Genetic and Epigenetic Kidney Diseases in Children

Question 1

What types of CKD are prevalent in childhood?

Answer 1

congenital anomalies of the kidney and urinary tract (CAKUT) - accounts for over 50% of all identified cases

primary glomoerular diseases causing nephrotic syndrome - 20% of cases

Question 2

What are the factors responsible for the true burden of pediatrick CKD?

Answer 2

genetic factors (CAKUT)

pre-natal programming due to sub-optimal maternal nutrition (epigenetics)

maternal obesity leading to vitamin D deficiency in the infant offspring

survival of low-birth weight and premature infants

childhood obesity/metabolic syndrome

survival from acute kidney injury in childhood

increased survival of extra-kidney chronic conditionss

Question 3

What is the process by which low birth weight and prematurity affects childhood kidney function?

Answer 3

prematurity and LBW

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reduced nephron number (oligonephropathy) - from time spent in the ICU

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hyperfiltration and glomerular hypertension

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systemic hypertension and proteinuria

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nephron loss and glomerulosclerosis

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CKD

Question 4

How does diabetes and obesity affect vitamin D transfer from mother to child?

Answer 4

decreased transfer in obese, non-diabetic mothers, as measured by cord blood 25-hydroxyvitamin D

Question 5

What are the consequences of vitamin D deficiency in an infant?

Answer 5

up-regulation of the renin-angiotensin system, predisposing to hypertension and reduced nephron mass additionally

Question 6

How does childhood obesity/metabolic syndrome affect kidney function?

Answer 6

increasing BMI associated with lower GFR

increased renal perfusion/filtration/filtration fraction

increased vasoconstriction and decrease vasodilation

podocyte injury/loss

BGM thickening

endothelial dysfunction

mesangial expansion/matrix deposition

Question 7

overexpression of fibroblast growth factor 23 (FGF23) and its role in kidney disease

Answer 7

increased phosphate excretion

decreased active vitamin D production

increased vitamin D catabolism

LVH and cardiac myocyte toxicity

an a priori predictor of AKI following cardiac bypass surgary

may be an improtant early marker of CKD in this population in follow-up

Question 8

What is the earliest sign of most forms of CKD at any age?

Answer 8

albuminuria - especially microalbuminuria

Question 9

What is currently recommended for screening in adults for early CKD?

Answer 9

detection recommended for adult-based screening for early CKD

Question 10

What are some associations with low nephron mass in children?

Answer 10

poor intra-uterine nutrition, low birth weight, and prematurity

Question 11

How does the lack of urine flow affect kidney development?

Answer 11

antimorphogenic - lead to agenesis of the kidney

Question 12

What is an important protein for the formation of the ureteric bud?

Answer 12

ret

concentration of transcription factors and proteins allow formation of the bud

Question 13

PAX2 in kidney development

Answer 13

critically important for the maintenance of branching morphegenesis

early morphogen that is turned off

too little - hypoplastic kidney and malformed ureter

too much - can promote development of Wilm’s tumor (most common tumor in children) and/or gross dysplasia, multicystic kidney that is completely nonfunctional

Question 14

How are miRNAs important in kidney development?

Answer 14

loss of miRNA has functional consequences:

• kidney hypoplasia
• cystic ureteric bud (uncommon)
• proteinuria

Question 15

epithelial morphogenesis

Answer 15

a process critical to the formation of various organs such as the vasculature, mammary glands, lungs, and kidneys

a simple epithelial tube grows by reiterative branching to form a complex epithelial tree structure

Question 16

cystic kidney definition

Answer 16

3 or more cysts in the kidney

Question 17

cystogen

Answer 17

an agent capable of inducing renal cyst formation or RCD

Question 18

multicystic kidney

Answer 18

multiple cystic lesions, most frequently sporadic

can be small, segmental, unilateral, or bilateral

Question 19

renal adysplasia

Answer 19

findings of either combined renal agenesis and renal dysplasia or a hereditary syndrome occur

Question 20

renal aplasia

Answer 20

an extreme form of dysplasia, in which a nubbin of dysplastic kidney caps a normal or an abnormal ureter

Question 21

epigenetic factors leading to pediatric CKD

Answer 21

maternal low-protein diet

maternal cigarette smoking

alcohol use

steroids

vitamin A deficiency

iron deficiency

high-salt diet

glucocorticoid exposure

NSAIDs

ACEi/ARBs

COX-2 exposure

testosterone

uteroplacentlal insufficiency

Question 22

How does cystic disease predict onset of ESRD?

Answer 22

much faster onset

likely due to an associated lack of nephrons

Question 23

What are the developmental alterations arising form vitamin D deficiency?

Answer 23

adipokines - leads to increased fat

upregulation of RAAS, reduction of vascular development in growing baby and long-term HTN

long-term insulin resistance

upregulation of inflammation and oxidative stress

changes in macrophages that are detrimental - inflammatory

Question 24

renal dysplasia

Answer 24

abnormal metabephric differentiation diagnosed histologically

can be diffuse, segmental, or focal

Question 25

Barker hypothesis

Answer 25

the lower the birthweight, the more likely the kidney is affected long-term

low birth weight associated with proteinuria consistent with the fact that a person is born with lower nephron mass

Question 26

How does hypertension affect nephron numbers in patients?

Answer 26

decreased nephron number in patients with higher blood pressure

Question 27

invasion of the metanephric mesenchyme by the urogenital bud

Answer 27

a fundamental step toward establishing the cytoarchitecture of the kidney and determining the number of nephrons, which from the filtration units of the adult kidney

anomalies in this process account for the majority of all developmental defects affecting the kidneys

Question 28

What is the adult phenotype of unrecognized childhood CKD?

Answer 28

essential hypertension early lin life

metabolic syndrome

young adult CKD with out “discernible” cause

microalbuminuria in the absence of “risk factors”

offspring with recognizable urinary malformation

low birth weight