NEPHROLOGY

Anemia and Bone Disease of Chronic Disease: Pathogenesis, Diagnosis, and Management

DOUGLAS SHEMIN, MD

24 27 EN

ABSTRACT to ascribe the increased mortality risk to one or even a few and metabolic bone disease accompany chronic causes. As part of a broad approach, these abnormalities (CKD), and worsen as CKD progresses. It can be evaluated and treated, thereby potentially decreas- is likely that both processes contribute to the increased ing the mortality risk. Reviewing the treatment of all of morbidity and mortality seen in CKD. This paper brief- these processes is beyond the scope of a short paper. But ly reviews the pathogenesis and diagnosis of anemia and two abnormalities associated with the decreased renal syn- bone disease in CKD, and summarizes recent consensus thetic function of CKD: anemia, due to decreased produc- guidelines for treatment. tion of , and bone disease, due to decreased KEYWORDS: , anemia, production of , decreased excretion of phosphorus, hyperparathyroidism and increased synthesis of parathyroid hormone (PTH), may present early in CKD. They are relatively easy to diagnose and treat, and provide an opportunity to the primary care provider to potentially decrease some risks associated with CKD. This paper will review the diagnosis and management INTRODUCTION of anemia and bone disease due to CKD. Chronic kidney disease (CKD) affects 10–15% of adults in the United States, is a group of disorders characterized by Anemia a progressive decline in the glomerular filtration and renal Anemia, defined as a Hgb < 11.0 g/dL, is common in CKD excretion of low molecular weight solutes. The severity of and worsens as the CKD stage increases: data from a large CKD is measured by the estimated glomerular filtration observational study showed an anemia prevalence of 1.3 % rate (eGFR), derived from the serum (SCr) level, in stage III, 5.2% in stage IV, and 44.1% in stage V CKD; once and demographic criteria: age, sex, and ethnicity. The nor- patients progress to , it exceeds 90%.5 The cause of mal eGFR is over 120 ml/min; as CKD worsens, the eGFR anemia is multifactorial, including deficiencies of vitamin declines. The current classification of CKD was introduced B12 or folate, defective intestinal absorption of iron due to in 2002 by the National Kidney Foundation (NKF)1 and subse- the presence of hepcidin, occult bleeding due to a qualita- quently adopted by the international group, Kidney Disease tive defect in function, hemolysis, or bone marrow Improving Global Outcomes (KDIGO).2 The cause of CKD disease. But the likely greatest contributor relates to CKD may be mellitus, , polycystic disease, itself: a defect in erythropoietin (EPO) production. chronic or other causes, but regardless of EPO is a 165 amino acid protein, which stimulates bone diagnosis, the NKF/KDIGO classification defines stage III as marrow receptors to produce red cell precursors and pro- an eGFR of 30–60 ml/min, stage IV as an eGFR of 15–30 ml/ mote their differentiation into mature erythrocytes. EPO min, and stage V CKD as an eGFR below 15 ml/min. is primarily synthesized in kidney cells, so progressive Many large observational studies demonstrate that car- loss of kidney function leads to decreased EPO production. diovascular morbidity and mortality increase as the stage EPO production normally can be increased thousandfold in advances.3 Recently, it has been shown that ( > response to tissue hypoxia in a process mediated by hypoxia 30 mg/gram creatinine/24 hour urine), independently of the inducible factor 1, and loss of this augmentation occurs in eGFR predicts morbidity and mortality.4 Patients with CKD CKD. These abnormalities are present in all causes of CKD, are at highest risk of all cause mortality if their eGFR is < with some exceptions: polycystic disease, for example, may 15 ml/min and urinary albumin excretion is > 300 mg/gram be associated with normal or high EPO production.6 creatinine, but in all age groups, mortality risk increases Until the mid to late 1980s, the only for the anemia below an eGFR of 60 ml/min.4 of CKD was vitamin and iron supplementation and blood CKD involves many pathophysiologic abnormalities: transfusions. Besides depleting the blood supply, over-reli- fluid overload, hypertension, accelerated atherosclerosis, ance on transfusions caused increase in and C in , malnutrition, , hyperkale- CKD patients, iron overload, and development of antibodies, mia, anemia, and metabolic bone disease and it is difficult increasing sensitization to potential renal transplants.

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The gene for EPO production was cloned in 1985; immedi- Bone Disease ately, EPO production began, and soon, many clinical trials Bone disease in CKD results from abnormalities of metab- showed that administration of exogenous EPO increased the olism of two ions: phosphorus and calcium, and two hor- Hgb in patients at all stages of CKD, and decreased trans- mones: 1,25 vitamin D (calcitriol) and PTH. Phosphorus in fusion dependence. Also, most clinical trials showed that the diet is absorbed in the gastrointestinal tract, has a molec- administration of EPO and its structural analogue, darbep- ular weight of 31 daltons and is water soluble, is filtered by oietin (with a longer half life) tends to improve subjective the kidney and its excretion decreases, and the serum level symptoms (fatigue, exercise tolerance, sexual dysfunction, rises, as the eGFR decreases in CKD. The increase in the cognitive function, and depression) in CKD in treated phosphorus level decreases the concentration of ionized and patients compared to controls7). These findings, along with albumin bound calcium, as a greater proportion of calcium suggestions that cardiovascular morbidity and mortality is bound to phosphorus. Renal hydroxylation of 25-vitamin was decreased with EPO treatment, and Medicare payment D to its active form (calcitriol) also decreases as a result of for erythropoietin in dialysis patients on dialysis, led to vir- progressive CKD. The presence of calcitriol is necessary for tually universal EPO treatment of the anemia in dialysis absorption of dietary calcium, and decreasing calcitriol, in patients and common treatment at earlier stages of CKD. addition to the high phosphorus level, leads to a drop in the But the Hgb target to which EPO therapy should be directed serum calcium concentration.14 was not well established. Three large, randomized, placebo The decrease in the serum calcium level stimulates cal- controlled trials, published between 2006 and 2009 addressed cium sensing receptors in the parathyroid gland to increase this issue. The trials all randomized anemic patients with transcription and synthesis of PTH. High serum phosphorus CKD to either a high or low Hgb target by varying the dose and low calcitriol level also independently increase release of EPO or darbepoietin. The Correction of and of PTH. The high PTH, which may be present as early in Outcomes in Renal Insufficiency (CHOIR) study randomized CKD as an eGFR of 40 ml/min, increases as CKD progresses. patients to Hgb normalization (mean achieved Hgb 13.5 g/ Most laboratories in the United States use an intact PTH dL) or partial correction (mean achieved Hgb 11.3) and found (i-PTH) assay, which measures both the biologically active that normalization of the Hgb was associated with a statis- PTH molecule and renally excreted inactive fragments, so tically greater rate of a composite outcome of cardiovascular as GFR worsens, the high intact PTH is due, in part, to this death or morbidity.8 The Cardiovascular Risk Reduction by artifactual effect.15 In a patient with normal renal function, Early Anemia treatment with Epoetin beta (CREATE) trial the elevated PTH would correct the low calcium and high randomized patients to full anemia correction (target Hgb phosphorus levels by increasing renal tubular reabsorption 13 -15 g/dL) or partial correction (target Hgb 10.5–11.5 g/ of calcium and decreasing reabsorption of phosphorus, but dL). There was a non-statistically significant trend towards this fails to occur as CKD progresses. So the metabolic bone a higher incidence of cardiovascular events in the full cor- abnormalities of CKD include (phos- rection group.9 Finally, the Trial to Reduce Cardiovascu- phorous level > 5.5 mg/dL), hypocalcemia, a low circulating lar Events with Aranesp Therapy (TREAT) trial compared calcitriol level, and a high level of PTH. targeting a Hgb of 13 g/dL with darbopoietin to placebo in Sustained elevation of the PTH causes two major problems CKD patients with diabetes, and found treatment to a higher in CKD. PTH regulates bone mineral content, and elevation Hgb target was not associated with a cardiovascular benefit, of the PTH increases osteoblastic, and more importantly, and was associated with a higher risk of stroke, and cancer osteoclastic activity, leading to decreased bone mineraliza- associated mortality.10 tion and growth, and an increased risk of fractures. In addi- The results of these trials have greatly influenced treat- tion, release of calcium and phosphorus from bone can lead ment of CKD associated anemia with EPO or darbopoi- to deposition of calcium and phosphorus in soft tissue and etin. In 2011, The Food and Drug Administration (FDA) blood vessels, contributing to accelerated atherosclerosis released an advisory statement that the target Hgb level in and arterial stiffening. There is an incremental relationship CKD patients should no longer be 10–12 g/dL, but should between elevation of the PTH level and cardiovascular mor- be replaced by a program of using the lowest possible EPO bidity and mortality.16 Low circulating levels of calcitriol are or darbepoetin dose necessary to avoid transfusions.11 The also associated with increased mortality.17 A high phospho- FDA later specified that although that treatment of CKD rus level is clearly identified with mortality in CKD patients associated anemia should be individualized, dosing of EPO treated with maintenance dialysis16 and there is now new or darbopoietin in an anemic patient with CKD should be evidence suggesting a relationship between elevation of the decreased once the Hgb level exceeds 11.0. The FDA guide- serum phosphorus and mortality in individuals with less lines were endorsed by the KDIGO advisory group in 2012 advanced CKD.18 and the American advisory group KDOQI (Kidney Disease for the metabolic bone abnormalities of CKD Outcomes Quality Initiative) in 2013.12,13 are aimed at correcting the abnormal levels of calcium, phos- phorus, calcitriol, and PTH, and hopefully decreasing the effects of bone abnormalities on mortality. Unfortunately,

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most of the data on these therapies are present in retrospec- in small observational studies, been linked with a greater tive, observational, or short-term prospective trials. But, degree of vascular calcification,25 and they should be avoided similar to guidelines on treatment of anemia in CKD, two in patients with hypercalcemia. main consortiums of experts, the KDIGO group, in 2009, and the KDOQI group in 2010, have established guidelines for the evaluation and treatment of metabolic bone disease CONCLUSION in CKD, and the guidelines are largely in agreement.19,20 Anemia and bone disease commonly occur as consequences In stage III CKD, both groups recommend measuring the of CKD, become more severe as CKD progresses, and con- calcium and phosphorus every 6–12 months, and the PTH tribute to the increased morbidity and mortality seen in level once, with follow-up levels depending on the circum- CKD. Both abnormalities can be relatively easily diagnosed. stance. In stage IV CKD, they recommend calcium and The specifics of treatment are subject to some debate, but phosphorus levels every 3–6 months and PTH levels every initial treatment, as summarized above, can readily be 6–12 months, and in stage V CKD, calcium and phosphorus administered by a primary care . measurements every 1–3 months, and PTH levels every 3 –6 months. In all CKD stages, the 25-vitamin D level should be measured at least once, with follow-up levels depending on References the circumstance. 1. National Kidney Foundation. K/DOQI Clinical Practice Guide- In all CKD stages, if 25–vitamin D deficiency (< 30 ng/ lines for Chronic Kidney Disease: Evaluation, Classification, ml) is detected, patients should be given nutritional vitamin and Stratification.Am J Kidney Dis. 2002;39:S1-S266. D (ergocalciferol). Because of decreased hydroxylation of 2. Kidney Disease Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO Clinical Practice Guideline for the Evalu- 25-OH vitamin D in advanced CKD, some experts suggest ation and Management of Chronic Kidney Disease. Kidney Int administration of calcitriol instead.21 In CKD stages III–V, Suppl. 2013;3:1-150. the calcium and the phosphorus level should be maintained 3. Go AS, Chertow GM, Fan D, et al. Chronic Kidney Disease and the Risks of Death, Cardiovascular Events, and Hospitalization. in the reference range, (for phosphorus, 2.7–4.6 mg/dL in N Engl J Med. 2004; 353[13]:1296-1305. stage III-IV, and 3.5–5.5 in stage V CKD). Although earlier 4. Hallan SI, Matsushita K, Sang Y, et al. Age and Association of position papers suggested tight control of the PTH level), Kidney Measures with Mortality and End-stage Renal Disease. KDIGO and KDOQI suggest maintaining the PTH level at JAMA. 2012; 308[22]:2349-2360. 2–9 times the upper limit of normal of the reference range; 5. Astor BC, Muntner P, Levin A, et al. Association of Kid- ney Function with Anemia: the Third National Health and this works out to be 150–600 pg/ml. Nutrition Examination Study (1988 – 1994). Arch Int Med. The details of achieving these targets are not specified, 2002;162[12]:1401-1408. but usually involve a combination of vitamin D, dietary 6. Goodkin DA, Fuller DS, Robinson BM, et al. Naturally Oc- curring Higher Hemoglobin Concentration Does Not Increase phosphorus restriction, and phosphorus binders. As above, Mortality among Patients. J Am Soc Nephrol. ergocalciferol, 50,000 to 100,000 IU per week, with substi- 2011;22[2]358-365. tution of calcitriol, 0.25 mcg daily as renal function wors- 7. Stevens L, Stigant C, Levin A. Should Hemoglobin be Normal- ens, should be prescribed to vitamin D deficient patients; ized in Patients with Chronic Kidney Disease? Semin Dialysis. 2002;15[1]8-13. calcitriol will also independently decrease the PTH level. 8. Singh AK, Szczech L, Kang TL, et al. Correction of Anemia However vitamin D products will increase the phosphorus with Epoetin Alfa in Chronic Kidney Disease. N Engl J Med. level, by increasing gastrointestinal phosphorus absorption. 2006;355[20]2085-2098. Dietary phosphorus restriction (5–10 mg/kg/day, compared 9. Drueke TB, Locatelli F, Clyne N, et al. Normalization of He- moglobin Level in Patients with Chronic Kidney Disease and to a usual phosphorus intake of 15–20 mg/kg/day) is the Anemia. N Engl J Med. 2006;355[20]: 2071-2084. first step. Phosphate restriction may entail protein restric- 10. Pfeffer MA, Burdmann EA, Chen CY, et al. A Trial of Darbopoie- tion, so this may require the involvement of a dietitian to tin Alfa in Type II Diabetes and Chronic Kidney Disease. N Engl avoid malnutrition. Ingestion of plant- based proteins leads J Med. 2009;361[21]:2019 –2032. to less hyperphosphatemia than ingestion of animal based 11. Food and Drug Administration. FDA Drug Safety Commu- nication: Modified Dosing Recommendations to Improve 22 proteins. the Safe use of Erythropoiesis Stimulating Agents in Chronic If dietary restriction fails to control the phosphorus level, Kidney Disease. 2011; http://www.fda.gov/drugs/drugsafety/ phosphate binders, which prevent gastrointestinal phospho- ucm259639.htm. 12. KDIGO Anemia Work Group, KDIGO Clinical Practice Guide- rus absorption, should be used, and there is some evidence line for Anemia in Chronic Kidney Disease. Kidney Int Suppl. that phosphorus binders improve morbidity and mortality 2012;2[4]:279-335. in CKD.23 13. Kliger AS, Foley RN, Goldfarb DS, et al. KDOQI US Commen- Phosphorus binders are calcium-based (calcium carbon- tary on the 2012 KDIGO Clinical Practice Guidelines for Ane- mia in CKD. Am J Kidney Dis. 2013;62[5]:849–859. ate, calcium acetate) or non-calcium based (sevelamer, or 14. Moorthi RN, Moe SM. CKD—Mineral and Bone Disorder: Core lanthanum). All phosphorus binders will lower the serum Curriculum 2011. Am J Kidney Dis. 2011;58[6]:1022-1036. phosphorus. There is no proven superiority of one class 15. Souberbielle JP, Roth H, Fouque DP. Parathyroid Measurement or agent over another.24 Calcium containing agents, have, in CKD. Kidney Int. 2010;77[2]93-100.

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16. Block GA, Klassen PS, Lazarus JM, et al. Mineral Metabolism, Author Mortality, and Morbidity in Maintenance Hemodialysis. J Am Douglas Shemin, MD, is Medical Director, Rhode Island Soc Nephrol. 2004;15[8]:2208-2218. Dialysis Program, Division of Kidney Diseases and 17. Ravani P, Malberti F, Tripepi G, et al. Vitamin D Levels and Hypertension, and Associate Professor of , The Alpert Patient Outcome in Chronic Kidney Disease. Kidney Int. of Brown University, Providence, RI. 2009;75[1]88-95. 18. Foley RN. Phosphate Levels and Cardiovascular Disease in the Correspondence General Population. Clin J Am Soc Nephrol. 2009;4[11]:1136- Douglas Shemin, MD 1139. Division of Kidney Diseases and Hypertension 19. Kidney Disease Improving Global Outcomes (KDIGO) CKD- MBD Work Group. KDIGO Clinical Practice Guidelines for the Rhode Diagnosis, Evaluation, Prevention, and Treatment of Chronic 593 Eddy Street Kidney Disease-Mineral and Bone Disorders (CKD-MBD). Kid- Providence, RI 02903 ney Int Suppl. 2009;113:S1-S130. 401-444-5445 20. KDOQI US Commentary on the 2009 KDIGO Clinical Prac- Fax 401-444-8453 tice Guideline for the Diagnosis, Evaluation, and Treatment of CKD-Mineral and Bone Disorder. Am J Kidney Disease. [email protected] 2010;55[5]:773-799. 21. Shoben AB, Rudser KD, de Boer IH, et al. Association of oral Calcitriol with Improved Survival in Nondialyzed CKD. J Am Soc Nephrol. 2008;19[8]:1613-1619. 22. Moe SM, Zidehsarai MP, Chambers MA, et al. Vegetarian Com- pared to Meat Dietary Protein Source and Phosphorus Homeo- stasis in Chronic Kidney Disease. Clin J Am Soc Nephrol. 2011; 6[2]:257-264. 23. Kovesdy CP, Kuchmak O, Lu JL, et al. Outcomes associated with Phosphorus Binders in Men with Non-Dialysis Dependent CKD. Am J Kidney Dis. 2010; 56[5]:842-851. 24. Block GA, Wheeler DC, Persky MS, et al. Effects of Phosphate Binders in Moderate CKD. J Am Soc Nephrol. 2012;23[10]:1407- 1415. 25. Goodman WG, Goldin J, Kuizon BD, et al. Coronary Artery Cal- cification in Young Adults with End Stage Renal Disease who are Undergoing Dialysis. N Engl J Med. 2000;342[20]:1478-1483.

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