312 Pediatric Nephrology

hydration these retun to normal. "The diagnosis is confirned by failure of the

or administration
urinary osmolality to rise following either water deprivation
of desmopressin (DDAVP) (see Chapter 2). 'The period of water deprivation
should not exceed 4-hr in infants and 7 to 8 hr In older children, following
should exceed
which, in normal children, the ratio ofurine to plasma osmolality
1.5. In patients with NDI, the urine osmolality does not rise above 200 mOsm/
6-hr following administration
kg, and urine output is not reduced during the
of 10 to 20 ug of intranasal DDVAP.

Treatment
A large intake of water is necessary to compensate for the urinary losses,
but dificult to ensure in infants. The parents need clear instructions to
that effect. Restriction of dietary sodium to 1 mEq/kg/day will reduce the
osmolar load and the need for associated water excretion. A low protein diet,
recommended for the same purpose, is notadvised since it may interfere with
growth. Administration of hydrochlorothiazide at a dose of 2 to 3 mg/kg/day,
when combined with sodium restriction, can lead to a significant reduction
of urine volume. Amiloride at 20 mg/1.73 m/day has an additive effect, since
both agents have different sites of action in the tubule (the former in the early
distal tubule and the latter in the cortical and medullary collecting duct).
Combination of the two agents also reduces the risk of hypokalemia.
Diureticsincrease sodium excretion resulting in contraction ofextracellular
sodium content that leads to an increase in proximal tubular reabsorption
of sodium and water. Thiazides probably also increase expression of the
AQP2 protein. Chronic thiazide therapy is associated with dyslipidemia,
hyperglycemia and hyperuricemia. Younger children tolerate indomethacin (2
mg/kg/day) better than amiloride, but its prolonged use is not recommended
since it may reduce GFR and cause gastrointestinal side effects. Future therapies
for NDI focus on enabling trafficking of functional AVPR2/AQP2 protein
trapped in endoplasmic reticulum to the site of their action, through chemical
or pharmacological chaperones.

Key points: Nephrogenic diabetes insipidus

Tubular unresponsiveness to ADH results in hyposthenuria and polyuria
Polydipsia, dehydration, fever and hypernatremia are common featuress
Administration of vasopressin does not lead to increase of urine osmolality over that
of plasma
Treatment is with sodium restriction and use of hydrochlorothiazide.

Bartter Syndrome
Bartter symdrome is a rare disorder characterized by
hypokalemia, metabolic
alkalosis, hyperreninemia, hyperaldosteronism, normal blood pressure and
urinary wasting of K, Na' and Cr.
Urinary prostaglandin (PGE2) levels are
elevated. While the disorder is uncommon, the diagnosis is often missed.
Children present in infancy with polyuria, polydipsia,
vomiting, constipaton
 Tubular Disorders 313

and failure to thrive. Recurrent episodes of debydration, muscle weaknessand

cramps are prominent in older children. The blood pressure is low normal for
age. Laboratory findings inctude severe hypokalemia(serum K' 1.5-2.5 mEq/L),
hypochloremia and metatbolic alkalosis. Urinary chloride concentration is
usualy more than 20 to 30 mEq/1.. Hyperuricemia and hyponatremia may
be present. The urinary fractional excretion of K', Na' and CI is increased.
Urinary calcium excretion is normal or high. Renal biopsy shows hyperplasia
of the juxtaglomerular appardtus.

Etiology
The molecular basis of Bartter syndrome is an inability to reabsorb chloride
and sodium in the thick part of the ascending limb of loop of lienle due to
defects in ion transporters (Table 15.5 and Plg. 15.7). Increased delivery
of sodium chloride to distal parts of the nephron leads to salt wasting,
hypokalemia, polyuria, volume contraction and stimulation of the renin-
angiotensin-aldosterone axis. While urinary sodium is recovered by an increase
mediated activity of the epithelial sodium channel, loss of
in aldosterone
chloride with ammonium or potassium results in hypochloremic metabolic
alkalosis and hypokalemia. Hypokalemia, volume contraction and elevated
angiotensin increase intrarenal prostaglandin E2 synthesis, which stimulates
the renin-angiotensin-aldosterone axis.

Presentation and Classification

Several subtypes of Bartter syndrome are now recognized (Table 15.5) that differ
from each other in the underlying defect, age of onset, severity of symptoms,
presence of urinary concentrating defect, other electrolyte abnormalities
including hypomagnesemia) and magnitude of urinary calcium excretion.
Defects in sodium chloride reabsorption bythe furosemide-sensitive sodium-
potassium-chloride co-transporter (NKCC2, type 1) or return of potassium to
the tubular lumen by the renal outer medullary potassium channel (ROMK,
type ) often present antenatally with polyhydramnios and severe neonatal
manifestations. Since potassium recycling also drives paracellular calcium and
magnesium reabsorption, these patients have significant hypermagnesiuria
and hypercalciuria. Newborns with Bartter syndrome type II may present withh
transient hyperkalemia due to impaired potassium secretion in the cortical
collecting duct.
Type III or classic Bartter syndrome, caused by impaired cellular exit of
chloride in the thick ascending limb through the basolateral chloride channel
CIc-Kb, typically has milder phenotype, possibly since cellular exit of chloride
through other channels, e.g, CIC-Ka, continues to occur. Sensorineural
deafness may be associated in subtype IV, caused by defective expression of
the chloride channel CIC-Ka or the barttin subunit of CIC-K, since complexes
of CIC-Ka/CIC-Kb and barttin are critical for potassium recycling in the inner
ear. Unlike subtypesI-V that are autosomal recessive conditions, subtype Vis
 TABLE 15.5: Tubular disorders with
hypokalemic metabolic alkalosis and normal or low blood pressure
Disorder Protein Gene, location Inheritance Presentation
Location
Bartter syndrome
Type 1 (antenatal BS) Bumetanide sensitive
Luminal membrane of SLC12A1;
sodium potassium chloride thick limb Autosomal Antenatal; polyhydramnios, prematurity. failure
ascending 15q15-q21.1 recessive to thrive, hypokalemic metabolic alkaiosis.
cotransporter-2 (NKCC2) (TAL) (AR) nephrocalcinosis
Type 2 (antenatal BS) Inwardly rectifying renal KCNJE; 11q24 AR
Luminal membrane
of TAL and cortical
Antenatal; polyhydramnios, prematurity.failure to
outer medullary potassium thrive,transient neonatal hyperkalemia:
channel (Kir1.1 or ROMK1) collecting duct nephrocalcinosis
Type 3 (classic BS) Chloride channel, kidney,B Basolateral membrane CLCNKB;1p36 AR Growth retardation, hypochloremic hypokalemic
(CIC-Ka) of TAL and distal metabolic alkalosis, less/no hypercalciuria. no
collecting duct (DCT) nephrocalcinosis, hypomagnesemia
4 beta subunit of Basolateral membrane BSND AR Antenatal; polyhydramnios, prematurity
Type
with sensorineural
4A: Barttin,
(antenatal BS chloride channel, kidney
of thin ascending limb, deletion, 1p31
deafness) (CIC-K) TAL and DCT
polyuria, hypokalemic merabolic alkalcsis:
sensorineural deafness; transient hypercalciuria. no
48:Chloridee channel, kidney, Basolateral membrane AR nephrocalcinosis; mild hypomagnesemia, chronic
A (CIC-Ka)
CLCNKA kidney disease
ofthinascending limb CLCNKB; 1p36
and TAL
Type 5 Calcium sensing receptor Basolateral membrane CASR Autosomal Hypokalemic metabolic alkalosis, hypocalcemia
(CaSR) of TAL (activating dominant hypercalciuria, low parathormone.
mutation); nephrocalcinosis, hypomagnesemia
3q13
Gitelman syndrome Thiazide sensitive sodium Luminal membrane SLC12A3; AR Hypokalemic metabolic alikalosis, hypecalciuria.
chloride cotransporter of DCT 16q13 hypomagnesemia, chondrocaicinosis
EAST/SeSAME Inwardly rectifying Basolateral membrane KCNJ10;1q23 AR Hypokaiemic metabolic alkalosis, hypocaiciura,
syndrome potassium channel Kir4.1 of DCT and cortical hypomagnesemia, epilepsy, ataxia, mentai
collecting duct retardation,sensorineural deafness
mental retardation and eecroyte mpalane
EASTepilepsy.ataxia,sensorineuraldeafnessandsalt-wastingtubulopathy:SseSAME seliaures,sensorineural deafness ataxia
 Tubular Disorders 3 1 5

Type I NKcc2 3 Na
Furosemide . Na'K' AT Pas0
2K'
CIC-Kb, Type l1, V8
CC-Ka

Bartin Type VA
Type l ROMK
....... CaSR
TypeV
Claudin 16/19 -
Ca Mg
Tubular lumen Voltage Interstitial nuid
-30 mV Voltage 0 mV
voltage-10 mv

Fig. 15.7: Mechanism of absorption of sodium and chloride ions in thick ascending limb of
loop of Henle. Transepithelial sodium chloride absorption is facilitated through coordinated
activity of the apical furosemide-sensitive sodium (Na") potassium (K) chloride (C)
cotransporter (NKCC2), renal outer membrane potassium (ROMK) channel, basolateral Na/
K-ATPase and basolateral Clc-Kb in the thick ascending limb and distal convoluted tubule)
or Cic-Ka (in the thin and thick ascending limbs). While the NKCC2 is the predominant
channel for sodium chloide reabsorption, the luminal exit of potassium through apical
ROMK channels is essential to replenish urinary potassium to ensure activity of the NKCC2
along the thick ascending limb, and provides the driving force for paracellular absorption of
calcium and magnesium. The exit of chloride from the basolateral side is mediated through
C- channels CIC-Ka and ClC-Kb that require a functioning beta subunit called barttin for
their proper membrane localization. The calcium sensing receptor (CaSR) inhibits ROMK
and NKCC2 activity, thus affecting salt reabsorption. Patients ith Bartter syndrome have
defective transepithelial transport of Na" and Cr due to a variety of defects in transport of
these ions, as depicted in textboxes and Table 15.5

inherited in an autosomal dominant manner, with gain in function mutation

mediating of basolateral calcium sensing receptor that
inCASR activation the
and leads
inhibits potassium recycling to hypocalcemic hypercalciuria with
low PTH levels.

Differential Diagnosis
Patients with Bartter syndrome are differentiated from those with nonrenal
causes of chloride loss, eg, chronic vomiting, chloride diarrhea, laxative abuse,
dietary deficiency and cystic fibrosis. In these conditions the urinary chloride
is <10 mq/L. Bartter syndrome types 1, II and V may cause
concentration
maternal polyhydramnios and preterm labor. The diagnosis is suggested by
high amniotic fluid chloride, postnatal polyuria (>15 mL/kg/day), low urine
osmolality (<300 mOsm/kg) and increased urinary PGE2. Hypercalciuria and
nephrocalcinosis are seen in types I and II but absent in type IV. Neonates
with defect in the ROMK channel (type 1) presenting with hyperkalemia
316 Pediatric Nephrolo9y

as mineralocorticoid deficiency or
and hypoatremia may be misdiagnosed
P'olyuria caused by nephrogenic diabetes
pseudohypoaldosteronism type I. with the EAST
insipidus is not associated with hyponatremla. Patlents
syndrome have severe neurologlcal features (Table 15.5).
(Tables 15.5 and
in patients wlth Gitelman syndrone
The presentation that However, the former
15.6) resemble
may for classic Bartter syndrome.
and low to normal
with metabolic alkalosis,
has milder renal salt wasting
chloride levels, hypokalemia, hypomagnesmia
and hypocalciuria. Fractional
before and after
excretion of chloride, reflecting distal chloride reabsorption,
saline diuresis, may
adminístration of a thiazide diuretic or during hypotonic
Bartter
syndrome.
from those with classic
not reliably distinguish these patients in the distal tubule include
salt transport
Other causes of dysfunction of
sarcoidosis, Kearns Sayre syndrome
and
Sjogren syndrome, Dent disease,
or cytotoxic drugs
aminoglycosides, prostaglandins
cystinosis, and therapywith the metabolic
Chronic administration diuretics may mimic
of
abnomalities
(eg,cisplatin).seen with Bartter or Gitelman syndromes.

Management
Bartter syndrome is directed towards replacing losses, by luid,
Therapy in treatment
supplementation. The usual
sodium, potassium and chloride and administration
consists ofpotassium supplements (1-3 mEq/kg/day)
decrease the
of indomethacin (2-3 mg/kg/day)>Cyclooxygenase inhibitors
for fever and contribute to
elevated prostaglndins that are responsible
concomitant inhibition
Salt and water
supplements alone without
polyuria. doesnot improve and may aggravate salt and water
of prostaglandin synthesis
wasting in antenatal forms of Bartter syndrome. While ibuprofen (30 mg/
Side effects
kg/day) has similar effects, indomethacin is used more widely.
of indomethacin include vomiting, abdominal pain, peptic ulcer and renah
decrease in polyuria and'
toxicity. Treatment results in clinical improvement, to above 3.5
improved growth; serum potassium levels often do not incre
mEq/L. Angiotensin converting enzyme inhibitors, receptorblockers or renin
inhibitors have been used to aid potassium retention and decrease proteinuria,
a few.
a Tatecomplication.Magnesiumsupplements might be required in
Outcomes
Growth failure and recurrent dehydration with dyselectrolytemia are
common. In contrast to Bartter types I and II which are most severe during
the perinatal period and show improved growth with aggressive therapy
patients with classic and type IV disorders may worsen in adulthood. Prolonged
use of prostaglandin synthesis inhibitors can be associated with increased
gastrointestinal intolerance. Patients with chronic volume contraction and
those with type IV disease are at risk of chronic kidney disease. Hypokalemia
and hypomagnesemia predispose to cardiac
arrhythmias and QT prolongation
 Tubular Disorders 3 1 7

Key polnts: Bartter syndrome

Clinical features include faiure to thrive, polyuria aned polyedipsia
Metabolic alkalosis, hypokalemla, hyponatremia and increased urinary chloride loss
are characteristic
.In the infantlle form, bypercalclurla and nephrocaleinosis are seen; fetal polyuria may

cause polyhydramntos
.Treatment consists of potasslum supplementation and use of indonethacin.

DISORDERS WITH RENAL MAGNESIUM WASTING

Magnesium is a major cation whose deficlency manifests as enhanced
neuromuscular excitability (tetany, carpopedal spasms), hypocalcemia and
cardiac arrhythmías. Magnesium homeostasis depends on the balance between
intestinal uptake and renal excretion. Intestinal absorption involves active
transcellular transport, mediated by the channcls transient receptor potential
melastatin related type 6 (TRPM6) or 1TRPM7, and a passive paracellular
pathway. Only 15 percent of filtered Mg" is absorbed proximally; 70 percent
in the thick ascending limb and 15 percent in the distal convoluted tubule,
leaving 3 to 5 percent to be excreted in the urine. In the thick ascending limb,
passive paracellular reabsorption of magnesium is mediated by claudin-16 and
on of sodium mediated
-19 (Fig.15.7), and depends the active reabsorption
by NKCC, recycling of potassium into the lumen via ROMK, and effux of
sodium and chloride via the Na'K"-ATPase and CIC-K, respectively. The Ca
sensing receptor (CaSR) inhibits ROMK and prevents paracellular Ca" and
Mg* reabsorption. In the distal convoluted tubule, Mg* is absorbed by active
transport through TRPM6, the activity ofwhich is influenced by its intracellular
concentration, pH and other factors (Fig. 15.8).

Etiology
Hypomagnesemia is commonly the result of poor enteral intake and
malabsorption, but may be secondary to renal wasting in acquired tubular
diseases (chronic pyelonephritis, interstitial nephritis, postobstructive
diuresis, acute tubular necrosis) or occur as an adverse eftect of therapy
with osmotic or thiazide diuretics, cisplatin, carboplatin, calcineurin
inhibitors or aminoglycosides. Magnesium wasting may also be seen in
patients with Gitelman syndrome, EAST syndrome and classic and antenatal
Bartter syndrome with sensorineural deafness. Disorders associated with
hypomagnesemia and hypermagnesuria are summarized in Table 15.6.

Gitelman Syndrome
Gitelman syndrome, also known as familial hypokalemic hypomagnesemia,
is a rare autosomal recessive salt-lQsing tubulopathy characterized by
hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. The
únderlying mechanism is a defect in the apical thiazide-sensitive, sodium
the listaltuhule. and biochemical
chloride cotransporter(NcCT)in Clinical
318 Pediatric Nephrology

Hypormagnesemin
Na TA
TAL)
(ype 8)
Renal cysts and
Gitelman Na diabetes syndrome
syndromo NCCT Isolated dorninant
Thiazldes HNF-1 3Nn7 Na'
ATPase ypon ernta
ucleus
Ma
wiI semia TRPMG EASTISeSAME
Kira 4.1
(DCT, GCD) synoreme
hypocalcemia Acidosis
(type 1) Tacrolimu8
CIC-Kb
Barlin
TRPV5- Isolated recessive

Hypomagesemia EGF+hypormagnesemia
(ype 4)
with myokymia |KVI.T R

Cetuxima0
EGFK78-estradio
Claudin-1619 (TAL) Ca Mg
FHHNC (pes 3.5) Vollage Interstiial fuid
-30 mV voltage mV
Tubular y
VoItage-10 mV

Fig. 15.8: Absorption of sodium, chloride and magnesium ions in the distal convoluted

tubule (DCT). Transepithelial sodium chloride absorption is mediated by the electroneutral

thiazide-sensitive sodium chloride co-transporter (NCCT) with basolateral exit via the Na"7
K-ATPase and CIC-Kb/barttin. Unlike the thick ascending limb (TALI, there is no active
participation in luminal transport of potassium; however, the Kir4.1 channel in the basolateral
membrane allows for recycling of potassium ions entering the tubular cells and counters
movement of the extruded sodium. More distal parts of the DCT express the epithelial
sodium channel (ENaC) as the main pathway for apical sodium reabsorption. Reabsorption of
magnesium and calcium in the DCT is active and transcelular in nature, consisting of uptake
through selective ion channels (TRPM6 and TRPVS, respectively), unlike in the TAL, where
the passive paracellular absorption of these cations through the
claudin 16 and 19 channels
is influenced by ROMK and CaSR channel activity (Figure 15.7). CcD cortical collecting duct;
EAST syndrome epilepsy ataxia sensorineural deafness and tubulopathy: EGF epidermal
growth factor, EGF-R EGF receptor FHHNC familial hypomagnesemia with hypercalciuria
and nephrocalcinosis

manifestations mimic classic Bartter syndrome, including metabolic alkalosis

and hypomagnesemia. However, the symptoms are generally milder and
LuSually appearin olderschoolgoing childrenandadults. Variability is reported
in age at
presentation, severity of symptoms and biochemical abnormalities.
Patients may be detected following the incidental finding of hypokalemia, or
when evaluated for growth retardation,
constipation or enuresis. There are
episodes of muscular weakness, cramps and fatigue, vomiting, abdominal
pain and tetany; polyuria and growth retardation are mild.
Urinary calcium excretion is low, due to increase in paracellular calcium
reabsorption in the
proximal tubule (parallel to sodium
secondary to volume depletion). Features in Gitelman reabsorption,
thiazide
administration, including normal or low syndrome mimic chronc
metabolic acidosis, bloodpressure, hypokalemi
hypomagnesemia and hypocalciuria. The combinano
 Contd...
Disorder Protein Location Gene, Locus Inneriturice Presentarron
Renal DCI
hypomagnesemia with Potassium channel Kv1.1 KCNA1;12p13 AD Episodic progressive ataxia, myokymia
myokymia recurrent cramps; tetany
Renal cysts and diabetes AR
Hepatocyte nuclear factor 1 DCT,CCD HNF1B;17q12 Maturity onset diabetes; hypocalciuria,
syndrome
hypermagnesuria; cystic dysplasia,
glomerulocystic kidney disease
DCT Mitochondrial coded Maternal
Hypomagnesemia and metabolic Mitochondrial-coded tRNA
syndrome isoleucine) isoleucine t-RNA
Hypomagnesemia,hypercholesterolemia
hypertension
(MTT)
AD hypoparathyroidism (Bartter Calcium magnesium sensing TAL, DCT AD Onset in childhcod; sezures,
syndrome type 5)
ctivating mutation of
receptor (CasR) CASR;3q13 carpopedal spasms; hypocalcemia.
nypomagnesemia; low PIH
Gitelman syndrome Thiazide sensitive sodium DCT SLC12A3,16q13 AR Hypokalemic metabolic alkalosis,
chloride cotransporter hypocalciuria, hypomagnesemia,
(NCCT) chondrocalcinosis
EAST/SeSAME syndrome Potassium channel Kir4.1 DCT KCNJ10;1q23 AR Hypomagnesemia. hypocalciuria,
epilepsy, ataxia, sensorineural deafness
and tuculopatny
AD,autosomal dominant; AR, autosomal recessive; CCD, cortical collecting duct; DCT, distal convoluted tubule; TAL, thick ascending limb.
 Tubular Disorders 321

hypocalcluria
ofBarter with renalmagnesium wasting distinguishes Citelrman from
syndrome and imost magnesium losing states (Tables 15.5 and 15.6).
Hypomagnesemia with hypokalemia confers a high risk of cardiac
arrhythmias in patients with Gitelman syndrome. Treatment is with orai
supplementation of potasslum and magnesiun.

EAST Syndrome
Mutations in the gene KCNJ10 encoding the K' channel Kir4.I cause a rare
autosomal recessive disorder characterized by epilepsy, ataxia,sensorineural
deafness tubulopathy,
and salt-wasting termed EAST or SeSAME (seizures,
sensorineural deafness, ataxia, mental retardation, and clectrolyte
imbalance)
syndrome. KNCJ1O(Kir4.1) is expressed in the brain, inner ear, eye and kidneys.
The renal salt wasting is caused by transport defects in the distal convoluted
tubule where KCNJ10 plays an important role as a basolateral K" channel
(Fig. 15.8), with K* recycling across the basolateral membrane enabling
normal activity of Na-K"-ATPase. Renal abnormalities mimic findings in
Gitelman syndrome, including urinary Na" loss, activation of renin angiotensin
aldosterone axis, hypokalemic metabolic alkalosis, hypomagnesemia and
hypocalciuria.
HYPOKALEMIC METABOLIC
ALKALOSIS AND HYPERTENSION
Hypertension in childhood may rarely be secondary to single gerne mutations,
inherited in an autosomal dominant or recessive fashion, that lead to increased
epithelial sodium or chloride reabsorption, high urinary potassium secretion,
suppression of plasma renin activity (PRA) and/or excessive mineralocorticoid
action with hypokalemic metabolic alkalosis (Table 15.7 and Fig. 15.9).
Findings that prompt the consideration of these entities include family history
of childhood onset hypertension, abnormal potassium levels (low or high),
metabolic alkalosis or acidosis and suppressed renin secretion. Hypertension
may be mild and electrolyte abnormalities subtle or lacking. The electrolyte
abnormalities are distinguished from Bartter and Gitelmansyndrome byelevated
blood pressure, euvolemia and decreased levels of plasma renin activity.
The monogenic disorders grouped under'mineralocorticoid hypertension
include: () increased production of aldosterone (glucocorticoid remediable
aldosteronism, familial hyperaldosteronism, familial glucocorticoid
resistance); (ü) increased production of otherhormones with mineralocorticOld
action (two forms of congenital adrenal hyperplasia); (ii)
pre-receptor
disorder with loss of selectivity of the mineralocorticoid receptor (apparent

mineralocorticoid excess); (iv) receptor disorder with constitutive activation

of the mineralocorticoid receptor (Geller syndrome); and (w) post-receptor
disorder with enhanced function of the epithelial sodium channel (Liddle
syndrome). Except for conditions included in (i) above, where plasma levels
of aldosterone are high and PRA low, all other conditions are characterized by
low plasma aldosterone and PRA.
5 1 6 Pediatric Nephrology

Dlsorder
Functional Volding
Key points: tractinlections, enuresis with
in case
Voiding disorder is suspected of recurrent urinary
vesicoureteric reflux
and persistent small frequer
daytime symptoms time symptoms, holding maneuvers,
Nocturnal enuresis with day b l a d d e r neck on MCI
residtue and elongation o
voiding pattern, insignificant
postvoicd
indicates detrusor overactivity bladder with postvoid urine i
recurrent UTI, infrequent
voicding, large
Straining, McU on suBEests dystunctional voiding
bladder
VUR and a spinning top
absence of bladder
sphincter dyssynergla detrusor overactivity, bladder sphincter
with possible
studies characterize and identily
Urodynamic underactive bladder
dyssynergia and the and clean
medications, bladler retraining intermittent
Judicious use anticholinergic
of
catheterization are useful in management

ENURESIS
Enuresis is a common problem often causing
considerable distress to the
as normal, nearly complete, evacuation of
child and his family. It is defined
time at least twice a month after
the fifth year
the bladder at a wrong place and
of life. As a rule the bed will be soaking wet as against incontinence, which is
the bladder. Hence enuresis is to
loss of urine without normal emptying of
be differentiated from continuous or intermittent incontinence or dribbling.
but that of continuous or daytime
The c a u s e of enuresis is always functional,
incontinence is usually organic.
Bladder control is usually attained between the ages of one and five years.
diurnal and nocturnal control
More than85 percent children will have complete
15 of children gain continence at a
by five years of age. The remaining percent
rate of approximately 15 percent per year and by adolescence 0.5 to 1 percent
children continue to have enuresis. Up to the eleventh year, enuresis is twice
as common in boys as it is in girls; thereafter the incidence is similar or slighty
higher in girls.

Classification
Enuresis is primary when the child has never been dry and secondary when
bedwetting starts after a minimum period of six months of dryness at night.
It is termed monosymptomatic if it is not accompanied by any lower urinary
tract symptoms. This differentiation helps determine the need for extensive
evaluation. Children with uncomplicated enuresis require no further
evaluation. The importance lies in differentiating primary monosymptomat
nocturnal enuresis from the more complex voiding disorder presenting wt
daytime intermittent incontinence.

Etiology
There is no single definite underlyingg cause for enuresis; the condition ma
be multifactorial. Attempts to identify the possible cause in a patient can heip
translate into therapeutic options.
 Disorders of Micturition 5 1 7

Maturational Delay

a i e is the
most likely cause of nocturnal enuresis since spontaneous cure
sincrease with age and the sequence to dryness mimics the pattern
rates

normal children. The developnent of fine and gross notor skils

s e e n

take a
to reach specific milestones and have
may be delayed. Boys onger
reater incidence of enuresis. The second to fifth years are a sensitive time
r development of nocturnal bladder control and episodes causing anxiety
at a later time may result
uring this period, increase the risk of enuresis, Stress
in s e c o n d a r y e n u r e s i s .

Genetics
The likelihood of a child having nocturnal enuresis is 40 percent if one parent

and 70 percent it both parents had enuresis. Nocturnal enuresis has been
linked to at least 8, 12, 13, and 22. ENURI gene is identified
four chromosomes
the long arm of chromosome 13. The mode of inheritance appears to be
on
autosomal dominant with reduced penetrance, modulated by other genes
It helps to ask the parents the age at which they
and environmental factors.
attained continence.

Sleep Factors
Alack ofinadequate arousal is believed to impair vasopressin secretion leading
to polyuria. Enuretic children are deep sleepers
and "wake up" signals from
and
the full bladder in these children, may switch deep sleep to only light sleep
not to a complete arousal. Obstructive sleep apnea may be an additional risk
factor in obese children with primary monosymptomatic enuresis.

Antidiuretic Hormone
Antidiuretic hormone has a circadian rhythm, with increased secretion
Alack
occurring during the night and peaksecretion between 4 a.m. and 8 a.m.
of this circadian rhythm or impaired response of the kidneys to antidiuretic
may be a possible etiology for nocturnal enuresis.

Bladder Capacity
The balance between bladder capacity and nocturnal urine production may
be the ultimate determinant of whether or not an enuresis will ocur. The
functional capacity, i.e. the volume of urine that the bladder can hold when
awake or asleep, may be reduced in children with enuresis.This is determined
as the largest volume voided after measuring each void for 3 consecutive days
and is compared to the estimated bladder capacity (based on age).

Investigations
Le
SS than 5percent ofchildren with nocturnal enuresis have an organic basis.
Theseie aare with no
children with a normal urinary stream daytime symptoms
5 1 8 Pediatric Nephrology
to good histo
However it is important elicit a
disorder. with uncomplicate
suggestive ofa voiding examination, children
an initial can heln
on
and A
Based history evaluation. simple questionnaire disorder
no further an underlyingvoiding
enuresis require of
features suggestive n e e d to be referred to the
with
evaluate patients symptoms may
A child with
daytime monosymptomatic enuresis Cann
(Table 24.6). whereasa
child with
pediatric nephrologist
c a r e physician. in all
be treated by the primary and for glucosuria
children.
infection
to out
rule anomalies and also
Urinalysis is done underlying renal
Abdominal ultrasonography
helps exclude relevant
Indian children who may
residue. This is in
look
for a significant postvoid USGorsubscquent evaluation followinga urinary
antenatal excludes a n
not have had either an examination
anatomical
tract infection. Clinical
and neurological alone may not bring out
incontinence. Often history
cause for
continent child
and the pediatrician needs
or neurological the older
the daytime symptoms in for daytime voiding
as described (Table
24.3) to look
to add the voiding diary three days with a record
maintained for two to
abnormalities. The voiding diary voiding disorder
is useful to rule out a possible
of daytime accidents or wetting, in patients with suspected
Additional procedures such as the
MCU should be done
study is not indicated since
neurological or urological dysfunction. Urodynamic enuresis.
it offers little in the management
of patients with uncomplicated

Treatment
to the
enuresis prevents psychological damage
Timely t r e a t m e n t ofnocturnal
No therapeutic plan is ideal for all
childad provides relief to the family. single
ABLE 24.6: Checklist for enuresis
bladder dysfunction*
Symptoms suggestive of underlying
of urine in the underpants or underpants soaking wet
Leakage of urine during the day: drops
Intermittent or continuous leakage every day
History of daytime incontinence after 3% years of age
Urinary frequency (number of voids) (<3 or >8/day)
Urgency
Holding maneuvers observed
Child observed to be pushing to pass urine
Interrupted urinary stream, or several small volume voids
History of urinary tract infections or malformations of kidneys, urinary tract or spinal cord

Bowel habits*
Constipation with/without fecal soiling of underpants

Psychological, behavioral or psychiatric problems

Evidence of attention deficit hyperactivity disorder, autism
History of motor and/or learning disabilities or delayed development

Drinking habits
Drinking excess fluids as observed by caretakers
Drinks more fluids in the evening
Drinks fluids during the night
*Children with any of these signs or symptoms should be evaluated for a underlying functiona
voiding disorder
518 Pediatric Nephrology
elicit a good histo
disorder. However
it is important to story.
suggestive ofa voiding with uncomplicated
and initial examination, children
Based on history an
A simple questionnaire heln
can
further evaluation.
enuresis require no
voiding disorder
evaluate patients with
features suggestive of a n underlying
need to be referred to the
(Table 24.6). A child with daytime symptoms may
monosymptomatic enuresis can
whereas a child with
pediatric nephrologist
be treated by the primary
care physiclan.
infection and for glucosuria in all children.
Urinalysis is done to rule out anomalies and also
Abdominal ultrasonography underlyingrenal
helps excludeis relevant in Indian children who may
This
look for a significant postvoid residue.
antenatal USGor subsequent evaluation followinga urinary
nothave had either an examination excludes an anatomical
tract infection. Clinical and neurological
for incontinence. Often history alone may not bring out
or neurological cause
continent child and the pediatrician needs
the daytinme symptoms in the older
to add the voiding diary as described (Table 24.3) to look for daytime voiding
to three days with a record
abnormalities. The voiding diary maintained for two
disorder.
accidents or wetting, is useful to rule outa possible voiding
of daytime
Additional procedures such as the MCU should be done in patients with suspected

neurological or Urodynamic study is not indicated since

urological dysfunction.
it offers little in the management of patients with uncomplicated enuresis.

Treatment

Timely treatment of nocturnal enuresis prevents psychological damage to the

childsad provides relief to the family. No single therapeutic plan is ideal for all

TABLE 24.6: Checklistfor enuresis

Symptoms suggestive of underlying bladder dysfunction*
Leakage of urine during the day: drops of urine in the underpants or underpants soaking wet
Intermittent or continuous leakage every day
History of daytime incontinence after 3% years of age
Urinary frequency (number of voids) (<3 or >8/day)
Urgency
Holding maneuvers observed
Child observed to be pushing to pass urine
Interrupted urinary stream, or several small volume voids
History of urinary tract infections or malformations of kidneys, urinary tract or spinal cord
Bowel habits*
Constipation with/without fecal soiling of underpants
Psychological, behavioral or psychiatric problems
Evidence of attention deficit hyperactivity disorder, autism
History of motor and/or learning disabilities or delayed development
Drinking habits
Drinking excess fluids as observed by caretakers
Drinks more fluids in the evening

Drinks fluids during the night

Children with any of these signs or symptoms should be
voiding disorder
evaluated for a
underlying functiona
 Disorders of Micturition 519
Assessing the level of motivation of the
pat nd the choice of treatment is patient and his parents prior
to important. The decision about when to
is
start treatment guided by
the degree of
concern and the
motivation on
of the child rather than the parents. part
o
ere is little objective evidence that fluids in the evening, random
kening of the child tovoid or punitivewithholding
measures result in cesation of enuresis.
aw r Caffeinated drinks like tea, coffee and
sodas should be avoided in the
ng, Adequate fluid intake
during the day as 40 in the morning, 40
is recommended. Various
entin the afternoon and 20 percent in the eveningpercent
dalities oftreatment are available for the treatmentof enuresis. The final choice
af the modality of treatment is best left to the child and parent.

Motivational Therapy
The success of any form of therapy depends to a large extent on the child
being motivated to work towards sleeping dry. He is reassured and provided
is easier a of bed weting in the parent has
emotional support. ihis if history
been forthcoming. Every attemptismade to remove any feeling of guilt. The
benign nature of the disorder is explained to the child and parents. The child
should be encouraged for total involvement in the therapy with maintenance
of a dry night diary. Dry nights merit praise and encouraging words from
the parents. Twenty five percent of children may be cured with appropriate
motivational therapy alone.

Behavioral Modification
Behavioral therapy is the achievement of good bladder and bowel habits. The
child should be encouraged both to void frequently enough to avoid urgency
and daytime incontinence and to have a daily bowel movement. Behavioral
and a pediatrician with
therapy requires a supportive parent, a motivated child,
and avoiding daytime urgency
patience and time. Frequent relaxed voiding
helps. A note to the school teacher may be required to permit the child to use
the toilet frequently if required.

Alarms
of
nis involves the alarm device to elicit a conditioned response
use of an
Gradually the association with
Wakening to the sensation of a full bladder. a small
The alarm device consists of
daaer distention evokes micturition. or a mat under the bed-sheet and an
sor attached to the child's underwear, at the bedside. When
the child
tattached to the child's collar or placed alarm to ring. The
the activated causing the
s e n s o r s are
a etung the bed, term success. A third
months for better long
sed continuously for six well to
ofch therapy; these respond
thus treated mayrelapse on stopping
the en These alarm systems are nowavailable n
thne treatment as given initially. wake the child
the clock may be used to
however the ordinary alarm the bladder is full.
when
up OLY"*S
on at a critical time
to void in the toilet
OWn,
520 Pediatric Nephrology

Pharmacotherapy
treatment of nocturnal
A number of medications are used in the en
should be continued for 2 weeks i s
(Table 24.7). Therapy with these
It should be continued for thre
assessing and adjusting the dose.
six monthsefficacy
and then gradually weaned over three to four weeks. Relapse
if the drug is withdrawn abrunes
are high after stopping therapy especially
of the hormone vasopressin, acte
Desmopressin (DDAVP), an analog
a volume less
reducing the urine output to than the functional bladder capaci
Administration of DDAVP an hour before bedtime is particularly useful
patients showing high nocturnal urine production or a less concentrated
urine prior to therapy. It is useful when used in conjunction with the alarm, n
non-responders the intranasal spray dose may be increased to 40 ug/dayin a
stepwise manner. The wafer thin lyophylisate preparation is easy to administer
with a quick onset of action. DDAVP should ideally be continued until 28
consecutive dry nights have been achieved and then tapered gradually every
week over a three-week period. DDAVP reduces wet nights significantly but

TABLE 24.7: Medications for enuresis

Medication Dose DurationAge Side effects Precautions
(action) or use group

Desmopressin; Tablet 0.1-0.2 4weeks Any Hyponatremia, Limitfluid intake

(vasopressin mg/d dry; taper nasal 1 h before
analog, ADH Nasal spray 3 --4
from
Over medication until
tu fhness,
action) 10-40 ug/d weeks headache next morning
Oral lyophilisate epistaxis,
60-240 ug/d
Given 1-hr before
abdomina
pain, nausea
bedtime
Oxybutynin 5-20 mg/d in 3-6 >6 yrDry mouth, Adequate oral
(anticholinergic) divided doses months
fiushing, fluids, prevent
palpitations, constipation
constipation,
blurred vision

Tolterodine 1-2 mg/d in 1-2 3-6 5 yr Same as

(anticholinergic) divided doses months
Given 1-hr before oxybutynin;
less intense
bedtime

Imipramine 25-50 mg/d 3- >7 yr

(antidepressant, Given 1-hr before months, Anxiety, mood Use in selected
anticholinergic) bedtime disturbances, patients onlyi
Taper ECG done to rule
personality
change, out long Q2
palpitations

Doxazosin 0.5-1 mg/d 3-6 >6 yr Headache,

(alpha blocker) Blood pressure
months
fatigue, monitoring
dizziness,
hypotension
 Disorders of Micturition
521
of
rates are high on discontinuation
reless.headache and when usedtherapy.
Side efects inchude nasal
as an
sue are abdominal palnepistaxls
and nausea. intranasal spray. Other side
High fluid
Cwication characterized by lhyponatremia and intake might lead to water
The spray
administered under the supervision to preventseizures.
rose, or intentional overdose children sheould
from accidental
dose taken In the
dry nights. enthusiasm of achieving
Oral desmopressin may be used as an to the nasal
spray. The
a
at dose of0.2
to
nreparation isto given an nour belore bedtimealternative
0.6 mg daily achieve and continued for at mg increasing
dry nights least eight weeks,. The
a
orallyophilisate preparation is now available in India and can be given in dose
of 60-240 Ag/day. Ihe efficacy of DDAVP is sustained
use without affecing
throughout long-term
treatment interruptions
hematologY, biochemistry or blood pressure. Regular
a
are, however, recommended. The medication is most
uSeful when child needs to attend a
embarrassed by a wet bed.
camp or have a stay-over and may get
Anticholinergic drugs (oxybutynin) reduce uninhibited bladder contractions
and are useful in children who manifest
urgency with incontinence during the
daytime. It is preferably used above 6 years of age and the dose is increased in
a stepwise fashion to a maximum of20 mg per day. Oxybutinin maybe used as
an adjunct to the alarm or treatment with desmopressin, when either of them
fails as single therapy. Side effects include dryness of mouth, facial flushing,
palpitations and blurring of vision. Side effects are less with tolterodine, which
is well tolerated. It is effective and safe when administered in a dose of 1 mg
rwice a day for children aged 5 to 10 years. Single daily dose of 2 to 4 mg has
good compliance and minimal side effects.
Tricyclic antidepressants like imipramine alter the arousal-sleep
mechanisms and exert some anticholinergic effects. The drug is not
recommended for use in children younger than 7 years, and used selectively
because of side effects of anxiety, personality change and palpitations. The
current recommendation is to us it only as third-line therapy, when all
other therapeutic options have failed. Reboxetine, a noradrenaline-reuptake
inhibitor, is pharmacologically related to imipramine without apparent
cardiovascular toxicity, but its role is not defined.
be required when the
and those
Psychotherapy including emotional support mayin adolescents
lamily history reveals psychosocial stress especially
of on various
final outcome therapy depends
wth complicated enuresis. The the alarm device has better
short-term results but
actors. DDAVP has better
to desmopressin produce less
ng-term outcome. Thus, children who respond have smaller bladder capacities.
who
Oncentrated urine than nonresponders child needs to remain
best used under special situations, eg, if the
Is a friend's
Wnen camping out or staying over at place and in children with
cost and safety are considered,
rnal polyuria. If long-term efficacy, enuresis and a voiding
are superior. In patients with
duisalarms by reducing urinary
ounction DDAVP can enhance the effect of oxybutynin
522 Pediatric Nephrology
output and bladder filling, thus reducing uninhibited bladder contractin
other
The various treatment modalities available are not exclusive of each or
hould
lorm of therapy sho
combination
better. F'ailure
works one ot
and often a The model
or addition ofanother. three system viz.,
result in substitution with
release nocturnal polyuria, oxybutynie
ynin
vasopressin
desmopressin for low the alarm
and
bladder retraining for the overactive bladder
along with satisfactory. A combination of one
arousability from sleejp is usually
R e a s s u r a n c e of the child for dirers
enhance is ideal.
of these with motivational therapy the outcome.
Which modality to off
involvement in the therapy improves
the following categories:
the child in o n e ot
first c a n be guided by classifying the night and normal bladder
a normal urine output
during
Children with with a n adjunct
of desmopressin if
can be given the alarm,
capacity
required. bladder age willlikely be
Children with smaller than expected
capacity for
sensitive to the alarm. They also benefit
desmopressin-resistant and more
with use of anticholinergic agents.
normal bladder capacity respond
Children with nocturnal polyuria and
well to desmopressin.
Children with both excessive urine output and reduced bladder capacityy
with desmopressin
a combined therapy of alarm or anticholinergic
may find
useful.

Key points: Nocturnal enuresis

to prevent psychological effects
Enuresis is a benign condition, yet requires treatment
on the child and relief to the parents
Etiological factors include heredity, maturational delay, decreased bladder capacity,
to ADH
response
altered sleep rhythm or blunted
nocturnal enuresis does not require extensive evaluation
Primary monosymptomatic
Motivation and behavioral modification with the use of alarm devices are extremely

satisfactory a
Mesmopressin and anticholinergic medications have place in the treatment

LoWER URINARY TRACT SYMPTOMS

This generally represents a voiding disorder and lower urinary tract (LUT)
symptoms include increased voiding frequency, daytime incontinence,
urgency, hesitancy, straining,weak stream,intermittency,holdingmaneuvers,
a feeling ofincomplete emptying, postmicturitiondribble and genital or LUT
pain. It is managed with the combination of increased fluid intake, 2-hourly
bladder emptying and oxybutynin depending upon the underlying bladder
abnormality determined by urodynamic studies. This regimen should be
continued till intervals between bladder emptying can be increased to 3 to 4 hr.
Once the
child remains normal for three to six months, oxybutynin is tapered
Patients
over several weeks and then discontinued. with encopresis or stool
retention are administered a mild laxative to produce one soft bowel movement
per day. The treatment may be combined with DDAVP, or the enuresis alarm
to improve night-time continence, once the
daytime problem improves.
 Disorders of Micturition 523
INCONTINENCE

r a s the cause ior enuresis is functlonal, continuous incontinence or

Wh is most often due to either an anatomic or a
n A child with enuresis voíds to completlonanonaly neurogenic
intermittently, but the
e with incontinence is always wet due to constant dribbling. 'This is often
mpanied with excoriation of the pcrincal skin and a uriniferous odor to
dhe clothing. A detailed history will differentiate enuresis from incontinence.

Anatomical Causes

Exstrophy of the bladder, epispadias and urethral trauma are obvious causes
for incontinence. Ectopic ureters, urogenital sinus anomalies and posterior
urethral valves require appropriate imaging and a cystoscopic evaluation.
At times obese girls using western style toilets may not part their thighs
adequately and show incontinence on standing due to vaginal pooling, termed
vaginal voiding" Vaginal voiding and urethral diverticula are a cause for
pseudoincontinence. Evaluation for anatomical causes ofincontinenceinvolves
detailed history including previous medical and surgical treatment. A thorough
perineal, genital and rectal examination is important. Imaging, including MR
urography, may help diagnose a n ectopic ureter (Fig. 24.7). Surgical treatment
in many cases.
may be required

Neurogenic Bladder
Children with spinal dysraphism, spinal trauma, tumors or degenerative
disorders of the spine may develop a neurogenic bladder and are at risk for

besides incontinence. They form

renal damage having socially unacceptable
a distinct subset requiring treatment and long-term follow-up. The lesion may

a dysplastic kidney
Fig MR urography showing right ectopic ureter with
5 2 4 Pediatric Nephrology

meningomyelocele.
The bladder inner
closed open or
be obvious as in a autonomic neuronn
bifida occulta, sacral agenesis,
be afected in spina trauma. Clinical evaluation indy,
may cord t u m o r s o r
transverse myelitis, spinal attention to
evaluation with special palpation o
a detailed neurological s e n s a t i o n s over the
perineume
as the
tone and gait as well
lower back, anal of the
and
spine and
heel besides abdominal genital exanination. maging
or hydromyelia.
look for a tethered cord, syrinx
MRI are done to

Evaluation
or by means
involvement is ascertained clinically of
Once spinal cord ot the is carried out to
ultrasonography abdomen
radiological imaging, wall thickness, postvoid
bladder capacity and
determine kidney size, urinary dilatation. MCU is carried out to look
residue and evidence of upper tract
scars. If
for vesicoureteric reflux and DMSA
scintigraphy lor renal they are
of a study should
abnormal or if the child has dribbling urine, urodynamic
bladder contractility and external
be promptly carried out and the urinary
studies
sphincter characteristics evaluated. These need be repeated, since to
of lower tract dynamics
bladder dynamicschange with age. Three categories
can occur:
Bladder sphincter dyssynergia with or without detrusor hypertonicity
incontinent bladder
Synergic low pressure
Completely denervated bladder.
evaluation show
Only children with dyssynergia on initial or subsequent
deterioration of the upper tract. Renal function especially concentration and
acidification of urine need monitoring in presence of high pressure bladder
with or without reflux.

Treatment

Management aims at keepingthe patient dry, preventingurinary tract infections

and monitoring closely for upper tract changes and renal insufficiency. A child
with spinal dysraphism is likely to have an elimination disorder affecting
evacuation of both urinary bladder and bowel. Constipation can worsen
bladder function and needs early treatment. Use of laxatives with increase in
dietary roughage may help the child pass one to two semiforned stools per
day. In case of persistence of constipation and/or fecal soiling, daily enema
avoids the need for manual evacuation of the bowel.
Treatment of a neuropathic bladder depends on the characteristics of the
bladder and sphincter on urodynamic studies. In the presence of dribbling
significant postvoid residue or recurrent urinary tract infections the bladder
needs to be emptied. An attempt is made to use the Crede maneuver consisting
of suprapubic massage to cause a reflex bladder contraction. This maneuver
should be avoided in children with a reflux. In case this does not
evacuate
the bladder to completion, clean intermittent catheterization (CIC) shoula
be started. CIC initiated before the first birthday is more acceptable to the
 Disorders of Micturition 525
child and parents. It improves the outcome significantly on long-term studies
and prevents urinary tract infections. It helps in maintaining low intravesical
pressures and keeps the child relatively dry in between catheterizations.
Anticholinergic medications are useful in children with a high pressure
small
volume bladder, especially with superadded detrusor contractions
during the filling phase and alfa sympathomimetic medications help children
with lower motorneuron defects who are not dry between
catheterizations.
However, a denervated atonic sphincter is very difficult to manage and
responds poorly to medications. Antibiotic prophylaxis to prevent urinary tract
infection is recommended before initiation of CIC in children with a dilated
upper tract.
Detrusor hypertonicity or sphincter dyssynergia is associated with
increased risk of a worsening vesicoureteric reflux and or upper tract
deterioration with age. If the filling pressures are greater than 40 cm H,O and
voiding pressures are higher than 80 to 100 cm H0 treatment with oxcybutynin
reduces intravesical pressures. The use of oxybutynin along with CIC to empty
the bladder reduces the reflux and creates a safe bladder. It should be initiated
early when high-grade reflux is noted. Children who cannot empty their bladder
spontaneously need cICirrespective of the grade of reflux. Avesicostomy may
be required in infants whose upper urinary tract drainage fails to improve
1n spite ot antichoinergic medications and CIC. Other form of surgical
intervention include bladder augmentation in case ofa low capacity bladder,
urinary diversion for upper tract deterioration despite conservative measures,
to or reimplantation of
Sphincterotomy reduce bladder outlet obstruction
ureters in presence ofvesicoureteric reflux once the bladder is safe. In children
with difficulty in catheterization a Mitrofanoff conduit using the appendix
is created to enable catheterization through a stoma on the abdominal wall
(Fig. 24.8).

Fig. 24.8: Mitrofanoff conduit for clean intermittent catheterization

 Urinary Tract Infections 281
vUR, UTI and Renal Scarring
Along witlh intrarenal reflux, bacterial virulence and the host inflarnnatory
response influence the scarring process. Severe VUR without urinaryinfection
has experimentally been shown to produce renal scarring, and may be
important in neonates and infants with high intravesical pressure (e.g,
posterior urethral obstruction, neurogenic bladder). However, most reflux
associated scarring is the result of parenchymal infection introduced by
intrarenal reflux.

Diagnosis of VUR
Vesicoureteric reflux is diagnosed and graded on a radiocontrast MCU. A
standard reflux grading system that is widely used is shown in Figure 14.4.
Mild-to-moderate grades (1-111) include increased levels of reflux without
calyceal blunting, while in severe (1v-v) VUR there is marked dilatation and
tortuosity of ureter, gross dilatationofcalyces and intrarenal reflux (Fig, 14.5).
Radionuclide MCU (DRCG), which is more sensitive and has less radiation
exposure than radiocontrast MCU, is preferred for follow-up evaluation.

VUR and Renal Dysplasia

Antenatal ultrasonography often detects hydronephrosis with varying
enlargement of kidney in the fetus. In about 10 to 20 percent of boys with severe
VUR (grade IV-V) the kidneys are smail with smooth outline, without history
of UTI. Such kidneys probably represent renal maldevelopment ocCurring in
utero and show histological evidence of dysplasia. Severe grades of VUR and
renal dysplasia are uncommon in girls.

IV V

Fig.
)SSTS
14.4: Grading of VUR on micturating cystourethrogram.
nondilated distal ureter; grade ll:
ureter: grade ll: Reflux into dilated
Reflux into
ureter; grade
Grade l: Reflux into the
the upper collecting system in nondilated
V: Reflux into grossly dilated ureter; grade V:

Massive reflux with ureteral dilation and tortuosity and effacement of calyceal details
282 Pediatrie Nephrology

Fig. 14.5: Micturating cystourethrogram showing dilation of pelvicalyceal system

and ureter on right side, suggestive of grade VVUR.

Bladder Dysfunction and VUR

Voiding dysfunction is present in a large proportion of children with higher
grades of VUR that persist beyond the age of 2-3 years. Detrusor sphincter
dyssynergia, unstable bladderand dyscoordinated bladder have been observed
in such cases (Chapter 24). Such abnormalities should be
appropriately
managed especially if antireflux surgical procedure is considered.

Familial VUR

Siblings of children with VUR, especially those below

are investigated for reflux. If 18-months-old,
ultrasonographic evaluation shows dilated
pelvicalyceal system, DRCG or MCU is considered.

Resolution of VUR
Primary UR tends to resolve by the age of6 to
likelyto disappear than 10years. Grade I-III VUR is more
grades IV-V, resolution rates being 70 to
and 10 to 35 percent
the
90 pe the
respectively. Moreover, higher the grade of
longer it takes to resolve. vur
Therefore, persistence ofVUR
beyond 12 to 18 monu
 Urinary Tract Infections
283
should not invariably be regarded an indication for surglcal correction. VUR
occurring at all levels of intravesical pressure is less likely to resolve than that
seen only at peak pressures

Management
The management of VUR remains controverslal. Evidence of benefit from
treatingVUR is insufficient and reflux may be self-limiting in some patients.
Some of the renal parcenchymal damage associated with end-stage disease may
be due to congenital dysplasia. The objectlve of treatnent is to prevent renal
scarring from pyelonephrits. The risk ofscarringis highest in young children.
Newscars usually do not develop in children with normal renal scans at 4 to5
Surgical intervention can
years of age. eliminate or reduce the severity of reflux
and thus the likelihood of bacteria reaching the kidney.
Treatment options for vUR include antibiotic prophylaxis ith close
surveillance for UTI, surgical reimplantation and submucosal endoscopic
injection of Deflux. While medical therapy is the first choice in almost all
instances, it is important to consider the age of the patient, grade of refux,
renal function, history of recurrent UTI, presence of bladder dysfunction and
parental preference while deciding therapy. Long term antibiotic prophylaxis,
while awaiting spontaneous resolution of VUR, has been widely employed.
Such treatment prevents bacterial colonization, chiefly by Enterobacteriaceae,
at the urethral orifice thus reduces the incidence of ascending infection.
While antibiotic prophylaxis has been shown to reduce the risk of recurrent
febrile UTI, its efficacy in preventing renal scarring is questionable. In a
large, multicenter study (Randomized Intervention for Vesicoureteral Reflux,
RIVUR) it was found that antibiotic prophylaxis significantly reduced the risk
of recurrent febrile UTI in children with grade I-IV VUR, but the incidence of
renal scarring remained unchanged. Other studies report similar findings and
noted a risk of bacterial resistance with prolonged antibiotic usage.
The guidelines for management of VUR by the Indian Society of Pediatric
Nephrology are outlined in Table 14.5. Patients should initially receive
antibiotic prophylaxis, while awaiting spontaneous resolution of VUR. Close
surveillance for UTI is necessary. With lower grades of reflux prophylaxis may
be stopped after 1-year, and continued til the age of 5-years for those with
grade III-V reflux. Since risk of renal scarring is low after 5-years, antibiotic

VTABLE 14.5: Management of vesicoureteric reflux (VUR)

VUR grade Management
Grades I and II Antibiotic prophylaxis until 1 year old. Restart antibiotic prophylaxis if
breakthrough febrile UT
Grades l toV Antibiotic prophylaxis until 5 year old Consider surgery if breakthrough
febrile UTI
bladder dysfunction
Beyond 5 year: Prophylaxis continued if there is bowel
284 Pediatric Nephrology

bowel
prophylaxis can be
discontinuedil some reinuX persists. ASsociated
even
resolution
should be treated, as it may intertere with
of
bladder dysfunction
Surgical treatment may be
considered
1or patients with grade IIl-V reflux
VUR. lunction.
ol renal
there are recurrent UTI or deterioration
The antbiotic used should be
effective
against colitorm bacteria and achieve
a high urinary concentration with minimal alteration ot bowel flora. The

preterred are nitrofurantoin

agents
and
cotrimoxazole (lable 14.4) and given
as a single bedtime dose. Trimethoprim alone is as e r e c t v e as corimoxazole.

Breakthrough UTI may result from noncompliance or development of bacterial

trimethoprim. Nitrofurantoin may cause nausea and
resistance, mainly to

vomiting that may result in discontinuation ot

therapy in a proportion of
a n d those with
patients. Cephalexin or cefixime is prelerred in young intants
of the enzyme, glucose-6-phosphate-dehydrogenase. Amoxicillin
deficiency
and quinolones are unsuitable for prophylaxis because intestinal colonization
with E. coli resistant to these agents develops rapidiy. Reiniection of the urinary

with resistant bacteria may

tract
then
occur. Breakthrough UrT should be
promptly treated. The child may be trained to void again a few minutes after
initial bladder evacuation (double voiding) so that refluxed urine entering
the bladder is expelled. Regular timed voiding, every 4 to 5 hours, is advised.
Compliance with long-term therapy is crucial.

Key points: Management of VUR

Long-term antibiotic prophylaxis with nitrofurantoin or cotrimoxazole is used to prevent
recurrent UTI
egular urine cultures are not necessary and asymptomatic bacteriuriä is not treated
rophyaxis 15 Continued for 12 to l8 months in patients with grade 1-1I VUR, and up to
5-yr in those
wili higher grades ol reflux
Needfor compliance with long term therapy, surveillance for UTI and long- term follow-
up are explained
Ureteric reimplantation is considered for patients with bilateral grade IV-V VUR with
recurrent symptomatic UTI, or lack of compliance with prophylaxis
Bladder bowel dystuncion should be treated before
surgery
Cortical scarring may progress despite surgical (or spontaneous) resolution of VUR.

Surgical Treatment
Ureteric reimplantation or endoscopic submucosal injection of Detlux
considered for grade IV-VVUR that persists beyond 1 to 2 years. Surgery 1s
be delayed until this age since the chances should
of spontaneous resolutüon are
insignificant and reimplantation of a dilated
infant is ureter into the smallbladder or
an
technically challenging. Surgery
(i) recurrences of UTI while receiving
is also advised in
patients w
medical management; (ui)
prophylaxis; (i) noncompliance w
appearance of new scars or deterioration or
function during medical
therapy; and (iv)
Moderate to severe vUR in adolescent parental preference tor sug
girls may also be considered rot
surgical correction, since VUR is associated with
and
pyelonephritis during pregnancy and adverseasymptomatic bacteriu
fetal outcome.
Urete
 UrlnaryTract Infections285
reimplantation procedures suggested by Lich-Ciregoir, Politano-Leadbetter
and Cohen have been wicdely used with success rates of over 95 percent.
Eindoscoplc injection ofdextranomer/hyaluronic acid copolymer (Deflux)
beneath the intramural segment of ureter has increasingly been used to prevent
VUR. The success of this technique depends upon the grade of reflux, absence
ofbladder dyshunctlon, nound configuratton and surglcal expertise. Although
success rates of 60 to 90 percent are reported, recurrences of VUR may occur
in a significant proportion. 'The results are less satisfactory with higher grades
ofreflux, duplex collecting system, and in patients with dysfunctional voiding
or neuropathic bladder.
Bladder function is evaluated by urodynamic studies before surgery
and high pressure bladder appropriately managed. Chemoprophylaxis is
continued for 6 months after surgery. MCU to document cessation of reflux is
done 3 to 6 months after surgery. Since silent obstruction at the vesicoureteric
junction (and rarely at pelviureteric junction) may develop, ultrasonogaphy
is performed at 6 to 12 month intervals for 5 years.

Monitoring of Course
In asymptomatic patients, urine cultures are not necessary. Asymptomatic
bacteriuria is not treated. However patients with UTI with symptoms should be
promptly managed. Blood pressure, height, weight and serum creatinine level
are recorded every 6 months. Voiding cystography (DRCG or MCU) may be
performed after 2 to 3 years to document resolution ofreflux (Figs 14.6A to C).
Antibiotic prophylaxis can be discontinued after reflux resolves. USG is done
every year to monitor renal growth and cortical scarring. Follow-up DMSA
scans are limited to children having breakthrough UTI. Appearance of new
scars either on US or scintigraphy suggests the need for surgical treatment.

REFLUX NEPHROPATHY
Reflux nephropathy is characterized by gross, focal scarring of renal
parenchyma. The lesions are asymmetric and involve one or both kidneys.

A B

Figs 14.6A to C: Sequential radionuclide cystography in a boy with right vesicoureteric

reflux. Note the significant reflux with dilated ureter and pelvis (A), which has reduced on
repeat studies done after 12 months (B) and 36 months (C)