The Role of Iron and Erythropoietin in the Association of Fibroblast Growth Factor 23 with Anemia in Chronic Kidney Disease in Humans
Abstract
:1. Introduction
2. Experimental Section
2.1. Patients
2.2. Laboratory Methods
2.3. Statistics
3. Results
3.1. Study Cohort
3.2. Predictors of Hemoglobin Concentrations
3.3. Association of Iron Metabolism Biomarkers, EPO, and Inflammation with Hemoglobin Concentrations
3.4. Association of cFGF23, Phosphate, and Total Calcium with Iron Status, EPO, and Inflammation biomarkers
3.5. Association of cFGF23 with Erythrocyte Indices
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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CKD I | CKD II | CKD IIIa | CKD IIIb | CKD IV | CKD V | |
---|---|---|---|---|---|---|
n | 21 | 26 | 26 | 42 | 80 | 30 |
Sex (M/F) | 14/7 | 11/15 | 15/11 | 33/9 | 48/32 | 23/7 |
Age (years) | 35 (13.4) | 49 (16.4) | 61 (11.3) | 63 (12.7) | 62 (13.5) | 57 (15.2) |
BMI (kg/m2) | 27 (4.9) | 27 (5.9) | 28 (6.5) | 28 (4.8) | 27 (5.6) | 27 (5.9) |
Erythrocytes (T/L) | 4.9 (0.6) | 4.7 (0.4) | 4.4 (0.6) | 4.4 (0.5) | 4.1 (0.5) | 3.7 (0.6) |
Hemoglobin (g/dL) | 15 (1.8) | 14 (1.6) | 13 (1.6) | 13 (1.6) | 12 (1.5) | 11 (1.6) |
Hematocrit (%) | 42.6 (4.9) | 40.8 (4.3) | 38.7 (4.5) | 38.8 (4.2) | 35.8 (4.3) | 32.2 (5.1) |
MCV (fl) | 87 (4.1) | 88 (5.5) | 89 (4.4) | 89 (5.9) | 88 (6.3) | 87 (4.8) |
MCH (pg) | 30 (1.6) | 29 (2.1) | 30 (1.6) | 29 (1.9) | 29 (2.2) | 29 (1.6) |
MCHC (g/dL) | 34 (0.9) | 34 (1.2) | 33 (0.9) | 33 (1.1) | 33 (1.1) | 33 (1.3) |
RDW (%) | 13 (0.8) | 14 (2.4) | 14 (1.4) | 14 (1.2) | 14 (1.7) | 15 (1.5) |
Total calcium (mmol/L) | 2.4 (0.2) | 2.5 (0.1) | 2.4 (0.2) | 2.4 (0.1) | 2.3 (0.2) | 2.3 (0.2) |
Alb-corr calcium (mmol/L) | 2.3 (0.1) | 2.4 (0.1) | 2.4 (0.1) | 2.3 (0.1) | 2.3 (0.2) | 2.3 (0.3) |
Phosphate (mmol/L) | 1.0 (0.9–1.1) | 1.0 (1.0–1.1) | 1.1 (0.9–1.2) | 1.1 (1.0–1.2) | 1.2 (1.1–1.3) | 1.6 (1.–1.8) |
Creatinine (mg/dl) | 0.86 (0.79–0.98) | 0.99 (0.86–1.17) | 1.34 (1.19–1.5) | 1.88 (1.69–2.04) | 2.66 (2.27–3.07) | 5.05 (4.2–6.04) |
Protein (g/L) | 70.1 (9.2) | 70.6 (7.1) | 70.7 (7.1) | 70.6 (6.5) | 68.2 (6.3) | 69.3 (7.3) |
Albumin (g/L) | 44 (6.6) | 43 (4.6) | 41 (3.9) | 42 (4.1) | 41 (4.1) | 41 (4.2) |
PTH (pg/mL) | 22 (20–28) | 35 (29–57) | 45 (36–73) | 64 (48–86) | 107 (80–164) | 191 (10–323) |
eGFR (ml/min/1.73m²) | 101 (95–107) | 74 (69–78) | 51 (47–56) | 35 (32–38) | 23 (18–26) | 11 (1–13) |
cFGF23 (RU/mL) | 71 (66–127) | 107 (78–161) | 126 (105–187) | 221 (158–382) | 299 (195–450) | 820 (54–1837) |
iFGF23 (pg/mL) | 58 (55–68) | 68 (51–79) | 95 (81–110) | 119 (100–153) | 172 (132–264) | 924 (40–4676) |
Klotho (pg/mL) | 627 (385–1408) | 660 (614–699) | 644 (497–826) | 649 (552–803) | 522 (415–622) | 480 (413–549) |
CRP (mg/dL) | 0.2 (0.1–0.3) | 0.1 (0.1–0.6) | 0.4 (0.2–0.6) | 0.4 (0.2–0.9) | 0.3 (0.1–0.8) | 0.8 (0.4–1.8) |
IL-6 (pg/mL) | 1.5 (1.5–2.4) | 2.2 (1.5–5.8) | 4.3 (3–6.1) | 6.0 (4.5–10.8) | 6.4 (3.5–12.9) | 9.8 (6.6–16.5) |
25(OH)D (nmol/L) | 57 (43–70) | 51 (26–81) | 58 (35–79) | 59 (43–80) | 43 (26–72) | 36 (25–53) |
1,25(OH)2D (pmol/L) | 60 (41–74) | 52 (38–63) | 36 (30–46) | 34 (24–42) | 26 (19–34) | 22 (16–32) |
EPO (mU/mL) | 6.3 (4.4–9.9) | 8.5 (6.9–14.7) | 9.7 (7.4–16.7) | 13.0 (8.8–20.5) | 9.5 (7–14.7) | 10.8 (7–15.2) |
Hepcidin (pg/mL) | 17353 (7789–28894) | 24374 (9501–43820) | 29067 (18155–41327) | 27956 (19053–38164) | 31306 (16513–56586) | 48667 (32297–91577) |
Ferritin (µg/L) | 98 (46–147) | 111 (37–191) | 116 (70–216) | 103 (55–190) | 104 (50–174) | 119 (73–242) |
Transferrin (mg/dL) | 263.8 (40.1) | 273.7 (53.4) | 249.5 (48.5) | 252.2 (50.4) | 240.2 (39.5) | 217.3 (30.2) |
TSAT (%) | 28.9 (11.7) | 22.5 (8.8) | 25.1 (9.3) | 20.5 (7.5) | 22.2 (9.0) | 21.5 (6.9) |
Serum iron (µg/dL) | 112.0 (67–132) | 84.5 (72–105) | 86.0 (58–109) | 69.0 (52–79) | 69.0 (51–90) | 61.0 (53–72) |
sTFR (mg/L) | 1.2 (1–1.5) | 1.3 (1.1–1.9) | 1.3 (1.2–1.6) | 1.5 (1.3–1.8) | 1.4 (1.1–1.7) | 1.4 (1.1–1.8) |
PK (mg/g) | 137.0 (52–547) | 214.0 (84–1225) | 256.0 (82–1201) | 318.0 (129–1233) | 748.5 (229–1758) | 1717.0 (1073–2354) |
Dependent Variable | ||||||
---|---|---|---|---|---|---|
Hemoglobin (g/dL) | ||||||
Unadjusted | Adjusted Base Model | |||||
Biomarker | Beta | p | R2 | Beta | p | R2 |
cFGF23 (RU/mL) * | −0.65 (−0.78/−0.51) | <0.001 | 0.29 | −0.28 (−0.44/−0.11) | 0.001 | 0.49 |
iFGF23 (pg/mL) ** | −3.26 (−4.01/−2.51) | <0.001 | 0.25 | −1.04 (−2.1/0.03) | 0.057 | 0.45 |
Klotho (pg/mL) * | 1.04 (0.39/1.69) | 0.002 | 0.07 | 0.30 (−0.26/0.87) | 0.289 | 0.43 |
Total calcium (mmol/L) | 4.35 (3.09/5.6) | <0.001 | 0.17 | 2.15 (0.91/3.39) | <0.001 | 0.48 |
Alb-corr calcium (mmol/L) | 3.21 (1.67/4.75) | <0.001 | 0.07 | |||
Phosphate (mmol/L) * | −2.48 (−3.11/−1.84) | <0.001 | 0.21 | −0.75 (−1.42/−0.07) | 0.032 | 0.46 |
PTH (pg/mL) * | −0.65 (−0.83/−0.46) | <0.001 | 0.18 | −0.14 (−0.36/0.07) | 0.191 | 0.46 |
25(OH) (nmol/L) * | 0.46 (0.16/0.75) | 0.003 | 0.04 | 0.06 (−0.19/0.30) | 0.658 | 0.45 |
1,25(OH)2D (pmol/L) * | 0.89 (0.59/1.19) | <0.001 | 0.14 | 0.02 (−0.29/0.32) | 0.911 | 0.45 |
Serum iron (µg/dl) * | 1.41 (0.96/1.85) | <0.001 | 0.18 | 0.74 (0.33/1.16) | <0.001 | 0.46 |
Ferritin (µg/L) * | 0.09 (−0.1/0.28) | 0.37 | 0 | 0.07 (−0.09/0.22) | 0.404 | 0.45 |
Transferrin (mg/dl) | 0.01 (0/0.02) | 0.004 | 0.05 | 0 (−0.01/0.01) | 0.905 | 0.42 |
TSAT (%) * | 0.96 (0.51/1.41) | <0.001 | 0.09 | 0.56 (0.18/0.94) | 0.004 | 0.45 |
sTFR (mg/L) * | 0.31 (−0.3/0.92) | 0.321 | 0.01 | 0.47 (0/0.95) | 0.052 | 0.43 |
Hepcidin (pg/mL) * | 0.03 (-0.1/0.15) | 0.695 | 0 | 0.14 (0.04/0.24) | 0.007 | 0.47 |
EPO (mU/mL) * | −0.53 (−0.79/−0.28) | <0.001 | 0.07 | −0.34 (−0.53/−0.15) | <0.001 | 0.48 |
CRP (mg/dl) * | −0.16 (−0.3/−0.02) | 0.026 | 0.02 | 0.05 (−0.07/0.17) | 0.407 | 0.45 |
IL 6 (pg/mL) * | −0.47 (−0.64/−0.29) | <0.001 | 0.12 | 0 (−0.16/0.17) | 0.961 | 0.45 |
Dependent Variable | ||||||
---|---|---|---|---|---|---|
Hemoglobin (g/dL) | ||||||
* cFGF23 (RU/mL) | ** iFGF23 (pg/mL) | |||||
Model | Beta | p | R2 | Beta | p | R2 |
Base model | −0.28 (−0.44/−0.11) | 0.001 | 0.49 | −1.04 (−2.1/0.03) | 0.057 | 0.45 |
Iron model | −0.15 (−0.34/0.04) | 0.126 | 0.51 | −0.89 (−1.99/0.22) | 0.115 | 0.51 |
EPO model | −0.22 (−0.38/−0.05) | 0.012 | 0.51 | −0.83 (−1.89/0.22) | 0.121 | 0.48 |
Inflammation model | −0.28 (−0.45/−0.11) | 0.001 | 0.49 | −1.01 (−2.09/0.08) | 0.068 | 0.45 |
Independent Variable | ||||||
---|---|---|---|---|---|---|
* cFGF23 (RU/mL) | ** iFGF23 (pg/mL) | |||||
Dependent Variable | exp(Beta) | p | R2 | exp(Beta) | p | R2 |
TSAT (%) | 0.89 (0.85/0.94) | <0.001 | 0.17 | 0.95 (0.68/1.31) | 0.744 | 0.06 |
Serum iron (µg/dl) | 0.92 (0.88/0.96) | <0.001 | 0.25 | 1.04 (0.78/1.39) | 0.802 | 0.18 |
Ferritin (µg/L) | 0.89 (0.81/0.99) | 0.032 | 0.20 | 1.09 (0.56/2.14) | 0.795 | 0.17 |
Hepcidin (pg/mL) | 0.73 (0.63/0.85) | <0.001 | 0.22 | 0.72 (0.26/1.97) | 0.519 | 0.15 |
EPO (mU/mL) | 1.17 (1.08/1.27) | <0.001 | 0.11 | 1.57 (0.93/2.66) | 0.09 | 0.05 |
CRP (mg/dl) | 1.01 (0.88/1.16) | 0.863 | 0.17 | 0.63 (0.27/1.49) | 0.291 | 0.18 |
IL 6 (pg/mL) | 1.11 (1.01/1.22) | 0.029 | 0.32 | 1.19 (0.64/2.23) | 0.575 | 0.31 |
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Bielesz, B.; Reiter, T.; Hammerle, F.P.; Winnicki, W.; Bojic, M.; Gleiss, A.; Kieweg, H.; Ratzinger, F.; Sunder-Plassmann, G.; Marculescu, R. The Role of Iron and Erythropoietin in the Association of Fibroblast Growth Factor 23 with Anemia in Chronic Kidney Disease in Humans. J. Clin. Med. 2020, 9, 2640. https://doi.org/10.3390/jcm9082640
Bielesz B, Reiter T, Hammerle FP, Winnicki W, Bojic M, Gleiss A, Kieweg H, Ratzinger F, Sunder-Plassmann G, Marculescu R. The Role of Iron and Erythropoietin in the Association of Fibroblast Growth Factor 23 with Anemia in Chronic Kidney Disease in Humans. Journal of Clinical Medicine. 2020; 9(8):2640. https://doi.org/10.3390/jcm9082640
Chicago/Turabian StyleBielesz, Bernhard, Thomas Reiter, Fabian Peter Hammerle, Wolfgang Winnicki, Marija Bojic, Andreas Gleiss, Heidi Kieweg, Franz Ratzinger, Gere Sunder-Plassmann, and Rodrig Marculescu. 2020. "The Role of Iron and Erythropoietin in the Association of Fibroblast Growth Factor 23 with Anemia in Chronic Kidney Disease in Humans" Journal of Clinical Medicine 9, no. 8: 2640. https://doi.org/10.3390/jcm9082640