Chronic intrauterine exposure to endotoxin does not alter fetal nephron number or glomerular size

Abstract

A reduced nephron endowment early in life adversely impacts on long-term functional reserve in the kidney. A recent study has shown that acute exposure to chorioamnionitis during late gestation can adversely impact on nephrogenesis. The present study aimed to examine the effects of chronic, low-dose endotoxin exposure in utero, during the period of nephrogenesis, on nephron number and glomerular size in preterm lambs. Ewes were administered either endotoxin (lipopolysaccharide; 1 mg/day) or saline at 110-133 days of gestation (term approximately 147 days) via surgically implanted osmotic minipumps within the amniotic cavity. The ewes were induced to deliver preterm at 133 days gestation and the kidneys of the lambs were analysed at 8 weeks after term-equivalent age. Nephron number per kidney was determined using a combined optical disector and fractionator stereological approach; renal corpuscle size was also measured stereologically. At 8 weeks after term-equivalent age there was no significant effect of in utero exposure to endotoxin on bodyweight or kidney weight and there were no significant differences in nephron number, nephron density or renal corpuscle volume between groups. We conclude that chronic intrauterine inflammation during the period of nephrogenesis may not adversely impact on the number of nephrons formed within the kidney or on the volume of the renal corpuscle.

Preterm Birth and/or Factors that Lead to Preterm Delivery: Effects on the Neonatal Kidney

“…In the study by Galinsky et al [73] , there was a 20% reduction in nephron number, without any effect on body weight, when chorioamnionitis was induced in late gestation, using an acute intra-amniotic bolus dose of lipopolysaccharide (LPS, which initiates an inflammatory response similar to that observed with chorioamnionitis). Interestingly, however, when fetal lambs were exposed to a lower dose of LPS over a chronic period, during the period in gestation when nephrogenesis is rapidly ongoing, there were no observable detrimental effects on nephrogenesis [74]. Hence, it appears that with chronic low dose exposure that the kidney may be able to adapt, to prevent adverse effects on nephron formation.…”

“…Importantly, chorioamnionitis can lead to fetal inflammatory response syndrome (FIRS) [72], and this has been shown to adversely influence neonatal organ development. The effect of exposure to inflammation in utero on the fetal kidney has recently been examined in fetal sheep [73,74]. In the study by Galinsky et al [73] , there was a 20% reduction in nephron number, without any effect on body weight, when chorioamnionitis was induced in late gestation, using an acute intra-amniotic bolus dose of lipopolysaccharide (LPS, which initiates an inflammatory response similar to that observed with chorioamnionitis).…”

Prematurity, perinatal inflammatory stress, and the predisposition to develop chronic kidney disease beyond oligonephropathy

“…The first published study regarding nephron development shows that a single IA high-dose injection of LPS given at the equivalent of 33 weeks human gestation leads to a 23% reduction in nephron number and increased renal corpuscle volume in lambs [ 46 ]. On the other hand, chronic LPS administration at a lower dose between the equivalents of 30 to 36 weeks human gestation did not lead to a reduction in nephron number [ 47 ]. Therefore, these combined findings suggest that the extent of infection and its timing (acute vs. chronic) determine the impact of chorioamnionitis on kidney development.…”

A practical guide to the stereological assessment of glomerular number, size, and cellular composition

“…Although these techniques are relatively labor-intensive and time-consuming, they are considered the gold-standard techniques for these measurements at the present time. Many of these techniques have been developed or refined in John Bertram's laboratory (Bertram, 2001;Cullen-McEwen, Armitage, Nyengaard, & Bertram, 2012;Cullen-McEwen, Douglas-Denton, & Bertram, 2012;Puelles et al, 2014;Puelles et al, 2016) and are routinely used in our laboratory (often in collaboration with researchers from the Bertram lab) (Gubhaju et al, 2009;Maka et al, 2008;Mitchell, Louey, Cock, Harding, & Black, 2004;Ryan et al, 2018;Ryan, Atik, De Matteo, Harding, & Black, 2013;Sutherland et al, 2013;Sutherland, Ryan, Dahl, Albertine, & Black, 2016). In this article, we describe in "step-by-step" detail a number of these stereological techniques (including details on how to apply these techniques in the assessment of kidneys of differing sizes and levels of maturity), with the aim that these methodologies will be a valuable resource to other researchers in the field.…”