DEVELOPMENT PROGRAMMING OF CKD – FAULT IS NOT IN OUR

STARS BUT OUR EMBRYO

Dr Sudha EkambaramDNB(Ped),FPN, FISN(Singapore) Dep HOD Pediatric Nephrology

Dr Mehta’s Hospital

DEVELOPMENT PROGRAMMING OF CKD –FAULT IS NOT IN OUR STARS BUT OUR EMBRYO

The child is the father of man - William Wordsworth (1802)

This English Poet had observed that the child’s health could be continuum into man, long before Dr Barry Brenner in 1988

KIDADULT

ADULT

KID

INTRODUCTION

➢ CKD affects approximately 10% of the world’s adult population

➢ It is within the top 20 causes of death worldwide

➢ The recent emphasis on a “life course” approach outlined by the WHO in the Minsk Declaration is ’Optimisation of early development is important for true primary prevention of Non-Communicable Diseases including kidney diseases’

➢ It’s our responsibility to optimize care of the young for a healthy adulthood

Lancet. 2016;388:1545–1602. http://www.euro.who.int/__data/assets/pdf_file/0003/319305/3-Towardsnew-WHO-EAP-human-rights-based-SRH.pdf?ua=1.

MECHANISM OF FETAL & ADULT KIDNEY INJURY

By God’s grace the normally acquired nephron number is far in excess of what is needed for normal function

Individuals with low renal reserve are at risk, particularly following secondary insult (second hit) may lead to development of CKD

We shall review situations in which these numbers are down and theireffects in later child and adult hood

HELP

Charlton JR. Pediatr Nephrol 2014; 29: 2299–2308

2nd /3rd Hit

ObesityHigh saltDiabetes

AKIAging

Multi Hit Hypothesis

CAKUT

Tain YL. Int J Mol Sci. 2017, 18, 381

Schematic summary of the links between early life insult, mechanism underlying renal programming & programmed kidney disease

CASE

▪ Ms X aged 10 yrs, presented at 3 mo of age

▪ She was born by IVF conception, PT (28 wk), BW 1.02Kg, admitted in NICU

▪ Treated for RDS, sepsis, AKI, hypocalcemia

▪ Referred to us with hypercalcemia due to hypervitaminosis D

▪ Supportive care given

▪ Hypercalcemia settled

CASE

Her course for last 10 yrs …………………………

Date Wt (kg) BP U alb S Cr S HCO3 Kd size (cm) Treatment

28.04.10 1.02 NA NA 1.5 20 NA

06.08.10 2.1 60/40 + 0.6 19 RK 4.0, LK 4.1 Hypercalcemia

09.11.12 7.5 94/60 Trace 0.3 22 RK 5.5, LK 5.6 On bicarbonate

30.10.14 11.7 90/60 NIL 0.4 24 RK 6.0, LK 6.0 On bicarbonate

25.02.17 16.4 80/60 Trace 0.5 22 RK 7.0, LK 7.1 On bicarbonate

06.07.19 22.1(10th)126(25th)

100/60 Trace 0.6(GFR 86)

23 RK 7.1, LK 7.5 On bicarbonate

Miss X – USG in March 2016

Twin 2 – USG in March 2015

NEPHRON NUMBER & GESTATIONAL AGE

Late gestation is critical for nephrogenesis

60% nephrons formed during 3rd trimester

PT birth occurs while nephrogenesis is ongoing

Extreme & very PT nephrogenesis ceases 40d after birth

Hinchliffe SA. Lab Invest 1991; 64:777–784

INTERPLAY BETWEEN KIDNEY, EXPOSURES, RISK FACTORS & OUTCOMES IN PRETERM

Black MJ. Nephrology 2013;18:180–182

The major haemodynamictransition at time of birth -blood flow to kidney is ↑

Immature glomeruli notprepared for transition &their formation is affected

Acute kidney injuryNephrotoxic medicationsMechanical ventilationSub optimal nutritionInfections

PRETERM & CKD

BMJ 2019;365:l1346 | doi: 10.1136/bmj.l1346

PT birth & extremely PT birth wereassociated with nearly 2 – 3 fold risk of CKD,respectively from birth into mid-adulthoodThe association between PT birth & CKDwas strongest at ages 0-9 years (5.09, 4.11to 6.31; P<0.001), then weakened butremained increased at ages 10-19 years(1.97, 1.57 to 2.49; P<0.001) and 20-43years (1.34, 1.15 to 1.57)

Adjusted hazard ratios for CKD by GA at birth compared with full term birth, Sweden, 1973-2015

LBW & CKD

Vikse BE showed LBW & IUGR were associated with increased risk for ESRD with maximum follow-up of 38 yrs

Compared with BW in 10th to 90th centiles, births <10th centile had RR for ESRD of 1.7 (95% confidence interval 1.4 to 2.2; P <0.001)

Vikse BE. J Am Soc Nephrol 2008;19: 151–157

LBW & CKD

Long-term renal complications in a cohort of 78 ELBW was compared with 38 children born full-term. Patients were evaluated at a mean age of 6.7 years

• Mean serum cystatin C levels were significantly higher (0.64 vs. 0.59 mg/l; p=0.01) in ELBW

• Hypertension was diagnosed in 8 ELBW (p=0.5)• Microalbuminuria was detected in 5 ELBW children (p=0.17)

Authors conclude Long-term alterations in renal function and blood pressure could be determined only on following these patients up into late adulthood

2nd /3rd Hit

ObesityHigh saltDiabetes

AKIAging

Multi Hit Hypothesis

CAKUT

CASE

Newborn with normal antenatal USG and no other co-morbities was anuric for 24 hrs

His creatinine was increasing trend and USG showed normal sized kidneys with increase in echoes

What could be the reason?

Mother was prescribed Esmoprazole but was taking Enalapril for 3 months

The pharmacist had issued the wrong drug!!!

EFFECT ON NEPHRON ENDOWMENT BY DRUGS USAGE IN ANTENATAL PERIOD

ACE I & ARB reduce nephron formation & cause renal tubular dysgenesis

Dexamethasone to advance maturation of the fetal lung in PT delivery impairs fetal nephrogenesis

NSAIDs as tocolytic agents leads to tubular alterations & low nephron numbers

Fryer HJ. Nephron 2019;142:117–124

CASE

A 3 yr old female child was brought to OPD in May 2018 with history of recurrent UTI since 1 year of age. She was treated with 5 – 7 days of antibiotics with each episode

Mother had GDM requiring insulin, Term delivery, BW 3.1Kg

Antenatal scans showed renal anomaly but was not followed

Child is asymptomatic currently

How to proceed?

CASE

On examination:

Vitals stable

Systems within normal limits

Palpable bladder upto umbilicus +

USG (March 18):

RK – 6.4cm, LK – 10.8cm, bilateral UHN, UB – wall thickened (PVR – 85ml)

CASE

MCU

CASE

DMSA ( May 2018):

LK – 73% near normal function

RK – 27% reduced function

Multiple sites of inflammation/scars in both kidneys

CASE

Catheterized

Initiated on clean intermittent catheterization & night time drainage

Soda bicarbonate supplements

Date Creat Sodium Potassium Bicarb

10.5.18 0.9 138 4.5 18

17.5.18 0.6 136 4.2 20

09.7.18 0.5 137 4.3 21

2nd /3rd Hit

ObesityHigh saltDiabetes

AKIAging

Multi Hit Hypothesis

CAKUT

CASE

A 11 yr old boy was evaluated for short stature. He was found to have elevated S Cr & referred for further follow up

He was diagnosed with PUV at 31 weeks and was delivered at 34 weeks (pre term) due to oliguria. He had undergone PUV fulguration in the newborn period and has not been followed.

Had recurrent fever & received 5-7 days of antibiotics for each episode

On Examination:

Ht <3rd centile (short stature)

BP 120/70 ( stage 2)

CASE

USG (06/0/19):

RK – 13.7cm, LK – 12.7cm. B/L Gross UHN with increased echoes. UB – mild thickening of bladder wall

DMSA (18/06/19)

LK 25%, RK 75% (reduced function of both kidneys)

CASE

Date Creat Sodium Potassium Bicarb

30.4.08 1.4 139 5.3 14

02.1.09 0.8 140 4.9 16

10.8.19 3.1 142 3.6 18

This child is in CKD stage IV

2nd /3rd Hit

ObesityHigh saltDiabetes

AKIAging

Multi Hit Hypothesis

CAKUT

CAKUT & CKD

CAKUT account for 50% of pediatric kidney transplant

Obstructive nephropathy and hypoplasia/dysplasia is the leading cause

Monogenic mutations have been established in approximately 17% ofCAKUT, but in most cases, the etiology remains undetermined

It is likely the result of multiple genetic, epigenetic & fetal environmentalfactors

The Low Birth Weight and Nephron Number Working Group Nephron 2017;136:3–49

CAKUT & CKD

Hsu CW et al conducted a population based, case control study with 1994patients with childhood CKD (21 years of age at diagnosis) and 20,032controls in Washington state

They concluded that maternal GDM (OR 1.50; 95% CI, 1.07–2.09), maternaloverweight (OR 1.27; 95% CI, 1.05–1.52) and maternal obesity (OR 1.27; 95%CI, 1.05–1.55) were significantly associated with childhood obstructiveuropathy

Hsu CW, et al. J Am Soc Nephrol 2014; 25: 2105–2111.

LBW & CAKUT LEADING TO CKD

Vikse BE. J Am Soc Nephrol 2008;19: 151–157

The risk of CKD was found to be significantly higher among LBW with CAKUT compared with normal BW (OR 2.5; 95% CI, 1.6–3.7)

CAKUT & CKD

What is the reason for elevated creatinine in the second child?

Nephron number at birth is an important determinant of outcome

It is an important modulator of the decline in renal function over time

PREVENTIVE MEASURES

Today, most of the tiniest neonate survive & leave NICU without apparent morbidity

First generation of infants from “surfactant era” are now reaching young adulthood, it is possible there is already a silent epidemic of CKD in this population

Strategies to maximize nephron endowment at birth is not available at present

How can we prevent the renal complications in these children?

Moderate Risk

Yearly BP

Growth

Counselling

Visits

6 mo, 4 – 5 yrs

Adolescence

(S Cr, UPCR,APBM)

High Risk

Yearly BP

Growth

Counselling

Yearly UPCR

Visits

6 mo, 2 yrs, 4-5 yrs

Adolescence

(S Cr, UPCR, ABPM)

Very High Risk

Yearly BP

Growth

Counselling

Yearly UPCR

Visits

6mo

Annually

(S Cr, UPCR, ABPM)

Pediatrician

PediatricNephrologist

Preterm < 32 wkIUGR< 10th percentileSGA < 10th percentile

Neonatal & Childhood AKIObesity

BP > 95th percentile

1 risk factor 2 risk factor

FOLLOW UP

Recommended strategy for evaluation of renal dysfunction in PT

Michelle C Starr. Curr Opin Pediatr. 2018; 30(2): 228–235.

Preconception care

The Future !!!

RECOMMENDATION

▪ Preconception & pregnancy window should be considered as the earliestperiod to prevent adult non communicable diseases

▪ Importance of embryonic health should be given more emphasis in themedical curriculum, as well as during the training of midwives &gynaecologists

▪ Interventions to optimize fetal & child health can prevent adult noncommunicable diseases

▪ Preterm & LBW infants should be monitored regularly for hypertension,excessive weight gain, albuminuria & hyperglycaemia

RECOMMENDATION

▪ Antenatal renal anomalies needs appropriate counselling & follow up

▪ Exclusive breastfeeding should be promoted in the first 6 months, andother food sources should be introduced prudently to allow regular &balanced growth

▪ Parents should be counselled regarding avoidance of nephrotoxic agents inchildren with low renal reserve

▪ Children with abnormalities in kidney function or ultrasound should befollowed up by a Pediatric nephrologist when possible

THANK YOU

THANK YOU

PRECIOUS PAIR NEEDS YOUR CARE