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AppendixAppendices contents- Definition of type of anemia- ICD codes, NPU codes and ATC codes- Anemia trajectory over time Supplementary figures and tables contents Suppl. Figure 1. Overall study design: Inclusion of patients with newly identified CKD based on eGFR measurements, with examples of patients progressing to later stage CKD during follow-up.Suppl. Figure 2. Anemia distribution over time starting from the index date of any newly identified CKD (stages 3-5). First time point (0 months): closest hemoglobin (Hb) measurement to the index date during month 0-3 following CKD diagnosis. Second time point (6 months): closest Hb measurement to 6 months during month 4-9 following CKD diagnosis. Third time point (12 months): closest Hb measurement to 12 months during month 10-15 following CKD diagnosis. Suppl. Table 1. Incidence of anemia in patients with newly identified CKD stratified by erythrocyte volume.Suppl. Table 2. Incidence of anemia in patients with newly identified CKD stratified by erythrocyte hemoglobin content.Suppl. Table 3. Incidence of anemia in patients with newly identified CKD stratified by anemia grade.Suppl. Table 4. Distribution of anemia grades during the twelve months following the first anemia event in patients with CKD stages 3-5, Northern Denmark, 2009-2016.Definition of type of anemiaBy mean corpuscular volume (MCV): Microcytic anemia: MCV< 80 femtoliterNormocytic anemia: 80≤ MCV ≤ 100 femtoliterMacrocytic anemia: MCV >100 femtoliterBy mean corpuscular hemoglobin (MCH): Hypochromic anemia: MCH <27 picograms/cellNormochromic anemia: 27≤ MCH ≤ 31 picograms/cellHyperchromic anemia: MCH >31 picograms/cellICD codes, NPU codes and ATC codesCodebook of biomarkers. BiomarkerType of codeCodesCreatinineNPU codesNPU18016 NPU01807 NPU04998 ASS00356 ASS00354 ASS00355Analysis numbers716, 1155, 1807, 4998, 5224, 18016, 38926, 38927, 38928, 110266, 111016, 1311235, 1411235, 1511235, 1511236, 1511237, 1610154, 1610296, 1611807, 1710301, 1710552, 1711807, 1811807, 1817156, 1817428HemoglobinNPU codes (Central Region)AAA00359 AAA93003 AAB00012 AAB00216 ASS00112NPU codes (Northern Region)ASS00112 ASS00126 ASS00996 NPU02319Analysis numbers (Central Region)2319 117969 122572 122582 122672 111035 1817501 1523071 1524071 1610108 1712319 1812319Analysis numbers (Northern Region)1312101 1312150 1412101 1412150Type (NPU code)NPU01944Color (NPU code)NPU02320Codebook of pharmaceutical drugs used prior to baselineDrugATC codesAngiotensin-converting-enzyme inhibitors (ACE-i)C09A, C09BAngiotensin II receptor blockers (ARBs)C09C, C09DLoop diureticsC03CAspirinB01AC06, N02BA01, N02BA51Immunosuppressant useL04 GlucocorticoidsH02ABVitamin K antagonistsB01AAVariables used for exclusion or baseline characteristics. Codes are ICD-10 except when stated otherwise.DisorderType of codeCodesCancerDiagnosesC chapter (excluding non-melanoma skin cancer C44)Hereditary hematological diseaseDiagnosesD56, D57Chronic inflammatory diseaseDiagnosesM05 M32 K90.0Gastrointestinal bleedingDiagnosesI85.0, K22.6, K25.0, K25.4, K26.0, K26.4, K27.0, K27.4, K28.0, K28.2, K28.3, K28.4, K28.6, K29.0, K62.5, K92.0, K92.1, K92.2, K63.8B, K63.8CTransplantationDiagnosesT86.2, T86.3, T86.4, T86.8E, T86.8J, T81.7E1Procedures (procedural codes)KFQ, KGDG, KJJC, KJLE, KKASDialysisProcedural codeBJFDAny cardiovascular disease (incl. Stable angina pectoris, Myocardial infarction, Heart failure, Stroke, Atrial fibrillation/flutter, Heart valve disease, Venous thromboembolism)DiagnosesStable angina pectorisDiagnosesI20 (except I20.0), I251, I259. Patients with myocardial infarction will not be considered as having stable angina pectoris even if they have one of the above codesMyocardial infarctionDiagnosesI21, I22, I23Heart failureDiagnosesI50StrokeDiagnosesI60, I61, I63, I64Atrial fibrillation/flutterDiagnosesI48Heart valve diseaseDiagnosesI05, I06, I07, I08, I09.8, I34-I37, I39, I51.1A, Q22, Q23Venous thromboembolismDiagnosesI26, I80.1, I80.2, I80.3DiabetesDiagnosesE10, E11, E12, E13, E14, O24 (except O24.4), G63.2, H36.0, N08.3ATCA10A, A10BChronic pulmonary diseaseDiagnosesJ40, J41-J44, J45?J47, J60?J67, J68.4, J70.1, J70.3, J84.1, J92.0, J96.1, J98.2, J98.3Liver diseaseDiagnosesB18, B15.0, B16.0, B16.2, B19.0, I85, K70, K71, K72, K73, K74, K760, K76.6Anemia trajectory over time MethodsTo furthermore describe CKD patients’ anemia trajectory also after their first anemia event, we used two different approaches without censoring at the first anemia event. In the first approach, we visualized the flow of patients between different anemia grades over time in a Sankey plot: We grouped patients by anemia grade at 0, 6, and 12 months following the CKD index date, using the measured Hb closest to these time points within 0-3, 4-9, and 10-15 months after CKD, respectively, to assess anemia grade. Patients were classified as having no Hb measurement, No anemia, Mild anemia, Moderate anemia or Severe anemia or being dead.In the second approach, we defined the index date as the date of the first anemia event, and stratified patients by anemia grade at this event. We then tabulated the proportions of patients in groups by grade of anemia at 12 months after the first anemia event based on the last Hb measurement during 10-12 months, if any were available.ResultsAnemia distributions for the first 12 months following the date of newly identified CKD show that the majority of patients had either “no anemia” or “no Hb measurement” at 0 months (Suppl. Figure 2). Six months after the index date, few of these patients had mild anemia and even fewer had moderate or severe anemia (Suppl. Figure 2). Among patients with anemia at time 0, the majority retained the same anemia grade 6 and 12 months after their index date. Also, at one year after the first anemia event, the majority of patients with a Hb measurement recorded had repeated anemia events (Suppl. Table 4). The majority of CKD patients with a recorded Hb measurement retained the same anemia event grade in the subsequent year, regardless whether the index date was defined as the date of newly identified CKD or as the date of the first anemia event (Suppl. Table 4 and Suppl. Figure 2). Supplementary Figures and Tables Suppl. Figure 1. Overall study design: Inclusion of patients with newly identified CKD based on eGFR measurements, with examples of patients progressing to later stage CKD during follow-up Suppl. Figure 2. Anemia distribution over time starting from the index date of any newly identified CKD (stages 3-5). First time point (0 months): closest hemoglobin (Hb) measurement to the index date during month 0-3 following CKD diagnosis. Second time point (6 months): closest Hb measurement to 6 months during month 4-9 following CKD diagnosis. Third time point (12 months): closest Hb measurement to 12 months during month 10-15 following CKD diagnosis ADDIN Suppl. Suppl. Table 1. Incidence of anemia in patients with newly identified CKD stratified by erythrocyte volumeOutcomeCKD stage at index dateNN of eventsPerson-years1-year risk (95% CI)2-year risk (95% CI)3-year risk (95% CI)5-year risk (95% CI)Incidence rate per 100 person-years (95% CI)Crude hazard ratio (95% CI)Hazard ratio (95% CI) adjusted for sex, age, CCI category, and calendar yearMicrocytic anemiaAny CKD55,940547182,999.00.7 (0.6 - 0.8)0.9 (0.8 - 0.9)0.9 (0.9 - 1.0)1.1 (1.0 - 1.2)0.3 (0.3 - 0.3)N/AN/A3A 41,958412137,463.40.7 (0.6 - 0.8)0.9 (0.8 - 0.9)0.9 (0.8 - 1.0)1.1 (1.0 - 1.2)0.3 (0.3 - 0.3)(ref)(ref)3B 17,87518152,384.70.8 (0.7 - 0.9)0.9 (0.8 - 1.1)1.0 (0.9 - 1.2)1.1 (0.9 - 1.3)0.3 (0.3 - 0.4)1.08 (0.91 - 1.27)0.91 (0.77 - 1.08)4 5,1825713,453.30.9 (0.7 - 1.2)1.0 (0.8 - 1.3)1.1 (0.8 - 1.4)1.2 (0.9 - 1.5)0.4 (0.3 - 0.5)1.22 (0.93 - 1.61)0.93 (0.70 - 1.24)593152,416.00.4 (0.1 - 1.1)0.6 (0.2 - 1.2)0.6 (0.2 - 1.2)0.6 (0.2 - 1.2)0.2 (0.1 - 0.5)0.60 (0.25 - 1.44)0.47 (0.19 - 1.16)Normocytic anemiaAny CKD55,94012,703152,504.616.2 (15.9 - 16.5)19.7 (19.3 - 20.0)22.0 (21.6 - 22.4)25.2 (24.8 - 25.6)8.3 (8.2 - 8.5)N/AN/A3A 41,9588,474117,621.913.6 (13.3 - 14.0)17.1 (16.7 - 17.5)19.6 (19.2 - 20.0)23.2 (22.7 - 23.7)7.2 (7.1 - 7.4)(ref)(ref)3B 17,8755,18740,601.422.8 (22.2 - 23.5)26.6 (26.0 - 27.3)28.9 (28.2 - 29.6)31.5 (30.8 - 32.3)12.8 (12.4 - 13.1)1.61 (1.56 - 1.66)1.36 (1.31 - 1.40)4 5,1821,6709,862.128.6 (27.3 - 29.8)31.2 (30.0 - 32.5)32.7 (31.4 - 34.0)34.0 (32.6 - 35.3)16.9 (16.1 - 17.8)1.96 (1.86 - 2.07)1.60 (1.51 - 1.69)59312581,787.426.9 (24.1 - 29.8)27.6 (24.7 - 30.5)28.3 (25.3 - 31.2)28.5 (25.6 - 31.5)14.4 (12.7 - 16.3)1.70 (1.49 - 1.94)1.70 (1.49 - 1.94)Macrocytic anemiaAny CKD55,9401,503180,781.52.1 (2.0 - 2.2)2.4 (2.3 - 2.5)2.6 (2.5 - 2.8)2.9 (2.8 - 3.1)0.8 (0.8 - 0.9)N/AN/A3A 41,958926136,315.31.6 (1.5 - 1.8)2.0 (1.8 - 2.1)2.2 (2.0 - 2.3)2.5 (2.3 - 2.6)0.7 (0.6 - 0.7)(ref)(ref)3B 17,87566551,330.03.0 (2.8 - 3.3)3.5 (3.2 - 3.7)3.8 (3.5 - 4.0)4.0 (3.7 - 4.3)1.3 (1.2 - 1.4)1.76 (1.60 - 1.93)1.39 (1.27 - 1.53)4 5,18224913,019.54.2 (3.7 - 4.8)4.6 (4.1 - 5.2)4.8 (4.2 - 5.4)5.1 (4.5 - 5.7)1.9 (1.7 - 2.2)2.37 (2.07 - 2.73)1.81 (1.57 - 2.09)5931312,362.13.3 (2.3 - 4.6)3.3 (2.3 - 4.6)3.3 (2.3 - 4.6)3.3 (2.3 - 4.6)1.3 (0.9 - 1.9)1.64 (1.15 - 2.35)1.72 (1.19 - 2.47)OutcomeCKD stage at indexNN of eventsPerson-years1-year risk (95% CI)2-year risk (95% CI)3-year risk (95% CI)5-year risk (95% CI)Incidence rate per 100 person-years (95% CI)Crude hazard ratio (95% CI)Hazard ratio (95% CI) adjusted for sex, age, CCI category, and calendar yearHypochromic anemiaAny CKD55,940462183,225.00.5 (0.5 - 0.6)0.7 (0.6 - 0.7)0.8 (0.7 - 0.9)0.9 (0.8 - 1.0)0.3 (0.2 - 0.3)N/AN/A3A 41,958332137,673.60.5 (0.4 - 0.6)0.6 (0.6 - 0.7)0.8 (0.7 - 0.8)0.9 (0.8 - 1.0)0.2 (0.2 - 0.3)(ref)(ref)3B 17,87518952,410.20.8 (0.7 - 1.0)0.9 (0.8 - 1.1)1.0 (0.9 - 1.2)1.2 (1.0 - 1.4)0.4 (0.3 - 0.4)1.41 (1.19 - 1.66)1.18 (0.99 - 1.40)4 5,1825613,450.10.9 (0.7 - 1.2)1.0 (0.8 - 1.3)1.1 (0.8 - 1.4)1.2 (0.9 - 1.5)0.4 (0.3 - 0.5)1.52 (1.14 - 2.01)1.19 (0.89 - 1.60)593152,414.80.5 (0.2 - 1.2)0.5 (0.2 - 1.2)0.5 (0.2 - 1.2)0.5 (0.2 - 1.2)0.2 (0.1 - 0.5)0.76 (0.31 - 1.83)0.70 (0.29 - 1.71)Normochromic anemiaAny CKD55,9402,895177,393.93.3 (3.1 - 3.4)4.2 (4.1 - 4.4)4.9 (4.7 - 5.1)5.8 (5.6 - 6.0)1.6 (1.6 - 1.7)N/AN/A3A 41,9582,041133,697.12.9 (2.8 - 3.1)3.9 (3.7 - 4.1)4.6 (4.4 - 4.8)5.7 (5.4 - 5.9)1.5 (1.5 - 1.6)(ref)(ref)3B 17,8751,15050,186.34.7 (4.4 - 5.0)5.8 (5.5 - 6.2)6.3 (6.0 - 6.7)7.1 (6.7 - 7.5)2.3 (2.2 - 2.4)1.41 (1.32 - 1.51)1.22 (1.14 - 1.31)4 5,18234912,805.15.6 (5.0 - 6.2)6.3 (5.7 - 7.0)6.8 (6.1 - 7.5)7.3 (6.6 - 8.1)2.7 (2.4 - 3.0)1.57 (1.41 - 1.76)1.34 (1.19 - 1.51)5931582,285.75.8 (4.4 - 7.4)6.2 (4.7 - 7.8)6.5 (5.0 - 8.3)6.5 (5.0 - 8.3)2.5 (1.9 - 3.3)1.47 (1.13 - 1.92)1.56 (1.19 - 2.03)Hyperchromic anemiaAny CKD55,9401,695180,447.42.0 (1.9 - 2.1)2.5 (2.3 - 2.6)2.9 (2.7 - 3.0)3.4 (3.3 - 3.6)0.9 (0.9 - 1.0)N/AN/A3A41,9581,206135,759.31.8 (1.7 - 2.0)2.3 (2.2 - 2.5)2.7 (2.5 - 2.9)3.4 (3.2 - 3.6)0.9 (0.8 - 0.9)(ref)(ref)3B17,87568351,343.62.8 (2.6 - 3.0)3.3 (3.0 - 3.6)3.8 (3.5 - 4.0)4.2 (3.9 - 4.5)1.3 (1.2 - 1.4)1.41 (1.29 - 1.53)1.16 (1.07 - 1.27)4 5,18221313,130.53.7 (3.2 - 4.2)4.1 (3.5 - 4.6)4.2 (3.7 - 4.8)4.3 (3.8 - 4.9)1.6 (1.4 - 1.9)1.60 (1.39 - 1.85)1.31 (1.13 - 1.52)5931212,374.32.3 (1.4 - 3.4)2.3 (1.4 - 3.4)2.3 (1.4 - 3.4)2.3 (1.4 - 3.4)0.9 (0.5 - 1.4)0.88 (0.57 - 1.36)0.95 (0.62 - 1.48)Suppl. Table 2. Incidence of anemia in patients with newly identified CKD stratified by erythrocyte hemoglobin contentSuppl. Table 3. Incidence of anemia in patients with newly identified CKD stratified by anemia gradeOMCKD stageNN of eventsPerson-years1-year risk (95% CI)2-year risk (95% CI)3-year risk (95% CI)5-year risk (95% CI)Incidence rate per 100 person-years (95% CI)Crude hazard ratio (95% CI)Hazard ratio (95% CI) adjusted for sex, age, CCI category, and calendar yearMild anemia (grade 1) Any CKD55,94033,14699,207.541.4 (41.0 - 41.8)50.9 (50.5 - 51.4)57.4 (57.0 - 57.9)66.9 (66.4 - 67.3)33.4 (33.1 - 33.8)N/AN/A3A 41,95822,32682,451.135.5 (35.0 - 36.0)44.9 (44.4 - 45.4)51.5 (51.0 - 52.0)61.6 (61.0 - 62.2)27.1 (26.7 - 27.4)(ref)(ref)3B 17,87512,94521,480.355.8 (55.1 - 56.6)65.7 (65.0 - 66.4)71.9 (71.2 - 72.6)79.7 (79.0 - 80.4)60.3 (59.2 - 61.3)1.83 (1.80 - 1.87)1.54 (1.51 - 1.58)4 5,1824,3303,392.072.5 (71.3 - 73.7)80.7 (79.6 - 81.8)84.8 (83.7 - 85.8)88.8 (87.8 - 89.8)127.7 (123.9 - 131.5)2.91 (2.81 - 3.00)2.28 (2.20 - 2.36)5931886158.293.6 (91.7 - 95.1)95.8 (94.2 - 97.0)97.2 (95.8 - 98.1)97.3 (96.0 - 98.2)559.9 (523.6 - 598.0)5.54 (5.24 - 5.87)4.78 (4.48 - 5.10)Moderate anemia (grade 2)Any CKD55,94016,433152,434.314.4 (14.1 - 14.7)20.9 (20.5 - 21.3)26.3 (25.9 - 26.7)35.2 (34.7 - 35.6)10.8 (10.6 - 10.9)N/AN/A3A 41,95810,119118,805.811.2 (10.9 - 11.5)16.9 (16.5 - 17.3)21.7 (21.3 - 22.2)29.9 (29.3 - 30.4)8.5 (8.4 - 8.7)(ref)(ref)3B 17,8756,75140,932.420.2 (19.6 - 20.8)28.7 (28.0 - 29.4)34.9 (34.1 - 35.6)45.1 (44.3 - 46.0)16.5 (16.1 - 16.9)1.85 (1.80 - 1.91)1.53 (1.49 - 1.58)4 5,1822,7738,791.433.5 (32.2 - 34.8)43.9 (42.4 - 45.3)52.3 (50.8 - 53.7)62.3 (60.7 - 63.9)31.5 (30.4 - 32.7)3.31 (3.17 - 3.46)2.58 (2.47 - 2.70)5931735808.863.3 (60.0 - 66.4)77.8 (74.8 - 80.5)83.7 (80.9 - 86.2)87.9 (85.3 - 90.1)90.9 (84.4 - 97.7)7.68 (7.12 - 8.27)7.30 (6.75 - 7.89)Severe anemia (grade 3)Any CKD55,9405,721175,229.23.9 (3.7 - 4.0)6.2 (6.0 - 6.4)8.3 (8.1 - 8.6)12.4 (12.1 - 12.8)3.3 (3.2 - 3.4)N/AN/A3A 41,9583,456132,936.53.1 (3.0 - 3.3)5.0 (4.8 - 5.2)6.8 (6.6 - 7.1)10.4 (10.0 - 10.7)2.6 (2.5 - 2.7)(ref)(ref)3B 17,8752,25949,598.45.1 (4.8 - 5.4)8.2 (7.7 - 8.6)10.5 (10.0 - 11.0)15.6 (15.0 - 16.3)4.6 (4.4 - 4.7)1.73 (1.65 - 1.81)1.50 (1.43 - 1.57)4 5,1821,05612,102.79.0 (8.2 - 9.8)14.3 (13.3 - 15.4)18.5 (17.4 - 19.7)25.3 (23.9 - 26.7)8.7 (8.2 - 9.3)3.25 (3.04 - 3.48)2.65 (2.47 - 2.85)59313521,763.621.8 (19.1 - 24.6)32.4 (29.2 - 35.7)39.8 (36.3 - 43.3)46.0 (42.1 - 49.8)20.0 (17.9 - 22.2)7.23 (6.44 - 8.10)6.41 (5.70 - 7.20)Suppl. Table 4. Distribution of anemia grades during the twelve months following the first anemia event in patients with CKD stages 3-5, Northern Denmark, 2009-2016Anemia grade at first anemia eventNo anemiaMild anemiaModerate anemiaSevere anemiaMoved out of study areaDeadNo new Hb measureTotalMild anemia, % (n)19.0 (5,928)23.8 (7,432)2.8 (864)0.1 (39)0.3 (84)17.0 (5,314)37.0 (11,555)100 (31,216) Moderate anemia, % (n)11.5 (364)19.5 (618)7.8 (246)0.3 (11)0.3 (10)29.5 (934)31.1 (985)100 (3,168)Severe anemia, % (n)14.9 (92)14.1 (87)6.5 (40)0.8 (5)0.3 (2)33.9 (209)29.4 (181)100 (616)Abbreviations: CKD, chronic kidney disease; Hb, hemoglobin ................
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