Visual Abstract
Keywords: albuminuria, chronic kidney disease, hypertension, systolic blood pressure, prematurity, epidemiology and outcomes, children, blood pressure
Abstract
Background and objectives
Extremely low gestational age neonates born <28 weeks gestation are at risk for chronic disease. We sought to describe the prevalence of kidney outcomes by gestational age and determine risk factors for their development.
Design, setting, participants, & measurements
The Recombinant Erythropoietin for Protection of Infant Renal Disease (REPAIReD) study examined kidney outcomes of extremely low gestational age neonates enrolled in the Preterm Epo NeuroProtection Trial (PENUT) study. Kidney function, urine albumin, and BP were measured at 2-year (24±2 months) corrected gestational age. We compared outcomes across gestational age categories and evaluated associations between kidney-related outcomes and neonatal and maternal characteristics. The primary outcome was eGFR <90 ml/min per 1.73 m2 (CKD); secondary outcomes were spot urine albumin-creatinine ratio ≥30 mg/g (albuminuria) and either systolic BP or diastolic BP >90th percentile for height, age, and sex.
Results
A total of 832 survived to 2 years, and 565 (68%) had at least one outcome measured. Overall, 297 (53%) had one abnormal kidney outcome; 61 (18%) had an eGFR <90 ml/min per 1.73 m2, 155 (36%) had albuminuria, 65 (22%) had elevated systolic BP, and 128 (44%) had elevated diastolic BP. Gestational age (odds ratio, 0.94; 95% confidence interval, 0.89 to 0.99), birth weight z-score (odds ratio, 0.92; 95% confidence interval, 0.85 to 0.98), and prenatal steroids (odds ratio, 1.23; 95% confidence interval, 1.08 to 1.39) were associated with an eGFR <90 ml/min per 1.73 m2. An elevated systolic BP was associated with indomethacin use (odds ratio, 1.18; 95% confidence interval, 1.04 to 1.33) and Black race (odds ratio, 1.19; 95% confidence interval, 1.01 to 1.39); elevated diastolic BP was associated with male sex (odds ratio, 1.29; 95% confidence interval, 1.12 to 1.49), severe AKI (odds ratio, 1.24; 95% confidence interval, 1.04 to 1.48), and indomethacin use (odds ratio, 1.16; 95% confidence interval, 1.01 to 1.33).
Conclusions
Approximately 18% of extremely low gestational age neonates have CKD, 36% have albuminuria, 22% have an elevated systolic BP, and 44% have an elevated diastolic BP at 2 years of age. Gestational age, birthweight z-score, and prenatal steroids were associated with CKD. Male sex, Black race, indomethacin use, and severe AKI were associated with elevated BP.
Podcast
This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_07_19_CJN15011121.mp3
Advances in neonatal care have improved outcomes significantly for premature infants over the past five decades. Nearly 90% of infants weighing 501–1500 g survive to neonatal intensive care unit (NICU) discharge, and 60% of survivors leave the NICU without major neonatal morbidity (1). David Barker observed many “adult” diseases have their origins in fetal life (2–4), because evidence exists for fetal programing for premature infants developing obesity (5,6), hypertension (4), insulin resistance (7), coronary artery disease (2), and CKD (8,9) later in life.
Nephron development begins around 9 weeks of gestation and ends around 34–36 weeks, with the majority of nephrogenesis occurring in the third trimester. Postnatal nephron development is suboptimal in the extrauterine environment with potential exposures to nephrotoxic medications, hypoxic, and ischemic insults (10,11). Studies in premature neonates <32 weeks and low birthweight (LBW <2500 g) reveal higher risk for development of lower eGFR, microalbuminuria, and kidney failure as adults compared with normal birthweight controls (12). Very LBW (VLBW; <1500 g) neonates with AKI are at higher risk for an eGFR <90 ml/min per 1.73 m2 by school age (13). A national cohort study from Sweden identified a higher risk of CKD in the first 9 years of life in children born preterm and extremely preterm (<28 weeks gestation) (14). However, questions remain regarding the independent effect of prematurity, LBW, or extrauterine events (i.e., AKI) on long-term kidney disease. Additionally, timing of development of kidney abnormalities in extremely low gestational age neonates (ELGANs) and when and in whom to begin screening has not been determined.
We sought to answer these questions using an ELGANs cohort followed prospectively from birth to 2-years corrected age. The goal of this study was to describe the prevalence of, and identify risk factors for, development of an eGFR <90 ml/min per 1.73 m2, albuminuria, and elevated BP at 2-years corrected age.
Materials and Methods
Patient Population
Patients enrolled in the Preterm Epo Neuroprotection Trial (PENUT) (15–17) were eligible and enrolled in the Recombinant Erythropoietin for Protection of Infant Renal Disease (REPAIReD) study. REPAIReD is an ancillary study to PENUT to investigate both acute and chronic kidney disease in ELGANs. Patients were eligible if inborn between 24 0/7 and 27 6/7 weeks’ gestation at a PENUT study site. Parental consent was obtained prenatally or postnatally, as permitted by each site’s Institutional Review Board. Patients were excluded on the basis of known major life-threatening anomalies, chromosomal anomalies, disseminated intravascular coagulopathy, twin–twin transfusion, hydrops fetalis, or known congenital infection. Additional protocol details are published elsewhere (15–17). Results on the prevalence of AKI, mortality with AKI, and the effect of erythropoietin on outcomes in this cohort were published (18,19). This study was Institutional Review Board approved at all participating sites and registered with the Food and Drug Administration (IND12656) and ClinicalTrials.gov (NCT01378273) (Figure 1). Patients who survived to 2 years were included in this analysis if they had at least one measured outcome (eGFR, albumin-creatinine ratio [ACR], or two BP readings) at the 2-year follow-up (defined as 24±2 months corrected age).
Figure 1.
Consort diagram of extremely low gestational age neonates (ELGANs) included in long-term follow-up study. ACR, albumin-creatinine ratio.
Inpatient Data
Serum and urine were collected at protocol-specified times during the hospital course and then again at the 2-year follow-up visit. Research specimens were assessed for serum creatinine (SCr) and cystatin C on days 7, 9, and 14 at the Seattle Children's Hospital Clinical Laboratory using the two-point method with the Vitros 4600 (Ortho Clinical Diagnostic; Raritan, NJ). Cystatin C concentrations were analyzed using particle-enhanced immunonephelometry using the BN ProSpec System (Siemens Healthineers, Tarrytown, NY). Urine was collected as a bag specimen or with a cotton ball in the diaper. Urine at the 2-year follow-up was analyzed for ACR using the VITROS Chemistry Products mALB Reagent in conjunction with the VITROS Chemistry Products Calibrator Kit 24 on the 4600 Chemistry Systems. Urine creatinine was measured using the VITROS CREA Slide.
SCr measurements collected as part of clinical care were used for AKI determination. Daily AKI stages were determined by the SCr-based Kidney Diseases Improving Global Outcomes definition; stage 1 is defined as a 1.5–1.9× increase or an increase of 0.3 mg/dl within 48 hours from baseline creatinine, stage 2 is 2.0–2.9× increase, and stage 3 is ≥3× baseline or SCr ≥2.5 mg/dl. Nonbaseline creatinine measurements had to be >0.5 mg/dl to be considered for AKI calculation. To account for creatinine levels on postnatal days 0–2 that may represent that of the mother, we began AKI calculation on postnatal day 3. We defined severe AKI as stage 2 or 3.
Kidney-Related Measurements at Follow-Up
Our primary outcome measure for kidney disease was an eGFR <90 ml/min per 1.73 m2, using the new CKiDU25 equation (20).
Secondary outcomes included albuminuria (defined as ACR ≥30 mg albumin/g creatinine) and systolic and diastolic BP >90th percentile for age and sex on the basis of 2017 definitions (21). BP was measured with a Briggs Mabis Healthcare Manual Sphygmomanometer with BP cuff appropriate for patient size (Des Moines, IA). Standardization of procedures and personnel training was done across all sites. Two manual or automated BP measurements ≥5 minutes apart were taken and recorded. We used the lowest of the two readings to be conservative about our prevalence estimates (18) and included only those patients with two BP measurements. Patients with only one BP measurement (203; 41%) were excluded.
Statistical Analysis
Follow-up status and 2-year outcome data were categorized by gestational age at birth in weeks rounded down to the nearest week. Baseline characteristics were examined separately between those with and without each metric: eGFR, ACR, and elevated BP (systolic and diastolic). Unadjusted associations between baseline characteristics and primary and secondary outcomes were evaluated using unadjusted regression models. However, for weight, we adjusted for gestational age given large differences in weight across gestational age strata. Clinical and demographic data collected included: length (centimeters), Apgar score at 5 minutes, maternal ethnicity (Hispanic/not Hispanic); maternal highest level of education (high school or less/some college/college degree or higher); maternal diabetes; pre-eclampsia; multiple gestation; prenatal steroids; and receipt of indomethacin, vancomycin, and gentamicin. Patent ductus arteriosus was defined as a patent ductus arteriosus requiring treatment. Predefined serious adverse events recorded any time before hospital discharge included severe necrotizing enterocolitis defined as either stage 2b or 3, severe intraventricular hemorrhage defined as grade III or IV hemorrhage, and sepsis defined as culture proven and requiring BP support shock or new respiratory support. We also calculated weight gain from birth to discharge and discharge to 2-year follow-up.
A risk factor analysis was conducted using generalized estimating equations corrected for sibship clustering (22). The parent study allowed for enrollment of twins and triplets. Enrollment of such groups are considered clusters because the siblings will be correlated in their measures and outcomes. Specifically, logistic regression models were used for each binary metric and included the following limited set of risk factors that were chosen a priori: sex; gestational age rounded down to the nearest week; weight z-score defined as individual weight minus average weight for the respective gestational age divided by the standard deviation of weight by gestational age; self-described maternal race (White/Black/other); pre-eclampsia; maternal diabetes; prenatal steroids; severe AKI (stage 2/3 versus stage 0/1) within first 28 days; and receipt of indomethacin (mean [SD]) duration of therapy for indomethacin was 0.61 [1.10] days). Those with missing AKI status were treated as stage 0/1.
Sensitivity Analysis of Those Who Did Not Have Study Procedures Performed
To assess potential bias resulting from an unequal representation due to patient loss to follow-up status, we evaluated baseline characteristics between those who died before their 2-year follow-up, those with no complete outcome measures at follow-up, and those with at least one complete outcome measure at the 2-year follow-up visit (Table 1). Unadjusted linear and logistic regression models were applied to determine if the frequency differed according to whether 2-year follow-up data were captured. Subsequent comparisons were made among those with and without the outcomes of interest: eGFR, albuminuria, elevated systolic BP, and elevated diastolic BP (Supplemental Tables 1–6).
Table 1.
Baseline characteristics by 2-year follow-up status
| Characteristics | Died Before 2 Years | No Follow-Up or Measurements | 2-Year Follow-Up and Measurements |
|---|---|---|---|
| 91 | 267 | 565 | |
| Male, n (%) | 51 (56) | 140 (52) | 288 (51) |
| Gestational age, wk, n (%) | |||
| 24 | 33 (36) | 55 (21) | 139 (25) |
| 25 | 29 (32) | 77 (28.8) | 136 (24) |
| 26 | 18 (20) | 65 (24) | 137 (24) |
| 27 | 11 (12) | 70 (26) | 153 (27) |
| Birth weight, g (mean [SD]) | 702 (172) | 804.3 (178) | 815.7 (190) |
| Birth length, cm (mean [SD]) | 31 (3.0) | 33 (3.0) | 33 (3.0) |
| Small for gestational age, n (%) | 15 (16%) | 18 (7%) | 47 (8%) |
| Apgar 5 min score, median (IQR) | 6 (2–7) | 7 (6–8) | 7 (5–8) |
| Highest birth day SBP/DBP, median | 49/ 29 | 48/ 29.5 | 48/ 29 |
| Lowest birth day SBP/DBP, median | 32/ 19 | 34/ 21 | 34/ 21 |
| Severe AKI in first 28 d, n (%)a | 17 (19) | 39 (15) | 60 (11) |
| Maternal characteristics | |||
| Age, mean (SD)b | 30 (7) | 28 (6) | 29 (6) |
| Ethnicity, n (%) | |||
| Hispanic or Latino | 68 (75) | 216 (81) | 431 (76) |
| Not Hispanic or Latino | 23 (25) | 46 (17) | 128 (23) |
| Unknown/not reported | 0 (0) | 5 (2) | 6 (1) |
| Race, n (%)b | |||
| White | 65 (71) | 149 (57) | 387 (68) |
| Black | 23 (25) | 90 (34) | 126 (22) |
| Other | 2 (2) | 18 (7) | 35 (6) |
| Not reported | 1 (1) | 10 (4) | 17 (3) |
| Education, n (%)b | |||
| High school or less | 29 (32) | 89 (33) | 188 (33) |
| Some college | 27 (30) | 87 (32) | 168 (30) |
| College degree or greater | 20 (22) | 52 (19) | 152 (27) |
| Not reported | 15 (16) | 39 (15) | 54 (10) |
| Pregnancy-induced hypertension, n (%) | 9 (10) | 15 (6) | 46 (8) |
| Prenatal steroids, n (%) | 74 (81) | 240 (90) | 517 (91) |
| Pre-eclampsia, n (%) | 18 (20) | 35 (13) | 87 (15) |
| Multiple gestations, n (%) | 25 (27) | 65 (24) | 153 (27) |
| Diabetes, n (%) | 3 (3) | 15 (6) | 30 (5) |
| Lab data | |||
| SCr, mean (SD) [n] | |||
| Day 7 | 0.81 (0.3) [63] | 0.81 (0.24) [178] | 0.78 (0.22) [378] |
| Day 9 | 0.73 (0.38) [53] | 0.77 (0.26) [180] | 0.72 (0.19) [373] |
| SCr, mean (SD) [n] | |||
| Day 14 | 0.71 (0.25) [44] | 0.71 (0.27) [173] | 0.68 (0.24) [365] |
| Max day 7, 9, 14 | 0.89 (0.36) [63] | 0.86 (0.27) [181] | 0.83 (0.24) [384] |
| Mean day 7, 9, 14 | 0.78 (0.31) [63] | 0.76 (0.24) [181] | 0.73 (0.18) [384] |
| Cystatin C, mean (SD) [n] | |||
| Change day 0 to max day 7, 9, 14 | 0.18 (0.34) [52] | 0.30 (0.70) [158] | 0.27 (0.48) [319] |
| Change day 0 to mean day 7, 9, 14 | 0.03 (0.31) [52] | 0.16 (0.48) [158] | 0.12 (0.30) [319] |
| Day 0 | 1.24 (0.25) [83] | 1.26 (0.25) [160] | 1.28 (0.22) [324] |
| Day 7 | 1.35 (0.32) [51] | 1.43 (0.64) [158] | 1.37 (0.27) [322] |
| Day 9 | 1.29 (0.33) [49] | 1.47 (0.69) [164] | 1.40 (0.48) [316] |
| Day 14 | 1.38 (0.35) [31] | 1.41 (0.31) [141] | 1.43 (0.28) [304] |
| Max day 7, 9, 14 | 1.49 (0.32) [55] | 1.57 (0.66) [179] | 1.53 (0.46) [377] |
| Mean day 7, 9, 14 | 1.34 (0.27) [55] | 1.43 (0.45) [179] | 1.40 (0.29) [377] |
IQR, interquartile range; SBP, systolic blood pressure; DBP, diastolic blood pressure; SCr, serum creatinine.
Severe AKI is defined as stage 2 or 3 AKI at any time between day 3 and day 28 using Kidney Diseases Improving Global Outcomes creatinine-only definition.
Represents a significant difference (P<0.05) between the measurement and no measurement groups.
Statistical analyses were performed with R v3.5.1 software (R Foundation for Statistical Computing, Vienna, Austria).
Results
Of the 923 neonates in this study, 91 died before the 2-year follow-up (defined as 24±2 months cGA), 48 did not have follow-up, and four participants were missing their 2-year outcome. An additional 215 were excluded because they did not have at least one complete outcome measure. Families and sites were encouraged to participate in REPAIReD assessments, but not all agreed to the additional testing burden. In total, 565 participants (68%) had follow-up measurements at 2 years; 348 (42%) had an eGFR, 435 (52%) had an ACR, and 289 (35%) had two BP readings (Figure 1). Table 1 provides baseline characteristics by 2-year follow-up status. In general, those participants with and without assessments were similar except for maternal age, maternal race, and maternal education (all P<0.05). We did not find differences in AKI rates, cystatin C, or creatinine levels at baseline or day 7, 9, or 14 between those with and without 2-year outcome measurements.
Prevalence of Outcomes by Gestational Age
Table 2 reports results of the primary and secondary outcomes by gestational age; 348 (42%) had blood available to calculate GFR. Median (interquartile range; IQR) eGFR at 2 years was 102 ml/min per 1.73 m2 (95–115); 18% (95% confidence interval [95% CI], 14% to 22%) of the overall cohort had an eGFR <90 ml/min per 1.73 m2 at 2 years of age. The prevalence of eGFR <90 ml/min per 1.73 m2 was lower with higher gestational age; 26% of 24-week gestational age participants had a low eGFR compared with 17% of 25-week gestational age participants, 14% of 26-week gestational age participants, and 13% of 27-week gestational age participants (trend test P=0.03) (Figure 2).
Table 2.
The 2-year outcome summary by gestational age
| Kidney Outcome Measures | Total | 24 Weeks | 25 Weeks | 26 Weeks | 27 Weeks |
|---|---|---|---|---|---|
| 923 | 227 | 242 | 220 | 234 | |
| Survived to 2 years, n | 832 | 192 | 211 | 202 | 223 |
| 2-year height/weight available, n (%) | 702 (84) | 164 (85) | 180 (85) | 169 (84) | 189 (85) |
| Median height, cm (IQR) | 85 (82–88) | 84 (82–86) | 85.0 (82–87) | 85.0 (82–88) | 85.5 (82–88) |
| Median weight, kg (IQR) | 11 (10–13) | 11 (10–12) | 11 (10–13) | 12 (10–13) | 11.6 (10–13) |
| 2-year blood or urine sample available, n (%) | 531 (64) | 131 (68) | 132 (63) | 131 (65) | 137 (61) |
| eGFR score available, n (%) | 348 (42) | 84 (44) | 90 (43) | 84 (42) | 90 (40) |
| Median ml/min per 1.73 m2 (IQR) | 102 (95–115) | 99 (90–107) | 106 (95–122) | 105 (96–115) | 104 (94–116) |
| <90 ml/min per 1.73 m2, n (%) | 61 (17) | 22 (26) | 15 (17) | 12 (14) | 12 (13) |
| Albumin-creatinine ratio available | 435 (52) | 111 (58) | 109 (52) | 108 (54) | 107 (48) |
| Median, mg/g (IQR) | 21.8 (14–38) | 19 (14–40) | 23 (15–38) | 20 (12–38) | 24 (15–36) |
| ≥30 mg/g | 155 (36%) | 39 (35%) | 38 (35%) | 36 (33%) | 42 (39%) |
| BP value available | 289 (35%) | 58 (30%) | 71 (34%) | 68 (34%) | 92 (41%) |
| SBP 90th–94th percentile, n (%) | 19 (7) | 5 (9) | 6 (8) | 5 (7) | 3 (3) |
| SBP ≥95th percentile, n (%) | 46 (16) | 9 (15) | 13 (18) | 4 (6) | 20 (22) |
| Median SBP, IQR | 94 (88–100) | 93 (88–100) | 96 (88–102) | 94 (88–98) | 94 (89–101) |
| DBP 90th–94th percentile, n (%) | 39 (13) | 7 (12) | 12 (17) | 9 (13) | 11 (12) |
| DBP ≥95th percentile, n (%) | 89 (31) | 15 (26) | 22 (31) | 21 (31) | 31 (34) |
| Median DBP (IQR) | 56 (48–60) | 55 (48–58) | 58 (48–60) | 56 (48–60) | 56 (48–61) |
The percentage of patients with weight, blood, and/or urine available are out of the number of survivors to 2 years. IQR, interquartile range; SBP, systolic BP; DBP, diastolic BP.
Figure 2.
Box plots of eGFR by gestational age.
Median (IQR) ACR was 22 mg/g creatinine (14–38). In total, 155 participants (36%; 95% CI, 31% to 40%) had an ACR ≥30 mg/g creatinine at their follow-up visit. The rate of an ACR ≥30 mg/g creatinine was similar across gestational age groups and ranged from 33% to 39% (Supplemental Figure 1).
Median (IQR) systolic BP was 94 mm Hg (88–100). A total of 65 children (22%; 95% CI, 18% to 27%) had a systolic BP ≥90 percentile for age and height. Elevated systolic BP did not correlate with gestational age, with the highest prevalence noted in the 25-week group (27%); range 13%–27%. Median (IQR) diastolic BP was 58 mm Hg (48–60). There were 128 children (44%; 95% CI, 39% to 50%) who had a diastolic BP ≥90th percentile. Elevated diastolic BP had an increasing trend (P<0.05) with increasing gestational age.
Overall, 297 of 565 (53%; 95% CI, 47% to 58%) ELGANs had at least one abnormal kidney-related outcome at their 2-year follow-up visit.
Patient Characteristics and Risk Factor Analysis by Outcome
Low eGFR.
Table 3 compares participants with an eGFR <90 ml/min per 1.73 m2 to those with an eGFR >90 ml/min per 1.73 m2. Lower birthweight, shorter birth length, small for gestational age, and maternal pre-eclampsia, prenatal steroids, and vasopressor use were associated (P<0.05) with an eGFR <90 ml/min per 1.73 m2. On multivariable analysis, for every 1-week–higher gestational age, the odds of an eGFR <90 was lower by 6% (odds ratio [OR], 0.94; 95% CI, 0.89 to 0.99) and for every 1 SD–higher birthweight z-score, the odds of an eGFR <90 ml/min per 1.73 m2 was lower by 8% (OR, 0.92; 95% CI, 0.85 to 0.98). Receipt of prenatal steroids (OR, 1.23; 95% CI, 1.08 to 1.39) was associated with a higher odds of eGFR <90 ml/min per 1.73 m2 at follow-up (Table 4).
Table 3.
Baseline characteristics by 24-month eGFR (ml/min per 1.73 m2)
| Kidney Outcome Measures | eGFR ≥90 | eGFR <90 |
|---|---|---|
| 287 | 61 | |
| Sex, n (%) | ||
| Female | 134 (80) | 33 (20) |
| Male | 153 (84) | 28 (15) |
| Gestational age, wk, n (%) | ||
| 24 | 62 (74) | 22 (26) |
| 25 | 75 (83) | 15 (17) |
| 26 | 72 (86) | 12 (14) |
| 27 | 78 (87) | 12 (13) |
| Birth weight, g (mean [SD]) | 834 (179) | 696.8 (182) |
| Birth length, cm (mean [SD]) | 33 (3) | 31 (3) |
| Small for gestational age, n (%) | ||
| Yes | 16 (55) | 13 (45) |
| No | 271 (85) | 48 (15) |
| Apgar 5 min score, median (IQR) | 7 (5–7) | 7 (5–8) |
| Mother's race, n (%) | ||
| White | 198 (82) | 42 (17) |
| Black | 55 (79) | 15 (21) |
| Other | 20 (83) | 4 (17) |
| Unknown | 14 (100) | 0 (0) |
| Mother's ethnicity, n (%) | ||
| Hispanic or Latino | 78 (85) | 14 (15) |
| Not Hispanic or Latino | 208 (82) | 46 (18) |
| Unknown | 1 (50) | 1 (50) |
| Mother's education, n (%) | ||
| High school or less | 105 (86) | 17 (14) |
| Some college | 90 (81) | 21 (19) |
| College degree or higher | 74 (79) | 20 (21) |
| Unknown | 17 (89) | 2 (10) |
| Multiple gestations, n (%) | ||
| Yes | 82 (85) | 14 (15) |
| No | 205 (81) | 47 (19) |
| Prenatal steroids, n (%) | ||
| Yes | 266 (82) | 58 (18) |
| No | 20 (95) | 1 (5) |
| Pre-eclampsia, n (%) | ||
| Yes | 41 (67) | 20 (33) |
| No | 246 (86) | 41 (14) |
| Maternal diabetes | ||
| Yes | 18 (86) | 3 (14) |
| No | 269 (82) | 58 (18) |
| Treated for hypertension in first 2 wk, n (%) | 2 (100) | 0 (0) |
| Max AKI in first 28 days, n (%) | ||
| Severe (stage 2 or 3) | 28 (74) | 10 (26) |
| Not severe (stage 0 or 1) | 259 (83) | 51 (16) |
| Weight gain, g per day (mean [SD]) | ||
| Birth to hospital discharge | 22 (5) | 21 (4) |
| Hospital discharge to 24 mo | 11 (3) | 11.0 (3) |
| Severe necrotizing enterocolitis | ||
| Yes | 15 (88) | 2 (12) |
| No | 272 (82) | 59 (18) |
| Severe intraventricular hemorrhage | ||
| Yes | 32 (78) | 9 (22) |
| No | 255 (83) | 52 (17) |
| Severe sepsis | ||
| Yes | 21 (91) | 2 (9) |
| No | 266 (82) | 59 (18) |
| PDA | ||
| Yes | 139 (83) | 29 (17) |
| No | 148 (82) | 32 (18) |
| Vasopressors | ||
| Vasopressors only | 40 (83) | 8 (17) |
| Vasopressors + hydrocortisone | 55 (72) | 21 (28) |
| None | 192 (86) | 32 (14) |
| Medication | ||
| Indomethacin | ||
| Yes | 101 (83) | 21 (17) |
| No | 186 (82) | 40 (18) |
| Gentamicin | ||
| Yes | 276 (83) | 57 (17) |
| No | 11 (73) | 4 (27) |
| Vancomycin | ||
| Yes | 178 (83) | 36 (17) |
| No | 109 (81) | 25 (19) |
IQR, interquartile range; PDA, patent ductus arteriosus.
Table 4.
Multivariable model of risk factors for primary and secondary outcomes
| Kidney Outcome Measures | eGFR <90 mL/min per 1.73 m2 | Albumin-Creatinine Ratio ≥30 | Elevated Systolic BP | Elevated Diastolic BP |
|---|---|---|---|---|
| Baby sex | ||||
| Female | reference | reference | reference | reference |
| Male | 1.01 (0.91 to 1.11) | 0.93 (0.82 to 1.04) | 1.08 (0.96 to 1.21) | 1.29 (1.12 to 1.49) |
| Gestational age, wk | 0.94 (0.89 to 0.98) | 1.05 (0.99 to 1.11) | 0.97 (0.92 to 1.02) | 0.98 (0.92 to 1.04) |
| Baby weight z-score, g | 0.92 (0.85 to 0.98) | 1.02 (0.96 to 1.09) | 1.00 (0.93 to 1.07) | 1.07 (0.99 to 1.16) |
| Mother's race | ||||
| White | reference | reference | reference | reference |
| Black | 0.95 (0.82 to 1.10) | 1.11 (0.96 to 1.28) | 1.19 (1.01 to 1.39) | 1.12 (0.95 to 1.33) |
| Other | 0.98 (0.81 to 1.18) | 0.86 (0.72 to 1.03) | 0.90 (0.74 to 1.10) | 0.80 (0.62 to 1.04) |
| Pre-eclampsia | ||||
| No | reference | reference | reference | reference |
| Yes | 1.09 (0.89 to 1.33) | 0.98 (0.81 to 1.18) | 1.02 (0.83 to 1.24) | 1.24 (0.99 to 1.55) |
| Maternal diabetes | ||||
| No | reference | reference | reference | reference |
| Yes | 1.10 (0.84 to 1.45) | 1.15 (0.88 to 1.52) | 1.05 (0.79 to 1.40) | 1.24 (0.96 to 1.59) |
| Prenatal steroids | ||||
| No | reference | reference | reference | reference |
| Yes | 1.23 (1.08 to 1.39) | 1.01 (0.83 to 1.23) | 0.97 (0.80 to 1.18) | 1.00 (0.80 to 1.25) |
| Severe AKI first 28 d | ||||
| No | reference | reference | reference | reference |
| Yes | 1.07 (0.91 to 1.26) | 1.00 (0.83 to 1.20) | 0.92 (0.79 to 1.08) | 1.24 (1.04 to 1.48) |
| Indomethacin | ||||
| Yes | 0.99 (0.89 to 1.10) | 1.01 (0.90 to 1.13) | 1.18 (1.04 to 1.33) | 1.16 (1.01 to 1.33) |
| No | reference | reference | reference | reference |
Odds ratios and 95% confidence intervals are presented.
Albuminuria.
Albuminuria was associated with mother’s race because 34% of White mothers had children with albuminuria, compared with 47% of Black mothers (risk difference = 14%; 95% CI, 2% to 25%, P<0.001). There were no other differences between the groups (Supplemental Table 1). We did not find any associations between demographic and clinical variables and albuminuria at 2-year follow-up (Table 4).
Elevated BP.
Elevated diastolic BP occurred more frequently in males (58%) at 2-years corrected age. Those who gained more weight from birth to hospital discharge had elevated systolic BP and diastolic BP. Maternal education level was associated with elevated systolic BP; children whose mothers had a college degree had higher rates (31%) compared with those with some college education (9%) and those with high school or lower education level (25%). Indomethacin use was associated with elevated systolic BP. There were no other notable differences between the groups (Supplemental Table 2). Indomethacin use was associated with both elevated systolic BP (OR, 1.18; 95% CI, 1.04 to 1.33) and elevated diastolic BP (OR, 1.16; 95% CI, 1.01 to 1.33). Black maternal race was associated with elevated systolic BP (OR, 1.19; 95% CI, 1.01 to 1.39). In addition, male baby sex (OR, 1.29; 95% CI, 1.13 to 1.49) and severe AKI (OR, 1.24; 95% CI, 1.04 to 1.48) were also associated with higher odds for elevated diastolic BP (Table 4).
Discussion
In this large cohort of prospectively followed ELGANs, we found a high prevalence of abnormal kidney-related outcomes at 2-years corrected age. In total, 53% had evidence of at least one abnormal kidney-related outcome. Specifically, 18% had an eGFR <90ml/min per 1.73 m2, 36% had albuminuria, 22% had elevated systolic BP, and 44% had elevated diastolic BP. We found 24-week gestational age ELGANs had higher rates of eGFR <90 ml/min per 1.73 m2 and lower rates of elevated diastolic BP, but rates of albuminuria and elevated systolic BP were similar across gestational age. We did not find differences in AKI rates, cystatin C, or creatinine levels at baseline, day 7, 9, or 14 between those with and without kidney-related abnormalities at 2 years, suggesting that early markers of kidney function may not be related to longer-term outcomes.
Although we cannot attribute mechanisms to the associations we found, potential explanations are of interest. Prenatal steroids are known to decrease alveolar number and similar effects may be at play in the kidney, given the similar developmental time frame and gene pathways of both organs (23,24). Black race was associated with development of elevated systolic BP. Black race is associated with higher rates of prematurity and CKD (25); perhaps elevated systolic BP is an early manifestation of kidney injury in these children. The difference in follow-up between the Black and White participants could be related to structural issues that limit access to care or distrust of the medical system. We realize that race is a social construct; however, there are genetic risk factors, such as APOL1, that are associated with a greater risk of CKD in people of African descent (26,27), which may contribute to this association. Perhaps screening for APOL1 genetic variants in Black children with elevated systolic BP at 2 years would identify those at risk for progression early.
Infants born prematurely begin life in the NICU with an incomplete complement of immature nephrons (28). They are then exposed to a variety of external stressors that can hinder ongoing kidney development or cause additional nephron loss (29–31). Our findings expand the growing body of literature describing the risk of kidney complications in premature neonates and show that kidney dysfunction is evident as early as 2 years of age in extremely premature neonates. Most studies evaluating long-term outcomes have compared preterm infants to their term counterparts; however, this study is unique because it allows comparisons between neonates across 1-week differences in gestational age. Additionally, many studies will include neonates <35 weeks gestational age in their definition of prematurity. We have focused on only those born <28 weeks gestational age.
The risk factors and natural history for CKD progression in infants and children is poorly understood. In a recent cross-sectional study of neonates <35 weeks of gestation, both kidney length and eGFR were lower in preterm neonates who were small for gestational age compared with their preterm appropriate for gestational age neonates at 12–18 months of age (32). A retrospective study of 168 Japanese patients born <35 weeks gestation found a significant correlation between eGFR and gestational age, and approximately 11% of children had an eGFR <90 ml/min per 1.73 m2 without evidence of urinary abnormalities (33). The major differences between this study and ours is the inclusion of neonates >28 weeks gestation and the exclusion of all neonates who developed AKI during their NICU stay. In a study of approximately 5000 adolescents 12–15 years of age from the National Health and Nutrition Examination Survey, 23% of LBW adolescents had eGFR <90 ml/min per 1.73 m2 and 6% elevated systolic BP compared with 32% of VLBW adolescents with an eGFR <90 ml/min per 1.73 m2 and 11% with an elevated systolic BP. They did not find an association between birthweight and albuminuria in this cohort of patients (34). Our study focused on ELGANs only who automatically meet the definition of VLBW. We found a similar prevalence in our cohort for systolic BP but a lower prevalence of an eGFR <90 ml/min per 1.73 m2 at 2 years of age. Smaller cross-sectional studies of adolescents born preterm and VLBW support the associations with elevated systolic and diastolic BP compared with term controls (35,36). There are also studies that did not find associations between prematurity and kidney function or elevated BPs in children from 6 months to 12 years of age (37–39).
The strengths of this study include the large number of participants followed prospectively from many centers. This patient cohort was also well characterized with both clinical and laboratory data available throughout the NICU stay. Despite these strengths, we acknowledge the following important limitations. One limitation is that only approximately 50% of patients had data collected at their follow-up visits. The potential for bias on the basis of lost to follow-up is somewhat mitigated by our sensitivity analysis demonstrating that participant characteristics were similar between those who had follow-up data obtained and those who survived but did not provide data. We collected only one urine measurement at follow-up and many were not first morning urine samples. The cutoff value of urine ACR >30 mg/g (which is a surrogate for CKD in pediatric and adult populations) may not be applicable. However, in a recent study of healthy 2-year-olds in the Netherlands (40), the median ACR they reported was 14 mg/g compared with 21 mg/g in this cohort, and the rate of ACR >30 was 36% versus 24% in our cohort. Although we developed protocols to standardize BP measurements, these were done on 1 day and were not repeated. And, last, although we are using a standardized formula to estimate eGFR in children, this formula was not developed with many 2-year-old children, nor with those with eGFR >90 ml/min per 1.73 m2.
These findings have important implications for long-term care and management of premature infants and emphasize the need for neonatologists and nephrologists to discuss the risk of kidney issues and elevated BP with family members and health care providers before discharge from the NICU. Risk factors such as being small for gestational age, commonly reported to be associated with outcomes in premature neonates were not found in our cohort. We suggest screening all ELGANs with a serum creatinine and cystatin C, a urine collected for an ACR, and a BP measured at approximately 2 years of age. Those with abnormal findings should have repeat measurements and follow-up with a nephrologist. Additional studies are needed to better understand the role of albuminuria and BP screening in the evaluation for CKD sequelae in ELGANs. The global health burden of CKD is growing, and early recognition of modifiable risk factors for development and progression of CKD in ELGANs may help stem the growing tide of people with kidney failure.
Disclosures
K.A. Ahmad reports employment with MEDNAX National Medical Group and reports receiving research funding from Aerogen Pharma clinical trials research. D. Askenazi reports being a consultant for Baxter, Bioporto, Medtronic, Nuwellis, and Seastar; reports his institution receives grant funding for education and research that is not related to this project from Baxter, Medtronic, National Institutes of Health (NIH), Nuwellis, and Seastar; reports having an ownership interest in Zorroflow; reports receiving research funding from Baxter and Nuwellis; and reports patents pending on inventions in the neonatal nephrology space. P. Brophy reports receiving honoraria from American Board Medical Specialties; receiving royalties from UpToDate; and serving in an advisory or leadership role for the American Board of Medical Specialties. I.D. Frantz reports receiving research funding from Aerogen Pharma and Infant Bacterial Therapeutics. M.M. Gilmore reports receiving research funding from Fresenius Kabi. S. Goldstein reports consultancy agreements for MediBeacon; having an ownership interest in Akebia, Baxter Healthcare, Bayer, Bioporto, Inc., CHF Solutions, Fresenius, Kaneka, Inc., La Jolla Pharmaceuticals, MediBeacon, Medtronic, Otsuka, Reata, and Renibus; receiving research funding from Baxter Healthcare, Bioporto, CHF Solutions, ExThera, and La Jolla Pharma; receiving honoraria from Baxter Healthcare and Fresenius; patents or royalties with Vigilanz; serving in an advisory or leadership role for MediBeacon; and speakers bureau for Baxter Healthcare and Fresenius. P.J. Heagerty reports serving as a member of a data safety monitoring board for Verily and as a member of Board of Directors for Cancer Research and Biostatistics. S. Hingorani reports having consultancy agreements with Omeros. S.E. Juul reports receiving royalties from Elsevier. E.F. La Gamma reports receiving research funding from Aerogen Corp. All remaining authors have nothing to disclose.
Funding
The REPaIReD Study is an NIH National Institute of Diabetes and Digestive and Kidney Diseases–funded ancillary study (grant R01DK103608) designed to look at kidney outcomes in patients enrolled in the PENUT Trial, which is an NIH National Institute of Neurological Disorders and Stroke–funded trial (grants U01 NS077953 and U01 NS077955). The ClinicalTrials.gov identifier is NCT01378273.
Supplementary Material
Acknowledgments
The funder/sponsor did not participate in the work. Data on the short- and long-term kidney outcomes by treatment arm in this cohort have been previously published in the Journal of Pediatrics, 2020. We would like to thank Ms. Lynn Dill and Ms. Emily Pao for their assistance in coordinating the REPaIReD study. We would like to thank the additional primary investigators, co-investigators, clinicians, research personnel, study team, and families who participated in the PENUT study.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
Contributor Information
Collaborators: PENUT Primary Investigators and coauthors, Rajan Wadhawan, Sherry E. Courtney, Tonya Robinson, Kaashif A. Ahmad, Ellen Bendel-Stenzel, Mariana Baserga, Edmund F. LaGamma, L. Corbin Downey, Raghavendra Rao, Nancy Fahim, Andrea Lampland, Ivan D. Frantz, III, Janine Khan, Michael Weiss, Maureen M. Gilmore, Robin K. Ohls, Jean Lowe, Nishant Srinivasan, Jorge E. Perez, Victor McKay Billy Thomas, Nahed Elhassan, Sarah Mulkey, Vivek K. Vijayamadhavan, Neil Mulrooney, Bradley Yoder, Jordan S. Kase, Jennifer Check, Erin Osterholm, Thomas George, Michael Georgieff, Camilia R. Martin, Deirdre O’Reilly, Raye-Ann deRegnier, Nicolas Porta, Catalina Bazacliu, Frances Northington, Raul Chavez Valdez, Patel Saurabhkumar, Magaly Diaz-Barbosa, Todd Richards, John B. Feltner, Isabella Esposito, Stephanie Hauge, Samantha Nikirk, Amy Silvia, Bailey Clopp, Debbie Ott, Ariana Franco Mora, Pamela Hedrick, Vicki Flynn, Andrea Wyatt, Emilie Loy, Natalie Sikes, Melanie Mason, Jana McConnell, Tiffany Brown, Henry Harrison, Denise Pearson, Tammy Drake, Jocelyn Wright, Debra Walden, Annette Guy, Jennifer Nason, Morgan Talbot, Kristen Lee, Sarah Penny, Terri Boles, Melanie Drummond, Katy Kohlleppel, Charmaine Kathen, Brian Kaletka, Shania Gonzales, Cathy Worwa, Molly Fisher, Tyler Richter, Alexander Ginder, Brixen Reich, Carrie Rau, Manndi Loertscher, Laura Cole, Kandace McGrath, Kimberlee Weaver Lewis, Jill Burnett, Susan Schaefer, Karie Bird, Clare Giblin, Rita Daly, Kristi Lanier, Kelly Warden, Jenna Wassenaar, Jensina Ericksen, Bridget Davern, Mary Pat Osborne, Neha Talele, Evelyn Obregon, Tiglath Ziyeh, Molly Clarke, Rachel E. Wegner, Palak Patel, Molly Schau, Annamarie Russow, Kelly Curry, Lisa Barnhart, Charlamaine Parkinson, Sandra Beauman, Mary Hanson, Elizabeth Kuan, Conra Backstrom Lacy, Edshelee M. Galvis, Susana Bombino, Denise Martinez, Suzi Bell, Corrie Long, Christopher Nefcy, Mark A. Konodi, Phuong T. Vu Adam Hartman, T. Michael O’Shea, Roberta Ballard, Mike O’Shea, Karl Kuban, Jean Lowe, and John Widness
Author Contributions
D. Askenazi, P. Brophy, S. Goldstein, and S. Hingorani conceptualized the study; S. Hingorani was responsible for designing the study; P.J. Heagerty and R. Schmicker were responsible for designing the analysis plan and carrying out the analyses; S.E. Juul was responsible for coordinating data collection; K.A. Ahmad, M. Baserga, I.D. Frantz, M.M. Gilmore, J.Y. Khan, E.F. La Gamma, D.E. Mayock, and T. Robinson were responsible for coordinating and supervising data collection; S. Hingorani wrote the original draft; K.A. Ahmad, D. Askenazi, M. Baserga, P. Brophy, I.D. Frantz, M.M. Gilmore, S. Goldstein, P.J. Heagerty, S. Hingorani, S.E. Juul, J.Y. Khan, E.F. La Gamma, D.E. Mayock, T. Robinson, and R. Schmicker reviewed and edited the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Supplemental Material
This article contains the following supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.15011121/-/DCSupplemental.
Supplemental Table 1. Baseline characteristics by 2-year urine ACR.
Supplemental Table 2. Baseline characteristics by 2-year systolic BP and diastolic BP measurements.
Supplemental Figure 1. Box plots of urine albumin-creatinine ratio (ACR) by gestational age.
References
- 1.Horbar JD, Carpenter JH, Badger GJ, Kenny MJ, Soll RF, Morrow KA, Buzas JS: Mortality and neonatal morbidity among infants 501 to 1500 grams from 2000 to 2009. Pediatrics 129: 1019–1026, 2012 [DOI] [PubMed] [Google Scholar]
- 2.Barker DJ: The fetal origins of coronary heart disease. Acta Paediatr Suppl 422: 78–82, 1997 [DOI] [PubMed] [Google Scholar]
- 3.Barker DJ, Martyn CN: The fetal origins of hypertension. Adv Nephrol Necker Hosp 26: 65–72, 1997 [PubMed] [Google Scholar]
- 4.Barker DJ, Osmond C: Low birth weight and hypertension. BMJ 297: 134–135, 1988 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME: Obesity-induced hypertension: Interaction of neurohumoral and renal mechanisms. Circ Res 116: 991–1006, 2015 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Xita N, Tsatsoulis A: Review: Fetal programming of polycystic ovary syndrome by androgen excess: Evidence from experimental, clinical, and genetic association studies. J Clin Endocrinol Metab 91: 1660–1666, 2006 [DOI] [PubMed] [Google Scholar]
- 7.Fall CH, Barker DJ: The fetal origins of coronary heart disease and non-insulin dependent diabetes in India. Indian Pediatr 34: 5–8, 1997 [PubMed] [Google Scholar]
- 8.Carmody JB, Charlton JR: Short-term gestation, long-term risk: Prematurity and chronic kidney disease. Pediatrics 131: 1168–1179, 2013 [DOI] [PubMed] [Google Scholar]
- 9.Starr MC, Hingorani SR: Prematurity and future kidney health: The growing risk of chronic kidney disease. Curr Opin Pediatr 30: 228–235, 2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Brophy P: Maternal determinants of renal mass and function in the fetus and neonate. Semin Fetal Neonatal Med 22: 67–70, 2017 [DOI] [PubMed] [Google Scholar]
- 11.Rosenblum S, Pal A, Reidy K: Renal development in the fetus and premature infant. Semin Fetal Neonatal Med 22: 58–66, 2017 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Senra JC, Carvalho MA, Rodrigues AS, Krebs VLJ, Gibelli MABC, Francisco RPV, Bernardes LS: An unfavorable intrauterine environment may determine renal functional capacity in adulthood: A meta-analysis. Clinics (São Paulo) 73: e401, 2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Harer MW, Pope CF, Conaway MR, Charlton JR: Follow-up of Acute kidney injury in Neonates during Childhood Years (FANCY): A prospective cohort study. Pediatr Nephrol 32: 1067–1076, 2017 [DOI] [PubMed] [Google Scholar]
- 14.Crump C, Sundquist J, Winkleby MA, Sundquist K: Preterm birth and risk of chronic kidney disease from childhood into mid-adulthood: National cohort study. BMJ 365: 1346, 2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Juul SE, Comstock BA, Wadhawan R, Mayock DE, Courtney SE, Robinson T, Ahmad KA, Bendel-Stenzel E, Baserga M, LaGamma EF, Downey LC, Rao R, Fahim N, Lampland A, Frantz III ID, Khan JY, Weiss M, Gilmore MM, Ohls RK, Srinivasan N, Perez JE, McKay V, Vu PT, Lowe J, Kuban K, O’Shea TM, Hartman AL, Heagerty PJ; PENUT Trial Consortium : A randomized trial of erythropoietin for neuroprotection in preterm infants. N Engl J Med 382: 233–243, 2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Juul SE, Mayock DE, Comstock BA, Heagerty PJ: Neuroprotective potential of erythropoietin in neonates; design of a randomized trial. Matern Health Neonatol Perinatol 1: 27, 2015 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Juul SE, Vu PT, Comstock BA, Wadhawan R, Mayock DE, Courtney SE, Robinson T, Ahmad KA, Bendel-Stenzel E, Baserga M, LaGamma EF, Downey LC, O’Shea M, Rao R, Fahim N, Lampland A, Frantz ID 3rd, Khan J, Weiss M, Gilmore MM, Ohls R, Srinivasan N, Perez JE, McKay V, Heagerty PJ; Preterm Erythropoietin Neuroprotection Trial Consortium : Effect of high-dose erythropoietin on blood transfusions in extremely low gestational age neonates: Post hoc analysis of a randomized clinical trial. JAMA Pediatr 174: 933–943, 2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Askenazi DJ, Heagerty PJ, Schmicker RH, Brophy P, Juul SE, Goldstein SL, Hingorani S; PENUT Trial Consortium : The impact of erythropoietin on short- and long-term kidney-related outcomes in neonates of extremely low gestational age. Results of a multicenter, double-blind, placebo-controlled randomized clinical trial. J Pediatr 232: 65–72.e7, 2021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Askenazi DJ, Heagerty PJ, Schmicker RH, Griffin R, Brophy P, Juul SE, Mayock DE, Goldstein SL, Hingorani S; PENUT Trial Consortium : Prevalence of acute kidney injury (AKI) in extremely low gestational age neonates (ELGAN). Pediatr Nephrol 35: 1737–1748, 2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Pierce CB, Muñoz A, Ng DK, Warady BA, Furth SL, Schwartz GJ: Age- and sex-dependent clinical equations to estimate glomerular filtration rates in children and young adults with chronic kidney disease. Kidney Int 99: 948–956, 2021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Flynn JT, Kaelber DC, Baker-Smith CM, Blowey D, Carroll AE, Daniels SR, de Ferranti SD, Dionne JM, Falkner B, Flinn SK, Gidding SS, Goodwin C, Leu MG, Powers ME, Rea C, Samuels J, Simasek M, Thaker VV, Urbina EM; Subcommittee on Screening and Management of High Blood Pressure in Children : Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics 140: e20171904, 2017 [DOI] [PubMed] [Google Scholar]
- 22.Liang KY, Zeger SL: Regression analysis for correlated data. Annu Rev Public Health 14: 43–68, 1993 [DOI] [PubMed] [Google Scholar]
- 23.Bonadies L, Zaramella P, Porzionato A, Perilongo G, Muraca M, Baraldi E: Present and future of bronchopulmonary dysplasia. J Clin Med 9: E1539, 2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Wellik DM: Hox genes and kidney development. Pediatr Nephrol 26: 1559–1565, 2011 [DOI] [PubMed] [Google Scholar]
- 25.Moxey-Mims M: Kidney disease in African American children: Biological and nonbiological disparities. Am J Kidney Dis 72[Suppl 1]: S17–S21, 2018 [DOI] [PubMed] [Google Scholar]
- 26.Friedman DJ, Pollak MR: APOL1 and kidney disease: From genetics to biology. Annu Rev Physiol 82: 323–342, 2020 [DOI] [PubMed] [Google Scholar]
- 27.Robertson CC, Gillies CE, Putler RKB, Ng D, Reidy KJ, Crawford B, Sampson MG: An investigation of APOL1 risk genotypes and preterm birth in African American population cohorts. Nephrol Dial Transplant 32: 2051–2058, 2017 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Hughson M, Farris AB 3rd, Douglas-Denton R, Hoy WE, Bertram JF: Glomerular number and size in autopsy kidneys: The relationship to birth weight. Kidney Int 63: 2113–2122, 2003 [DOI] [PubMed] [Google Scholar]
- 29.Rodriguez MM, Gomez A, Abitbol C, Chandar J, Montané B, Zilleruelo G: Comparative renal histomorphometry: A case study of oligonephropathy of prematurity. Pediatr Nephrol 20: 945–949, 2005 [DOI] [PubMed] [Google Scholar]
- 30.Rodríguez MM, Gómez AH, Abitbol CL, Chandar JJ, Duara S, Zilleruelo GE: Histomorphometric analysis of postnatal glomerulogenesis in extremely preterm infants. Pediatr Dev Pathol 7: 17–25, 2004 [DOI] [PubMed] [Google Scholar]
- 31.Sutherland MR, Gubhaju L, Moore L, Kent AL, Dahlstrom JE, Horne RS, Hoy WE, Bertram JF, Black MJ: Accelerated maturation and abnormal morphology in the preterm neonatal kidney. J Am Soc Nephrol 22: 1365–1374, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Reddy KV, Pawale D, Shah M, Mouli D, Murki S: Assessment of renal growth and function in preterm infants at corrected age of 12-18 month. Indian Pediatr 57: 411–414, 2020 [PubMed] [Google Scholar]
- 33.Horie A, Abe Y, Koike D, Hirade T, Nariai A, Ito T, Katou F: Long-term renal follow up of preterm neonates born before 35 weeks of gestation. Pediatr Int (Roma) 61: 1244–1249, 2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Khalsa DD, Beydoun HA, Carmody JB: Prevalence of chronic kidney disease risk factors among low birth weight adolescents. Pediatr Nephrol 31: 1509–1516, 2016 [DOI] [PubMed] [Google Scholar]
- 35.South AM, Nixon PA, Chappell MC, Diz DI, Russell GB, Jensen ET, Shaltout HA, O’Shea TM, Washburn LK: Renal function and blood pressure are altered in adolescents born preterm. Pediatr Nephrol 34: 137–144, 2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Staub E, Urfer-Maurer N, Lemola S, Risch L, Evers KS, Welzel T, Pfister M: Comparison of blood pressure and kidney markers between adolescent former preterm infants and term controls. Children (Basel) 7: E141, 2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Edstedt Bonamy AK, Mohlkert LA, Hallberg J, Liuba P, Fellman V, Domellöf M, Norman M: Blood pressure in 6-year-old children born extremely preterm. J Am Heart Assoc 6: e005858, 2017 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Park B, Lee JW, Kim HS, Park EA, Cho SJ, Park H: Effects of prenatal growth status on subsequent childhood renal function related to high blood pressure. J Korean Med Sci 34: e174, 2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Vashishta N, Surapaneni V, Chawla S, Kapur G, Natarajan G: Association among prematurity (<30 weeks’ gestational age), blood pressure, urinary albumin, calcium, and phosphate in early childhood. Pediatr Nephrol 32: 1243–1250, 2017 [DOI] [PubMed] [Google Scholar]
- 40.Gracchi V, van den Belt SM, Küpers LK, Corpeleijn E, de Zeeuw D, Heerspink HJ: Prevalence and distribution of (micro)albuminuria in toddlers. Nephrol Dial Transplant 31: 1686–1692, 2016 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.