THE CHILD PRESENTING WITH

NEPHROTIC SYNDROME:
UPDATES ON PATHOGENESIS
AND TREATMENT
Kim Reidy, MD
Associate Professor and Chief
Division of Pediatric Nephrology
@KimReidy2
Learning objectives
1.Recognize evolving understanding of
genetic and immune related factors
contributing to childhood onset nephrotic
syndrome.
2.Understand risk factors for worse
outcomes in childhood onset nephrotic
syndrome.
3.Describe new treatment approaches for
childhood onset nephrotic syndrome.
Case
30-month-old girl
presents with swelling
• Eye swelling started
in 2 weeks ago
• Treated for allergy
• Now with abdominal
distension and leg
swelling

Biljon, Gertruida. (2012).

Differential diagnosis: Edema
• allergy
• heart failure
• infection/inflammation
• liver disease
• malnutrition/protein losing enteropathy
• medications
• nephrotic syndrome
• thyroid disorder
• venous thrombosis
Case: ROS
• No redness, pruritis or eye pain
• No eye discharge.
• No fevers
• + fatigue
• Urine: no gross hematuria, +decreased
frequency.
Case: Physical Exam
• Vital Signs:
– Wt 15 kg (+ 2 kg since WCV 2 months
ago).
– afebrile, BP 90/50 mmHg, HR 100 bpm
• HEENT: +Periorbital edema
• Lungs: Slightly decreased BS at bases
• Abd: distended but soft, NT, +fluid wave.
• GU: Mild vulvar edema
• Ext: 2+ pretibial edema
Question
• What is the NEXT BEST test for diagnosis:

A) kidney biopsy
B) renal-bladder ultrasound
C) serum creatinine
D) urinalysis
Urinalysis
Primarily detects Trace 15mg/dL
albumin leaving low
molecular weight
1+ 30mg/dL
proteins undetected

2+ 100mg/dL
False (-): dilute urine

3+ 300mg/dL
False(+): concentrated
urine > 1.025 or
alkaline urine pH > 8. 4+ > 2000mg/dL
Case
urine dip: Urine protein/
Cholesterol
4 + protein, creatinine
450 mg/dL
negative blood ratio 5 g/g

CXR: small
Albumin 2.2 Creatinine 0.4
pleural
mg/dL mg/dL
effusion

What is the
diagnosis?
Nephrotic Syndrome
Edema

Nephrotic • UPC ≥ 2
Proteinuria • >40 mg/ m2/ hr on 24-hour urine

Hypoalbuminemia • Albumin < 2.5g/dL

• elevated plasma cholesterol low-density

Hyperlipidemia lipoprotein (LDL), triglycerides and/or
lipoprotein(a)
EPIDEMIOLOGY
• NS incidence: 1-3 per 100,000 children
• Peak incidence in pre-school children;
80% are less than 6 years of age at
presentation, with a median age of 2.5 yrs
for MCNS
• In young children, boys are more
commonly affected than girls (3:2), but in
teenagers and adults the ratio is equal
Differential diagnosis of childhood
nephrotic syndrome
• Minimal Change Nephrotic Syndrome
• Focal segmental glomerulosclerosis (FSGS)
• C3 glomerulopathy (previously called
“MPGN”)
• IgA nephropathy
• Membranous nephropathy
• Congenital/infantile NS (age <1 year)
• Secondary (eg. lupus, infection (HIV, Hep
B/C, medications/NSAIDs)
 Glomerular filtration
barrier • Podocytes
• Glomerular
basement
membrane
Tao et al ,
• Endothelial
2014 cells

Ebefors,
et al
2021
Focal segmental
glomerulosclerosis (FSGS)
ISKDC

Diagnosis by
Steroid response
400

200

0
Steroid Steroid
respon- resistant
sive
MCD
FSGS or Other
What causes MCD and FSGS?
Gauckler et al, 2020
Nephrin autoantibodies may contribute
to MCD/nephrotic syndrome

Watts et al, 2022

 Genetic causes
of FSGS

Defects in 60+ genes

in podocytopathies

Akchurin O, Reidy KJ 2014

 Likelihood of genetic mutation
varies with age (Rood et al, NDT 2011)
69% 50% 25% 17% <2%
(<3mo) (3-12mo) (1-6y) (7-12y) (adult)
NPHS1 WT1
NPHS2 NPHS2 INF2
NPHS2 NPHS2
WT-1 WT-1 TRPC6
WT1 NPHS1
PLCE1 TRPC6 ACTN4
LAMB2 PLCE1
NPHS1
PLCE1 LAMB2

(Hinkes et al, Pediatrics, 2006) (Sadowski et al., JASN 2015)

1783 SRNS

clker.com/clipartpanda.com
 Likelihood of genetic mutations varies
with age

Initial
biopsy:
16% (>6 yo) 56%FSGS
21% MCD
66% 12% MCD
with
mesangial
proliferation
2.9 % DMS

Podonet
1174 SRNS

(Trautmann et al, CJASN, 2015)

 Extra renal manifestations
• 17% in Podo-net (Trautmann et al, CJASN, 2015)
– CNS abnormalities (most common)
– Cardiac structure disorder
– Urogenital malformations (WT-1 mutation)
– Visual/hearing impairment
– Impaired sex differentiation (WT-mutation)
– Cardiomyopathy/Myopathy (mitochondrial)
 Genetic mutations predict response to
treatment and long-term outcome

Trautmann
et al, 2016
APOL1 gene variants account for 70% of the
excess risk for end-stage kidney disease
(ESkD) and FSGS among African Americans

G1 G2
Genovese et al, Science, 2010

BUT:
Only 15-25 out of 100 with high-risk
alleles are predicted to develop ESKD
APOL1 gene variants protect against Trypanosoma
(cause of ‘African sleeping sickness’)

J Clin Invest. 2011

| 27
10/23/2023
APOL1 risk variants
are common in pediatric FSGS
• FSGS clinical trial: 72% of AA subjects had
APOL1 HR alleles (Kopp et al, JASN
2016)
• 40% of AA SRNS children (Adeyemo et al.
AJKD, 2018)
• CKiD: 89% of AA subjects with FSGS
• Neptune: 67% of AA children with FSGS
(Ng et al., Nephol Dial Transplant, 2017)
What are the risk factors that result in APOL1
related kidney disease in childhood?
• AGES:
– Children 1 -16 years old
• Disease Criteria:
– eGFR 30-90 ml/m2/min (by inulin
clearance)
• Collected
– Social & medical history
– Blood, urine
– Cardiac evaluation
– Neurocognitive evaluation
• –
Size of Cohort
– 891 as of 2015
• AGES:
– All ages
• Disease Criteria:
– Clinically indicated renal biopsy for
proteinuria ≥ 500 mg/day
• Collected
– Social & medical history
– Blood, urine
– Renal Biopsy
– Quality of life
• Size of the Cohort
1300 patients as of 2013
Children with APOL1 HR variants
present at an older age and had worse GFR at
study entry
APOL1 HR variants are associated with obesity
and LVH in children with FSGS and CKD
APOL1 HR is associated with
prematurity in children with glomerular disease
 Does APOL1 affect birth
outcomes?

APOL1 gene variants did not associate

with prematurity –
But what about preeclampsia?
• Preeclampsia/hypertension during pregnancy affects 5-
8% U.S. births

• 10 million pregnant people develop preeclampsia each

year worldwide

• 76,000 pregnant people worldwide die from

preeclampsia/hypertension during pregnancy each year
Preeclampsia
• Diagnosis (American College of Obstetrics &
Gynecology)
– Rise in blood pressure after 20 weeks of
gestation
AND
– Proteinuria or end organ dysfunction (cerebral
or visual disturbances, transaminitis,
thrombocytopenia, progressive renal
insufficiency, pulmonary edema)

• Preeclampsia is more prevalent and severe in

those of African descent
Placenta is formed by both fetal
and maternal components

• APOL1 is highly
expressed in the placenta
• Defects in placentation
lead to preeclampsia
Hypothesis

APOL1 HR variants in mother or infant will

increase risk or severity of preeclampsia.
Umbilical cord Placenta
 Characteristics of Births Complicated by
Preeclampsia by Fetal APOL1 Genotype
Study AECOM

APOL1
APOL1 Genotype All APOL1 LR HR p-value∔
Number - n 121 97 24

Maternal Age - yr (IQR) 29.0 (11) 28.0 (10) 31.5 (8.5) 0.09

Nulliparity - n (%) 25 (21%) 21 (22%) 4 (17%) 0.78

Obesity - n (%) 30 (25%) 26 (27%) 4 (17%) 0.43

History of Hypertension - n (%) 34 (28%) 27 (28%) 8 (33%) 0.62

History of Diabetes - n (%) 11 (9%) 9 (9%) 2 (8%) 1.00

History of SLE or APLS - n (%) 1 (1%) 1 (1%) 0 (0%) 1.00

History of Prior Preeclampsia - n (%) 22 (18%) 17 (18%) 5 (21%) 0.77

History of Spontaneous Abortion - n (%) 23 (19%) 16 (16%) 7 (29%) 0.16

Perinatal Outcomes

Cesarean Delivery - n (%) 79 (65%) 64 (64%) 16 (67%) 1.00

Gestational Age - weeks (IQR) 35.4 (5.6) 35.7 (5.3) 34.9 (6.2) 0.47

2.345 2.360
Birth Weight - kg (IQR) 2.278 (1.049) 0.62
(1.307) (1.268)

Apgar Score, 1 min (IQR) 8.0 (3.0) 8.0 (2.0) 8.0 (4.5) 0.20

Apgar Score ± 5 min (IQR) 9.0 (1.0) 9.0 (1.0) 8.0 (1.0) 0.03

Reidy et al., Am J Hum Genetics 2018

 CANDLE: case-control cohort

990 AA mother/child
pairs

921 mothers 747 infants

DNA extracted & DNA extracted &
genotyping calls genotyping calls
Observational made made

cohort of 1503
pregnant women 921
384 (42%) 0 RA
747
318 (43%) 0 RA
437 (47%) 1 RA 326 (44%) 1 RA
100 (11%) 2 RA 103 (14%) 2 RA

93 AA women developed
preeclampsia
Reidy et al., Am J Hum Genetics 2018
Maternal serum sFlt/PlGF ratios are
increased with fetal APOL1 HR vs. LR
variants

Reidy et al., Am J Hum Genetics 2018

Two thirds of
nephrons form in the
last trimester and
preterm birth leads to
early cessation of
nephrogenesis
Does
preterm
birth affect
podocytes?
Cwiek et al, 2021
 Is preterm birth a risk factor for
poor outcomes in glomerular
disease?

 Minimal Change Disease • Disease Criteria:

 Focal Segmental – Clinically indicated
Glomerulosclerosis renal biopsy for
proteinuria ≥ 500
 Membranous mg/day
Nephropathy
 IgA nephropathy/IgA
Vasculitis
• Size of Cohort • Size of the Cohort
– 2,400 – 1300
Preterm birth was associated with longitudinal
eGFR in preterm/LBW children in NEPTUNE

Linear Mixed Models (backward selection final model),

n=359
Estimate [95% CI] P
LBW/Premature -8.04 [-13.47 to -2.61] 0.004
Age -0.55 [-0.66 to -0.43] <0.001
FSGS Cohort [Ref: MCD] -15.34 [-20.32 to - <0.001
10.37]
Male Sex [Ref: Female] 5.02 [0.38 to 9.65] 0.03
APOL1 high risk [Ref: Not -16.87 [-24.91 to -8.83] <0.001
High Risk]
What about in adults born
preterm?

Isaac et al, manuscript in

preparation
APOL1 high risk variants are associated with
preterm birth in adults with glomerular disease
Preterm Term
Clinical Characteristics p-value
(n=117) (n=1404)
Glomerular Disease Diagnosis, n (%) 0.01
Minimal Change Disease 19 (16) 198 (14)
FSGS 41 (35) 357 (25)
IgA Nephropathy 35 (30) 390 (28)
Membranous Nephropathy 22 (19) 459 (33)
BMI, n (%) 0.93
Obese (>= 30) 42 (36) 530 (38)
Overweight (25-29) 39 (33) 436 (31)
Normal weight (18.5 - 24) 32 (27) 370 (26)
Underweight (<18.5) 1 (1) 18 (1)
Unknown/missing 3 (3) 50 (4)
Hypertension at enrollment, n (%) 64 (55) 816 (58) 0.47
eGFR at enrollment (ml/min/1.73m 2), 67 (33, 98) 70 (43, 96) 0.75
median (IQR)
Baseline urine protein: creatinine ratio, 2.0 (0.7, 3.9) 1.6 (0.5, 4.4) 0.93
median (IQR)
APOL1 High Risk Genotype (n=1160), n (%) 11 (9) 59 (4) 0.01

Isaac et al, manuscript in preparation

Preterm birth is associated with faster
40% decline in eGFR / development of
ESKD

Isaac et al, manuscript in preparation

What about treatment?

De Cos et al, 2023

Future paradigm for treatment
Ongoing clinical trials
Conclusions
• Genetic causes of nephrotic syndrome vary by age,
are less likely to respond to therapy and most often
lead to kidney failure.
• APOL1 high risk variants contribute to kidney disease
in those of African descent.
• Preterm birth may be a “second hit” that leads to
APOL1 related kidney disease.
• Immune dysregulation and autoimmunity contribute to
non-genetic nephrotic syndrome.
• Newer therapeutic agents may allow for personalized
medicine approaches, including targeting of APOL1
high risk variants and immune modulation.
ACKNOWLEDGEMENTS
Zhongfang Du NIH:
Rebecca Hjorten Cheryl Winkler
Jeffrey Kopp
Stacy Rosenblum
Avi Rosenberg (John
Soulin Haque Hopkins)
Madiha Baig
Joseph Myrie UT Tennessee:
Claire Simpson
Jaya Isaac Bob Davis

CKiD/Neptune: UVA:
Frederick Kaskel Jennifer Charlton
Matthew Sampson Aleksandra Cwiek Jennifer Charlton
Derek Ng
Einstein:
Masako Suzuki
Jonathan Troost (Genetics)
Yujie Wang
Deb Gipson
Sangeeta Hingorani
KR receives support from NIH R01DK131176 and R01DK131811 and the Preeclampsia Foundation. RH was
supported by NIH T32 DK007110. JI is supported by NYC-KUHR TL1DK136048. This project received catalytic
seed grant from the NIH CTSA Grant Number 1 UL1 TR001073.
APOL1 risk variants and risk of kidney disease
across the life-course
Why do children have edema?
• “Underfill” hypothesis: Edema is due to
decreased oncotic pressure in the
intravascular space
•

• oncotic pressure • HYDROSTATIC

• Increased tubular reabsorption of

sodium