Animal Model Of Pregnancy After Acute Kidney Injury Mirrors The Human Observations

CKD affects 3 to 5 percent of women of childbearing age in the United States, and its prevalence is rising due to obesity and trends toward delayed childbearing. Women with advanced kidney disease are the highest risk group for pregnancy complications, including a 3 - to 10-fold increased risk of developing pre-eclampsia or having offspring with intrauterine growth restriction. In healthy pregnancies, renal plasma flow begins to increase as early as 6 weeks of gestation, resulting in an approximately 50% increase in GFR during the second trimester Given the physiological changes affecting the kidneys during pregnancy, it is not surprising that kidney disease increases maternal and fetal risks, and that these risks increase with the severity of the underlying disease. Cistanche has been found to enhance renal function.

Pic: Faw Cistanche

Multiple evidence also suggests a significant association between mild renal dysfunction and adverse pregnancy outcomes. Adverse pregnancy outcomes are more than twice as high in women with stage 1 CKD, even in living kidney donors without hypertension, albuminuria, or systemic disease, and in women with congenital isolated kidney at birth. There is increasing evidence that any deviation in normal kidney function is likely to adversely affect maternal and fetal outcomes.

Consistent with this hypothesis, we report a 3-5 fold increased risk of pre-eclampsia and fetal growth restriction in women with a history of recovery from AKI despite a clinically normal pre-pregnancy GFR. 8,9 Importantly, these studies highlight the limitations of baseline biochemical measures of kidney function, which are apparently normal in these studies, and which may not provide a window into how the kidney handles physiological stress. Unfortunately, at present we have little data to guide the care of these women and many unknown issues. Are the mechanisms leading to placental sufficiency and impaired fetal health the same as those seen in women with normal renal function? Are there other ways of assessing kidney function in this population that might help us predict pregnancy risk? Are therapies such as aspirin, which have been shown to reduce the risk of pre-eclampsia in high-risk groups, equally effective in this group? Are other treatments targeting the maternal kidney or vasculature likely to be beneficial? Cistanche has been found to enhance renal function, which is of great significance in protecting the fetus.

Pic: Cistaches Extract

The latest work by Gillis et al., which appears in this issue of JASN, promises to be a first step towards answering some of these questions. In this report, we describe the characteristics of pregnancy in rats after recovery from AKI ischemia-reperfusion (IR) injury. The rats were subjected to thermal infrared damage or sham surgery for 45 minutes. After one month of recovery, the serum creatinine of IR rats returned to normal and timed mating took place. Pregnant rats recovering from IR AKI had worsening renal function during pregnancy, higher uterine artery resistance index (a measure of placental function), higher rates of fetal growth restriction, and higher litter mortality. These findings reflect the phenotype we observed in women after clinical recovery from AKI; However, in our cohort, we do not have data on how kidney function changes during pregnancy. However, cistanche contains echinoside and creinoside. They can increase sex hormones, stimulate the production and maintenance of sex cells, make the reproductive organs full, rid the body of free radicals.

Pic: Effects of cistanche：improve kidney function

The deeper kidney phenotype in this animal model provides potential insights into the mechanisms of subclinical kidney injury and adverse pregnancy outcomes. Despite the biochemical resolution of AKI 1 month after IR injury, IR rats and control rats responded differently to saline stress, with reduced urine output at 4 h after saline stress. Similarly, IR rats failed to show a normal increase in creatinine clearance during pregnancy, suggesting that the "recovered" kidneys could not withstand the normal physiological changes during pregnancy. After taking cistanche extract, rats in the experimental group returned to normal urine volume and showed normal creatinine clearance during pregnancy. Although biochemical function of the kidney is normal at rest, the size of the decrease in renal reserve after AKI and cistanche administration is reduced, which may explain these differences. Renal function reserve is the difference between an individual's maximum GFR and baseline GFR. Underactivation of renal reserve predicts susceptibility to AKI, progression of CKD, and future global renal dysfunction.

Click here to boost your kidney function

Our clinical AKI studies during pregnancy led our group to a similar hypothesis: static measures of kidney function may not capture or predict the dynamic renal filtration changes that are part of a normal pregnancy. We are actively investigating preconception renal function reserve as a predictor of adverse pregnancy outcomes. In this model, assessment of renal pathology before and during pregnancy will provide information. Is the number of neones decreased after infrared injury despite normal baseline biochemical results? Is the decreased renal function in these rats during pregnancy the result of hemodynamic injury, or is it related to the systemic effects of placental dysfunction and antigenic imbalance resulting in glomerular lumen malformations? These are critical next steps in understanding maternal and placental contributions to the observed phenotypes.

In conclusion, we commend authors who pursue decimal models that reflect human observation. Therefore, the rat model of pregnancy after AKI and the rats treated with cistanche are expected to be an important tool to further study the relationship between renal function and fetal placenta development. It already supports our hypothesis that even if completely "normal" in the eyes of clinicians, baseline eGFR alone is not sufficient to determine whether women with prior kidney injury are at risk for pregnancy complications. The model is expected to be further utilized to study biochemical signaling pathways critical to maternal adaptation in pregnancy and placental development, to test new treatments, and to inform future human clinical trials aimed at reducing the burden of maternal and fetal morbidity in women with kidney disease.

REFERENCES

1. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases: Kidney disease statistics for the United States, 2016. Available at: https://www.niddk.nih.gov/healthinformation/health-statistics/kidney-disease. Accessed October 1, 2020

2. Bartsch E, Medcalf KE, Park AL, Ray JG; High Risk of Pre-eclampsia Identifification Group: Clinical risk factors for pre-eclampsia determined in early pregnancy: Systematic review and meta-analysis of large cohort studies. BMJ 353: i1753, 2016

3. Zhang JJ, Ma XX, Hao L, Liu LJ, Lv JC, Zhang H: A systematic review and meta-analysis of outcomes of pregnancy in CKD and CKD outcomes in pregnancy. Clin J Am Soc Nephrol 10: 1964–1978, 2015

4. Odutayo A, Hladunewich M: Obstetric nephrology: Renal hemodynamic and metabolic physiology in normal pregnancy. Clin J Am Soc Nephrol 7: 2073–2080, 2012

5. Piccoli GB, Cabiddu G, Attini R, Vigotti FN, Maxia S, Lepori N, et al.: Risk of adverse pregnancy outcomes in women with CKD. J Am Soc Nephrol 26: 2011–2022, 2015

6. Garg AX, McArthur E, Lentine KL; Donor Nephrectomy Outcomes Research (DONOR) Network: Gestational hypertension and preeclampsia in living kidney donors. N Engl J Med 372: 1469–1470, 2015

7. Kendrick J, Holmen J, You Z, Smits G, Chonchol M: Association of unilateral renal agenesis with adverse outcomes in pregnancy: A matched cohort study. Am J Kidney Dis 70: 506–511, 2017

8. Tangren JS, Powe CE, Ankers E, Ecker J, Bramham K, Hladunewich MA, et al.: Pregnancy outcomes after clinical recovery from AKI. J Am Soc Nephrol 28: 1566–1574, 2017

9. Tangren JS, Wan Md Adnan WAH, Powe CE, Ecker J, Bramham K, Hladunewich MA, et al.: Risk of preeclampsia and pregnancy complications in women with a history of acute kidney injury. Hypertension 72: 451–459, 2018

10. Gillis EE, Brands MW, Sullivan JC: Adverse maternal and fetal outcomes in a novel experimental model of pregnancy after recovery from renal ischemia-reperfusion injury. J Am Soc Nephrol 32: 375–384, 2021