Chronic Kidney Disease, Iron-deficiency Anemia
Conditions
Keywords
anemia, iron, kidney disease, progression, glomerular filtration rate
Brief summary
The long-term goal is to assess the fall in kidney function measured by glomerular filtration rate (GFR) when patients with chronic kidney disease (CKD) are exposed to intravenous iron (IVIR). We hypothesize that in subjects with mild to moderate CKD, infusion of intravenous iron (IVIR), will generate oxidative stress and cause an inflammatory response that will be associated with a more rapid decline in glomerular filtration rate (GFR) compared to oral iron.
Detailed description
Intravenous iron is commonly utilized and is likely a mechanism of renal injury in patients with CKD. This proposal will provide translational data on the role of intravenous iron to progression of kidney disease in patients with CKD. Comparison of IV iron with oral iron will allow testing the hypothesis that IVIR will generate an inflammatory response and albuminuria in the short-term, that will directly lead to a greater rate of fall in GFR, in the long-term, compared to oral iron. We hypothesize that after administration of one gram of IV iron over a course of 8 weeks, renal injury as documented by albuminuria (and fall in GFR) will be increased with IV iron sucrose therapy compared to those randomized to oral iron therapy. A randomized, parallel group, controlled trial will be performed. GFR will be measures every 6 months for two years in 200 participants by iothalamate clearances.
Interventions
DRUGIV Iron
IV iron sucrose 200 mg over 2 hours baseline visit, week 2, week 4, week 6 and week 8 for a total of 1000mg total dose. Further cycles of iv iron may be used based on periodic monitoring of iron stores.
DRUGFerrous Sulfate
Oral ferrous sulfate 325mg three times daily over 8 weeks. Further cycles of oral iron may be used based on periodic monitoring of iron stores.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Indiana University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age greater than 18 years * Calculated GFR by MDRD formula \< or = 60ml/min/1.73m2. We will use the MDRD formula that incorporates serum creatinine, age, race and sex, but not albumin, and blood urea nitrogen. * Presence of anemia and iron deficiency. Anemia will be defined as blood hemoglobin concentration \<12g/dL and iron deficiency will be defined using National Kidney Foundation/Kidney Disease Outcome Quality Initiative (NFK-K/DOQI) Guidelines as serum ferritin concentration of \<100ng/mL or serum transferrin saturation of \<25%.
Exclusion criteria
* Pregnant or breastfeeding women or women who are planning to become pregnant or those not using a reliable form of contraception (oral contraceptives, condoms, and diaphragms will be considered reliable). * Known hypersensitivity to iron sucrose (Venofer), iothalamate meglumine (Conray 60, Mallinckrodt) or iodine. * Anemia that requires RBD transfusion (Hgb \<8g/dL) or may potentially need transfusion (active gastrointestinal bleeding). It would be unsafe to withdraw 150 mL blood over the study in such anemic patients. * Presence of acute renal failure defined as an increase in the baseline serum creatinine concentration of 0.5 mg/dl over 48 hours. This would produce oxidative stress by itself, may give unreliable rate of decline in renal function and may confound results. * History of IVIR use within 1 month of the study (may confound results of the study if the baseline oxidative stress is increased). * Evidence of iron overload (serum ferritin \>800ng/nl or transferrin saturation \>50%) * Anemia not caused by iron deficiency eg. sickle cell anemia. * Surgery or systemic or urinary tract infection within 1 month. * Organ transplant recipient or therapy with immunosuppressive agents. Nasal or inhaled corticosteroids will be permitted.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Rate of Decline in mGFR in the Two Groups - Oral and IV Iron | Baseline, 2 years | Plasma clearance of iothalamate was measured by administering an IV bolus of 5 mL of iothalamate meglumine and sampling 2 mL of blood at 0, 5, 10, 20, 30, 45, 60, 90, 120, 150, 180, 240, and 300 min after injection. Iothalamate was measured by high-performance liquid chromatography. Plasma clearance was calculated using a two-pool model using validated pharmacokinetic software. The mean modeled iothalamate mGFR slope (e.g., change from baseline to 2 years) in each group (IV iron vs. oral iron) was then calculated after adjustment for baseline log urinary protein/creatinine ratio. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proteinuria | Baseline, 2 years | Proteinuria was estimated using measurements of urinary protein and creatinine before iron administration at baseline and at periodic intervals thereafter. Mean change from baseline log urinary protein/creatinine ratio (g/g) is reported at 2 years. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| IV Iron IV Iron: IV iron sucrose 200 mg over 2 hours baseline visit, week 2, week 4, week 6 and week 8 for a total of 1000mg total dose. Further cycles of iv iron may be used based on periodic monitoring of iron stores. | 67 |
| Oral Iron Ferrous Sulfate: Oral ferrous sulfate 325mg three times daily over 8 weeks. Further cycles of oral iron may be used based on periodic monitoring of iron stores. | 69 |
| Total | 136 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Active when terminated by DSMB | 15 | 14 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | IV Iron | Oral Iron | Total |
|---|---|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 10.7 | 67.8 years STANDARD_DEVIATION 11.5 | 65.5 years STANDARD_DEVIATION 11.3 |
| eGFR | 34.3 ml/min per 1.73m2 STANDARD_DEVIATION 10.2 | 34.7 ml/min per 1.73m2 STANDARD_DEVIATION 10 | 34.5 ml/min per 1.73m2 STANDARD_DEVIATION 10 |
| Proteinuria High proteinuria stratum (≥3g/g) | 9 participants | 9 participants | 18 participants |
| Proteinuria Low proteinuria stratum (<3g/g) | 58 participants | 60 participants | 118 participants |
| Race/Ethnicity, Customized Black | 27 participants | 18 participants | 45 participants |
| Race/Ethnicity, Customized Hispanic | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized White | 38 participants | 51 participants | 89 participants |
| Sex: Female, Male Female | 17 Participants | 15 Participants | 32 Participants |
| Sex: Female, Male Male | 50 Participants | 54 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 45 / 67 | 47 / 69 |
| serious Total, serious adverse events | 37 / 67 | 40 / 69 |
Outcome results
Primary
Mean Rate of Decline in mGFR in the Two Groups - Oral and IV Iron
Plasma clearance of iothalamate was measured by administering an IV bolus of 5 mL of iothalamate meglumine and sampling 2 mL of blood at 0, 5, 10, 20, 30, 45, 60, 90, 120, 150, 180, 240, and 300 min after injection. Iothalamate was measured by high-performance liquid chromatography. Plasma clearance was calculated using a two-pool model using validated pharmacokinetic software. The mean modeled iothalamate mGFR slope (e.g., change from baseline to 2 years) in each group (IV iron vs. oral iron) was then calculated after adjustment for baseline log urinary protein/creatinine ratio.
Time frame: Baseline, 2 years
Population: Modeled iothalamate mGFR slope (e.g., change from baseline to 2 years) was calculated for each group (IV iron vs. oral iron) after adjustment for baseline log urinary protein/creatinine ratio.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IV Iron | Mean Rate of Decline in mGFR in the Two Groups - Oral and IV Iron | -4.0 Slope (ml/min per 1.73m2 per year) |
| Oral Iron | Mean Rate of Decline in mGFR in the Two Groups - Oral and IV Iron | -3.6 Slope (ml/min per 1.73m2 per year) |
Comparison: The analysis of the primary outcome was intention to treat, if the patient received at least one dose of the randomized drug (which was the case for each subject). A linear mixed model was used with GFR as the outcome variable. Fixed effects were indicator variables for time (treated as a continuous variable), treatment, and their interaction. Random effects were subject and time with unstructured covariance; statistical inference was made using the maximum likelihood estimator.p-value: 0.7995% CI: [-2.9, 2.3]Mixed Models Analysis
Secondary
Proteinuria
Proteinuria was estimated using measurements of urinary protein and creatinine before iron administration at baseline and at periodic intervals thereafter. Mean change from baseline log urinary protein/creatinine ratio (g/g) is reported at 2 years.
Time frame: Baseline, 2 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| IV Iron | Proteinuria | 0.287 g/g |
| Oral Iron | Proteinuria | 0.251 g/g |
Comparison: The secondary analysis examined the mean change from baseline proteinuria (log protein to creatinine ratio) at 2 years. The between-groups difference in mean change from baseline is reported with a 95% confidence interval and the p-value from the Wald test.p-value: 0.8395% CI: [-0.294, 0.365]Mixed Models Analysis