Measures of adiposity correlate with renal filtration in young nulliparous women: An observational cohort study

Summary Objective Renal hyperfiltration, which has been documented in severe obesity and obesity‐associated hypertension, can occur with hypertensive disorders of pregnancy. Identification of prepregnancy risk factors for unrecognized renal hyperfiltration could inform screening and intervention strategies to protect against pregnancy complications. In young, healthy, nulliparous women, associations between associations between measures of adiposity, insulin resistance, and renal vascular resistance were thus evaluated. Methods This is a secondary analysis of a prospective observational trial characterizing associations of prepregnancy and late‐pregnancy maternal physiology. Seventy‐nine nulligravid women aged 18‐42 years without major medical conditions were assessed for percent android body fat using dual‐energy X‐ray absorption. Renal cortical vessel blood flow resistance index (CVRI) was determined using Doppler ultrasonography. Creatinine clearance was calculated from 24‐hour urine collection. Results Renal CVRI inversely correlates with body mass index (r = ‐0.23, p = 0.047), percent android fat (r = ‐0.30, p = 0.008), and supine pulse (r = ‐0.44, p < 0.001). Creatinine clearance is positively associated with BMI and HOMA‐IR. In regression modeling, supine pulse (r2 = 0.22, p < 0.001) and cardiac index (r2 = 0.05, p = 0.045) predict renal CVRI, whereas HOMA‐IR (r2 = 0.11, p = 0.008) and cardiac output (r2 = 0.06, p = 0.039) predict creatinine clearance. Measures of adiposity are not independently predictive of either measure. Conclusions In healthy young women, measures of adiposity and insulin resistance correlate positively with renal filtration. Preclinical manifestations of renal hyperfiltration may have implications for pregnancy outcomes.


| INTRODUCTION
The majority of reproductive-aged women in the United States are either overweight or obese as defined by body mass index (BMI) greater than 25.0 kg/m 2 . 1 Conditions associated with obesity, including hypertension and metabolic syndrome, have been linked to elevated renal filtration. Obesity-associated hypertension has been correlated with increased renal plasma blood flow. [2][3][4][5] Metabolic syndrome, as defined by central obesity (waist circumference of 88 cm in women), dyslipidemia, hypertension, and fasting hyperglycemia, is also tied to a number of risk factors for renal dysfunction. 6 Severe obesity O R I G I N A L A R T I C L E has been associated with increased measures of renal filtration, independent of clinical hypertension, or diabetes mellitus. [6][7][8] In healthy young men, increasing BMI correlates with increasing creatinine clearance. 9 However, the relationship between obesity and renal hyperfiltration has yet to be described in young healthy women in the absence of any pregnancy influence.
Of particular concern in young nulliparous women is the development of preeclampsia in their first pregnancy. Preeclampsia, typically characterized by hypertension and renal injury, is a significant contributor to both maternal and neonatal morbidity and mortality. [10][11][12] Sensitive, cost-effective, prepregnancy, and early-pregnancy predictors remain elusive, and current recommendations for determining risk rely on patient history when deciding to initiate preeclampsia prophylaxis in nulliparous pregnant patients. 10,13 Obesity is a known risk factor, conferring a 1.6-to-3.3-times increased likelihood of developing preeclampsia. 14 The mechanism by which excess adiposity contributes to hypertensive disease of pregnancy is not well understood. Established chronic kidney disease, a major risk factor for preeclampsia, is associated with a fivefold increased risk, 13,15 but subclinical forms of renal dysfunction are not routinely assessed in patients.
The aim of this study is to determine the relationship between measures of obesity, renal filtration, and subclinical biochemical markers of metabolic syndrome in otherwise healthy, young, nulliparous women. Among a cohort of such women, it was hypothesized that a significant association exists between indices of obesity and biochemical markers of metabolic syndrome, including difference in renal vascular resistance.

| METHODS
A secondary analysis of a single-center cohort study was conducted, which included nulliparous women recruited as part of a prospective trial characterizing associations between prepregnancy and latepregnancy maternal physiology from November 2010 to June 2014. 16 Eligible participants were between the ages of 18 to 42 years with self-reported menstrual cycles of regular frequency and duration (from 26 to 35 days) who were planning pregnancy within the coming year. Excluded were women with preexisting diagnoses of hypertension, type 2 diabetes mellitus, autoimmune disease, or other major medical conditions. Study participants were evaluated after a three-day calorie, sodium, and potassium-controlled meal plan that was supplied to the patients as part of the protocol. Evaluations took place during the follicular phase of their menstrual cycle after an overnight fast. Participants were instructed to refrain from decongestants and nonsteroidal anti-inflammatory medications for 48 hours prior to assessment, as well as caffeine and alcohol for 24 hours prior to evaluation.

| RESULTS
Seventy-nine healthy, nulligravid women consented and enrolled in the study. The cohort was young, with mean age 30   In regression modeling, CVRI was predicted by resting supine pulse (r 2 = 0.22, p < 0.001) and cardiac index (r 2 = 0.05, p = 0.045).

| DISCUSSION
In this cohort of young, healthy, nulliparous women, with predomi- In a cohort of women planning pregnancy in the coming year, these findings raise questions as to the implication of baseline renal function as it relates to adverse pregnancy outcomes. While long-term metabolic and cardiovascular risks associated with preeclampsia have been well established, 22,23 mounting evidence suggests that preeclampsia may be an early manifestation of subclinical cardiovascular disease, as well as other elements of the metabolic syndrome including dyslipidemia and insulin resistance rather than an independent risk factor for the subsequent development of cardiovascular disease. [24][25][26][27][28][29][30] Sensitive, cost-effective prepregnancy and early-pregnancy predictors of preeclampsia remain elusive, 10  Strengths of this study include standardized, detailed physiologic evaluation with multimodal characterization of both obesity and renal F I G U R E 2 Creatinine clearance is positively associated with HOMA-IR in a cohort of young, healthy nulliparous women. Each subject (blue data point) is manifested with creatinine clearance as it corresponds to body mass index. Linear fitting demonstrates a positive association filtration. This is the first report of such associations among healthy, nulliparous, reproductive-aged women. Such women are generally at low risk of adverse health outcomes; however, in light of increasing rates of pregnancy-related morbidity and mortality, these insights can play an important role identifying risks for renal dysfunction during an initial pregnancy.

| CONCLUSION
Among a cohort of healthy, nulliparous women, renal vascular resistance decreases continuously with increasing obesity, whereas creatinine clearance and increasing insulin resistance is elevated with increasing BMI. This is consistent with a preclinical manifestation of renal hyperfiltration seen in metabolic syndrome, and may have important implications for a group of women planning reproduction in the near future as well as for their long-term health.

FUNDING
This study was supported by the National Institutes of Health under grant HL 71944.