Fetal Nephrology: A Quaternary Care Center Experience

Abstract

Key Points

• Specialized fetal centers see a highly complex subset of patients with CAKUT with a predominance of complex or syndromic disease.

• The mortality rate for fetuses with complex developmental anomalies and CAKUTs or bilateral CAKUTs is high.

• Prenatal genetic testing was highly variable with limited diagnostic utility while focused postnatal genetic testing had much higher yield.

Background

Congenital anomalies of the kidney and urinary tract (CAKUTs) represent 15%–20% of prenatally diagnosed abnormalities. Maternal characteristics, the frequency of various forms of kidney disease including CAKUT referred for prenatal nephrology consultation, and their perinatal outcomes are less well defined.

Methods

A retrospective chart review was performed of fetal CAKUT and other forms of kidney disease referred for prenatal nephrology consults at Texas Children's Hospital Fetal Center from January 1, 2012, to December 31, 2018.

Results

Two hundred seventeen prenatal nephrology consultations were performed during the study period, representing 4.7% of total Fetal Center referrals at a mean estimated gestational age of 25.2±5.7 weeks. Maternal characteristics were as follows: The mean age was 29.3±5.6 years; 14% had advanced maternal age; 10% had a family history of CAKUT or ESKD; 5% had diabetes mellitus; and 5% of pregnancies were in vitro fertilization-assisted. Fetal characteristics were as follows: 62.7% of fetuses were male and 16% had CAKUT associated with multiple congenital anomalies. The most common prenatal diagnoses were lower urinary tract obstruction in 71 (32.7%), unilateral renal agenesis or multicystic dysplastic kidney (MCDK) in 52 (24.9%), bilateral agenesis or MCDK in 22 (10.1%), and bilateral cystic kidney disease in 19 (8.8%). Seventy-six percent of patients received genetic counseling. One hundred forty-one (64.9%) patients had some form of prenatal genetic testing with a positivity rate of 5.7%. Postnatal characteristics were as follows: 61 (28.1%) patients were seen in prenatal consultation only and no follow-up was available. Of the remaining 156 pregnancies, 136 (86.3%) were viable and delivered at a mean gestational age of 35.2±3.8 weeks. Of these, 100 (64%) survived to discharge. Additional postnatal genetic testing was obtained in 27 infants with a positivity rate of 59%.

Conclusions

Overall perinatal mortality for this cohort as a whole was high (35.8%). While prenatal genetic testing had a limited diagnostic utility, targeted postnatal genetic testing had a much higher diagnostic yield.

Introduction

Over the past few decades, there have been dramatic improvements in fetal imaging, the development of sophisticated molecular diagnostic techniques, and fetal therapeutics. These advances have led to the formation of centers of excellence devoted to optimizing maternal and fetal care in pregnancies with complex health issues. The need for engagement of pediatric subspecialists in these fetal centers of excellence to provide prenatal counseling and diagnostic and therapeutic support has resulted in the emergence of new focus within pediatric nephrology, namely fetal nephrology. Congenital anomalies of the kidney and urinary tract (CAKUTs) are among the most commonly identified prenatal anomalies and have been reported to comprise between 15% and 20% of all prenatally identified fetal anomalies.¹ While many of these anomalies are minor or isolated problems, such as unilateral pyelectasis or unilateral renal agenesis, CAKUT is a highly heterogeneous group of disorders for clinical phenotype and short and/or long-term implications for the health of the fetus. This is particularly evident in fetuses with CAKUT in the setting of syndromic disorders, lower urinary tract obstruction (LUTO), various forms of renal dysplasia/hypoplasia, or cystic kidney disease.² There are surprisingly little data either on the spectrum of kidney and urologic disease seen in specialized fetal centers or on the outcomes of fetuses with highly complex developmental anomalies. Despite these limited data, there is growing evidence that prenatal counseling with subject matter experts involving discussions of disease pathogenesis, prognosis, clinical management, and treatment options is highly valued by parents, particularly if it is provided in a manner which allows informed decision making, emotional adjustment, and the ability to define goals of care.³

In 2011, the Fetal Center at Texas Children's Hospital, one of the largest fetal referral centers in the United States with over 900 new patient referrals annually, formed a multidisciplinary care team consisting of dedicated pediatric nephrologists, pediatric urologists, maternal fetal medicine and fetal intervention specialists, pediatric radiologists, and genetic counselors, all of whom are focused on the care of mothers and fetuses with nephrologic and urologic disorders including CAKUT. The purpose of this article was to report our fetal nephrology experience over the past 8 years.

Methods

This is a single-center retrospective study at a large quaternary pediatric hospital, Texas Children's Hospital. All referrals with a presumed diagnosis of any form of nephrologic or urologic disorder identified prenatally by fetal ultrasonography and subsequent evaluation at the fetal nephrology clinic from January 1, 2012, to December 31, 2018, were included. Referrals that were never evaluated at the fetal nephrology clinic were excluded.

Baseline maternal characteristics (maternal age, maternal comorbidities, exposures, previous pregnancies, gestational age, and amniotic fluid index), fetal malformations (renal and extrarenal) described by the fetal medicine team on prenatal imaging reports (either fetal ultrasound and/or magnetic resonance imaging), as well as pre and/or postnatal genetic testing, including noninvasive prenatal testing (NIPT), karyotyping, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), candidate gene sequencing or whole-exome sequencing (WES), evaluations, were obtained. Fetal and neonatal outcomes included perinatal and neonatal survival and RRT requirements at neonatal intensive care unit (NICU) discharge. Patients who were not delivered at our institution were considered lost to follow-up if data regarding pregnancy viability was not available for review. Statistical analysis was performed using STATA for descriptive statistics, including means, medians, and frequencies, where applicable. These studies were approved by the Baylor College of Medicine Institutional Review Board (IRB).

Results

A total of 4620 referrals were seen at the Fetal Center between 2011 and 2018. Of those, 217 were seen at the fetal nephrology clinic: 4.6% of the total Fetal Center referrals. Sixty-one of these referrals were seen in consultation only, and no information about pregnancy viability was available. From the 156 referrals, of which we have data about pregnancy viability, additional postdelivery data were not available for 27 patients (Figure 1).

Figure 1.

Distribution, delivery, and pregnancy outcomes for fetal nephrology consults.

Maternal Characteristics

The average estimated gestational age (EGA) at the time of consultation was 25.2 weeks (±5–7 weeks) (Table 1). The mean maternal age was 29.3 years (±5.6 years), with 13.8% being classified as advanced maternal age (i.e., older than 35 years); median Gravida 2 and Parity 1. Eleven pregnancies were assisted by in vitro fertilization (IVF). Maternal ethnicity was self-reported as predominantly White (41.7%), followed by Hispanic (35.3%) and Black (17.6%). The majority (87%) had no maternal comorbidities reported. However, 11 patients had preexisting diabetes mellitus (5%), 7 with chronic hypertension (2.3%), and 1 with exposure to an angiotensin-converting enzyme inhibitor (ACEi). Two mothers had a known diagnosis of autosomal dominant polycystic kidney disease (ADPKD). Two women had prior pregnancies complicated by LUTO; one had a prior pregnancy loss from bilateral multicystic dysplastic kidney disease; and one had a prior IUFD from bilateral renal agenesis. Twenty-one patients (10%) had a positive family history for some form of kidney disease including nephrotic syndrome, CAKUT, CKD, or ESKD: one with a family history on congenital nephrotic syndrome, seven with a family history of a solitary kidney, one with a family member with a duplicated ureter, three families with adult-onset (older than 18 years) CKD/ESKD of uncertain etiology, one with a family history of ESKD from systemic lupus erythematous, and eight families with a history of late-onset ESKD (older than 60 years) secondary to either diabetes mellitus or hypertension. Excluding patients with a family history of congenital nephrotic syndrome or a family history of ADPKD, there was no clear association of a family history of kidney disease and prenatal kidney disease, with the exception of three patients with unilateral renal agenesis and another family member with a solitary kidney.

Table 1.

Maternal characteristics (n=217)

Characteristic	Value
Maternal age, yr, mean (SD)	29.3 (±5.6)
Ethnicity, n (%)
White	90 (41.5)
Hispanic	77 (35.4)
Black	38 (17.6)
Asian	10 (4.6)
Other/not reported	2 (0.9)
Comorbidities, n (%)
Diabetes mellitus	11 (5)
Hypertension	7 (3.2)
Other	34 (15.6)
None	163 (75)
Gestational age at consultation, wk, mean (SD)	25.2 (5–7)
Amniotic fluid, n (%)
Anhydramnios	64 (29.4)
Oligohydramnios	36 (16.5)
Normal	111 (51.2)
Exposures, n (%)
None	205 (94.4)
Insulin	3 (1.3)
ACEi	1 (0.5)
Other	8 (3.7)

Fetal Characteristics

Most fetuses were male (62.7%), with a small number (6.9%) having either undetermined or unknown sex at the time of evaluation (Table 2). The most common prenatal CAKUT diagnoses referred to the fetal nephrology clinic were LUTO (32.7%) and unilateral multicystic dysplastic kidney (MCDK) (15.6%). Referrals for isolated hydronephrosis or pelviectasis were uncommon (<7% of all referrals). One-third of fetuses had at least one additional nonurinary anomaly identified prenatally (primarily heart, lung, or brain defects).

Table 2.

Fetal characteristics by prenatal imaging studies (n=217)

Fetal Characteristic	Value, n (%)
Sex
Male	136 (62.7)
Female	66 (30.4)
Undetermined/unknown	15 (6.9)
Kidney and urologic anomalies
Bilateral echogenic	4 (1.8)
Bilateral cystic disease	19 (8.8)
Dysplasia/hypoplasia	6 (2.7)
Cystic dysplasia	12 (5.5)
Agenesis
Bilateral	18 (8.3)
Unilateral	18 (8.3)
MCDK
Bilateral	4 (1.8)
Unilateral	34 (15.6)
LUTO	71 (32.7)
Ectopia	15 (6.7)
Hydronephrosis	14 (6.9)
Other	2 (0.9)
Other anomalies	81 (37)
Heart	26 (11.9)
Lung	28 (12.9)
Brain/spinal	9 (4.1)
Other	18 (8.3)

MCDK, multicystic dysplastic kidney; LUTO, lower urinary outlet obstruction.

Genetic Evaluation

For the entire cohort, most (76%) received counseling by certified genetic counselors. Of those who did not receive genetic counseling (n=52), 38 (73%) were referred to the Fetal Center for isolated unilateral MCDK, renal ectopia, unilateral hydronephrosis, or unilateral isolated renal agenesis, and either the referring provider specifically asked for nephrology consultation only or the patient declined genetic counseling. Fourteen patients with complex anomalies (bilateral renal agenesis, bilateral cystic kidney disease or LUTO) declined genetic counseling as part of their evaluation.

Prenatal genetic testing was highly variable within the referral population (Figure 2). Overall, 35% of patients had no prenatal genetic testing. While this was clustered in patients with less complex lesions for which there are no clear genetic associations, such as unilateral MCDK, unilateral agenesis, and renal ectopia, it is important to note that genetic testing of any kind was declined in over 30% of patients with bilateral cystic disease, bilateral dysplasia, or hypoplasia and over 40% of patients with bilateral renal agenesis. Overall, 30% of patients had NIPT only while 35% of patients had a range of fetal genetic testing performed. Not surprisingly, the phenotype with the highest percentage of fetal testing was the LUTO cohort (52%) because normal FISH and chromosome screening was required to qualify for vesicoamniotic shunt (VAS) placement.

Figure 2.

Distribution of prenatal genetic testing by phenotype.

Of the 141 patients who had prenatal genetic testing (NIPT, karyotyping, FISH, CMA, targeted gene sequencing, or WES), the overall positivity rate was 5.7% (Table 3). Two patients had confirmatory candidate gene sequencing based on either clinical phenotype or maternal carrier screening, and six had abnormal NIPT/CMAs (Table 3). Of the 109 patients for whom there were neonatal outcome data, there was no neonatal genetic testing in 75% of patients because of either a clinical phenotype with very low probability of diagnostic benefit (isolated renal agenesis, isolated unilateral MCDK, isolated hydronephrosis, and patients with LUTO, n=64) or the absence of parental consent (n=18). Additional genetic testing was obtained in 27 neonates, of which 16 patients had a positive result (Table 4); WES testing was positive in eight patients with 10 nondiagnostic studies; six patients had either targeted gene or phenotype-specific gene panel testing that was diagnostic; and three patients had abnormal chromosomal microarray studies. The overall diagnostic yield from genetic testing in the highly enriched population was 59% (16/27).

Table 3.

Spectrum of prenatal genetic anomalies in fetuses with kidney or urologic anomalies (n=8)

No.	Phenotype	Other Anomalies	Carrier Screening	Karyotyping	CMA	Targeted Sequencing
1	Right renal agenesis	Cleft lip and palate, small stomach		Normal	Normal	CHD7 (AD): C3768C>G (heterozygous)
2	Bilateral renal cysts	—	Positive	—	0.676 kb deletion, 6p12.3p12.2 (PKHD1)	PKHD1 (AD) sequencing: c.10452dupT
3	Bilateral renal cysts	Congenital diaphragmatic hernia	—	—	1.77Mb deletion, 17q12 (HNF1β)	—
4	Cystic dysplasia bilateral	Cystic hygroma, congenital heart defect	—	Monosomy X	—	—
5	Bilateral hydronephrosis	Absent uterus	—	—	35 Mb Triplication/tetrasomy, 3q26.1q29	—
6	LUTO	Ventricular septal defect, small pulmonary artery, abnormal cerebellum	—	Trisomy 13	—	—
7	LUTO	—	—	—	2.13 MB deletion 5q35.2 ->q35.3. (NSD1, Sotos syndrome)
8	Congenital nephrotic syndrome	—		—	—	NPHS1 (AR): c.45_46; 2 bp duplication Homozygous

CMA, chromosomal microarray analysis; LUTO, lower urinary outlet obstruction.

Table 4.

Spectrum of genetic anomalies in neonates with kidney or urologic anomalies (n=16)

No.	Phenotype	Other Anomalies	Genetic Testing	Diagnosis	Variant
1	Renal agenesis, unilateral, and cystic kidney	CCAM	WES	PKD-3 (AD)	GANAB: c.2806C>T (heterozygous)
2	Bilateral cysts	Polydactyly	WES	BBS (AR)	BBS1: c.1169T>G (homozygous)
3	Bilateral cysts	CHAOS syndrome, club feet	WES	Townes Brock (AD)	SALL1: c.826C<T (heterozygous)
4	Bilateral cysts	—	KFMa	ARPKD (AR)	PKHD1: c.3761_3762delCCinsG (homozygous)
5	Bilateral cysts	—	KFM	ARPKD (AR)	PKHD1: c.851C>T; c.10035T>C (compound heterozygous)
6	Bilateral cysts	Situs inversus, congenital heart defects	WES	ARPKD (AR)	PKHD1: c.3615T>A; c.8348T>C (compound heterozygous)
7	Cystic dysplasia	Anal atresia, small thorax	WES	Joubert syndrome	AHI1 (AR): c.305dupA CEP290 (AR): c.2951A>T WDR19 (AR): c.1325C>T RPGIP1L (AR): c2938A>G
8	Echogenic bilaterally	—	KFM	ADPKD (AD)	PKD1: c.11159G>A (heterozygous)
9	Dysplasia with crossed fused ectopia	—	BOR panel sequencing	BOR syndrome (AD)	EYA1: c.705T>A (heterozygous)
10	Unilateral dysplasia	Multiple anomalies including cloacal malformation	Ciliopathies panel	BBS (AR)	TCTN2: c.524dupT; c.652_659dupCTCTGCTC (compound heterozygous)
11	Bilateral hypoplasia	Intrauterine growth retardation, ventricular septal defect, A-V canal defect	CMA	Mosaic trisomy 22
12	Hydronephrosis, unilateral, and echogenic right kidney	—	CMA	HNF-1β/TCF2	17q12: 1–2 Mb loss
13	Bilateral hydronephrosis	Dandy-Walker malformation, dysmorphic facies	Noonan's sequencing panel:	Noonan's (AD)	KRAS: c.458A>T (heterozygous)
14	LUTO	—	WES:	NPHP (AR)	NPHP3: c.1189C>T (heterozygous) NPHP2(INVS): c.725C>T (heterozygous)
15	LUTO	—	WES:	NPHP (AR)	BBS10 (AR); c.271dupT (heterozygous) CENPJ (AR): c.1434delG (heterozygous)
16	Unilateral MCDK, ureterocele	Ventricular septal defect	CMA and FISH	22q11.21: 2.5 Mb deletion	Velocardiofacial syndrome

MCDK, multicystic dysplastic kidney; LUTO, lower urinary outlet obstruction; WES, whole-exome sequencing.

Parental testing in one patient with an HFN1-β deletion confirmed that the patient had a de novo mutation; parental testing was declined in the other case as both parents were healthy and did not have known diabetes. The causal association of the GANAB mutation is less certain because parental testing revealed an identical heterozygous mutation in the mother, who was asymptomatic and declined any further testing or imaging studies. Of the two maternal patients with known ADPKD, the fetal US for one patient was normal and newborn follow-up was performed at the referral center outside the TCH system; in the other case, bilateral maternal renal cysts were identified at the 20-week fetal ultrasound screening. The fetal US noted only echogenic kidneys bilaterally without overt cyst formation; maternal genetic confirmation of ADPKD was available before delivery of the infant.

Fetal and Neonatal Outcomes

Of the 129 patients for whom fetal or neonatal outcomes were available, 73 were discharged home, 20 pregnancies were nonviable, and 36 neonates died before NICU discharge (Table 5). The median age at the time of death was 1 day of life (interquartile range, 1-53). Of the 36 neonates who died, 75% had multiple developmental anomalies. The cause of death was pulmonary hypoplasia in 32% of patients (n=11), comfort care/redirection of life support in 32% (n=11), and complications of ESKD in 8.3% (n=1), with the remaining 36% (n=12) dying from various other causes. There was 100% mortality in the subset of patients who presented with bilateral cystic kidney disease and anhydramnios; two had IUFDs; and the remainder expired shortly after delivery from respiratory failure. Those surviving to discharge (n=73) were delivered at a mean gestational age of 35.7 weeks and had a mean length of stay of 43.5 days (SD ±62 days). Two of the surviving patients were discharged to hospice care, and five patients were discharged on chronic dialysis.

Table 5.

Fetal and neonatal outcomes (n=129)

Parameter	Nonviable Pregnancies (n=20)	Neonatal Death (n=36)	Discharged from NICU (n=73)
Kidney/urologic diagnosis, n (%)	15.5%	27.9%	56.6%
Unilateral agenesis or MCDK	2 (10)	2 (5.5)	19 (26)
Isolated	0	1
Complex	2	1
Bilateral Agenesis or MCDK	9 (45)	9 (25)	0
LUTO	5 (25)	12 (33)	29 (39.7)
Bilateral cystic disease	3 (15)	7 (19.4)	4 (5.4)
Hydronephrosis	0	1 (2.8)	6 (8.2)
Ectopia	1 (5)	0	7 (9.5)
Other	1 (5)	7 (19.4)	8 (10.3)
Other anomalies, n (%)	15 (75)	27 (75)	22 (30.1)
Genetic counseling, n (%)	17 (85)	26 (72)	48 (65.8)
Genetic diagnosis, n (%)	3 (15)	7 (19.4)	5 (6.8)
RRT, n (%)	0	2 (5.5)	5 (6.8)

NICU, neonatal intensive care unit; MCDK, multicystic dysplastic kidney; LUTO, lower urinary outlet obstruction.

Discussion

Limited literature exists currently to inform our practice of fetal nephrology counseling, given the high variability and poor genotype/phenotype correlation. Because CAKUTs are a common anomaly representing approximately 20% of all anomalies identified by prenatal ultrasonographic evaluation, a considerable number of referrals for consultations by pediatric nephrologists or urologists to support parents and physicians in clinical decision making during pregnancy would be expected. In our experience, prenatal nephrology consultation rates represented only 4.7% of all fetal center referrals, a number which is four to five-fold lower than expected based on frequencies of CAKUT reported in the population as a whole. This lower referral rate likely represents a bias toward referral of a subgroup of more complex CAKUT patients for consultation at specialized fetal centers.

In our study, the proportion of complex anomalies (i.e., LUTO, bilateral agenesis and MCDK) was 43% of the patients, which is in contrast to previous population-based prevalence studies which identified around 10% with complex CAKUT.² The availability of fetal intervention for LUTO (i.e., VAS placement) at our center may be one of the drivers for this observation. Thirty-seven percent of our referrals were CAKUT in association with other congenital anomalies, which is in alignment with prior studies that have reported multiple anomalies in 6%–50% of patients.^2,4-7 This large variability probably reflects the difference in sample sources, as studies derived from large national databases are more likely to reflect lower frequencies of other associations, when compared with single or multi referral center data, because isolated and less severe cases predominate in the former and more complex cases can drive referral bias in the latter. We speculate that, in our center, nephrology service evaluations are biased to those at high risk including fetuses who potentially may require renal replacement therapy in the immediate postnatal period or have CAKUT with multiple congenital anomalies requiring the care of multiple medical and surgical pediatric subspecialists.

The postnatal mortality for our cohort was 43%, with the primary causes of death being either severe pulmonary pathology or redirection of care in two-thirds of this subset. It is difficult to interpret this percentage in the context of the full spectrum of CAKUTs, particularly as those with unilateral or isolated kidney disease had much more favorable outcomes. This also reflects in the higher survival rates in the subset of patients who declined genetic testing, who predominantly had unilateral or isolated renal anomalies. Morbidity and mortality in CAKUT depend, in large part, on the severity of oligohydramnios and its association with pulmonary hypoplasia, bilateral genitourinary anomalies, and the association with multiple organ anomalies.^8-13 Given our high-risk population with a high prevalence of above mentioned characteristics, it is likely this mortality is significantly higher when compared with the population at large. Overall, this underlines the need to develop objective clinical tools (i.e., clinical algorithms, scoring systems) based on disease-specific risk factors rather than single center or large database descriptions, which may limit clinical application in specific clinical scenarios. For the kidney-specific outcomes, only five patients were discharged on dialysis, representing 4.6% of those who were discharged from NICU. Other than those who were discharged on dialysis, available data did not permit for the determination of CKD status of all patients at the time of discharge.

Genetic testing is an evolving field that has been increasingly incorporated in fetal medicine, driving enhanced counseling and clinical decision making. CAKUT is a genetically heterogeneous disease; thus, the prenatal genetic testing approach is complex. Often CAKUT is the first manifestation of a syndromic disorder, and genetic testing may improve the clinical evaluation of subtler manifestations after birth.¹⁴ However, prenatal testing is not always welcomed by expecting parents for a wide array of reasons. In this study, over 30% of patients with bilateral disease refused genetic testing of any kind prenatally. One potential explanation for this may be the perception of reduced utility given limited prenatal interventions available with some pathologies in contrast to the LUTO phenotype where VAS is possible. In addition, more severe anomalies often require more complex testing techniques, and therefore, parents in these cases might be less likely to pursue genetic testing because of an increased time for test completion, the complexities of understanding the testing approaches, maternal risk associated with fetal testing, and a lack of willingness to act on information provided by genetic testing. This is a critical issue because prenatal genetic testing can offer short- and long-term benefits for families, especially when a genetic risk is identified for current or future siblings. From a medical standpoint, this would provide more information to better predict perinatal outcomes by further characterizing high-risk populations. In this cohort, over 50% of the more complex patients in whom additional postnatal genetic testing was performed had positive genetic testing results, with single gene mutations and chromosomal anomalies identified. Barriers to genetic testing, both structural and psychosocial, should be evaluated in future studies.

Finally, there is some literature reporting that prenatal counseling with experts may ease parental anxiety and can provide clarity regarding postnatal care expectations.³ The value of prenatal counseling will likely improve as new developments and outcomes data are incorporated into predicative modeling tools. Given current limitations and gaps in predicting outcomes, this is better attended at large fetal centers with multidisciplinary teams with experience in the prenatal and postnatal care of fetuses, particularly with the more severe and complex phenotypes. Regardless, given the wide spectrum of renal and urologic disorders seen in these patients, most if not all parents should have some form of prenatal counseling to provide parental education and reassurance if no other interventions are pursued.

There is a wide range of renal and urologic disorders, including CAKUT and cystic kidney disease, that present during pregnancy. The spectrum of diseases has highly variable phenotypes and complex genotype-phenotype correlations. It is difficult to generalize from the current literature given variabilities in reporting and likely institutional variations in prevalence, incidence, and practices for disease management. The disease complexity and high mortality rates support the need for prenatal consultation with an experienced multidisciplinary care team. Efforts should be made to develop objective diagnosis-specific clinical algorithms and testing strategies that incorporate both genetic and prenatal risk factors, which are practical and useful when counseling expecting parents.

Disclosures

M.C. Braun reports the following: Consultancy: Apellis Pharmaceuticals. C.J. Koh reports the following: Research Funding: Pfizer, Olympus, and Allergan. All remaining authors have nothing to disclose.

Funding

None.

Author Contributions

Conceptualization: Joseph R. Angelo, Michael C. Braun, Catherine Joseph, Chester J. Koh, Auda M. Plaud Gonzalez, Samantha R. Stover.

Data curation: Auda M. Plaud Gonzalez.

Formal analysis: Joseph R. Angelo, Michael C. Braun, Catherine Joseph, Chester J. Koh, Auda M. Plaud Gonzalez, Samantha R. Stover.

Investigation: Joseph R. Angelo, Auda M. Plaud Gonzalez.

Methodology: Joseph R. Angelo, Michael C. Braun, Auda M. Plaud Gonzalez.

Writing – original draft: Auda M. Plaud Gonzalez.

Writing – review & editing: Joseph R. Angelo, Michael C. Braun, Catherine Joseph, Chester J. Koh, Ahmed Nassr, Auda M. Plaud Gonzalez, Samantha R. Stover.

Data Sharing Statement

All data are included in the manuscript and/or supporting information.