Genetic and Epigenetic Kidney Diseases in Children Flashcards
What types of CKD are prevalent in childhood?
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
What are the factors responsible for the true burden of pediatrick CKD?
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
What is the process by which low birth weight and prematurity affects childhood kidney function?
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
How does diabetes and obesity affect vitamin D transfer from mother to child?
decreased transfer in obese, non-diabetic mothers, as measured by cord blood 25-hydroxyvitamin D
What are the consequences of vitamin D deficiency in an infant?
up-regulation of the renin-angiotensin system, predisposing to hypertension and reduced nephron mass additionally
How does childhood obesity/metabolic syndrome affect kidney function?
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
overexpression of fibroblast growth factor 23 (FGF23) and its role in kidney disease
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
What is the earliest sign of most forms of CKD at any age?
albuminuria - especially microalbuminuria
What is currently recommended for screening in adults for early CKD?
detection recommended for adult-based screening for early CKD
What are some associations with low nephron mass in children?
poor intra-uterine nutrition, low birth weight, and prematurity
How does the lack of urine flow affect kidney development?
antimorphogenic - lead to agenesis of the kidney
What is an important protein for the formation of the ureteric bud?
ret
concentration of transcription factors and proteins allow formation of the bud
PAX2 in kidney development
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
How are miRNAs important in kidney development?
loss of miRNA has functional consequences:
- kidney hypoplasia
- cystic ureteric bud (uncommon)
- proteinuria
epithelial morphogenesis
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
cystic kidney definition
3 or more cysts in the kidney
cystogen
an agent capable of inducing renal cyst formation or RCD
multicystic kidney
multiple cystic lesions, most frequently sporadic
can be small, segmental, unilateral, or bilateral
renal adysplasia
findings of either combined renal agenesis and renal dysplasia or a hereditary syndrome occur
renal aplasia
an extreme form of dysplasia, in which a nubbin of dysplastic kidney caps a normal or an abnormal ureter
epigenetic factors leading to pediatric CKD
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
How does cystic disease predict onset of ESRD?
much faster onset
likely due to an associated lack of nephrons
What are the developmental alterations arising form vitamin D deficiency?
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
renal dysplasia
abnormal metabephric differentiation diagnosed histologically
can be diffuse, segmental, or focal
Barker hypothesis
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
How does hypertension affect nephron numbers in patients?
decreased nephron number in patients with higher blood pressure
invasion of the metanephric mesenchyme by the urogenital bud
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
What is the adult phenotype of unrecognized childhood CKD?
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
