and vitamin B12 deficiency NOTE. A useful way of considering posttransplantation anemia is to divide it into that which develops early (within the first 6 months) and late (after the first 6 months) postengraftment. Some causes of posttransplantation anemia can occur either early or late.
ics, and malignancy). In most cases, causation is likely to be multifactorial, and there is considerable interplay of risk factors. Cases to illustrate this are shown in Figs 1 (early) and 2 (late posttransplantation anemia). Recent surveys are suggestive that both early and late posttransplantation anemia is becoming more common.18,19 There are potentially very rare, but well-characterized, causes for profound anemia, including infection with parvovirus B1928 and thrombotic microangiopathy secondary to calcineurin-inhibitor or sirolimus therapy.29 However, a number of common risk factors for posttransplantation anemia have emerged consistently from a series
of studies (including those cited). These include recipient sex, race, renal function, iron depletion, cytomegalovirus (CMV) status and prophylaxis, donor age, immunosuppressive regimen, use of ACE inhibitors/angiotensin II receptor blockers (ARBs), and others. Of these, the factor that appears to exert the greatest influence on anemia prevalence and severity is renal function/eGFR. For example, Karthikeyan et al30 determined the prevalence of CKD in 459 renal transplant recipients who were at least 6 months posttransplantation (mean, 7.7 years). CKD was present in 412 of these patients (60% had CKD stage 3). By stage 3, a total of 28.6% of patients were admin-
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AFZALI ET AL
Fig 1. Early posttransplantation anemia; evolution of hemoglobin concentrations during the first 12 months in a renal transplant recipient. A patient with a hemoglobin level of 15 g/dL (150 g/L), established on hemodialysis therapy, received a cadaveric single kidney allograft. Erythropoietin therapy (12,000 IU/wk of epoetin alfa) was stopped at transplantation. Graft function was delayed by 3 weeks, during which time dialysis continued. Serum creatinine level reached a plateau at 1.6 mg/dL (142 mol/L), immediately followed by CMV disease (fever, leukopenia, and CMV direct antigen test positivity) and the use of intravenous ganciclovir. Posttransplantation anemia was severe between weeks 2 and 7 and hemoglobin level did not return to normal until week 26. The patient was not administered EPO during this time. To convert serum creatinine in mol/L to mg/dL, divide by 88.4; hemoglobin in g/dL to g/L, multiply by 10.
istered recombinant human EPO (rHuEPO; 6.6%) or had a hemoglobin level less than 11 g/dL (⬍110 g/L; 22%). This increased to 27% and 33% for stage 4 patients and 33% and 50% for stage 5 patients.30 Our own findings31 in a population of 1,511 transplant recipients identified renal function as the strongest individual predictor of hemoglobin level (r ⫽ 0.33; P ⬍ 0.0001). It is important to appreciate that kidney transplant recipients have decreased kidney function and thus are at risk for anemia. Nevertheless, for most renal transplant recipients, eGFR is approximately 50 to 60 mL/min (0.83 to 1 mL/s) in the first year after renal transplantation, equating to KDOQI CKD stages 2 to 3.32 In the absence of other pathological states, anemia in nontransplantation patients with CKD would not be expected to be significant at this level of renal function (although clearly exceptions occur), highlighting the existence of risk factors other than GFR in the transplantation setting. An alternative explanation that should be borne in mind is that estimates of GFR derived from creatinine-based
calculations might not be correct in transplant recipients (the Modification of Diet in Renal Disease equation has not been validated in transplant recipients), potentially leading to misclassifications of CKD stage. Nevertheless, in the TRESAM Study, epidemiological characteristics of the population suggested a strong association between allograft function and anemia, but subjects who received a second or third allograft were more likely to be anemic than if it was their first allograft. Subjects who experienced rejection episodes were more likely to be anemic than if no rejection was experienced, and therapy with ACE inhibitors/ ARBs, mycophenolate mofetil (MMF), or azathioprine (AZA) also was associated with anemia. Use of sirolimus was not analyzed in this audit because the drug was not used clinically at that time. Donor age older than 60 years was an independent risk factor for anemia, whereas a diagnosis of adult polycystic disease was protective. Sex was not associated with anemia in this cohort.18
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Fig 2. Late posttransplantation anemia; evolution of hemoglobin concentration from 13 to 70 months postengraftment in the same patient as Fig 1. Renal transplant function was stable, with serum creatinine level around 1.6 mg/dL (142 mol/L) on cyclosporine, AZA, and prednisolone therapy. Hemoglobin level briefly reached 16.3 g/dL (163 g/L; hematocrit, 54%). However, serum creatinine levels slowly deteriorated from 14 to 50 months postengraftment, reaching 2.2 mg/dL (195 mol/L). A renal biopsy was performed, showing CAN. Cyclosporine therapy was discontinued in favor of sirolimus, started at month 52. Although serum creatinine level improved to 1.8 mg/dL (160 mol/L), hemoglobin level decreased quickly from 15.5 g/dL (155 g/L) in month 50 to 9.4 g/dL (94 g/L) in month 61. Sirolimus therapy was discontinued at month 61 (because of skin rash, edema, dyslipidemia, and anemia), and MMF was substituted. Only a small increase in hemoglobin levels followed. Iron status was normal throughout. To convert serum creatinine in mol/L to mg/dL, divide by 88.4; hemoglobin in g/dL to g/L, multiply by 10.
In this review, we concentrate on the contribution to posttransplantation anemia from rHuEPO level, iron deficiency, use of ACE inhibitors/ ARBs, and choice of immunosuppressive regimen. EPO Levels Anemia related to CKD is characterized by EPO deficiency or EPO resistance. Serum EPO levels would be expected to normalize after engraftment, but most information regarding posttransplantation serum EPO levels comes from the era when calcineurin-inhibitor use (especially cyclosporine A) was ubiquitous. This drug introduces a potential confounder because it induces vasoconstriction of afferent renal arterioles and might be expected to induce more renal ischemia and thus stimulate more EPO production.33 Conversely, some murine studies suggested a paradoxical depression of EPO levels after engraftment with cyclosporine immunosuppression.34 There are no comparative data for
tacrolimus and no data from patients undergoing calcineurin-free immunosuppression. Besarab et al35 and Lee et al36,37 reported serum EPO levels immediately after renal transplantation. Both found that serum EPO levels increased within 1 to 3 days of engraftment in which there was immediate graft function and remained elevated for several weeks. Conversely, delayed graft function seemed to be accompanied by an early EPO level peak within the first 4 days that was not associated with an increase in hematocrit, and then a return to baseline.33,38 The mechanism of this increase is unknown, but it may be caused by EPO accumulation within the ischemic graft during storage and transport.39 However, acute rejection episodes, particularly if occurring early postengraftment, cause a rapid decrease in EPO levels that is reversible on successful treatment of rejection35 (additionally, acute rejection episodes lead to downregulation of genes involved in hemoglobin transcription
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and synthesis, iron and folate binding, and transport40). There may be significant heterogeneity in serum EPO levels when stable graft function is established. Nampoory et al41 measured serum EPO levels in a population of stable patients at least 1 year post–renal transplantation. They identified 12 anemic subjects; 10 subjects had low serum EPO levels relative to hematocrit (EPO deficiency), whereas 2 subjects had high levels relative to hemoglobin level (EPO resistance). In a similar fashion, the nonanemic cohort showed low EPO levels in 5 of 11 subjects and high levels in the remaining 6 patients.41 Although suggestive of heterogeneity in engrafted EPO production and a high prevalence of both EPO deficiency and EPO resistance, this study was seriously flawed by incorrect understanding of appropriate ferritin levels in patients with CKD. Nevertheless, there are some theoretical reasons why an EPO-resistant state may develop after renal transplantation. Some of these are “legacies” of dialysis, including iron deficiency, ongoing hyperparathyroidism, and chronic inflammation.22,25 Others are specific to the postengraftment milieu, namely, such myelotoxic drugs as co-trimoxazole, ganciclovir, azathioprine, MMF, and sirolimus and acute or chronic infections.22,25 To summarize, serum EPO levels fluctuate in accordance with renal function level; poorer allograft function is associated with lower EPO levels. In addition, given that some risk factors for EPO resistance persist or are acquired in the postengraftment setting, some patients show relative EPO resistance. Iron Status Iron deficiency in the healthy population is considered to be “absolute” when iron stores are depleted (characterized by low ferritin concentrations [⬍10 ng/mL] and absence of storage iron in bone marrow). Some degree of failure of iron utilization is considered typical of the uremic milieu, most frequently as a consequence of chronic inflammation. Hence, functional iron deficiency often is inferred from low serum ferritin levels (⬍100 ng/mL), low percentage of transferrin saturation,42,43 or red blood cell hypochromasia greater than 10%.44 Marrow levels of storage iron usually are not low in this setting.
AFZALI ET AL
After transplantation and restoration of EPO production by the engrafted kidney, use of iron in the manufacture of hemoglobin increases, placing the patient at risk for developing iron deficiency. One difficulty in studying iron status in an engrafted individual is that the optimal iron status for transplant recipients, even those with normal renal function, is unknown. It is unclear whether a transplant recipient with normal eGFR and ferritin level less than 100 ng/mL should be classified as having functional iron deficiency. The lack of data is highlighted by repetitive observations of a number of studies that showed a general paucity of investigation of iron status in these individuals. The study of Mix et al22 showed that fewer than a quarter of transplant recipients, however anemic they may have been, underwent even the most basic assessment of iron status.22 Furthermore, the largest survey of anemia in renal transplant recipients (TRESAM) provides no useful information about iron status as a factor contributing to anemia.18 In similar fashion, the series of Shibagaki and Shetty21 of 192 patients reported that only 31 of 86 individuals who were anemic by WHO criteria had iron indices checked during the first posttransplantation year (and half of those had indices consistent with functional iron deficiency).21 Data for iron status are provided largely by small studies using only a single measurement of a single index of ferrodynamics. Karakus et al45 reported on 100 anemic (for at least 6 months after engraftment) adult renal transplant recipients (WHO definition) with a mean hemoglobin level of 10.2 ⫾ 1.4 g/dL (102 ⫾ 14 g/L) in women and 9.9 ⫾ 1.3 g/dL (99 ⫾ 13 g/L) in men. In this cohort, 60 subjects had normocytic anemia, 30 subjects had macrocytic anemia, and 10 subjects had microcytic anemia. Every subject with microcytic anemia had evidence of “iron deficiency,” although the report did not define this predicate, whereas a greater number had folate or vitamin B12 deficiencies (again, undefined). However, this report excluded all patients with a serum creatinine level greater than 2 mg/dL (⬎188 mol/L) and therefore is not representative of the transplant population as a whole, particularly because functional iron deficiency tends to be a feature of advancing CKD.45 Karthikeyan et al30 determined the prevalence of CKD and its complications in 459 renal trans-
ANEMIA AFTER RENAL TRANSPLANTATION
plant recipients. They found ferritin levels less than 100 ng/mL in approximately 50% of patients with CKD stages 3 to 5, whereas transferrin saturation was less than 20% in 0% of patients with CKD stage 1, but 75% of patients with CKD stage 5.30 Additionally, the low mean hemoglobin level in the cohort of Karakus et al45 compared with nearly every other reported series precludes generalization of these findings. The prevalence of anemia and indicators of iron status also were examined by Lorenz et al.23 Their cross-sectional study included a larger series of 438 adult subjects; anemia, defined by WHO criteria, was present in 39.7%. Having quantified indices of iron status, namely, serum ferritin, transferrin saturation, and percentage of hypochromic red blood cells (HRBCs), they concluded that levels of serum ferritin and transferrin saturation were poor markers of functional iron deficiency because only 10.1% of severely anemic patients had ferritin values less than 12 ng/mL and only 29% had transferrin saturations less than 15%. However, the majority of severely anemic patients had HRBC values in the upper quartile (52% and 64% for men and women, respectively). Frequently, serum ferritin level can be misleading because it is affected by a number of factors, including acute-phase responses. In adult subjects, there also is evidence of an influence of race on iron status. The study of Moore et al20 more than 10 years ago showed a greater prevalence of iron deficiency in transplant recipients of African-American than non–AfricanAmerican race. Admittedly, this was a small study of 51 subjects with only 6 months of follow-up posttransplantation. In this early posttransplantation period, iron deficiency may be related to such confounding factors as the surgery itself and frequent phlebotomy. In pediatric practice, functional or absolute iron deficiency states were reported to be much more common than in adult medicine. Kausman et al26 carried out a cross-sectional analysis of 50 pediatric renal transplant recipients and showed not only a very high prevalence of anemia (60%), but also a high prevalence of iron deficiency, in 34% of all subjects. In this population, serum iron levels correlated best with anemia. Unfortunately, serum iron levels can be affected by a number of different factors, such as acute-phase
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responses, and variations in serum iron levels are considerable. To summarize, despite the caveats rehearsed here, it is apparent that the prevalence of iron deficiency, whether absolute or functional, is high among renal allograft recipients, whereas investigation into iron status in these subjects is poorly undertaken. The exact optimum index of iron status has yet to be elucidated, with differences between reports explainable in part by the generally small sample sizes, time of measurement postengraftment, and, possibly, race. The importance of iron indices that suggest “functional iron deficiency” in subjects with normal renal function has not yet been determined, whereas the value of iron supplementation in this setting needs to be investigated further. Much more detailed information, using a battery of indices to characterize iron stores (both storage and utilizable iron), is required, as are more reports of the utility of iron supplementation in this setting. Until these data are obtained, it can be said that functional and/or absolute iron deficiency probably is an important underrecognized, but treatable, contributor to posttransplantation anemia. This is important to recognize because intravenous iron supplementation now is common in both adult8 and pediatric26,43 renal patients. ACE Inhibitors/ARBs The 2 most common causes of long-term graft loss remain death with a functional graft, usually from a marked excess of cardiovascular mortality, and CAN, the term given to the development of fibrotic processes and marked vasculopathy leading to progressive allograft dysfunction with variable proteinuria and hypertension.46,47 Without doubt, there is a significant contribution to this from long-term exposure to calcineurin inhibitors.48,49 Hypertension, dyslipidemia, and proteinuria, which accelerate renal functional decrease in patients with CAN, also impact negatively on cardiovascular prognosis. Additionally, a patient with a failing allograft is exposed to all the cardiovascular risks of a patient with CKD who did not undergo transplantation, with the additional problems of long-term immunosuppression, which carries its own cardiovascular and nephrotoxic detriment. Thus, ACE inhibitors and ARBs now are used increasingly for cardio-
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protective50 and renoprotective reasons51,52 in the transplant community. In the general population, there is evidence that these drugs have a modest population effect in decreasing hematocrit and cause a decrease in plasma EPO concentrations53; they now form the main medical management of patients with posttransplantation polycythemia. Whether increasing use of these drugs will lead to more anemia is an important question. Most studies examining this association in the transplant setting were carried out in a retrospective cross-sectional manner or involved small numbers of subjects. If, as expected, the effect of ACE inhibitors/ARBs on the population hemoglobin level is small, analysis of small patient numbers may fail to detect a difference and lead to false rejection of a true null hypothesis (type I error). The largest study to assess this association was the TRESAM survey (n ⫽ 4,263), in which 25.9% of patients were administered ACE inhibitors and 10.3% of patients were administered ARBs.18 There was no difference between ACE-inhibitor–treated and naïve cohorts in terms of hemoglobin levels or anemia prevalence, but there was a small difference in hemoglobin levels between ARB-treated (hemoglobin, 12.9 g/dL [129 g/L]) and ARBnaïve (hemoglobin, 13.2 g/dL [132 g/L]) patients. As can be seen, actual differences in hemoglobin levels between the groups were small and may be considered by some as not of clinical significance. A more significant effect on hemoglobin levels was observed by investigators retrospectively analyzing the combination of ACE inhibitors/ARBs with AZA.54 In this setting, patients administered an ACE inhibitor/ARB with AZA had lower hemoglobin levels than those administered AZA alone (11.5 ⫾ 2.0 g/dL [115 ⫾ 20 g/L] versus 14.0 ⫾ 1.6 g/dL [140 ⫾ 16 g/L], respectively). However, patient numbers were very small (n ⫽ 10 in each group). Another small historical retrospective study of renal transplant recipients also showed a significant decrease in hemoglobin levels in 15 engrafted subjects started on ACE-inhibitor/ARB therapy within 6 months of starting the drug (from 13.1 g/dL [131 g/L] to 11.0 g/dL [110 g/L]).55 This issue is not settled definitely. In the largest negative study to date, Inigo et al52 reported on the use of the archetypal ARB losartan in a retrospective survey of 276 renal transplant recipi-
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ents. They found significant deceases in blood pressure, proteinuria, and rate of renal functional decline and excellent tolerability. Of note, they found no difference in the rate of anemia in subjects once started on this drug. A smaller series examined patients started on ACE-inhibitor/ ARB therapy in the 90 days immediately after renal transplantation. They could identify no difference in hemoglobin levels between cases and controls, although it must be admitted that patient numbers were very small in this study (17 subjects and 19 controls who had been administered a calcium channel blocker for hypertension instead).56 Although there is the potential for ACE inhibitors and ARBs to worsen anemia, in practice, for most patients, this is of very limited clinical relevance and should not stand in the way of more widespread use of these agents for their cardioprotective/renoprotective effects. Having said that, there may be more “susceptible” subjects for whom hemoglobin levels may decrease more on ACE-inhibitor/ARB therapy than for the treated population mean57; thus, in selected cases, some thought could be given to engineering a “drug holiday” to test whether hemoglobin levels increase after discontinuation. Immunosuppressive Drugs There are many potentially myelotoxic/myelosuppressive drugs used in the posttransplantation setting. The complexity of drug regimens, with multiple potentials for drug interactions combined with other factors, such as viral and bacterial infections, conspire to have a significant role in the development of posttransplantation anemia. The effect of corticosteroids on erythropoiesis has been studied for some time. Glucorticoids sustain the formation of murine erythroid colonies in vitro58 and enhance proliferation of erythroid cells in the presence of limiting amounts of EPO59 and through interaction with c-Kit.60 In humans, patients with Addison disease commonly are anemic, whereas subjects with Cushing syndrome frequently have an elevated red blood cell count, hemoglobin level, and hematocrit.61 Some patients with immune thrombocytopenic purpura showed increased hemoglobin levels and red blood cell counts upon treatment with prednisolone.62 It therefore was theorized that
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steroid-withdrawal protocols in transplantation could be associated with the development of anemia. A recent large report detailing the effect of various immunosuppressive alterations (“minimizations”; removing either steroids or MMF from tacrolimus-based immunosuppression) showed that steroid elimination was associated with more hematologic adverse effects (leukopenia and anemia) in patients administered only MMF and tacrolimus than in patients administered all 3 drugs.63 However, this study is confounded by the observation that steroids decrease mycophenolic acid levels64; withdrawal of steroids in this setting therefore may contribute to anemia through the effect of elevated mycophenolic acid levels, rather than loss of the steroid itself. With regard to calcineurin inhibitors, effects of cyclosporine A and tacrolimus on bone marrow are very small in practice and of no clinical significance. These agents frequently are used for the management of aplastic anemia with good outcome.65 Nevertheless, these drugs are associated rarely with peripheral destruction of red blood cells. Hemolytic uremic syndrome can occur after administration of calcineurin inhibitors (or OKT3)66-68 and may threaten the function of the transplant, while a change in small vessels engendered by calcineurin inhibitors also has the potential to cause microangiopathic hemolytic anemia.66,69,70 In practice, these syndromes are rare complications of these drugs. Historically, the oldest myelotoxic immunosuppressant drug in current (if decreasing) use is AZA. Bone marrow suppression with AZA most commonly presents with leukopenia and thrombocytopenia. Macrocytosis and anemia also occur with long-term use.25 AZA is a purine analogue that is converted rapidly into 6-mercaptopurine after oral administration. Bone marrow suppression with this drug is much more common and severe with homozygous or heterozygous mutations of thiopurine methlytransferase, a cytosolic enzyme that catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds and is the most important enzyme in the degradation pathway of AZA. Severe life-threatening pancytopenic crises were reported with these mutations,70 and 10% of subjects are heterozygous for these
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genes.71 In addition, very rare cases of pure red cell aplasia (PRCA) were reported with AZA.72 MMF is a potent inhibitor of inosine monophosphate dehydrogenase. T and B lymphocytes depend exclusively on the de novo synthesis pathway for purine synthesis to guanosine nucleotides in which inosine monophosphate dehydrogenase acts as an intermediary. Erythrocytosis theoretically should not be affected because red blood cells use the salvage pathway. However, in clinical practice, it is clear that use of MMF and mycophenolic acid is associated with suppression of all bone marrow cell lines. This observation is supported by the literature. In 503 patients recruited into the Tricontinental MMF study, a prospective, double-blind, multicenter trial comparing the safety and efficacy of MMF and AZA with standard immunosuppression, leukopenia, anemia, and thrombocytopenia were reported in 19%, 15%, and 9% of patients administered 2 g/d of MMF and 35%, 9%, and 5% of patients administered 3 g/d at 1 year of follow-up. The incidence of anemia with AZA therapy was 10%.73 By 3 years of follow-up, leukopenia, anemia, and thrombocytopenia were reported in 19.9%, 15.8%, and 8.8% of patients administered 2 g/d and 37.8%, 11.6%, and 6.1% of patients administered 3 g/d of MMF (9.3% incidence of anemia with AZA by this stage).74 Wang et al75 presented a meta-analysis of 20 trials containing 6,387 subjects that investigated the incidence of adverse effects with 2 or 3 g/d of MMF with AZA. Their findings suggested no statistically significant differences in relative risk (RR) for developing anemia between subjects in different treatment arms, although, as expected, the RR for developing anemia was consistently greater than 1 in all treatment arms.75 Additionally, the TRESAM survey showed significantly lower hemoglobin levels for patients administered any immunosuppressive drug combination that included MMF.18 However, in this cohort, the observed differences were small (hemoglobin, 13.1 ⫾ 2.0 g/dL [131 ⫾ 20 g/L] versus 13.4 ⫾ 2.1 g/dL [134 ⫾ 21 g/L]; P ⬍ 0.05) and may be explained in part by a lower GFR in the group administered MMF. In addition to its myelotoxic effects, PRCA was reported with MMF use.76,77 This is a rare complication, although Engelen et al76 reported an incidence of 4 in 30 patients. An additional
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complexity involves the subtle nuances of pharmacodynamic interactions between mycophenolic acid and its metabolites and calcineurin inhibitors and sirolimus, such that increased mycophenolic acid levels, with increased marrow and bowel toxicity, can occur.78 Kuypers et al,79 using careful and detailed drug concentration monitoring protocols, showed that anemia in this setting was related consistently to the mycophenolic acid area under the curve (AUC0-12). Sirolimus is a macrolide that inhibits the mammalian target of rapamycin, thereby impeding cell-cycle progression. Effects of sirolimus are seen mostly on nonerythroid progenitors, including megakaryocytes and leukocytes. However, an effect of sirolimus on erythrocyte production was reported that correlated with drug dose and blood level. In a recent study of sirolimus with cyclosporine, anemia occurred in 16% of patients administered 2 mg/d and 27% of patients administered 5 mg/d. In particular, the combination of sirolimus and MMF clearly is very potent in causing bone marrow suppression.80 Kreis et al81 reported a 43% incidence of anemia in patients administered sirolimus and MMF compared with 29% for patients administered cyclosporine and MMF. Renders et al82 showed that low-dose sirolimus therapy in combination with concentration-adjusted MMF dosing led to improved organ function, but 3 of 11 patients required more EPO to correct worsening anemia. Augustine et al83 reported 214 patients with either kidney or kidney-pancreas allografts treated with either sirolimus- (n ⫽ 87) or MMF-based (n ⫽ 127) immunosuppression. At 12 months, the incidence of anemia was 31% with MMF and 57% with sirolimus. Sirolimus remained a significant correlate of lower hemoglobin levels in all patients.83 From these diverse studies, 1 theme emerges: namely, several drugs in common use to achieve transplant immunosuppression have the potential to cause posttransplantation anemia. In particular, sirolimus, especially in combination with MMF, has a marked tendency to decrease hemoglobin levels. EFFECT OF POSTTRANSPLANTATION ANEMIA
CKD is a well-known and clearly established significant risk factor for cardiovascular disease84-87 and death after the onset of cardiovas-
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cular disease.88 Similarly, a number of studies showed that anemia is a risk factor in the nonrenal population for poor outcome after myocardial infarction88 and vascular death in patients with preexisting chronic heart failure.89 However, because patients with “significant” CKD were excluded from most important key interventional clinical trials, our knowledge of cardiovascular disease epidemiology, pathophysiology, screening, and therapy in patients with CKD is limited to mainly small clinical trials or larger observational studies. Even less is known for renal transplant recipients. Nevertheless, death with a functional graft from an excess of cardiovascular disease remains the most common cause of graft loss in the long term.90,91 A number of studies recently attempted to describe the effect of posttransplantation anemia on patient outcome. Yeo et al92 carefully reviewed the evidence for various conventional and nonconventional cardiovascular risk factors in dialysis patients and transplant recipients. For transplant recipients, risk factors for the development of congestive cardiac failure included diabetes, decreased plasma albumin level, increased systolic blood pressure, African-American race, CMV infection, and older age. Decreased hemoglobin level conferred an odds ratio of 1.24 for each 1-g/dL (10-g/L) decrease in hemoglobin level for the development of congestive cardiac failure. A retrospective analysis by Rigatto et al93 of left ventricular hypertrophy in 473 renal transplant recipients free from cardiovascular disease at 12 months showed that congestive cardiac failure, ischemic heart disease, and left ventricular failure are all important late complications of renal transplantation and risk factors for death. Their analysis concurred with that of Yeo et al93 by concluding that a 1-g/dL (10-g/L) decrease in hemoglobin level carries an independent RR for de novo cardiac failure of 1.36 (P ⬍ 0.001) in the posttransplantation setting. In a previous similar study of 638 engrafted individuals free from cardiovascular disease at 12 months, the same group reported that a 1-g/dL (10-g/L) decrease in hemoglobin level portended independent RRs for de novo heart failure of 1.24 (95% confidence interval [CI], 1.10 to 1.39; P ⬍ 0.001), all-cause death of 1.16 (95% CI, 1.07 to 1.26; P ⬍ 0.001), and cardiovascular death of 1.15 (95% CI, 1.01
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to 1.30; P ⫽ 0.03) at 1 year.94 Their data did not support lower hemoglobin level as a risk factor for the de novo development of ischemic heart disease, but the analysis was restricted to a univariate estimate of risk (RR, 1.03; 95% CI, 0.08 to 1.18; P ⫽ 0.7 in univariate analysis).93 Djamali et al95 performed a retrospective study of 404 cadaveric renal transplant recipients with type 1 diabetes at the University of Wisconsin. They found that more than 60% of the study cohort had a hematocrit less than 30% at least once during the first 30 days posttransplantation. Increasing hematocrit (⬎30%) led to a decrease in risk ratio for a cardiovascular event compared with a hematocrit less than 30% (RR, 0.237; P ⫽ 0.015). This association remained significant in a multivariate analysis that also included age and history of pretransplantation ischemic heart disease. Additionally, Arias et al96 examined the effects of late posttransplantation anemia by reviewing a cohort of 70 renal transplant recipients with CAN who returned to dialysis therapy and comparing them with 122 patients with CKD entering dialysis therapy for the first time. Their findings showed that patients established on dialysis therapy because of graft failure had poorer renal function at the time of entering dialysis therapy and more profound anemia. Furthermore, morbidity in terms of number of hospital admissions and days of hospitalization during the first year after initiation of dialysis therapy was considerably greater in the graft-failure group. Unfortunately, this observation related less clearly to anemia than to uremia.96 In one of the very few prospective studies, Winkelmayer et al97 examined 438 renal transplant recipients from a large transplant clinic for all-cause mortality and allograft loss. Hemoglobin and detailed iron status parameters were assessed at baseline. During 7.8 years of followup, there were 129 deaths and 208 grafts were lost. Using multivariate analysis, they found that anemia (defined as hemoglobin ⬍ 10 g/dL [⬍100 g/L]) was not associated with mortality or graft loss. Patients with HRBCs greater than 10% (indicating some iron deficiency) had twice the mortality risk of subjects with HRBCs less than 10.97 The significance of these findings and any practical therapeutic implications therefore remain unclear.
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As can be seen, there is a dearth of prospective descriptive studies, with most investigators confined to retrospective analysis. In part, this is a restriction imposed by numbers because the number of transplantations and the follow-up required to generate a study of sufficient power are more than most centers can manage on their own. Most investigators seem to agree that the presence of low hemoglobin levels correlates with poorer outcomes in transplant recipients. Whether this is a phenomenon directly caused by anemia itself or a causative factor in association with anemia (such as immunosuppression and iron deficiency) cannot be gauged from these studies. As ever, well-designed prospective trials are required. TREATMENT OF POSTTRANSPLANTATION ANEMIA WITH ERYTHROPOIESIS-STIMULATING AGENTS
Only a few studies systematically examined the use of erythropoiesis-stimulating agents in patients with posttransplantation anemia. It is important to differentiate early from late posttransplantation anemia with treatment, as with cause, because the success of erythropoiesisstimulating agents in increasing hemoglobin levels may be related to the cause of the anemia and clinical reasons for anemia correction may be different. (For example, in patients with early posttransplantation anemia, it may be beneficial to increase hemoglobin levels to decrease renal medullary hypoxia postengraftment, or in those with late posttransplantation anemia, to decrease cardiovascular disease burden). This was shown convincingly by Van Biesen et al98 in a recent report of a small series of 40 patients administered epoetin beta, 100 U/kg 3 times weekly subcutaneously, from the day of transplantation if their hemoglobin level at engraftment was less than 12.5 g/dL (⬍125 g/L). Twenty-two of 40 patients required rHuEPO therapy. After 3 months postengraftment, there was no significant difference in hemoglobin levels between the rHuEPO-treated and naïve groups or in the proportion of patients reaching the target hemoglobin level (although the EPOtreated group achieved the target hemoglobin level of ⬎ 12.5 g/dL [⬎125 g/L] faster). Serum creatinine values were not different between the 2 groups. The investigators concluded there was
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no clinically relevant advantage to immediate postengraftment administration of rHuEPO to transplant recipients with early posttransplantation anemia.98 In addition, a favorable impact for treatment of posttransplantation anemia with EPO has yet to be shown convincingly. In 2002, Becker et al99 published an article in which they examined (in retrospect by database analysis) the charts and records of 166 subjects administered rHuEPO at least 18 days after transplant function (thereby including both early and late posttransplantation anemia). eGFR was 27.6 mL/min (0.46 mL/s) and hematocrit was 30.6% at the start of rHuEPO treatment. After rHuEPO administration (average weekly dose, 9,689 IU; average duration, 206 days), hematocrit increased to 32.7% and there was significant improvement in the slopes of reciprocalized plasma creatinine values over time, indicating improvement in renal function.99 This interesting and stimulating observation is seriously flawed because 100% of subjects were administered calcineurin inhibitors at the start of rHuEPO therapy, but only 19% remained on calcineurin inhibitor therapy by day 100 of treatment. It is very clear that a decrease in calcineurin inhibitor blood concentration alone can lead to dramatic improvements in allograft function regardless of rHuEPO treatment, hematocrit, or hemoglobin level.49 Kawaguchi et al100 reported that use of rHuEPO to influence cardiac function and quality of life when hematocrit was increased to approximately 36% by administration of rHuEPO to patients with “mild” impairment of renal function (creatinine ⬍ 2.1 mg/dL [190 mol/L]) after renal transplantation (late posttransplantation anemia). Twenty-five patients were analyzed for cardiac function, blood data, and quality of life in a prospective study encompassing 8 months of rHuEPO treatment. Using a once-weekly subcutaneous dose of 6,000 IU of epoetin beta, hematocrit increased into the range of 33% to 36%, and hemoglobin level, to 11 to 12 g/dL (110 to 120 g/L). Among cardiac function tests, left ventricular end-diastolic diameter and left ventricular mass index decreased significantly. Quality of life did not show significant changes after rHuEPO administration.100 This is in contrast to the quality-of-life investigation of Rebollo et al,101 who studied the use of epoetin beta
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in 17 anemic renal transplant recipients with decreasing renal function caused by CAN (late posttransplantation anemia). Scores for the 36Item Short-Form Health Survey and a battery of other indices improved significantly after rHuEPO therapy, in parallel with increasing hematocrits (P ⬍ 0.05 and P ⬍ 0.01 for improvement in 36-Item Short-Form Health Survey scores).101 Unfortunately, the majority of these studies are small in nature and retrospective in design. The prospective studies have a short follow-up. As such, they are inadequately designed for elucidating the effects of treating anemic patients posttransplantation with erythropoiesis-stimulating agents, and an adequately designed multicenter controlled trial is needed. One can tentatively propose that it is possible that correction of anemia in the posttransplantation setting would have the same benefits in terms of symptom improvement and patient survival as anemia correction in pretransplantation patients with CKD, but this needs to be investigated prospectively. In addition, it is far from established whether erythropoiesis-stimulating agents themselves have a beneficial effect beyond correction of anemia alone. With regard to safety, there is the potential for causing or exacerbating hypertension with erythropoiesis-stimulating agents. The erythropoietin receptor is widely distributed in the cardiovascular system, including endothelial cells and vascular smooth muscle. Binding of EPO to these receptors therefore can cause hypertension, and up to 20% to 30% of all renal patients develop hypertension after treatment with erythropoiesisstimulating agents.102 PRCA is not a problem in the setting of transplantation because immunosuppressive agents that prevent organ rejection also protect against PRCA.103 The most efficacious treatment for PRCA in patients with CKD or dialysis patients is kidney transplantation.103 CONCLUSION
Posttransplantation anemia is present in more than 50% of transplant recipients at some stage in their transplant history, and in snapshot crosssectional series, it is present (depending on definition) in a quarter to one third of subjects. Posttransplantation anemia occurs early and then late after renal transplantation; late posttransplan-
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tation anemia often occurs in association with a CAN-related decrease in GFR. Median hemoglobin values in larger series tend to be in the range of 12.5 to 13.0 g/dL (125 to 130 g/L). Only approximately 10% to 15% of patients have severe anemia (eg, hemoglobin ⬍ 10 g/dL [⬍110 g/L]). Important causes include eGFR/renal function, immunosuppressive drugs, and iron deficiency. It is apparent that the prevalence of iron deficiency, whether absolute or functional, is high among renal allograft recipients, whereas investigation into iron status in these subjects is poorly undertaken. Anemia is a cardiovascular risk factor that appears to be particularly important in the genesis of posttransplantation congestive cardiac failure. This is important to take into account, especially when dealing with transplant recipients with decreasing renal function who are exposed to anemia, renal bone disease, and acidosis, as nontransplantation patients with CKD are. Evidence shows many opportunities to improve the medical management of these failing allograft recipients, and these opportunities are not always taken.104 The present situation, in which posttransplantation anemia is commonplace, but investigation and treatment are rare, does not rest on a secure evidence base. The studies available for scrutiny that examine the use of rHuEPO for anemia correction in patients with posttransplantation anemia are few in number, small in size, and short term in followup. They are largely inadequate, except to show that rHuEPO corrects hemoglobin levels, and one can infer that patients with posttransplantation anemia have approximately similar rHuEPO requirements as predialysis patients with CKD and require less rHuEPO than dialysis patients. One needs to distinguish carefully between the potential benefit of rHuEPO therapy for early posttransplantation anemia (prevention of renal allograft medullary hypoxia in the context of extensive ischemia-reperfusion injury in cadaveric or non–heart-beating allografts) as opposed to the longer term benefits of rHuEPO use for patients with late posttransplantation anemia, which might include prevention of dilated cardiomyopathy and slowing of deteriorating allograft function.105 Although several of the newer immunosuppressive drugs clearly contribute to the burden of anemia in renal transplant (and other
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solid-organ transplant) recipients, there are very sound immunologic reasons for choosing these therapies, and anemia, like hypertension, dyslipidemia, diabetes, and gout, will be seen as another systemic/metabolic side effect to be dealt with medically. Moreover, there is a complex trade-off that needs to be examined, ideally by using large cohorts, in which the use, for example, of sirolimus de novo to spare the use of calcineurin inhibitors with their long-term nephrotoxic potential or the use of ACE inhibitors/ ARBs in patients with CAN may lead to significant prolongation of renal function (and decrease late posttransplantation anemia), but at the shortterm expense of some early posttransplantation anemia. Several larger, longer term cohort/observational/interventional studies to examine this area in greater detail clearly are needed. In particular, we need to know whether posttransplantation anemia is increasing in prevalence as less steroid and more sirolimus/MMF is used posttransplantation, when rHuEPO is required in posttransplantation anemia, and what hemoglobin level to aim for using rHuEPO. Recent meta-analyzed evidence reinforces the need to carefully consider the optimal hematocrit in each patient, especially those with cardiovascular disease.106 We also need to know which rHuEPO is more effective, what benefits to expect from anemia correction (these might be different for early compared with late posttransplantation anemia), and what other adjunctive methods we may have to use to augment erythropoiesis in this patient population. REFERENCES 1. Eschbach JW, Adamson JW: Anemia of end-stage renal disease (ESRD). Kidney Int 28:1-5, 1985 2. Silverberg DS, Wexler D, Blum B, et al: Anemia in chronic kidney disease and congestive heart failure. Blood Purif 21:124-130, 2003 3. Snyder JJ, Foley RN, Gilbertson DT, et al: Hemoglobin levels and erythropoietin doses in hemodialysis and peritoneal dialysis patients in the United States. J Am Soc Nephrol 15:174-179, 2004 4. Macdougall IC: Erythropoietin and renal failure. Curr Hematol Rep 2:459-464, 2003 5. Roger SD, McMahon LP, Clarkson A, et al: Effects of early and late intervention with epoetin alpha on left ventricular mass among patients with chronic kidney disease (stage 3 or 4): Results of a randomized clinical trial. J Am Soc Nephrol 15:148-156, 2004 6. Locatelli F, Pisoni RL, Combe C, et al: Anemia in hemodialysis patients of five European countries: Associa-
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tion with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 19:121-132, 2004 7. Gouva C, Nikolopoulos P, Ioannidis JP, et al: Treating anemia early in renal failure patients slows the decline of renal function: A randomized controlled trial. Kidney Int 66:753-760, 2004 8. Afzali B, Goldsmith DJ: Intravenous iron therapy in renal failure: Friend and foe? J Nephrol 17:487-495, 2004 9. Evans RW, Rader B, Manninen DL, for the Cooperative Multicenter EPO Clinical Trial Group: The quality of life of hemodialysis recipients treated with recombinant human erythropoietin. JAMA 263:825-830, 1990 10. Grutzmacher P, Scheurmann E, Low I, et al: Correction of renal anemia by recombinant human erythropoietin: Effects on myocardial function. Contrib Nephrol 66:176184, 1988 11. Delano BG: Improvements in quality of life following treatment with r-HuEPO in anemic hemodialysis patients. Am J Kidney Dis 14:14-18, 1989 12. Consensus Development Conference Panel: Morbidity and mortality of renal dialysis: An NIH consensus conference statement. Ann Intern Med 121:62-70, 1994 13. Magee CC, Pascual M: Update in renal transplantation. Arch Intern Med 164:1373-1388, 2004 14. Offermann G: Immunosuppression for long-term maintenance of renal allograft function. Drugs 64:13251338, 2004 15. WHO: Nutritional Anemia. World Health Organization Technical Report Series No. 405. Geneva, Switzerland, World Health Organization, 1968 16. National Kidney Foundation: K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease. Am J Kidney Dis 37:S182-S238, 2001 (suppl 1) 17. The Renal Association: Treatment of Adults and Children With Renal Failure. Standards and Audit Measures (ed 3). London, UK, Royal College of Physicians of London and the Renal Association, 2002 18. Vanrenterghem Y, Ponticelli C, Morales JM, et al: Prevalence and management of anemia in renal transplant recipients: A European survey. Am J Transplant 3:835-845, 2003 19. Vanrenterghem Y: Anemia after renal transplantation. Nephrol Dial Transplant 19:SV54-SV58, 2004 (suppl 5) 20. Moore LW, Smith SO, Winsett RP, et al: Factors affecting erythropoietin production and correction of anemia in kidney transplant recipients. Clin Transplant 8:358-364, 1994 21. Shibagaki Y, Shetty A: Anemia is common after kidney transplantation, especially among African Americans. Nephrol Dial Transplant 19:2368-2373, 2004 22. Mix TC, Kazmi W, Khan S, et al: Anemia: A continuing problem following kidney transplantation. Am J Transplant 3:1426-1433, 2003 23. Lorenz M, Kletzmayr J, Perschl A, et al: Anemia and iron deficiencies among long-term renal transplant recipients. J Am Soc Nephrol 13:794-797, 2002 24. Molnar MZ, Novak M, Ambrus C, et al: Anemia in kidney transplanted patients. Clin Transplant 19:825-833, 2005
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