Abstract: SA-PO556

Tubular Immaturity Underlies Erythropoietin-Deficiency Anemia of Prematurity

Session Information

  • Developmental Biology
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Developmental Biology and Inherited Kidney Diseases

  • 401 Developmental Biology

Author

  • Asada, Nariaki, Keio University School of Medicine, Tokyo, Japan
Background

Kidneys are physiologically hypoxic and produce erythropoietin (EPO) after birth by sensitively detecting oxygen levels. Preterm neonates, especially those less than 32 weeks of gestation, develop EPO-deficiency anemia, known as anemia of prematurity (AOP). In AOP, immature kidneys cannot produce sufficient EPO in response to anemia even when renal injuries are absent. It remains unclear how kidneys start to produce EPO after birth.

Methods

Neonatal mice were used as AOP model since they are physiologically born premature. To confirm factors associated with AOP in human, correlation of hemoglobin levels with fraction excretion of sodium (FENa), urinary creatinine to beta 2-microglobulin ratio (uCr/uβ2MG), serum creatinine, birth weight, or gestational age were evaluated in prospective observational study of 18 preterm patients at age 14 days and 21 days.

Results

Mice at postnatal day 14 (P14) showed physiological anemia and elevated renal EPO production. Mice at P7, however, showed AOP-like deficient renal EPO production regardless of the same degree of anemia. Pimonidazole staining showed that kidneys at P14 were more hypoxic than those at P7. There were no difference in the expression of αSMA or the density of peritubular capillaries. The expression of transporters NHE3, NKCC2, NCC, αENaC, and Megalin were significantly low at P7 compared to P14. Suppression of tubular reabsorption by losartan or short-term use of diuretics decreased EPO, pimonidazole-positive area, and hematocrit at P14. Upregulating reabsorption by long-term use of diuretics increased the expression of sodium transporters, EPO production, pimonidazole-positive hypoxic area, and hematocrit at P7, suggesting that low tubular oxygen consumption for reabsorption is a cause of deficient EPO production at P7. Prolyl hydroxyrase inhibitor (PHDi) also ameliorated AOP. In preterm patients, hemoglobin levels were correlated with FENa and uCr/uβ2MG, but not with serum creatinine, birth weight, or gestational age.

Conclusion

AOP is caused by insufficient hypoxic environment due to low oxygen consumption by immature tubules. Kidneys start to produce EPO as tubules mature and renal oxygen levels decrease. PHDi can be a therapeutic option for AOP in preterm patients.

Funding

  • Private Foundation Support