Every year in Canada, 1500 babies are born ≤29 weeks' gestational age (GA) and the majority survive to adulthood. Preterm birth occurs during a critical period of nephrogenesis. Antenatal and postnatal exposure to various insults may permanently disrupt normal kidney development. Indeed, preterm children have reduced nephron number and altered glomerular architecture, which may lead to glomerular hyperfiltration thus perpetuating renal damage. However, the long-term consequences of preterm birth on renal function remain under-studied. The existing reports on glomerular function have yielded contradictory results and were limited by use of imprecise estimates of glomerular filtration rate (GFR) or small sample size. Yet, a registry-based study has shown the increased risk of chronic kidney diseases (CKD) in individuals born preterm. In addition, individuals born preterm have higher blood pressure. As mechanisms for hypertension following preterm birth are being unravelled, the role of the kidneys, which is key in chronic hypertension, is to be determined. So far, we have shown a relationship between smaller kidney size and increased blood pressure. A better understanding of the early markers of kidney dysfunction following preterm birth will facilitate screening and intervention to halt progression to CKD as there are currently no long-term renal follow-up guidelines for individuals born preterm. This proposal builds on our previous works on long-term health outcomes of preterm birth and experimental model of prematurity-related conditions and renal development. We aim to assess glomerular function and renal vasoactive regulatory factors in relation to blood pressure using precise measures in a cohort of young adults born preterm ≤29 weeks versus full-term controls. We further take advantage of our previous assessment of this cohort (Health of Adults born Preterm Investigation (HAPI) - CIHR 2014-18) to evaluate changes in estimated GFR and albuminuria over a 5-year period.
Given that preterm birth is associated with reduced nephron endowment and higher glomerular area on renal histology suggesting compensatory glomerular hyperfiltration, we postulate that : Hypothesis 1: mGFR relative to total kidney volume is higher in adults born preterm vs. to full-term controls. Hypothesis 2: mGFR relative to kidney volume is associated with plasma renin activity, aldosterone, copeptin and apelin levels. Levels of these vasoactive factors may correlate to blood pressure values. Hypothesis 3: Rates of decline in eGFR and increase in albuminuria is more important in the preterm vs. full-term group. Hypertension at baseline predicts faster decline in eGFR and increase in albuminuria. Decrease in eGFR and increase in albuminuria correlate with increasing blood pressure over time. Hypothesis 4: Higher baseline copeptin levels and, reciprocally, lower baseline apelin levels are associated with faster decline in eGFR and increase in albuminuria. Our overarching aim is to assess long-term glomerular function in adults born preterm ≤29 weeks' GA versus full-term controls. 1. To assess the association between preterm birth and measured GFR, compared to estimated GFR, in young adulthood (18-40 years). 2. To examine the association between mGFR and vasoactive humoral factors involved in kidney hemodynamics (plasma renin activity, aldosterone, copeptin, apelin) in relation to blood pressure in young adults born preterm versus full-term controls. 3. To compare changes in eGFR and albuminuria over a 5-year period in relation to change in blood pressure in young adults born preterm versus full-term controls. 4. To determine whether baseline levels of copeptin and apelin can predict changes in eGFR and albuminuria over a 5-year period in young adults born preterm versus full-term controls.
Study Type
OBSERVATIONAL
Enrollment
157
The study compares young adult subjects born premature (\< 29 weeks) versus term \> 37-41 weeks)
StJustine's Hospital
Montreal, Quebec, Canada
mGFR relative to kidney volume (scintigraphy), measurement 1
First, whole-kidney mGFR is measured from the plasma clearance of a radionuclide labeled tracer, 99mTc-DTPA, using the slope-intercept method and single-compartment simplification. A single bolus of 300 microcuries (11.1 mega-Becquerels) of 99mTc-DTPA is injected in one arm and plasma sampling for activity concentration (Hidex Automatic Gamma Counter) is performed in the other arm at 90, 120, 150 and 180 minutes. Calculation of mGFR is as follow: mGFR = (Q/Co) x (0.693/T1/2) where Q the injected dose and Co the extrapolated plasmatic activity at time 0.107 If needed, correction for the rapid component of the time activity curve is performed using the Brochner-Mortensen equation. Value of mGFR is then corrected to the patient's BSA, derived from measured weight and height using DuBois' formula, and expressed in mL/min/1.73 m2. Estimated effective dose of the procedure is 0.054 mSv.
Time frame: 90 minutes
mGFR relative to kidney volume (scintigraphy), measurement 2
First, whole-kidney mGFR is measured from the plasma clearance of a radionuclide labeled tracer, 99mTc-DTPA, using the slope-intercept method and single-compartment simplification. A single bolus of 300 microcuries (11.1 mega-Becquerels) of 99mTc-DTPA is injected in one arm and plasma sampling for activity concentration (Hidex Automatic Gamma Counter) is performed in the other arm at 90, 120, 150 and 180 minutes. Calculation of mGFR is as follow: mGFR = (Q/Co) x (0.693/T1/2) where Q the injected dose and Co the extrapolated plasmatic activity at time 0.107 If needed, correction for the rapid component of the time activity curve is performed using the Brochner-Mortensen equation. Value of mGFR is then corrected to the patient's BSA, derived from measured weight and height using DuBois' formula, and expressed in mL/min/1.73 m2. Estimated effective dose of the procedure is 0.054 mSv.
Time frame: 120 minutes
mGFR relative to kidney volume (scintigraphy), measurement 3
First, whole-kidney mGFR is measured from the plasma clearance of a radionuclide labeled tracer, 99mTc-DTPA, using the slope-intercept method and single-compartment simplification. A single bolus of 300 microcuries (11.1 mega-Becquerels) of 99mTc-DTPA is injected in one arm and plasma sampling for activity concentration (Hidex Automatic Gamma Counter) is performed in the other arm at 90, 120, 150 and 180 minutes. Calculation of mGFR is as follow: mGFR = (Q/Co) x (0.693/T1/2) where Q the injected dose and Co the extrapolated plasmatic activity at time 0.107 If needed, correction for the rapid component of the time activity curve is performed using the Brochner-Mortensen equation. Value of mGFR is then corrected to the patient's BSA, derived from measured weight and height using DuBois' formula, and expressed in mL/min/1.73 m2. Estimated effective dose of the procedure is 0.054 mSv.
Time frame: 150 minutes
mGFR relative to kidney volume (scintigraphy), measurement 4
First, whole-kidney mGFR is measured from the plasma clearance of a radionuclide labeled tracer, 99mTc-DTPA, using the slope-intercept method and single-compartment simplification. A single bolus of 300 microcuries (11.1 mega-Becquerels) of 99mTc-DTPA is injected in one arm and plasma sampling for activity concentration (Hidex Automatic Gamma Counter) is performed in the other arm at 90, 120, 150 and 180 minutes. Calculation of mGFR is as follow: mGFR = (Q/Co) x (0.693/T1/2) where Q the injected dose and Co the extrapolated plasmatic activity at time 0.107 If needed, correction for the rapid component of the time activity curve is performed using the Brochner-Mortensen equation. Value of mGFR is then corrected to the patient's BSA, derived from measured weight and height using DuBois' formula, and expressed in mL/min/1.73 m2. Estimated effective dose of the procedure is 0.054 mSv.
Time frame: 180 minutes
Whole-kidney GFR (MRI)
Whole-kidney GFR is a product of nephron number and single-nephron GFR. As a surrogate for single-nephron GFR, we are examining mGFR in relation to total kidney volume (i.e. mGFR per cm3 of kidney volume), which is reduced in adults born preterm and correlates to a certain extent to nephron number. Total kidney volume is measured by multi-parametric magnetic resonance imaging (MRI), which also allows for a comprehensive assessment of kidney structure and hemodynamics. No contrast is injected. Images are acquired using a Philips Ingenia 1.5T MRI system and a 16/32 channels dStream Torso coil (Philips). To quantify total kidney volume, localizer scans at end expiration are acquired using balanced turbo field echo and balanced fast field echo in three orthogonal planes. Volume is then calculated by manually tracing the kidney on the coronal images using Philips Intellispace Portal.
Time frame: 1 hour
Rate of glomerular hyperfiltration
We also examine rate of glomerular hyperfiltration, which is typically described as ˃95th percentile of a reference population. The prevalence of single-nephron glomerular hyperfiltration is estimated by assessing the proportion of participants born preterm with a ratio of mGFR to total kidney volume ˃95th percentile calculated in participants born full-term.
Time frame: 30 minutes
Biomarker of vasoregulatory mechanisms, kidney level, Renin
Plasma renin activity is determined by measuring the mass of angiotensin-1 generated per volume of human plasma in one hour, using a PRA ELISA assay (IBL-America, MN, USA).
Time frame: 60 minutes
Biomarker of vasoregulatory mechanisms, kidney level, Aldosterone
Plasma aldosterone is assessed using a high sensitivity ELISA assay (IBL-America), with a range of 7.75 - 1000 pg/ml and expected plasma aldosterone values of at least 40 pg/ml113.
Time frame: 60 minutes
Biomarker of vasoregulatory mechanisms, kidney level, Copeptin
Plasma copeptin is assessed in the plasma using the BRAHMS KRYPTOR compact PLUS system available at London Health Sciences Centre, London, ON.
Time frame: 60 minutes
Biomarker of vasoregulatory mechanisms, kidney level, Apelin
Plasma apelin-12 is assessed using an ELISA assay (Phoenix Pharmaceuticals, CA, USA).
Time frame: 60 minutes
Blood pressure
Blood pressure (systolic and diastolic) is measured after seated rest for 5 min before blood sampling using an automated oscillometric device (Dinamap, GE Healthcare) according to the Canadian Hypertension Education Program. Blood pressure is measured in both arms and the average of 3 measures taken at 1-min intervals on the arm with highest readings is used. Participants also undergo 24-hour ambulatory blood pressure measurement (ABPM, Spacelabs Medical, Washington) on their non-dominant arm.
Time frame: 10 minutes
Albuminuria
Albumin to creatinine ratio (ACR) is obtained from a spot urine collection.
Time frame: 5 minutes
Estimated GFR
Estimated GFR is calculated using validated Full Age Spectrum (FAS) equation, with and without correction for height115 (with IDMS standardized creatinine), as this equation has been shown to be more accurate than the CKD-Epi equation in young adults.
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Time frame: 5 minutes
Renal ultrasound and Doppler, Volume
Morphologic studies of kidneys including size (volume)
Time frame: 10 minutes
Renal ultrasound and Doppler, Echogenicity
Morphologic studies of kidneys including echogenicity (cortex and medulla)
Time frame: 10 minutes
Renal ultrasound and Doppler, urinary tract
Morphologic studies of kidneys including urinary tract
Time frame: 10 minutes
Renal ultrasound and Doppler, arterial resistive index
Morphologic studies of kidneys including arterial resistive index.
Time frame: 10 minutes
Liver echography
Morphologic study of the liver using the echography machine, including the volume.
Time frame: 15 minutes
Muscle ultrasound
Ultrasound imaging examinations of the musculoskeletal system, through the rectus femoris muscle. Images of the rectus femoris will be recorded while the participant is in a sitting position.
Time frame: 10 minutes
Muscle elastography
For the elastography, the participant will stay still while the share wave is applied. Finally, ultrasound images of the rectus femoris will be recorded in three different states: 1) relaxed position, 2) maximal voluntary contraction and 3) sub-maximal voluntary contraction, using a dynamometer. A 30-second rest period will be implemented between contractions to minimize potential fatigue effects.
Time frame: 30 minutes
Muscular strength
Measured in accordance with the standardized test protocol produced by the Canadian Society for Exercise Physiology (CSEP, 2013), using a dynamometer.
Time frame: 15 minutes
Muscular endurance
Measured in accordance with the standardized test protocol produced by the Canadian Society for Exercise Physiology (CSEP, 2013), using a dynamometer.
Time frame: 15 minutes
Physical activity
Measured using accelerometry for 7 seven consecutive days.
Time frame: 7 days
Aerobic capacity and endurance test
Six-minute walking test (6MWT) assesses distance walked over 6 minutes.
Time frame: 6 minutes
Questionnaire #1
Current medication, alcohol, drugs use 2)
Time frame: 5 minutes
Hydration levels, plasma electrolytes
Plasma electrolytes measured by the Hospital clinical biochemistry.
Time frame: 15 minutes
Hydration levels, plasma osmolality
Plasma osmolality measured by the Hospital clinical biochemistry.
Time frame: 30 minutes
Hydration levels, urine electrolytes
Urine (spot) electrolytes measured by the Hospital clinical biochemistry.
Time frame: 30 min
Hydration levels, urine osmolality
Urine (spot) osmolality measured by the Hospital clinical biochemistry.
Time frame: 30 minutes
Hydration levels, plasma hematocrit
Plasma hematocrit measured by the Hospital clinical biochemistry.
Time frame: 30 minutes
Hydration levels, plasma total proteins
Plasma total proteins measured by the Hospital clinical biochemistry.
Time frame: 30 minutes
Cardiometabolic risk factors, glycated hemoglobin
Glycated hemoglobin in plasma measured by the Hospital clinical biochemistry.
Time frame: 15 minutes
Cardiometabolic risk factors, plasma lipids
Plasma lipids measured by the Hospital clinical biochemistry.
Time frame: 15 minutes
Cardiometabolic risk factors, BMI
BMI, calculated using the weight in kg and the height in meters.
Time frame: 15 minutes
Cardiometabolic risk factors, waist-to-hip
Waist-to-hip ratio using the measurement of the hip and waist in centimeters
Time frame: 10 minutes
Questionnaire # 2
Socio-economic status from the parents and the participant Occupation and education level (achieved or ongoing), parental education/income for students, primary earner status, personal income. Family history: Parental health history of cardiovascular, metabolic or renal diseases.
Time frame: 10 minutes
Questionnaire #3
Obstetrical and neonatal history: (a) maternal: smoking, prepregnancy BMI, hypertension, diabetes, prenatal corticosteroids, chorioamnionitis Neonatal: GA (based on date of last period and/or obstetric ultrasound), birth weight and percentile as per Hadlock for preterm subjects (intrauterine growth curves) and Kramer (postnatal birth weight) for term controls, APGAR, major complications/conditions (mechanical ventilation, O2 and parenteral nutrition duration, umbilical arterial lines, sepsis, acute renal failure, necrotizing enterocolitis, bronchopulmonary dysplasia, ultrasound brain lesions, surgeries, medications (nephrotoxic antibiotics, steroids, indomethacin, diuretics), and length of hospital stay). Data are obtained from medical records.
Time frame: 2 hours
SF-36
Quality of life and functional status
Time frame: 10 minutes
WHO questionnaire
Quality of life and functional status
Time frame: 10 minutes
Diet, food frequency questionnaire
Food frequency questionnaire
Time frame: 35 minutes
Diet, 24-hour meal interview
24-hour meal interview
Time frame: 10 minutes
MAPA
Monitoring device for 24 hours blood pressure measurement.
Time frame: 24 hours