Oral or IV Iron: Follow up from a previous #nephjc chat

A few months ago, we discussed this trial from Rajiv Agarwal and his team from Indiana, which found increased serious adverse vents with IV iron, in CKD patients. The latest issue of Kidney International now has some interesting correspondence, with two critical letters, and a substantive reply from Rajiv Agarwal.

Rajiv Agarwal

Rajiv Agarwal

Among the criticism is one from Iain Macdougall and Simon Rogers, questioning the methodology - and why these results are different from the FIND-CKD trial (free PMC link), which did test a different IV iron formulation (iron carboxymaltose in FIND-CKD, iron sucrose in REVOKE), against a lower dose of oral iron. The reply from Dr Agarwal is worth reading in full, but this table highlights the details.


The IV versus PO iron conundrum for Tuesday and Wednesday

Joel said he would write the summary. Suzanne said she would write the summary and in the end wires got crossed and they both wrote the summary. Sigh. We are ardent conservationists and strongly believe that no part of the buffalo should go to waste so here is Dr. Norby's summary of this week's NephJC article:

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

Rajiv Agarwal, John W Kusek, and Maria K Pappas

Kidney International advance online publication 17 June 2015

doi: 10.1038/ki.2015.163


Anemia is common in patient with stages 3-5 chronic kidney disease (CKD) due to decreased erythropoietin production as well as iron deficiency, including the functional iron deficiency that can develop while using erythropoiesis-stimulating agents (ESA).

The KDIGO Clinical Practice Guideline for Anemia in CKD recommends (grade 2C) the use of IV iron in adult patients with CKD note yet on dialysis if 1) an increase in hemoglobin level is desired to avoid or minimize blood transfusions and ESA use and/or to alleviate symptoms potentially related to anemia and 2) TSAT is ≤30% and ferritin is ≤500 ng/ml. The Guideline also states that a 1-3 month trial of oral iron may be considered for patients not yet on dialysis.

Safety and risks of IV iron use in the non-dialysis CKD population are not fully understood although an author of the current study, Agarwal, along with other colleagues previously demonstrated that IV iron use can lead to increased oxidative stress, endothelial damage, and even renal injury.

The hypothesis of the current study, REVOKE (randomized trial to evaluate intravenous and oral iron in chronic kidney disease), was that IV iron would result in greater decrease in kidney function compared with oral iron in iron-deficient patients with moderate to severe CKD not yet on dialysis.


Design: open-label, parallel-group, active-control, single-center randomized trial

Setting: A safety-net hospital and a VA Hospital, both in Indianapolis, IN; August 2008 – November 2014.

Inclusion criteria:

  • ≥18 years old
  • eGFR 21-60 ml/min/1.73 m2, not on dialysis
  • Hemoglobin <12 g/dl
  • Serum ferritin <100 ng/ml or serum transferring saturation <25%

Exclusion criteria:

  • Pregnant or breast feeding females
  • Known hypersensitivity to any intravenous iron, iothalamate meglumine (Conray 60, Malinckrodt) or iodine
  • Severe anemia that required imminent red blood cell (RBC) transfusion (Hgb <8 g/dL) or the potential need for imminent RBC transfusion (e.g., active bleeding) 
  • Persons with acute kidney injury
  • History of intravenous iron use within the month prior to screening
  • Iron overload (serum ferritin >800 ng/nl or transferrin saturation >50%)
  • Anemia not caused by iron deficiency (e.g., sickle cell anemia)
  • History of surgery or systemic or urinary tract infection within the past month
  • Organ transplant recipients
  • Persons currently being treated with immunosuppressive agents

Randomization and Blinding: 1:1 ratio, using computer generated permuted blocks, randomized to either oral iron or IV iron using concealed opaque envelopes

Primary outcome: 

  • Difference between treatment groups in slope of mGFR decline from baseline to 2 years adjusted for the log of baseline urinary protein/creatinine ratio compared with baseline at 8 weeks, 6 months, 12 months, and 24 months after randomization.  

Secondary outcomes:

  • further adjustment of the primary outcome for age, sex, race (Black vs. non-Black), angiotensin-converting enzyme/angiotensin receptor blocker use, and the presence or absence of cardiovascular disease (all determined at baseline)
  • between-group % change in proteinuria from baseline to 8 weeks
  • difference between hemoglobin response between treatment groups
  • change in KDQOL

Statistical analysis:

  • Intention-to-treat, if the participant received at least one dose of study medication
  • Linear mixed model with GFR as outcome variable
  • Assumptions: mean rate of decline in GFR of 4 ml/min per 1.73 m2 per year in the oral iron group and a 50% greater decline in the IV iron group and a cumulative rate of dropout of 25%
  • Recruitment target of 100 patients for each treatment group with a minimum duration of follow-up of 2 years to achieve 82% power to detect hypothesized difference in decline in kidney function at the 5% level of significance
  • 2-sided t-test considered significant for p<0.05


Participants were treated over 8 weeks beginning at the time of randomization. Those randomized to the IV iron group received iron sucrose 200 mg IV over 2 h at weeks 0, 2, 4, 6, and 8. Participants randomized to oral iron were counseled to take ferrous sulfate 325 mg three times daily for 8 weeks.


Trial was terminated early due to higher serious adverse event rate in IV iron group (199 per 100 patient years) compared with oral iron group (168.4 per 100 patient years); adjusted incidence rate ratio 1.60 (1.28–2.00), P<0.0001.  Statistically significant increases in infections and cardiovascular events were observed. In particular, the incidence of lung and skin infections was increased 3-4x and of hospitalization for heart failure was increased 2x in the IV iron group after adjusting for the more favorable baseline characteristics in that group.

Decrease in mGFR between groups was similar between both groups, -3.6 ml/min per 1.73 m2 per year for oral iron group and -4 ml/min per 1.73 m2 per year for IV iron group. 

Hemoglobin increase, change in proteinuria over time, ESA use, and need for blood transfusions were not significantly different in the 2 groups. KDQOL domain scores did not change over time in either group.


Since this study was limited to patients with stage 3-4 CKD not yet on dialysis, results cannot be generalized to patients already on dialysis. 

The primary outcome of comparing decline in mGFR between groups could not be evaluated due to early termination of the study due to safety concerns related to increased risk of infection and cardiovascular events.  While additional studies evaluating the long-term safety of IV iron use in this population are necessary, should the oral route be preferred when initiating iron supplementation in patients with stage 3-4 CKD?  Moreover, based on the time course of hemoglobin increase in patients in the oral iron group of this study, it would seem reasonable that a trial of oral iron be given to patients with CKD not yet on dialysis for a full 3 months, rather than at least 1 month and up to 3 months as suggested in the KDOQI guidelines.