A randomized trial of intravenous and oral iron in chronic kidney disease

Abstract

Although iron is commonly used to correct iron deficiency anemia (IDA) in chronic kidney disease (CKD), its effect on kidney function is unclear. To assess this, we randomly assigned patients with stage 3 and 4 CKD and IDA to either open-label oral ferrous sulfate (69 patients to 325 mg three times daily for 8 weeks) or intravenous iron sucrose (67 patients to 200 mg every 2 weeks, total 1 g). The primary outcome was the between-group difference in slope of measured glomerular filtration rate (mGFR) change over two years. The trial was terminated early on the recommendation of an independent data and safety monitoring board based on little chance of finding differences in mGFR slopes, but a higher risk of serious adverse events in the intravenous iron treatment group. mGFR declined similarly over two years in both treatment groups (oral -3.6 ml/min per 1.73 m(2), intravenous -4.0 ml/min per 1.73 m(2), between-group difference -0.35 ml/min per 1.73 m(2); 95% confidence interval -2.9 to 2.3). There were 36 serious cardiovascular events among 19 participants assigned to the oral iron treatment group and 55 events among 17 participants of the intravenous iron group (adjusted incidence rate ratio 2.51 (1.56-4.04)). Infections resulting in hospitalizations had a significant adjusted incidence rate ratio of 2.12 (1.24-3.64). Thus, among non-dialyzed patients with CKD and IDA, intravenous iron therapy is associated with an increased risk of serious adverse events, including those from cardiovascular causes and infectious diseases.

Figure 1

Time course of hemoglobin and iron parameters Hemoglobin change from baseline to 3 months in the oral iron group was 0.61 g/dL and in the IV iron group 0.69 g/dL (difference + 0.08 (95% CI −0.34 to +0.51, p = 0.72). Difference at 6 months (0.22 g/dL, p=0.3), 12 months (−0.04 g/dL, p=0.85) and 24 months (0.15 g/dL, p=0.56) were also not statistically significant. Transferrin saturation change from baseline to 3 months in the oral iron group was 0.03 and in the IV iron group 0.05 (difference + 0.024 (95% CI −0.004 to +0.052, p = 0.10). Difference at 6 months (0.026, p=0.08), 12 months (−0.04 g/dL, p=0.85) and 24 months (− 0.024 g/dL, p=0.14) were also not statistically significant. Log total iron binding capacity change from baseline to 3 months in the oral iron group was −0.031 (p=0.13) and in the IV iron group −0.098 (p<0.001) (difference − 0.067 (95% CI −0.122 to −0.012, p = 0.02). Differences in change from baseline at 6 months (−0.030, p=0.31), 12 months (−0.075 g/dL, p=0.015) and 24 months (−0.01, p=0.74) were small. Log ferritin change from baseline to 3 months in the oral iron group was −0.20 (p=0.01) and in the IV iron group 0.84 (p<0.001) (difference 0.63 (95% CI 0.41 to 0.85, p < 0.001). Differences between groups in change from baseline at 6 months (0.39, p=0.001), 12 months (0.21g/dL, p=0.085) and 24 months (0.04, p=0.77) diminished.

Figure 2

Time course of change in measured GFR using plasma iothalamate clearance. Plasma iothalamate clearances were measured at 5 time points over 2 years (baseline, 8 weeks, 6 months, 1 year and 2 years). Error bars indicate one standard error of the modeled mean at each time point. The numbers at the bottom each of the figures denote the number of subjects with measurements in each of the two groups. Observed means for each group are shown just above the x-axis and were similar to modeled means. Figure 2a shows the modeled slopes over 2 years adjusted for baseline log urine protein/creatinine ratio. This was the primary end point of the study. Slope for oral iron −3.6 mL/min/1.73m² per year, IV iron − 4.0 mL/min/1.73m² per year, between group difference −0.35 mL/min/1.73m² per year (95% confidence interval (CI) −2.9 to 2.3, p=0.79). Figure 2b is a model further adjusted for age, sex, race, ACE or ARB use, and cardiovascular disease. This was the secondary end point: slope for oral iron −3.8 mL/min/1.73m² per year, IV iron − 3.9 mL/min/1.73m² per year, between group difference by 0.11 mL/min/1.73m² per year (95% confidence interval (CI) −2.7 to 2.5, p=0.94).

Figure 3

Time course of kidney disease quality of life by treatment group Least square mean estimates of health related quality of life scores are shown over time by two treatment groups. Error bars are one standard error of the mean. None of the comparisons were statistically different over time or between groups over time. Higher scores mean denote a higher health related quality of life. Other domains of the KDQOL (data not shown) were also not significant.