Introduction to Pediatric Nephrology

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Introduction to Pediatric Nephrology

• 19/11/08

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Kidney ontogenesis

• The embryological development of the kidney is a
  long and continuous process which begins in the
  3rd week and is completed by about 34-35 weeks of
  fetal life.
• Kidney organogenesis is characterised by 3
  distinct and linked stages pronephros,
  mesonephros and metanephros.

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Kidney ontogenesis

• In humans, the first two are transient structures
  with little excretory capacity but they are
  important for the appropriate development of the
  metanephros, which is the direct precursor of the
  adult kidney.

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METANEPHROS

• The final stage of the kidney is the
  differentation of the metanephros and arise from
  the ureteric bud and the metanephric blastema
  (mesenchyme).
• The renal pelvis, major and minor calyces and
  terminal collecting duct are formed by the
  10-13th wks of ges.
• After morphogenesis each kidney contains approx a
  million nephrons.

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Renal development
nefrotomy
aorta
Przednercze
Pronephros
3 t.z.
4-8 t.z.
przewód Wolffa

Mesonephros
Sródnercze
5 t.z.
stek
paczek moczowodowy
Nerka ostateczna
Metanephros
blastema nerki ostatecznej
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Antenatal Period

• The most common cause is physiologic dilation.
• Metanephric urine production begins at 8 weeks,
  even before ureteral canalization is complete.
• Transient obstruction with hydronephrosis occurs.

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Embryology
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MOLECULAR ASPECT

• The development of the metanephric kidney depends
  on inductive interaction between the ureteric bud
  (UB) and the metanephric mesenchyme (MM).
• A large number of genes have been found to be
  crucial during kidney development.

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Nephrons

• In the fetus at 36 weeks gestation there is an
  adult complement of nephrons- approx. one million
• All further growth of the kidney is via
  hyperplasia mainly in the tubules.

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Fetal kidney

• Nephrogenesis is completed between the 28 and
  36th gestational week in the human, the renal
  tissue and particularly the tubular cells
  continue to develop postnatally.
• Several of the major transporters in the tubular
  epithelial cells undergo postnatal maturation

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Fetal kidney

• Outer cortical glomeruli are relatively
  underperfused compared with inner cortical
  glomeruli.
• Following birth, renal perfusion to superficial
  cortical nephrons rises compared with deeper
  glomeruli

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Fetal kidney

• Angiotensin-converting enzyme inhibitors and
  angiotensin-receptor antagonists impair
  nephrogenesis and so are contraindicated in
  pregnancy

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Production of urine

• Production of urine starts at the age of 10-12
  weeks of gestation
• 1. very dilute urine
• 2. small amount of urine
• Fetal urine is a major constituent of amniotic
  fluid and urinary flow rate increases from
  12ml/hr at 32 weeksgestation to 28ml/hr at 40
  weeksgestation.
• Similar increases are described during the
  maturation of premature newborns.

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Glomerular Filtration Rate (GFR)

• Glomerular filtration begins between the 9th and
  12th week of gestation in humans.
• The GFR is relatively low at birth especially in
  the premature infant.
• The values of GFR nearly double between 3 and 7
  days and thereafter GFR continues to increase, by
  1 to 2 yrs of age the GFR is the same as in an
  older child- 80 of mature kidney.

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GFR
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Kidney of newborn

• The kidney of the newborn infant has a limited
  capacity to regulate the excretion of fluid and
  electolytes.
• The high sodium excretion during the first 2 to 3
  weeks often results in a negative sodium balance
  and predisposes to hyponatremia.

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Creatinine Clearance

• Newborn 40-65 ml/min/1.73 m2
• lt40 yrs 97-137 ml/min/1.73 m2

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Creatinine Clearance
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Creatinine Clearance
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Cefotaxime

• Dose 50mg/kg/dose
• 30-36 weeks 0-14 days BD, gt14 days TDS
• 37-44 weeks 0-7 days BD, gt7 days TDS
• gt45 weeks QID
• Renal failure severe renal failure (lt10
  ml/min/1.73 m2) loading dose normal after that
  25mg/kg same frequency

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Ceftriaxone

• Dose 100 mg/kg loading , 80 mg/kg OD
• Renal failure severe renal failure (lt10
  ml/min/1.73 m2) 50mg/kg OD

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Ceftazidime

• Dose 30-50 mg/kg/dose
• 30-36 weeks 0-14 days BD, gt14 days TDS
• 37-44 weeks 0-7 days BD, gt7 days TDS
• gt45 weeks TDS
• Renal failure
• Moderate renal failure (10-50 ml/min/1.73 m2)
  same dose OD
• severe renal failure (lt10 ml/min/1.73 m2)
  ½ dose OD

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AMIKACIN

• lt36 weeks 12 mg/kg/OD
• gt36 weeks 15 mg/kg/od
• In renal failure serum concentration should be
  estimated

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Ampicillin

• Dose 25-50 mg/kg/dose, upto 100 mg also
• 30-36 weeks 0-14 days BD, gt14 days TDS
• 37-44 weeks 0-7 days BD, gt7 days TDS
• gt45 weeks QID
• Renal failure
• Moderate renal failure (10-50 ml/min/1.73 m2)
  same dose 8-12 hrly
• severe renal failure (lt10 ml/min/1.73 m2)
  same dose OD

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MEROPENEM

• 20-40 mg/kg/dose
• 40mg/kg/dose 8hourly in meningitis or pseudomonas
  infection
• Renal failure
• Moderate renal failure (10-50 ml/min/1.73 m2) ½
  dose 12 hrly
• severe renal failure (lt10 ml/min/1.73 m2)
  ½ dose OD

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PIP-TAZO

• 50-100 mg/kg/dose
• 30-36 weeks 0-14 days BD, gt14 days TDS
• 37-44 weeks 0-7 days BD, gt7 days TDS
• gt45 weeks TDS
• Renal failure
• 40-80 ml/min/1.73 m2 6hourly
• 20-40 ml/min/1.73 m2 8 hourly
• lt20 ml/min/1.73 m2 12 hourly

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VANCOMYCIN

• 10-15 mg/kg/dose
• 30-36 weeks 0-14 days BD, gt14 days TDS
• 37-44 weeks 0-14 days BD, gt14 days TDS
• gt45 weeks QID
• Renal failure
• Avoid if possible, In Anuric give 15 mg/kg every
  many days

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Renal failure in the newborn

• Renal failure in the newborn
• severe asphyxia,
• the majority suffered from nonoliguric renal
  failure

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CAKUT

• Congenital
• Anomalies of
• Kidney and
• Urogenital
• Tract

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CAKUT

• Chronic renal failure (children)
• Obstructive nephropathy- 47
• Reflux nephropathy- 18,5
• Hypo/dysplasia 8,7

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RENAL ABNORMALITIES

• Renal agenesis
• bilateral? fetal death- Potter syndrome 14000
  pregnancies
• unilateral? other organ- 12900
  pregnancies abnormalites

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Renal abnormalities
Agenesis Aplasia
Hypoplasia
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RENAL ABNORMALITIES

• Hydronephrosis

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RENAL ABNORMALITIES

• Obstractive uropathy
• a/ ureteropelvic junction obstruction- dilated
  renal pelvis with/ without caliectasis and no
  dilation of the ureter
• b/ ureterovesical junction obstruction
  (megaureter)- pelviectasis and caliectasis with
  significant ureter dilation

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RENAL ABNORMALITIES

• c/ posterior urethral valve
• d/ ureterocele- cystic dilatation of the distal
  ureter that protrudes into the urinary bladder,
  may extend past the bladder into urethra
• e/ ectopic ureters
• f/ constriction (stenosis)of urethra

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Posterior urethral valve
Type I Type II Type III
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Duplication of urinary tract
Ureter Ureter Ureter duplex
fissus
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RENAL ABNORMALITIES

• Vesico- ureteral reflux

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Vesico-ureteral reflux
Frequency of VUR Isolated 1 (0.4-4)
UTI in the past 29-50 Siblings with
VUR 32-45 Mothers with VUR
in the past 60
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Frequency of VUR according to the childs age
Pediatrics 1999, 103,4
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RENAL ABNORMALITIES

• Polycystic kidney
• autosomal dominant p.k.disease
• autosomal recessive p.k. disease

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Kidney ontogenesis
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PRONEPHROS

• Pronephros is a transitory non-functional kidney,
  the first tubules appear the middle of the 3rd
  week and arise from intermediate mesodermal
  cells.
• The pronephric tubules persist for only a short
  time and undergo degeneration by the 5th week.
• At the time the pronephros is degenerating the
  mesonephric tubules and duct are developing.

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Pronephros
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Vesico- ureteral reflux
                                                                                     

• Normal kidney, ureter, and bladder

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Vesico- ureteral reflux
Grade I Vesicoureteral Refluxurine (shown in
blue) refluxes part-way up the ureter
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Vesico- ureteral reflux

• Grade II Vesicoureteral Refluxurine refluxes
  all the way up the ureter

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Vesico- ureteral reflux

• Grade III Vesicoureteral Refluxurine refluxes
  all the way up the ureter with dilatation of the
  ureter and calyces (part of the kidney where
  urine collects)

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Vesico- ureteral reflux

• Grade IV Vesicoureteral Refluxurine refluxes
  all the way up the ureter with marked dilatation
  of the ureter and calyces

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Vesico- ureteral reflux

• Grade V Vesicoureteral Refluxmassive reflux of
  urine up the ureter with marked tortuosity and
  dilatation of the ureter and calyces

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Primary VUR reflux
A - Reflux B Possible reflux C No reflux
1 - odc. sródscienny moczowodu 2 - odc.
podsluzówkowy
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International Classification of VUR
Io IIo IIIo
IVo Vo
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Ureterocoele

• a thin-walled cystic swelling of the lowermost
  part of the ureter in its path through the
  bladder muscle. Ureterocoeles may be either
  intravesical (in which the orifice of the ureter
  and the cyst itself protrude into the bladder
  lumen) or ectopic (in which the ureterocoele is
  in the submucosa of the bladder and some part
  extends into the bladder neck or urethra). A
  ureterocoele is believed to be the result of a
  defect in the muscular coat of the ureter, and
  often a defect in the bladder wall itself.
  Congenital stenosis of the ureteric orifice in
  the bladder wall is thought to give rise to
  ureterocoele, and it is commonly associated with
  ectopic ureters. It is relatively common in both
  children and young adults, and is bilateral in
  approximately 10 of cases. It is more likely to
  occur in females, and is often accompanied by
  other congenital urinary tract anomalies.
  Ureterocoeles which occur on single ureters may
  also be intravesical (formerly referred to as
  simple ureterocoele) or ectopic.

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Theory

• speculative theory by Mackenzie (1996) essential
  hypertension develops in those born with a
  reduced numbers of nephrons congenital
  oligonephropathy.
• Low-birth-weight infants are at particular risk
  for this problem.

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TUBULAR FUNCTION BASIC PRINCIPLES

• Absorption the movement of solute or water from
  tubular lumen to blood, is the predominant
  process in the renal handling of Na, Cl-, H2O,
  HCO3-, glucose, amino acid, protein, PO4, Ca,
  Mg, urea, uric acid and others.
• Secretion the movement of solute from blood or
  cell interior to tubular lumen, is important in
  the renal handling of H, K, NH4, and a number
  of organic acids and bases.

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Proximal Tubule

• absorb the bulk of filtered small solutes . These
  solutes are present in p.t. fluid at the same
  concentration as in plasma.
• Approx. 60 of the filtered Na, Cl-, K, Ca,
  and water and more than 90 of the filtered HCO3-
  are absorbed along the p.t.
• Reabsorbs virtually all the filtered glucose and
  AA by Na-dependent cotransport.
• Phosphate transport is regulated by PTH.
• Secretion (terminal portion of p.t.) organic,
  anions and cations.

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Loop of Henle

• dilution of the urine
• reabsorption of Mg

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Distal Nephron

• distal tubule, connecting tubule, collecting
  tubule
• final adjustments in urine composition, tonicity
  and volume
• aldosterone and vasopressin, regulate acid and
  potassium excretion

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Types of Membrane Transport Mechanisms Used in
the Kidney

• Facilitated or carrier mediated Glucose,
  urea GLUT1 carrier, urea carrier
• Active transport (pumps) Na, K, Ca,
  H Na,K-ATPase, H-ATPase, Ca-ATPase
• Cotransport Cl-, glucose, AA, formate,
  phosphate Na-K-Cl cotransporter
• Countertransport Bicarbonate, H Cl/ HCO3
  exchanger, Na/H antiporter
• Osmosis H2O Water channels (aquaporins)

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Mechanism of Na Absorption

• tubular Na absorption- primary active transport-
  driven by other enzyme Na,K-ATPase- translocates
  Na out of the cells/ K into cells
• the generation of net Na movement from tubular
  lumen to blood is the asymmetrical distribution
  of this enzyme (exclusively present in the
  basolateral membrane- the blood side of all
  nephron segments)

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Na balance

• Immaturity of the tubules in premature infants
  leads to acidosis and salt wasting, which may
  impair growth.
• Premature newborn infants have shifting volume
  and salt balance in the first week of life and
  diuresis experienced by these infants between 24
  and 48hrs of life results from expansion of the
  extracellular space with mobilization of lung
  fluid.
• Term newborn accomplish positive Na balance
  despite a diet low in sodium (breast milk)
• Glucosteroids regulate renal Na excretion for
  only limited periods during maturation.

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Blood pressure and hypertension in the newborn

• no correlation between blood pressure and
  birthweight below 2000g was found
• mechanically ventilated infants and those with
  low Apgar scores have lower blood pressure than
  healthy controls.

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MESONEPHROS

• Mesonephros appears in the 4th week of gestation
  as a more complex structure immediately after the
  involution of the pronephric tubules.
• Mesonephros contains the vesicles -the precursor
  of mesonephric nephron and the mesonephric duct.
  The proximal end of the mesonephric duct forms a
  2-layered cup, Bowmans capsule.

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MESONEPHROS

• The glomerulus is completed after capillaries
  vascularise this primitive Bowmans capsule.
• The mesonephric nephrons are capable of producing
  urine by the 9th weeks of gestation and continue
  to do so until their involution.
• At the mesonephric stage, most cells in this
  organ have involuted by the 11th-12th week as the
  metanephros begins functioning.

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MOLECULAR ASPECT

• A large number of genes have been found to be
  crucial during kidney development.
• These genes encode for transcription factors
  (WT1, Pax2), growth factors (GDNF) and there
  receptors, adhesion molecules.
• Gene Pax2 encodes for a transcription factor
  expressed in the kidney as well as in the optic
  cup, vesicle and other parts of CNS.
• This gene is one of the first expressed during
  kidney ontogenesis in the UB and in the induced
  MM.

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MOLECULAR ASPECT

• A spontaneous Pax2 mutant mouse model revealed
  that the major cause of renal hypoplasia is
  reduced branching of the UB resulting in kidneys
  with fewer nephrons
• (? the number of UB cells undergoing programmed
  cell death during nephrogenesis)
• Pax2 transcription factor Renal-coloboma syn
  10q13
• HNF1? transcription factor renal hypoplasia,
  diabetes 17q21