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

Study Overview
=================
Brief Summary
-----------------
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.

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. To assess the association between preterm birth and measured GFR, compared to estimated GFR, in young adulthood (18-40 years). 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. 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. 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.

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

Conditions
-----------------
Prematurity; Extreme

Intervention / Treatment
-----------------
* Other: Preterm birth


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Born preterm<br>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<br>* The study compares young adult subjects born premature (< 29 weeks) versus term > 37-41 weeks)<br>|
| Born term<br>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<br>* The study compares young adult subjects born premature (< 29 weeks) versus term > 37-41 weeks)<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Extremely preterm, Clinical study, Developmental origin of adult health and disease, Prematurity, Renal system, Cardiovascular system