Anemia is generally defined as hemoglobin of less than 13.0 g/dL in men and less than 12.0 g/dL in premenopausal women. Anemia of chronic kidney disease (CKD) is a form of normocytic normochromic, hypoproliferative anemia. Among other complications of CKD, it is frequently associated with poor outcomes in CKD and increases mortality.
Anemia in chronic renal disease is a multifactorial condition, the widely accepted etiology being decreased renal production of erythropoietin, the hormone that is responsible for the stimulation of red blood cells production. Decreased erythropoietin has recently linked with downregulation of hypoxia-inducible factor (HIF), a transcription factor that regulates gene expression of erythropoietin. Other mechanisms include uremia (leading to RBC deformity responsible for hemolysis), folate and vitamin B12 deficiency, iron deficiency, bleeding due to dysfunctional platelets, and rarely blood loss from hemodialysis. RBC fragmentation by injured renovascular endothelium in selected conditions such as glomerulopathy and malignant hypertension exacerbates the anemia, which explains why anemia can be particularly severe in renal glomerulopathies, including glomerulonephritis, diabetic nephropathy, for the degree of excretory failure.
The condition usually starts to develop following a greater than 50 percent loss of the kidney function, typically when the glomerular filtration rate (GFR) decreases to less than 60 mL/min. The severity of anemia tends to worsen as chronic kidney disease (CKD) progresses. The deficiency in renal production of erythropoietin and the severity of anemia do not always tend to correlate with the severity of renal dysfunction.
Clinical presentation of anemia of renal disease is not different from that of anemia due to other causes. Common symptoms include:
Commonly observable signs include:
Common workup required to diagnose the condition include,
Normocytic normochromic anemia and peripheral reticulocytopenia are observable on CBC with a peripheral smear.
Unfortunately, due to high serum ferritin levels secondary to chronic inflammation in CKD, serum iron indices are not accurately indicative of the degree of iron deficiency in dialysis patients, thus raising the standard cutoffs of iron responsiveness. The Dialysis Patients’ Response to IV Iron With Elevated Ferritin (DRIVE) study demonstrated that intravenous iron is beneficial in dialysis patients even in the setting of ferritin as high as 1200 ng/mL if the transferrin saturation is less than 30%.
Measuring serum erythropoietin levels are discouraged in CKD, and is not usable as an indicator of a renal source of the anemia, because, in kidney disease, there is 'relative erythropoietin deficiency,' that is, an inappropriate rise in erythropoietin levels for the severity of anemia.
Bone marrow may show erythroid hypoplasia, which correlates to the reports of resistance of bone marrow to erythropoietin.
Treatment directs toward improving renal function (when possible) and measures aimed at increasing red blood cells production. ESAs, together with iron supplementation, is the treatment of choice in anemia of CKD.
Treatment of anemia in CKD has come a long way. Before the advanced treatment options that are available today, the main treatment option used to be blood transfusions, which came with numerous complications including infections, hemosiderosis, fluid overload, transfusion reactions, etc. It started with the use of androgens in the 1970s to avoid transfusion in patients with CKD. After that, in the 1980s, the development of recombinant EPO followed by erythropoiesis-stimulating agents (ESAs) revolutionized the management of anemia in CKD. Although initially instituted to avoid transfusions, they were soon known to have various positive effects, including improved survival and quality of life, improved cardiac function and mortality associated with it, lower hospitalizations, and lower costs.
Recombinant human erythropoietin and darbepoetin alfa are the two ESAs generally used in the management of anemia in CKD. They are fairly similar in efficacy and side effect profile, except for the longer half-life of darbepoetin alfa, thus allowing for less frequent dosing.
As per KIDGO guidelines, in patients with CKD who are not on dialysis, ESAs are typically considered when hemoglobin level drops below 10 g/dl, but is individualized depending on various factors, including symptoms related to anemia, dependence on transfusions, the rate of drop in hemoglobin concentration, and response to iron therapy. In these patients, erythropoietin (50 to 100 units/kg IV or SC) is usually given every 1 to 2 weeks, and darbepoetin alfa dosing is every 2 to 4 weeks.
In patients who are on dialysis, ESAs are usually avoided unless the hemoglobin level is between 9 and 10 g/dL. In this subset, erythropoietin is given with every dialysis, i.e., three times a week, whereas darbepoetin alfa is dosed to once a week.
Generally, the peak rise in RBCs in response to ESAs occurs at 8 to 12 weeks. However, in around 10% to 20% of cases, anemia can be resistant to ESAs. Common adverse effects of ESAs include seizures, the progression of hypertension, clotting of dialysis access, the progression of malignancy and higher mortality in cancer patients.
In all patients with CKD, regardless of the need for dialysis, goal hemoglobin with the use of ESAs is less than 11.5 g/dL. Multiple trials were done to assess the superiority of target hemoglobin to 'high normal' versus lower range. These trials, including CHOIR, NHCT and TREAT trials demonstrated higher mortality, thrombosis, adverse cerebrovascular and cardiovascular events due to higher levels of ESAs when used for target hemoglobin greater than 11 g/dl. These events are likely related to the effect of ESAs on vascular remodeling and causing vasoconstriction. CHOIR trial also showed that patients requiring higher levels of ESAs to achieve target hemoglobin had worse outcomes. The discovery of stated side effects of ESAs, when used to target high normal hemoglobin levels, raised questions about the benefits of ESAs beside avoidance of transfusions, which has led to growing interest in looking for alternative etiologies and thus, management for anemia of CKD.
Patients with CKD have increased risk of iron deficiency, due to impaired dietary iron absorption, chronic bleeding due to platelet dysfunction from uremia, frequent phlebotomy, and blood trapping in the dialysis apparatus. This deficiency, in addition to depletion of the circulating iron pool by stimulation of erythropoiesis by ESAs, makes iron supplementation the core of treatment of anemia in CKD. Due to decreased absorption of oral iron, intravenous iron is preferable in hemodialysis patients.
KIDGO recommends target transferrin saturation between 20 to 30% and ferritin level 100 to 500 ng/mL in patients with CKD who are not on dialysis. In patients with ESRD on dialysis receiving intravenous iron, goal transferrin saturation of 30 to 50% and ferritin higher than 200 ng/mL. Iron has correlations with a risk of acute toxicity and infection, which should be weighed against the benefits in individual patients.
The management of anemia of CKD is not simple. It requires an integrated approach by an interprofessional team consisting of the nephrologist, PCP including the nurse practitioner, physician assistant, physician, nursing, pharmacy, and occasionally also a hematologist may be necessary to help achieve the best possible outcomes. Also, the involvement of a nutritionist is essential for avoidance and/or treatment of the deficiency of vitamins that can exacerbate the anemia of kidney disease.
|||Nutritional anaemias. Report of a WHO scientific group. World Health Organization technical report series. 1968; [PubMed PMID: 4975372]|
|||McClellan WM,Flanders WD,Langston RD,Jurkovitz C,Presley R, Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study. Journal of the American Society of Nephrology : JASN. 2002 Jul; [PubMed PMID: 12089390]|
|||Collins AJ,Li S,St Peter W,Ebben J,Roberts T,Ma JZ,Manning W, Death, hospitalization, and economic associations among incident hemodialysis patients with hematocrit values of 36 to 39%. Journal of the American Society of Nephrology : JASN. 2001 Nov; [PubMed PMID: 11675424]|
|||Bernhardt WM,Wiesener MS,Scigalla P,Chou J,Schmieder RE,Günzler V,Eckardt KU, Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. Journal of the American Society of Nephrology : JASN. 2010 Dec; [PubMed PMID: 21115615]|
|||Wang GL,Jiang BH,Rue EA,Semenza GL, Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proceedings of the National Academy of Sciences of the United States of America. 1995 Jun 6; [PubMed PMID: 7539918]|
|||Agarwal AK, Practical approach to the diagnosis and treatment of anemia associated with CKD in elderly. Journal of the American Medical Directors Association. 2006 Nov; [PubMed PMID: 17098634]|
|||Hsu CY,McCulloch CE,Curhan GC, Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the Third National Health and Nutrition Examination Survey. Journal of the American Society of Nephrology : JASN. 2002 Feb; [PubMed PMID: 11805181]|
|||Tessitore N,Solero GP,Lippi G,Bassi A,Faccini GB,Bedogna V,Gammaro L,Brocco G,Restivo G,Bernich P,Lupo A,Maschio G, The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2001 Jul; [PubMed PMID: 11427634]|
|||Mittman N,Sreedhara R,Mushnick R,Chattopadhyay J,Zelmanovic D,Vaseghi M,Avram MM, Reticulocyte hemoglobin content predicts functional iron deficiency in hemodialysis patients receiving rHuEPO. American journal of kidney diseases : the official journal of the National Kidney Foundation. 1997 Dec; [PubMed PMID: 9398141]|
|||Coyne DW,Kapoian T,Suki W,Singh AK,Moran JE,Dahl NV,Rizkala AR, Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) Study. Journal of the American Society of Nephrology : JASN. 2007 Mar; [PubMed PMID: 17267740]|
|||Radtke HW,Claussner A,Erbes PM,Scheuermann EH,Schoeppe W,Koch KM, Serum erythropoietin concentration in chronic renal failure: relationship to degree of anemia and excretory renal function. Blood. 1979 Oct; [PubMed PMID: 476305]|
|||Korte W,Cogliatti SB,Jung K,Riesen W, Mild renal dysfunction is sufficient to induce erythropoietin deficiency in patients with unexplained anaemia. Clinica chimica acta; international journal of clinical chemistry. 2000 Feb 25; [PubMed PMID: 10686284]|
|||DeGowin RL,Lavender AR,Forland M,Charleston D,Gottschalk A, Erythropoiesis and erythropoietin in patients with chronic renal failure treated with hemodialysis and testosterone. Annals of internal medicine. 1970 Jun; [PubMed PMID: 5448750]|
|||Richardson JR Jr,Weinstein MB, Erythropoietic response of dialyzed patients to testosterone administration. Annals of internal medicine. 1970 Sep; [PubMed PMID: 5455991]|
|||Eschbach JW,Egrie JC,Downing MR,Browne JK,Adamson JW, Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. The New England journal of medicine. 1987 Jan 8; [PubMed PMID: 3537801]|
|||Macdougall IC,Lewis NP,Saunders MJ,Cochlin DL,Davies ME,Hutton RD,Fox KA,Coles GA,Williams JD, Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin. Lancet (London, England). 1990 Mar 3; [PubMed PMID: 1968526]|
|||Perkins R,Olson S,Hansen J,Lee J,Stiles K,Lebrun C, Impact of an anemia clinic on emergency room visits and hospitalizations in patients with anemia of CKD pre-dialysis. Nephrology nursing journal : journal of the American Nephrology Nurses' Association. 2007 Mar-Apr; [PubMed PMID: 17486947]|
|||Maddux FW,Shetty S,del Aguila MA,Nelson MA,Murray BM, Effect of erythropoiesis-stimulating agents on healthcare utilization, costs, and outcomes in chronic kidney disease. The Annals of pharmacotherapy. 2007 Nov; [PubMed PMID: 17895328]|
|||Carrera F,Burnier M, Use of darbepoetin alfa in the treatment of anaemia of chronic kidney disease: clinical and pharmacoeconomic considerations. NDT plus. 2009 Jan; [PubMed PMID: 19461859]|
|||Egrie JC,Browne JK, Development and characterization of novel erythropoiesis stimulating protein (NESP). Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2001; [PubMed PMID: 11402085]|
|||Winearls CG,Oliver DO,Pippard MJ,Reid C,Downing MR,Cotes PM, Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet (London, England). 1986 Nov 22; [PubMed PMID: 2877323]|
|||Szczech LA,Barnhart HX,Inrig JK,Reddan DN,Sapp S,Califf RM,Patel UD,Singh AK, Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney international. 2008 Sep; [PubMed PMID: 18596733]|
|||Besarab A,Bolton WK,Browne JK,Egrie JC,Nissenson AR,Okamoto DM,Schwab SJ,Goodkin DA, The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. The New England journal of medicine. 1998 Aug 27; [PubMed PMID: 9718377]|
|||Bello NA,Lewis EF,Desai AS,Anand IS,Krum H,McMurray JJ,Olson K,Solomon SD,Swedberg K,van Veldhuisen DJ,Young JB,Pfeffer MA, Increased risk of stroke with darbepoetin alfa in anaemic heart failure patients with diabetes and chronic kidney disease. European journal of heart failure. 2015 Nov; [PubMed PMID: 26423928]|
|||Fishbane S,Berns JS, Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin. Kidney international. 2005 Sep; [PubMed PMID: 16105069]|
|||Fudin R,Jaichenko J,Shostak A,Bennett M,Gotloib L, Correction of uremic iron deficiency anemia in hemodialyzed patients: a prospective study. Nephron. 1998; [PubMed PMID: 9678430]|
|||Markowitz GS,Kahn GA,Feingold RE,Coco M,Lynn RI, An evaluation of the effectiveness of oral iron therapy in hemodialysis patients receiving recombinant human erythropoietin. Clinical nephrology. 1997 Jul; [PubMed PMID: 9247776]|
|||Macdougall IC, Intravenous iron therapy in patients with chronic kidney disease: recent evidence and future directions. Clinical kidney journal. 2017 Dec; [PubMed PMID: 29225819]|