Treatment of anemia in difficult-to-manage patients with chronic kidney disease

The management of anemia of chronic kidney disease (CKD) is often challenging. In particular, for patients with underlying inflammation, comorbid type 2 diabetes or cancer, those hospitalized, and recipients of a kidney transplant, the management of anemia may be suboptimal. Responsiveness to iron and/or erythropoiesis-stimulating agents, the mainstay of current therapy, may be reduced and the risk of adverse reactions to treatment is increased in these difficult-to-manage patients with anemia of CKD. This review discusses the unique patient and disease characteristics leading to complications and suboptimal treatment response. New treatment options in clinical development, such as hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, may be particularly useful for difficult-to-treat patients. In clinical studies, HIF-PH inhibitors provided increased hemoglobin levels and improved iron utilization in anemic patients with non–dialysis-dependent and dialysis-dependent CKD, and preliminary data suggest that HIF-PH inhibitors may be equally effective in patients with or without underlying inflammation. The availability of new treatment options, including HIF-PH inhibitors, may improve treatment outcomes in difficult-to-manage patients with anemia of CKD. The management of anemia of chronic kidney disease (CKD) is often challenging. In particular, for patients with underlying inflammation, comorbid type 2 diabetes or cancer, those hospitalized, and recipients of a kidney transplant, the management of anemia may be suboptimal. Responsiveness to iron and/or erythropoiesis-stimulating agents, the mainstay of current therapy, may be reduced and the risk of adverse reactions to treatment is increased in these difficult-to-manage patients with anemia of CKD. This review discusses the unique patient and disease characteristics leading to complications and suboptimal treatment response. New treatment options in clinical development, such as hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, may be particularly useful for difficult-to-treat patients. In clinical studies, HIF-PH inhibitors provided increased hemoglobin levels and improved iron utilization in anemic patients with non–dialysis-dependent and dialysis-dependent CKD, and preliminary data suggest that HIF-PH inhibitors may be equally effective in patients with or without underlying inflammation. The availability of new treatment options, including HIF-PH inhibitors, may improve treatment outcomes in difficult-to-manage patients with anemia of CKD. The current treatment options for patients with anemia of chronic kidney disease (CKD), as discussed by others in this issue of the supplement, include i.v. iron, erythropoiesis-stimulating agents (ESAs), and red blood cell (RBC) transfusions.1Kidney Disease Improving Global OutcomesKDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int Suppl. 2012; 2: 283-287Google Scholar However, management of anemia in CKD is often challenging, and is further complicated by certain patient characteristics, thereby limiting treatment options. The 2012 Kidney Disease Improving Global Outcomes clinical guideline for anemia of CKD recommends balancing the potential benefits of treatment with i.v. iron or ESA therapy against the risks of adverse reactions.1Kidney Disease Improving Global OutcomesKDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int Suppl. 2012; 2: 283-287Google Scholar In particular, i.v. iron may cause anaphylaxis (although rare), or delayed complications, such as serious infections or cardiovascular events.2Agarwal R. Kusek J.W. Pappas M.K. A randomized trial of intravenous and oral iron in chronic kidney disease.Kidney Int. 2015; 88: 905-914Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar,3Faich G. Strobos J. Sodium ferric gluconate complex in sucrose: safer intravenous iron therapy than iron dextrans.Am J Kidney Dis. 1999; 33: 464-470Abstract Full Text Full Text PDF PubMed Google Scholar ESA therapy has been associated with an increased risk of all-cause mortality, stroke, hypertension, thrombosis, and dialysis vascular access thrombosis.4Koulouridis I. Alfayez M. Trikalinos T.A. et al.Dose of erythropoiesis-stimulating agents and adverse outcomes in CKD: a metaregression analysis.Am J Kidney Dis. 2013; 61: 44-56Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar The potential risks associated with i.v. iron and ESA therapy, and reduced responsiveness to therapy may preclude and/or complicate current treatment options for some patients, making anemia management in these patients more difficult (Table 1). Many patient types can present unique challenges in the management of anemia of CKD, including frail elderly patients with CKD, who have an increased mortality risk,5Wu P.Y. Chao C.T. Chan D.C. et al.Contributors, risk associates, and complications of frailty in patients with chronic kidney disease: a scoping review.Ther Adv Chronic Dis. 2019; 10 (2040622319880382)Crossref Scopus (22) Google Scholar and patients with multiple comorbidities, such as inflammation, type 2 diabetes, or cancer, hospitalized patients, and kidney transplant recipients, who often have reduced responsiveness to iron and/or ESA therapy and may have an increased risk of adverse outcomes with these agents.Table 1Challenges associated with treatment of anemia in difficult-to-manage patients with anemia of CKDPatient groupChallenges of anemia managementInflammationAcute inflammation can reduce response to iron and ESA therapyDiabetesPrevalence of anemia is higher in patients with DKD than nondiabetic CKDAnemia has earlier onset and is more severeIncreased subclinical inflammationClinical inertia regarding initiating anemia managementCancerTransfusions can lead to complications but necessary in some patientsESA therapy can increase risk of tumor progression, VTE, and deathNo guidelines for ESA use in anemic CKD patients with cancerPatients who are hospitalizedDifficulties in transition of care from nephrologist to hospitalistAnemia can increase length of hospitalizationHb levels decrease during and after hospitalization with prolonged recoveryPatients that have received a kidney transplantPost-transplant anemia has a high prevalence and increases the risk of death, loss of graft function, congestive HFHigh-dose ESA does not improve short-term allograft functionLong-term low-dose ESA may prevent progression of allograft nephropathyCKD, chronic kidney disease; DKD, diabetic kidney disease; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; HF, heart failure; VTE, venous thromboembolism. Open table in a new tab CKD, chronic kidney disease; DKD, diabetic kidney disease; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; HF, heart failure; VTE, venous thromboembolism. This review summarizes the reasons why anemia management in patients with multiple comorbidities is particularly challenging and discusses new treatment options, including the potential role of hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, in patients with difficult-to-manage anemia of CKD. Anemia of inflammation is prevalent in several chronic conditions with prolonged systemic immune activation, including cancer, heart disease, inflammatory bowel disease, rheumatoid arthritis, and CKD.6Kassebaum N.J. Jasrasaria R. Naghavi M. et al.A systematic analysis of global anemia burden from 1990 to 2010.Blood. 2014; 123: 615-624Crossref PubMed Scopus (926) Google Scholar Anemia of inflammation is caused by activation of immune system mediators, which restrict iron absorption, impair erythropoiesis, and decrease the survival of erythrocytes (Figure 1).7Weiss G. Ganz T. Goodnough L.T. Anemia of inflammation.Blood. 2019; 133: 40-50Crossref PubMed Scopus (238) Google Scholar,8Zarychanski R. Houston D.S. Anemia of chronic disease: a harmful disorder or an adaptive, beneficial response?.CMAJ. 2008; 179: 333-337Crossref PubMed Scopus (91) Google Scholar Inflammation is associated with functional iron deficiency, which occurs when iron is sequestered in organs and the availability of this stored iron is restricted.9Begum S. Latunde-Dada G.O. Anemia of inflammation with an emphasis on chronic kidney disease.Nutrients. 2019; 11: 2424Crossref Scopus (16) Google Scholar,10David V. Martin A. Isakova T. et al.Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production.Kidney Int. 2016; 89: 135-146Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar Functional iron deficiency may be caused by increased hepcidin production,9Begum S. Latunde-Dada G.O. Anemia of inflammation with an emphasis on chronic kidney disease.Nutrients. 2019; 11: 2424Crossref Scopus (16) Google Scholar,11Mercadal L. Metzger M. Haymann J.P. et al.The relation of hepcidin to iron disorders, inflammation and hemoglobin in chronic kidney disease.PLoS One. 2014; 9e99781Crossref PubMed Scopus (48) Google Scholar which is stimulated by proinflammatory cytokines.12Canali S. Core A.B. Zumbrennen-Bullough K.B. et al.Activin B induces noncanonical SMAD1/5/8 signaling via BMP type I receptors in hepatocytes: evidence for a role in hepcidin induction by inflammation in male mice.Endocrinology. 2016; 157: 1146-1162Crossref PubMed Scopus (73) Google Scholar,13Nemeth E. 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Goldberg M.A. Effect of inflammatory cytokines on hypoxia-induced erythropoietin production.Blood. 1992; 79: 1987-1994Crossref PubMed Google Scholar and decreases erythropoietin-mediated stimulation of erythropoiesis.17Wagner M. Alam A. Zimmermann J. et al.Endogenous erythropoietin and the association with inflammation and mortality in diabetic chronic kidney disease.Clin J Am Soc Nephrol. 2011; 6: 1573-1579Crossref PubMed Scopus (48) Google Scholar Patients with advanced CKD will often have both functional and absolute iron deficiency,9Begum S. Latunde-Dada G.O. Anemia of inflammation with an emphasis on chronic kidney disease.Nutrients. 2019; 11: 2424Crossref Scopus (16) Google Scholar mainly due to reduced synthesis of erythropoietin.18Nangaku M. Eckardt K.U. Pathogenesis of renal anemia.Semin Nephrol. 2006; 26: 261-268Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar Renal mass decreases with progression of CKD, leading to erythropoietin deficiency. In patients with dialysis-dependent end-stage kidney disease (ESKD), blood losses during hemodialysis and frequent blood sampling further contribute to anemia.9Begum S. Latunde-Dada G.O. Anemia of inflammation with an emphasis on chronic kidney disease.Nutrients. 2019; 11: 2424Crossref Scopus (16) Google Scholar Management of anemia in patients with CKD and inflammation needs to consider both the cause of the systemic inflammation and the exacerbation of anemia of CKD. In patients with CKD, inflammation may induce poor response to iron (particularly oral iron) therapy, most likely due to reduced intestinal iron absorption.19Ueda N. Takasawa K. Impact of inflammation on ferritin, hepcidin and the management of iron deficiency anemia in chronic kidney disease.Nutrients. 2018; 10: 1173Crossref Scopus (46) Google Scholar An increase in serum ferritin to >500 ng/ml, particularly when accompanied by a decrease in hemoglobin and transferrin saturation levels, is indicative of inflammation.20Rambod M. Kovesdy C.P. Kalantar-Zadeh K. Combined high serum ferritin and low iron saturation in hemodialysis patients: the role of inflammation.Clin J Am Soc Nephrol. 2008; 3: 1691-1701Crossref PubMed Scopus (90) Google Scholar Because of increases in hepcidin levels, despite increases in ferritin, higher doses of i.v. iron or ESA therapy may be needed for maintenance of hemoglobin levels in patients with CKD and inflammation.19Ueda N. Takasawa K. Impact of inflammation on ferritin, hepcidin and the management of iron deficiency anemia in chronic kidney disease.Nutrients. 2018; 10: 1173Crossref Scopus (46) Google Scholar,21Ogawa T. Nitta K. Erythropoiesis-stimulating agent hyporesponsiveness in end-stage renal disease patients.Contrib Nephrol. 2015; 185: 76-86Crossref PubMed Scopus (19) Google Scholar Concurrent inflammation or infection is also associated with poor response to ESA therapy in patients with anemia of CKD.1Kidney Disease Improving Global OutcomesKDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int Suppl. 2012; 2: 283-287Google Scholar High C-reactive protein levels are associated with ESA hyporesponsiveness in patients with CKD22Ingrasciotta Y. Lacava V. Marcianò I. et al.In search of potential predictors of erythropoiesis-stimulating agents (ESAs) hyporesponsiveness: a population-based study.BMC Nephrol. 2019; 20: 359Crossref PubMed Scopus (6) Google Scholar and may be predictive of less stable hemoglobin levels.23de Francisco A.L. Stenvinkel P. Vaulont S. Inflammation and its impact on anaemia in chronic kidney disease: from haemoglobin variability to hyporesponsiveness.NDT Plus. 2009; 2: i18-i26Crossref PubMed Google Scholar In clinical practice, patients with a temporary peripherally inserted central catheter often develop subclinical inflammation and therefore require higher ESA doses for anemia correction. Concurrent periodontal infection may also be associated with increased inflammation. The 2012 Kidney Disease Improving Global Outcomes guideline recommended treating specific causes of ESA hyporesponsiveness, including any underlying inflammation.1Kidney Disease Improving Global OutcomesKDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int Suppl. 2012; 2: 283-287Google Scholar In patients with ESKD receiving renal replacement therapy, ESA hyporesponsiveness caused by chronic inflammation may be managed by the use of biocompatible hemodialysis membranes, ultrapure dialysate, or treatment with ascorbic acid, vitamin E, or statins.21Ogawa T. Nitta K. Erythropoiesis-stimulating agent hyporesponsiveness in end-stage renal disease patients.Contrib Nephrol. 2015; 185: 76-86Crossref PubMed Scopus (19) Google Scholar Type 2 diabetes contributes to an increased risk of macrovascular and microvascular complications,24Fowler M.J. Microvascular and macrovascular complications of diabetes.Clin Diabetes. 2008; 26: 77-82Crossref Scopus (976) Google Scholar and diabetes is the most common cause of CKD.25Foley R.N. Collins A.J. End-stage renal disease in the United States: an update from the United States Renal Data System.J Am Soc Nephrol. 2007; 18: 2644-2648Crossref PubMed Scopus (346) Google Scholar Macrovascular complications, including cardiovascular disease and cardiorenal syndrome, often complicate anemia management, as discussed in detail by McCullough in this issue of the supplement. The development and progression of diabetic kidney disease (DKD) is caused by microvascular changes in the kidney.26Weir M.R. Renal effects of sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes and renal impairment.Postgrad Med. 2019; 131: 367-375Crossref PubMed Scopus (2) Google Scholar Diabetes is also associated with inflammation, which is stimulated and exacerbated by hyperglycemia, dyslipidemia, and arterial hypertension.27Pappa M. Dounousi E. Duni A. Katopodis K. Less known pathophysiological mechanisms of anemia in patients with diabetic nephropathy.Int Urol Nephrol. 2015; 47: 1365-1372Crossref PubMed Scopus (18) Google Scholar The added burden of diabetic macrovascular and microvascular sequelae, including glomerular hypertrophy and tubulointerstitial fibrosis, further complicates the management of anemia in patients with DKD. The prevalence of anemia among patients with DKD may be increased by vitamin deficiency, low dietary iron, and poor glycemic control,28Bajaj S. Makkar B.M. Abichandani V.K. et al.Management of anemia in patients with diabetic kidney disease: a consensus statement.Indian J Endocrinol Metab. 2016; 20: 268-281Crossref PubMed Scopus (9) Google Scholar and is higher than in those with nondiabetic CKD.29Loutradis C. Skodra A. Georgianos P. et al.Diabetes mellitus increases the prevalence of anemia in patients with chronic kidney disease: a nested case-control study.World J Nephrol. 2016; 5: 358-366Crossref PubMed Google Scholar,30Al-Khoury S. Afzali B. Shah N. et al.Anaemia in diabetic patients with chronic kidney disease—prevalence and predictors.Diabetologia. 2006; 49: 1183-1189Crossref PubMed Scopus (46) Google Scholar In fact, the presence of diabetes is associated with a 4-fold increase in the risk of anemia in patients with CKD.30Al-Khoury S. Afzali B. Shah N. et al.Anaemia in diabetic patients with chronic kidney disease—prevalence and predictors.Diabetologia. 2006; 49: 1183-1189Crossref PubMed Scopus (46) Google Scholar In all stages of CKD, serum ferritin levels are higher in diabetic versus nondiabetic patients, indicating increased subclinical systemic inflammation in diabetic patients.29Loutradis C. Skodra A. Georgianos P. et al.Diabetes mellitus increases the prevalence of anemia in patients with chronic kidney disease: a nested case-control study.World J Nephrol. 2016; 5: 358-366Crossref PubMed Google Scholar Erythropoietin deficiency is considered one of the contributors to the development of anemia in diabetes,31Jones S.C. Smith D. Nag S. et al.Prevalence and nature of anaemia in a prospective, population-based sample of people with diabetes: Teesside anaemia in diabetes (TAD) study.Diabet Med. 2010; 27: 655-659Crossref PubMed Scopus (25) Google Scholar with low erythropoietin levels being predictive of a rapid decline in estimated glomerular filtration rate.32Fujita Y. Doi Y. Hamano T. et al.Low erythropoietin levels predict faster renal function decline in diabetic patients with anemia: a prospective cohort study.Sci Rep. 2019; 9: 14871Crossref PubMed Scopus (9) Google Scholar Iatrogenic anemia may occur in patients with DKD who are treated with thiazolidinediones, which cause hemodilution by increasing plasma volume, or angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, which lower hemoglobin levels via inhibition of the renin-angiotensin-aldosterone system.28Bajaj S. Makkar B.M. Abichandani V.K. et al.Management of anemia in patients with diabetic kidney disease: a consensus statement.Indian J Endocrinol Metab. 2016; 20: 268-281Crossref PubMed Scopus (9) Google Scholar Anemia appears to develop earlier in patients with DKD, even before glomerular filtration rate is severely reduced, compared with patients with nondiabetic CKD.30Al-Khoury S. Afzali B. Shah N. et al.Anaemia in diabetic patients with chronic kidney disease—prevalence and predictors.Diabetologia. 2006; 49: 1183-1189Crossref PubMed Scopus (46) Google Scholar The severity of anemia is also greater in diabetic versus nondiabetic patients with CKD across all stages of disease.27Pappa M. Dounousi E. Duni A. Katopodis K. Less known pathophysiological mechanisms of anemia in patients with diabetic nephropathy.Int Urol Nephrol. 2015; 47: 1365-1372Crossref PubMed Scopus (18) Google Scholar,28Bajaj S. Makkar B.M. Abichandani V.K. et al.Management of anemia in patients with diabetic kidney disease: a consensus statement.Indian J Endocrinol Metab. 2016; 20: 268-281Crossref PubMed Scopus (9) Google Scholar Furthermore, the presence of diabetes in patients with anemia of CKD compounds the risk of adverse cardiovascular outcomes, retinopathy, and CKD progression.28Bajaj S. Makkar B.M. Abichandani V.K. et al.Management of anemia in patients with diabetic kidney disease: a consensus statement.Indian J Endocrinol Metab. 2016; 20: 268-281Crossref PubMed Scopus (9) Google Scholar,33Mohanram A. Zhang Z. Shahinfar S. et al.Anemia and end-stage renal disease in patients with type 2 diabetes and nephropathy.Kidney Int. 2004; 66: 1131-1138Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar Despite the high risk of adverse outcomes in patients with DKD and anemia, clinical inertia exists regarding the initiation of iron or ESA therapy in these patients.28Bajaj S. Makkar B.M. Abichandani V.K. et al.Management of anemia in patients with diabetic kidney disease: a consensus statement.Indian J Endocrinol Metab. 2016; 20: 268-281Crossref PubMed Scopus (9) Google Scholar Studies have indicated that iron parameters (i.e., serum ferritin, transferrin saturation) are not routinely assessed and treatment of anemia is often inadequate in patients with diabetes.34Idris I. Tohid H. Muhammad N.A. et al.Anaemia among primary care patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD): a multicentred cross-sectional study.BMJ Open. 2018; 8e025125Crossref PubMed Scopus (21) Google Scholar,35Stevens P.E. Schernthaner G. 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Gandra S.R. et al.Timing of erythropoiesis-stimulating agent initiation and adverse outcomes in nondialysis CKD: a propensity-matched observational study.Clin J Am Soc Nephrol. 2010; 5: 882-888Crossref PubMed Scopus (16) Google Scholar The randomized TREAT study in patients with type 2 diabetes and CKD showed that ESA therapy with darbepoetin alfa (dose adjusted to maintain hemoglobin levels of approximately 13 g/dl) was not associated with a reduced risk of death or major cardiovascular and kidney events compared with placebo.37Pfeffer M.A. Burdmann E.A. Chen C.Y. et al.A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.N Engl J Med. 2009; 361: 2019-2032Crossref PubMed Scopus (1557) Google Scholar However, a subsequent analysis of the TREAT study found that poor initial response to ESA therapy may lead to an increased risk of cardiovascular events or death when ESA doses are escalated to meet the hemoglobin target level of approximately 13.0 g/dl.38Solomon S.D. 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