The Extended Use of Eculizumab in Pregnancy and Complement Activation–Associated Diseases Affecting Maternal, Fetal and Neonatal Kidneys—The Future Is Now?

Abstract

Excessive complement activation is involved in the pathogenesis of many diseases and the kidney is an organ with particular susceptibility to complement-mediated injury. Apart from paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), there are several other diseases with clear evidence of complement activation affecting both maternal and fetal kidneys during pregnancy and causing long-term adverse outcomes. Several novel drugs have been recently developed for blocking the complement cascade, including purified plasma proteins, new monoclonal antibodies, recombinant proteins, small molecules, and small interfering RNA agents. Eculizumab, the humanized monoclonal IgG2/4-antibody targeting C5 was approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treatment of two rare diseases: PNH in 2007 and aHUS in 2011. There is an increasing number of publications of successful use of eculizumab for off-label indications, e.g., in pregnant women with antiphospholipid syndrome, sickle-cell anemia, and HELLP syndrome. These severe diseases are associated with both high maternal and fetal morbidity and mortality rate and substantial prematurity. Eculizumab has considerably improved overall outcome of patients with PNH and aHUS, enabling safe pregnancy for many women. Prolongation of pregnancy and the use of eculizumab, even for only a few weeks, may protect not only maternal renal function, but also alleviate acute and long-term renal consequences of prematurity in offspring.

Relapse of Atypical Hemolytic Uremic Syndrome During Pregnancy in a Patient on Eculizumab Maintenance Treatment: A Case Report

“…Our patient had a spontaneous pregnancy during maintenance Eculizumab treatment with normal fetal development, complicated by pre-eclampsia by week 20 of gestation and aHUS relapse at week 26 of gestation. A form of pre-eclampsia with severe features and HELLP syndrome were considered the differential diagnosis [16,17]; nevertheless, the previous history of aHUS and the absence of elevation of ALT/AST enzymes oriented the diagnosis towards an aHUS relapse. She had several risk factors for the development of pre-eclampsia, namely pre-existing hypertension [18] and chronic kidney disease [19].…”

Shaping of the nephron – a complex, vulnerable, and poorly explored backdrop for noxae impairing nephrogenesis in the fetal human kidney

“…An ambiguous role is played by drugs administered to preterm and low birth weight babies. The therapeutic benefit of drugs is balanced against the frequently unknown nephrotoxic potential [12][13][14][15].…”

Peripartum hyperhemolysis prophylaxis and management in sickle cell disease: A case report and narrative review

“…48 There are multiple cases of normal complement levels in exposed newborns. 47,49,50 It has also been suggested that low complement levels may be related to prematurity associated with the underlying disease. 51,52 Further data are needed to conclusively determine whether this drug is safe to be used during pregnancy.…”