Heme Iron Polypeptide HIP is a new-generation oral iron that uses the heme porphyrin ring to supply iron to absorption sites through a membrane protein, heme carrier protein 1, on the intestinal mucosa. In contrast to nonheme iron transported into the body through DMT1 affected by hepcidin, oral HIP can be better absorbed in patients with CKD and those with chronic inflammation . Three RCTs were conducted to evaluate the bioavailability, tolerability, and efficacy of HIP in patients with CKD. Nagaraju et al. evaluated the effects of HIP on Hgb levels and iron profiles in adult patients with NDD-CKD. A total of 40 eligible participants were randomized to receive oral HIP or IV iron sucrose. No differences in Hgb level, TSAT, ESA dose, or adverse effects were observed between the two groups after six months of treatment, but ferritin levels were significantly higher in the IV iron sucrose group .

These results suggest that oral HIP administration may be a reasonable option for iron supplementation in patients on HD receiving ESA therapy. The HEMATOCRIT trial was a multicenter open-label, randomized controlled trial comparing the efficacy of HIP with oral nonheme iron for managing anemia in patients undergoing peritoneal dialysis (PD). They randomized 62 eligible patients on PD to receive either HIP or ferrous sulfate for six months. Although HIP has a significantly higher cost than nonheme iron, it was found to have no apparent benefits regarding safety or efficacy in patients on PD in terms of ferritin level and TSAT [112]. In summary, although early clinical data in healthy individuals suggest that orally administered HIP has superior bioavailability and tolerability compared with nonheme iron, current evidence shows that the effects of HIP administration on Hgb level, TSAT, and required EPO dose in patients with CKD who have anemia are not significantly different from those of IV iron or orally administered nonheme iron. In contrast to traditional iron agents, HIP is associated with low ferritin levels. Moreover, the cost of HIP is considerably Int. J. Mol. Sci. 2021, 22, 1008 10 of 19 higher than that of nonheme iron agents.

A more extensive study must be conducted before HIP is widely adopted for iron supplementation in patients with CKD. 5.4. Sucrosomial Iron SI is an innovative oral iron formulation in which ferric pyrophosphate is protected by a phospholipid bilayer and a sucrosomial shell. The unique structure enables iron absorption through various means (endocytosis, the paracellular pathway, and the M cells of Peyer’s patches) independent of DMT1 on the enterocyte surface The specific route of absorption in M cells causes iron to enter the lymphatic system instead of the blood. The high bioavailability of this preparation is likely due to bypassing of the conventional iron absorption pathway . The safety and favorable tolerance of SI have been investigated in patients with various conditions, including CKD , solid tumors , IBD and celiac disease . Pisani et al. conducted an open-label RCT on patients with NDD-CKD to compare SI with IV ferrous gluconate administration in terms of the ability to ameliorate anemia.

The results indicated that both could increase Hgb levels, but the increase was greater for IV iron administration. After the cessation of supplementation, the Hgb levels in the group receiving IV iron supplementation remained stable, but those in the SI group returned to the baseline level. IV iron administration demonstrated a greater effect on the repletion of iron stores, but the SI group had fewer adverse events . Evidence is lacking regarding the long-term efficacy and safety of SI administration for the treatment of anemia in patients with CKD.