Assessment of Renal Function in Adults Born Preterm: The HAPI-Kidney Study

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Prematurity; Extreme
• Intervention / Treatment: Other: Preterm birth

Detailed Description

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 (Actual): 157

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • StJustine's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 36 years (Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Participants are recruited from the HAPI study, which included 101 individuals born ≤29 weeks in the province of Quebec in 1987-97 (including 83 from CHU Ste-Justine (CHUSJ) who were similar to non-participant survivors for neonatal characteristics), and 105 individuals born full-term recruited among friends/siblings and through advertisement.

Description

Inclusion Criteria:

• Born preterm ≤29 weeks or full-term at 37-41 weeks;
• For full-term controls only, birthweight ˃2500g;
• Aged 18-40 years;
• Participants with type-2 diabetes can be included.

Exclusion Criteria:

• Currently pregnant due to administration of radionucleotides and impact on GRF,
• Severe neurosensory deficit preventing test completion,
• History of characterized kidney disease independent of preterm birth, including type-1 diabetes, glomerulopathies (e.g. nephrotic syndrome, glomerulonephritis), polycystic kidney disease, polycystosis, severe uropathy (Grade 4 or 5 RVU, severe hydronephrosis (SFU IV and V), posterior valve history), history of nephrectomy, exposure to radiotherapy or chemotherapy - given that we are interested in isolating the effects of preterm birth and that prevalence of these conditions is not increased in individuals born preterm,
• In case of contra-indication to MRI scanning (which should be rare in the young population studied), the participant will still be given the opportunity to complete the other examinations.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Born preterm; Inclusion : Born preterm ≤29 weeks Aged 18-40 years Participants with type-2 diabetes Exclusion : Currently pregnant due to administration of radionucleotides and impact on GFR Severe neurosensory deficit preventing test completion History of characterized kidney disease independent of preterm birth, including type-1 diabetes, glomerulopathies (e.g. nephrotic syndrome, glomerulonephritis), polycystic kidney disease, polycystosis, severe uropathy (Grade 4 or 5 RVU, severe hydronephrosis (SFU IV and V), posterior valve history), history of nephrectomy, exposure to radiotherapy or chemotherapy - given that we are interested in isolating the effects of preterm birth and that prevalence of these conditions is not increased in individuals born preterm In case of contra-indication to MRI scanning (which should be rare in the young population studied), the participant will still be given the opportunity to complete the other examinations.	Other: Preterm birth; The study compares young adult subjects born premature (< 29 weeks) versus term > 37-41 weeks)
Born term; Inclusion : Born full-term at 37-41 weeks Birthweight ˃2500g Aged 18-40 years Participants with type-2 diabetes Exclusion : Currently pregnant due to administration of radionucleotides and impact on GFR Severe neurosensory deficit preventing test completion History of characterized kidney disease independent of preterm birth, including type-1 diabetes, glomerulopathies (e.g. nephrotic syndrome, glomerulonephritis), polycystic kidney disease, polycystosis, severe uropathy (Grade 4 or 5 RVU, severe hydronephrosis (SFU IV and V), posterior valve history), history of nephrectomy, exposure to radiotherapy or chemotherapy - given that we are interested in isolating the effects of preterm birth and that prevalence of these conditions is not increased in individuals born preterm In case of contra-indication to MRI scanning (which should be rare in the young population studied), the participant will still be given the opportunity to complete the other examinations.	Other: Preterm birth; The study compares young adult subjects born premature (< 29 weeks) versus term > 37-41 weeks)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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.	30 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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.	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.	60 minutes
Biomarker of vasoregulatory mechanisms, kidney level, Apelin	Plasma apelin-12 is assessed using an ELISA assay (Phoenix Pharmaceuticals, CA, USA).	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.	10 minutes
Albuminuria	Albumin to creatinine ratio (ACR) is obtained from a spot urine collection.	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.	5 minutes
Renal ultrasound and Doppler, Volume	Morphologic studies of kidneys including size (volume)	10 minutes
Renal ultrasound and Doppler, Echogenicity	Morphologic studies of kidneys including echogenicity (cortex and medulla)	10 minutes
Renal ultrasound and Doppler, urinary tract	Morphologic studies of kidneys including urinary tract	10 minutes
Renal ultrasound and Doppler, arterial resistive index	Morphologic studies of kidneys including arterial resistive index.	10 minutes
Liver echography	Morphologic study of the liver using the echography machine, including the volume.	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.	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.	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.	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.	15 minutes
Physical activity	Measured using accelerometry for 7 seven consecutive days.	7 days
Aerobic capacity and endurance test	Six-minute walking test (6MWT) assesses distance walked over 6 minutes.	6 minutes
Questionnaire #1	Current medication, alcohol, drugs use 2)	5 minutes
Hydration levels, plasma electrolytes	Plasma electrolytes measured by the Hospital clinical biochemistry.	15 minutes
Hydration levels, plasma osmolality	Plasma osmolality measured by the Hospital clinical biochemistry.	30 minutes
Hydration levels, urine electrolytes	Urine (spot) electrolytes measured by the Hospital clinical biochemistry.	30 min
Hydration levels, urine osmolality	Urine (spot) osmolality measured by the Hospital clinical biochemistry.	30 minutes
Hydration levels, plasma hematocrit	Plasma hematocrit measured by the Hospital clinical biochemistry.	30 minutes
Hydration levels, plasma total proteins	Plasma total proteins measured by the Hospital clinical biochemistry.	30 minutes
Cardiometabolic risk factors, glycated hemoglobin	Glycated hemoglobin in plasma measured by the Hospital clinical biochemistry.	15 minutes
Cardiometabolic risk factors, plasma lipids	Plasma lipids measured by the Hospital clinical biochemistry.	15 minutes
Cardiometabolic risk factors, BMI	BMI, calculated using the weight in kg and the height in meters.	15 minutes
Cardiometabolic risk factors, waist-to-hip	Waist-to-hip ratio using the measurement of the hip and waist in centimeters	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.	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.	2 hours
SF-36	Quality of life and functional status	10 minutes
WHO questionnaire	Quality of life and functional status	10 minutes
Diet, food frequency questionnaire	Food frequency questionnaire	35 minutes
Diet, 24-hour meal interview	24-hour meal interview	10 minutes
MAPA	Monitoring device for 24 hours blood pressure measurement.	24 hours

Collaborators and Investigators

• Sponsor: St. Justine's Hospital
• Collaborators: Canadian Institutes of Health Research (CIHR); Centre hospitalier de l'Université de Montréal (CHUM); European Georges Pompidou Hospital; Centre for Interdisciplinary Research in Rehabilitation of Greater Montreal
• Investigators: Principal Investigator: Anne Monique Nuyt, MD, StJustine's Hospital; Principal Investigator: Thuy Mai Luu, MD, StJustine's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2021
• Primary Completion (Actual): March 1, 2024
• Study Completion (Estimated): December 30, 2025

Study Registration Dates

• First Submitted: January 14, 2021
• First Submitted That Met QC Criteria: January 27, 2021
• First Posted (Actual): February 3, 2021

Study Record Updates

• Last Update Posted (Actual): July 11, 2025
• Last Update Submitted That Met QC Criteria: July 8, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Prematurity; Cardiovascular system; Clinical study; Extremely preterm; Developmental origin of adult health and disease; Renal system
• Additional Relevant MeSH Terms: Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Premature Birth
• Other Study ID Numbers: HAPI-Kidneys

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD that underlie results in a publication
• IPD Sharing Time Frame: 1 year after all the results are published
• IPD Sharing Access Criteria: Request of collaboration through data access will be examined by the PI's.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No