A PREGNANCY EFFECT ON MATERNAL KIDNEY LIFESPAN AND FETAL OUTCOMES IN MICE WITH CKD TREATED WITH RAMIPRIL, EMPAGLIFLOZIN, FINERENONE. IMPLICATIONS FOR FEMALE KIDNEY DISEASE MANAGEMENT

A pregnancy drastically increases kidney workload, which increases the risk of women with chronic kidney disease (CKD) to preeclampsia, accelerated loss of maternal kidney function as well as poor fetal outcomes. Research in this domain remains focused on short term follow-up of eGFR and proteinuria post-pregnancy but not on long-term major adverse kidney events. This study aimed to investigate the kidney lifespan associated with a single pregnancy during CKD with and without treatment with inhibitors of the renin-angiotensin system (RAS), sodium-glucose transporter-2 (SGLT-2), and mineralocorticoid receptor (MR) using a preclinical model of progressive CKD, known not to survive a pregnancy when untreated.

Female Col4a3-deficient mice with established Alport nephropathy were randomized into four groups: 1) vehicle only (nil), 2) late treatment starting at 6 weeks of age, 3) early treatment starting at 3 weeks of age, and 4) early treatment with one pregnancy, all with food admixtures of ramipril (10 mg/kg), empagliflozin (30 mg/kg), and finerenone (10 mg/kg). During pregnancy, only dual therapy with empagliflozin and finerenone was administered post-mating, as ACE inhibitors may have adverse effects on neonates. Full triple therapy was given post-delivery. Primary endpoint was mean time to the symptomatic stage of uremia (known to be followed by uremic death, shortly).

Mean survival time of non-pregnant and untreated Alport nephropathy mice up to the uremic stage of CKD was 62.90±7.340 days (vehicle). Late onset of triple therapy prolonged survival time to 97.70±23.68 days (late), early onset of triple therapy to 137.6±27.15 days (early), respectively. With in intercurrent pregnancy, survival time was reduced to 96.50±19.71 days despite an early onset of therapy, respectively (Figure A). While all groups showed late-stage weight loss, the pregnancy group exhibited a more pronounced decline postpartum, suggesting an accelerated health decline after pregnancy (Figure B). The maternal pregnancy rate in the early therapy group was significantly reduced to 42.85% compared to WT group (Figure C). At 1 week post-partum, the survival rate of pups from the early therapy group was markedly lower than that of pups from the WT group (33% vs. 100%, respectively), indicated the maternal environment played a critical role in offspring viability (Figure D). Consistent with the observed impairments in maternal health, offspring of WT dams displayed significantly greater body weights than offspring of KO dams (4.817 ± 0.584 g vs. 2.989 ± 0.076 g, respectively, at 1 week post-partum) (Figure E). These findings underscore the profound influence of maternal health on early postnatal growth and development. 

Our results show that early triple therapy of CKD can have a major impact on kidney survival and even allow a pregnancy in mice that would not survive a pregnancy without. However, the pregnancy itself significantly reduces the renoprotective effect of such a triple therapy, probably because the additional kidney workload imposed by a pregnancy accelerates CKD progression despite renoprotective therapy. Another conclusion is that human studies focussing on short-term analysis of surrogate markers can be misleading. Our findings inform about the long-term kidney benefits of CKD combination therapy as well as the negative impact of a pregnancy on kidney lifespan kidneys. Counseling females with CKD on these lifetime risks is needed.