21  Urologic Aspects of Pediatric Nephrology
Michael C. Braun, MD, and Chester J. Koh, MD
INTRODUCTION
Although many parents and patients consider them to be the same
specialty, pediatric urologists and pediatric nephrologists train through
very different pathways and often provide different viewpoints on
urinary tract abnormalities. This is especially with regard to surgical
and medical management, respectively, of the kidneys and the urinary
tract, where the two specialties are tightly partnered in the treatment
of the anatomic and functional effects of urinary tract malformations
and acquired diseases. This chapter is designed to highlight topics
and viewpoints in pediatric nephrology of which pediatric urologists
should be aware, where the collaborative expertise of pediatric
nephrologists and pediatric urologists is usually needed for optimal
acute and chronic patient care.
RENAL FUNCTION, FLUID, AND ELECTROLYTE
HOMEOSTASIS
Renal Development
Renal morphogenesis is a complex, temporally and spatially regulated
process by which precursor cells develop into a structurally and
functionally normal kidney. Abnormal or dysregulated renal develop-
ment results in a wide range of renal abnormalities collectively known
as congenital anomalies of the kidney and urinary tract (CAKUT)
and that compose the most common cause of end-stage renal
disease (ESRD) in children. In humans, kidney and urinary tract
development begins at approximately 3 weeks’ gestation with the
formation of the initial urinary excretory precursor, the pronephros,
which undergoes complete involution (Combes et al., 2015; Little
et al., 2012; Short and Smyth, 2016). At roughly 4 weeks’ gestation,
the mesonephros forms, followed at 5 weeks by the metanephros.
Unlike the pronephros, the mesonephros is both functional and
integral to the mature urinary tract. In males, residual segments of
the mesonephric duct form the vas deferens, prostate, the seminal
vesicles, as well as part of the epididymis; segments of the mesonephric
tubules form the testicular efferent ductules. In females, the meso-
nephric ducts persist as the epoophoron and paroophoron. The
metanephros, arising from metanephric mesenchyme, forms the
mature nephron segments. In contrast, the ureteric bud gives rise to
the renal collecting duct, the renal pelvis, and the ureters. By 34 to
36 weeks’ gestation, nephrogenesis is complete, and the structural
and functional relationship of each nephron segment is fully devel-
oped. On average, 1 million (range 0.2 to 2.7 million) individual
nephrons in each kidney arise from embryonic precursor cells.
Concurrent with the morphogenesis of the kidney, functional
development of the fetal kidney also progresses with increasing
gestational age. Prenatally, the placenta controls fluid and electrolyte
homeostasis, and the primary function of the fetal kidney is the
production of urine to maintain amniotic fluid volume. In the later
stages of gestation, urine output, tubular function, and glomerular
filtration increase with gestational age.
After birth, the neonatal kidney undergoes physiologic changes
to adapt to the extrauterine environment; rapid changes occur over
the first several weeks and continue until reaching adult levels at 1
to 2 years of life.
Glomerular Filtration Rate
Glomerular filtration rate (GFR) refers to the volume of filtrate formed
by the movement of plasma across the glomerular filtration barrier
per unit of time. GFR is influenced by a number of factors, one of
which is renal blood flow. This relationship between renal blood
flow and GFR is evident as changes in both occur during fetal and
postnatal development (Schell et al., 2014). Prenatally, the percentage
of cardiac output received by the placenta is significantly greater
than the fetal kidney. Postnatally, renal blood flow increases from
3% to 4% of total cardiac output to between 12% to 16% in the
first year of life (Quigley, 2012). The increase in neonatal renal blood
flow is caused by a combination of increased cardiac output and a
marked decrease in renal vascular resistance relative to the increase
in cardiac output. Several factors mediate the decrease in renal vascular
resistance. These include a redistribution of intrarenal blood flow
distribution, with an increase in intrarenal blood flow from the
juxtamedullary glomeruli located in deeper regions of the renal cortex
to glomeruli in the outer renal cortex. Furthermore, the renin-
angiotensin system (RAS) plays an important role regarding changes
in renal blood flow. Increasing levels of angiotensin II increase mean
arterial pressure and vasoconstriction of the renal efferent arteriole,
which in turn increases GFR by increasing glomerular capillary
pressure. Plasma renin, angiotensin II, and angiotensin-converting
enzyme (ACE) levels increase in late gestation and postnatally
are higher in the first 2 weeks of life than in adulthood. Additionally,
prostaglandins and nitric oxide exert vasodilatory effects, lower renal
vascular resistance, and counterbalance the vasoconstrictive effects
of the RAS activation (Gleason, 1987).
Prenatal and neonatal GFR is significantly lower than adult
GFR levels (Schwartz et al., 2009). Because of placental effects,
plasma creatinine concentrations in the first 48 hours after delivery
reflects maternal rather than neonatal renal function. Under normal
circumstances, by 7 days of life, creatinine levels fully reflect neonatal
renal function and are normally less than 0.5 mg/dL in term infants.
Subsequently, GFR doubles in term infants over the first 2 weeks of
life and increases steadily until reaching adult levels by 2 years of age.
Tubular Function
Glomerular filtration is only the first step in the homeostatic processes
required of the kidney. Concurrent with the maturation of GFR,
there are morphologic and physiologic changes, particularly with
respect to the renal tubules, that lead to maturation of the ability
to maintain fluid and electrolyte homeostasis.
Both term and preterm neonates possess a higher total body
water than older children and adults that is as much as 70% to
90% of total body weight (Gattineni and Baum, 2015). Although
neonates have the ability to dilute urine to as low as 50 mOsm/L,
their urinary concentrating ability is limited, thus promoting negative
free water balance. Normal free water loss is as much as 1% to 2%
loss of total body weight per day over the first 5 days of life in term
neonates and even higher in preterm neonates. There are a number
of factors that reduce the ability of the neonatal kidney to generate
a concentrated urine including decreased responsiveness to antidiuretic
hormone (ADH) and immaturity of the renal tubules. The immaturity
of the tubules is both structural and functional. Structurally, the
341
342 PART III  Pediatric Urology
renal tubules increase in length with age, particularly the thick
ascending limb of the loop of Henle. At birth, the activity of the
sodium-potassium ATPase (Na+,K+-ATPase) exchanger, which drives
sodium transport, is low but increases in the immediate neonatal
period, with a peak increase at around 2 to 3 weeks of life. Finally,
there is an increase in the concentration of urea in the medullary
interstitium, which is required for the generation and maintenance
of the countercurrent multiplier that is essential for the formation
of concentrated urine.
Developmental Changes in Glomerular Filtration Rate and
Tubular Function
The maintenance of the balance of sodium is an important function
of the neonatal kidney. The ability of a neonate to conserve sodium
in the first week of life is limited with an ensuing initial negative
sodium balance during the first week of life, which shifts to a positive
sodium balance by 2 to 3 weeks of age. The natriuresis seen during
the first week of life is mediated primarily by increased levels of
atrial natriuretic peptide. The maturational responses to achieve
sodium homeostasis include elongation of the tubular segments,
which creates a larger surface area for reabsorption and upregulation
of the number or activity of transporters in renal tubular cell mem-
branes. Additionally, endocrine and paracrine mechanisms including
the renin-angiotensin-aldosterone system (RAAS), catecholamines,
cortisol, and thyroid hormone drive sodium homeostasis. Elevated
levels of renin and aldosterone stimulate sodium reabsorption in
the proximal tubule, the thick ascending limb of the loop of Henle,
and cortical collecting ducts. Similarly, increased levels of catechol-
amines directly or indirectly through the RAAS pathway stimulate
sodium reabsorption. Furthermore, increases in both cortisol and
thyroid hormone stimulate tubular sodium transporters.
The newborn kidney has a limited capacity to excrete potassium
and tends to have higher serum potassium values than older children.
The limited renal capacity of the neonatal kidney to excrete potassium
is thought to be caused by the reduced number and responsiveness
of the Na+,K+-ATPase exchanger and the potassium transporters in
the distal tubule and cortical collecting ducts. Normally, 65% to 75%
of filtered potassium is passively reabsorbed by the proximal tubule
(Palmer, 2015; Zhou et al., 2004). The remainder of potassium
reabsorption occurs in the thick ascending limb of the loop of Henle
via NKCC2, and much smaller amounts are reabsorbed in the distal
tubule and cortical collecting ducts via the Na+,K+-ATPase exchanger.
Urinary potassium excretion however is predominantly mediated via
the apical renal outer medullary potassium (ROMK) channel of the
cortical collecting ducts. Although the levels of circulating aldosterone
are noted to be higher in neonates, the neonatal kidney has a decreased
responsiveness to aldosterone activation. The postnatal increase in
potassium secretory capacity is largely related to increased activity of
the Na+,K+-ATPase exchanger and an increase in the number of ROMK
channels in the cortical collecting ducts, which in turn increases tubular
responsiveness to aldosterone.
In the neonate, the mechanisms of urinary acidification and
bicarbonate reabsorption are immature, and neonatal serum
bicarbonate levels are lower than that seen in adults. As renal
acidification and bicarbonate reclamation improve over the first 3
to 4 weeks of life, there is a steady rise in net acid excretion and
plasma bicarbonate reabsorption (Quigley et al., 2004). The primary
site of bicarbonate reabsorption is the proximal tubule, where 80%
of filtered bicarbonate is reabsorbed. The sodium-hydrogen exchanger
3 (NHE3) and H+-ATPase, which both secrete H+ into the proximal
tubular lumen, drive HCO3 reabsorption in the proximal tubule.
Carbonic anhydrase IV (CA), which catalyzes the conversion of
secreted H+ and filtered bicarbonate (HCO3) into carbon dioxide
(CO2) and water, are less active in the newborn, limiting the ability
to absorb HCO3 and secrete an acid load. With maturation, the
activity of these mechanisms increases, resulting in a concurrent
increase in serum HCO3 concentration. The final step in urinary
acidification occurs through the secretion of H+ via the apical H+-
ATPase in the cortical collecting ducts. Maturational increases in the
activity of this transporter is essential to acid-base homeostasis. A
critical factor affecting this process is the postnatal increase in glu-
cocorticoid production, which has been shown to promote an increase
in the number of NH3 antiporters, which are essential for ammonia
generation.
At birth, neonatal serum levels of calcium are higher than
those seen in adults (Schell-Feith et al., 2010). There is a fall in
serum calcium levels in the first day of life. The maturation of renal
tubular calcium regulation is not fully understood. Although there
is a rise in serum parathyroid hormone (PTH) levels associated with
the falling calcium levels, neonates are typically in negative calcium
balance marked by relative hypercalciuria. It is likely that neonates
have a blunted response to the effects of PTH either directly or
indirectly, which limits proximal tubule calcium reabsorption through
both paracellular and transcellular pathways and calcium reabsorption
in the distal tubule by the TRPV6 channel. Neonates have a much
higher renal reabsorption of phosphate compared with adults. Renal
tubular reabsorption of phosphate can be as high as 99% immediately
after birth and remain greater than 90% during the neonatal period
(Kaskal et al., 1988). The reabsorption of phosphorus is mediated
largely via the tubular transporters, such as the 2Na-Pi IIc antiporter,
which are more active in the immature kidney. As circulating levels
and tubular responses to PTH increase after birth, the level of
phosphorus reabsorption falls as the kidney matures.
KEY POINTS
• CAKUT is the most common cause of ESRD in children.
• Prenatal and neonatal GFR is significantly lower than adult
GFR levels.
• The maintenance of the balance of sodium is an important
function of the neonatal kidney.
• The newborn kidney has a limited capacity to excrete
potassium and tends to have higher serum potassium
values than in older children.
HEMATURIA (MICROSCOPIC AND GROSS)
Hematuria is one of the most common reasons for referral to pediatric
nephrologists and urologists. Hematuria can present as either gross
hematuria with red or “tea-colored” urine, or microscopic hematuria
with yellow urine with a positive dipstick for blood. Microscopic
hematuria is defined as clear yellow urine with a positive urine
dipstick for blood with greater than five red blood cells per high-power
field in a freshly spun urine sample. Isolated microscopic hematuria
is reported to occur in approximately 1% of school-age children
(Dodge et al., 1976; Vehaskari et al., 1979). Less than 25% of these
children will have hematuria on repeated testing, and most will
have spontaneous resolution of hematuria within 1 year of pre-
sentation. The incidence of gross hematuria is difficult to ascertain,
however, it is estimated to account for slightly more than 0.1% of
pediatric emergency room visits. Although isolated microscopic
hematuria is most commonly a benign condition, the differential
diagnosis is quite broad, and a definitive diagnosis is determined
in less than 30% of patients. Gross hematuria typically prompts
more urgent referral and evaluation, and in the majority of cases,
an underlying diagnosis can be made.
A detailed history should be obtained to determine if the hematuria
is painless, intermittent or persistent, and microscopic or gross.
Associated symptoms should be sought including a history of trauma,
abdominal pain, fever, dysuria, voiding dysfunction, rash, joint pain,
weight gain, swelling, exercise, headaches, or visual changes. A detailed
family history should also be obtained with a focus on hematuria,
bleeding disorders, hearing loss, urolithiasis, sickle cell disease, and
renal disease. Vital signs including blood pressure should be carefully
measured. A thorough physical examination should be performed,
with particular attention to blood pressure, rashes, joint abnormalities,
edema, abdominal or flank pain, abdominal masses, and perineal
abnormalities.
The critical step in the evaluation of hematuria is the examination
of a freshly voided urine sample that includes microscopic assessment.

Grossly bloody or red urine is indicative of nonglomerular bleeding,
and brown or “tea-colored” urine is suggestive of a glomerular origin
of the hematuria. In all patients with gross hematuria, urine
microscopy is essential to confirm the presence of red blood cells
(RBCs). The absence of RBCs in grossly bloody urine with a positive
urine dipstick for heme is strongly suggestive of hemoglobinuria
or myoglobinuria. The urine sediment should be examined closely
for the presence of crystals, which are suggestive of urolithiasis, and
the presence of white blood cells or bacteria are suggestive of urinary
tract infection. A semiquantitative assessment of RBC number should
be done, including RBC morphology, as uniformly normal RBC
morphology is suggestive of lower urinary tract bleeding, and dys-
morphic or “crenallated” RBCs are suggestive of glomerular disease.
Urine sediment should be carefully examined for the presence of
RBC casts, which define glomerular nephritis. In patients with
suspected glomerular disease, a quantitative assessment of proteinuria
should be performed. Based on the history, physical findings, and
complete assessment of the urine, a logical and structured evaluation
can be performed.
Patients with findings suggestive of glomerular disease, pro-
teinuria, hypertension, edema, or evidence of systemic disease
should have a baseline evaluation of their renal function, serum
electrolytes, complete blood counts, serum albumin, complement
C3 and C4 levels, and ASO or anti-DNase B titers. Referral to a
pediatric nephrologist is often warranted. Renal cysts, most commonly
in polycystic kidney disease, can also present with gross hematuria.
Patients with fever, abdominal pain, dysuria, or frequency should
have urine cultures done as urinary tract infections are the most
common cause of gross hematuria in children. A history of trauma,
abdominal or flank pain associated with gross hematuria often
accompanied with frank clots should prompt urologic evaluation,
and imaging by computed tomography (CT) is often warranted. In
patients with a family history of urolithiasis, gross hematuria,
abdominal or flank pain, and a history of passing gravel, imaging
such as renal ultrasonography or CT should be done and also may
include a comprehensive evaluation for renal stones. Other rare
causes include urinary obstruction, tumors, coagulopathies, and
vascular malformations.
The causes of hematuria in children are numerous (Box 21.1),
and the assessment of children with microscopic hematuria is based
on associated history and physical features combined with urinary
findings. In patients with an unremarkable history including family
history and who are asymptomatic and have only isolated microscopic
hematuria without proteinuria, the evaluation can be limited to
testing the parents for hematuria and measurement of urinary calcium
excretion. The value of urinary tract imaging in children with
microscopic hematuria is controversial. The yield of routine ultra-
sonography is low, and reported findings are frequently of little
clinical significance. When microscopic hematuria persists for several
months, decisions on the need for urinary tract imaging should be
based on associated clinical findings. Voiding cystourethrograms
and cystoscopy are rarely helpful and are not indicated for the routine
evaluation of children with isolated microscopic hematuria. In patients
with a positive family history, personal history, abnormal physical
findings, or urinary findings in addition to hematuria, a more
comprehensive evaluation is recommended. Typically this would
include a complete blood count, serum electrolytes, creatinine,
albumin, C3, C4, ASO titer, antinuclear antibody (ANA) testing,
and a quantitative measurement of urinary protein excretion.
Additional testing such as hearing screening, hemoglobin electro-
phoresis, imaging, and genetic testing should be individualized.
PROTEINURIA
Proteinuria is another common finding that prompts referral to a
pediatric subspecialist. It is important to recognize that urine
contains protein under physiologic conditions and that children
excrete urine free of protein frequently when evaluated by the
semiquantitative dipstick method. Urinary protein excretion varies
by body mass and renal maturity. A normal urine protein-to-creatinine
Chapter 21  Urologic Aspects of Pediatric Nephrology 343
BOX 21.1  Causes of Hematuria in Children
MACROSCOPIC
Transient
Hypercalciuria/nephrolithiasis
Glomerulonephritis (all types)
Cystitis
Exercise
Congenital anomalies of the urinary tract
Benign urethrorrhagia
Wilms tumor or bladder tumor
Bleeding dyscrasia
Renal vein thrombosis
Papillary necrosis
Nutcracker syndrome
MICROSCOPIC
Transient
Hypercalciuria/nephrolithiasis
Glomerulonephritis (all types)
Cystitis/pyelonephritis
Exercise
Congenital anomalies of the urinary tract
Thin basement membrane disease
Drugs
Interstitial nephritis
Sickle cell disease/trait
KEY POINTS
• Isolated microscopic hematuria is reported to occur in
approximately 1% of school-age children.
• Most children with microscopic hematuria will have
spontaneous resolution within 1 year of presentation.
• Gross hematuria and a urinalysis with no RBCs and a
positive heme dipstick is strongly suggestive of
hemoglobinuria or myoglobinuria.
ratio in a newborn is less than 0.7 mg/mg, and less than 0.2 mg/
mg in older children. If a timed collection is obtained, physiologic
urinary protein excretion is typically less than 4 mg/m2/h. Healthy
adolescents and adults excrete less than 150 mg of protein in a
24-hour period. Urinary protein consists of both filtered plasma
proteins and secreted tubular proteins. Although most filtered proteins
are of low molecular weight, albumin accounts for nearly 30% of
the total protein found in “normal” urine.
Proteinuria is categorized as either transient, orthostatic, or fixed
(Box 21.2) (Hogg et al., 2000; Vehaskari and Rapola, 1982). Transient
proteinuria is characterized by disappearance of proteinuria after
a positive test and accounts for more than 75% of patients with
isolated proteinuria. Typically, transient proteinuria occurs in
association with fever or exercise. In an otherwise healthy child,
transient proteinuria is a benign condition. Orthostatic proteinuria
commonly occurs in adolescents and is defined as proteinuria only
when the patient is in an upright position. Patients are otherwise
healthy and do not have other evidence of renal disease. A diagnosis
of orthostatic proteinuria is made by the measurement of urinary
protein in the first-void urine and in a second sample after the patient
has been upright for several hours (Abitbol et al., 1990). In orthostatic
proteinuria, the initial first-void urine sample has normal protein
values (protein-to-creatinine ratio <0.2 mg/mg), and the upright
urine has increased levels of urine protein. Orthostatic proteinuria is
usually transient and benign in nature; however patients should be
closely evaluated to confirm that they are otherwise asymptomatic and
344 PART III  Pediatric Urology
BOX 21.2  Causes of Proteinuria
Transient
Exercise
Fever
Stress/illness
Orthostatic
Fixed
Drugs (chemotherapy, aminoglycosides, heavy metal
intoxication)
Tubular disease (acute tubular necrosis, interstitial nephritis,
cystic kidney diseases, Fanconi syndrome, graft-versus-
host disease)
Reflux nephropathy
Glomerulonephritis: acute and chronic, all forms, including
minimal change nephrotic syndrome
Other chronic renal disease (obstructive uropathy, congenital
renal dysplasia, permanent residual dysfunction from
acute disease [e.g., cortical necrosis, hemolytic uremic
syndrome, glomerulonephritis])
Diabetes mellitus
Protein overload syndromes (hemolysis, rhabdomyolysis,
hypergammaglobulinemia)
have normal renal function and blood pressure. It is recommended
that patients with orthostatic proteinuria be followed annually to
ensure that there is no progression in their clinical findings. Fixed
proteinuria is persistent and not dependent on postural changes.
Protein excretion should be quantified either by a timed collection
if possible or by first-void urine protein-to-creatinine ratio. Fixed
proteinuria requires a more thorough evaluation.
The differential diagnosis of proteinuria is quite broad, and the
evaluation of patients with persistent proteinuria should be focused
on identifying the underlying etiology of the proteinuria. It is essential
to obtain a complete and thorough history and physical examination
including a comprehensive family history with attention to family
members with autoimmune disease, renal disease, diabetes, and
ESRD. Associated symptoms should be sought including a history
of fever, gross hematuria, excessive urinary foaming, growth failure,
rash, joint pain, weight gain, swelling, headaches, or visual changes.
Vital signs including blood pressure should be carefully measured.
A thorough physical examination should be performed with particular
attention to blood pressure, rashes, joint abnormalities, and edema.
Laboratory investigation should be tailored to findings on the history
and physical examination, but often include measurement of serum
creatinine, albumin, electrolytes, complete blood count, cholesterol,
and triglycerides. If the patient has evidence of systemic disease
or glomerular nephritis, testing should include C3, C4, and ANA
screening. Further diagnostic testing will be dependent on the results
of these screening tests. If the screening studies are normal and the
patient has persistent proteinuria, renal biopsy may be warranted
to determine the underlying diagnosis.
KEY POINTS
• It is important to recognize that urine contains protein
under physiologic conditions and especially with fever and
exercise.
• Transient proteinuria accounts for more than 75% of
patients with isolated proteinuria.
• If a patient with proteinuria has evidence of systemic
disease or glomerular nephritis, testing should include C3,
C4, and ANA screening.
BOX 21.3  Common Age Ranges for Presentation of
Glomerular Diseases
YOUNGER THAN 1 YEAR OF AGE
Congenital infections
Diffuse mesangial sclerosis
Genetic diseases:
Congenital nephrotic syndrome (CNS) and infantile nephrotic
syndrome
Denys-Drash and Frasier syndromes
1 TO 10 YEARS OF AGE
Acute poststreptococcal glomerulonephritis (GN)
Minimal change nephrotic syndrome (MCNS)
Focal segmental glomerulosclerosis (FSGS)
Henoch-Schönlein purpura (HSP)
Hemolytic uremic syndrome (HUS)
7 YEARS OF AGE AND OLDER
Systemic lupus erythematosus (SLE)
Systemic vasculitis
Idiopathic crescentic GN
Membranoproliferative GN (MPGN)
Immunoglobulin A nephropathy
Idiopathic and secondary FSGS
Membranous nephropathy (MN)
Alport syndrome
Nail-patella syndrome
Pulmonary-renal syndromes (Goodpasture syndrome
[antiglomerular basement memebrane disease])
GLOMERULAR DISEASE
Glomerular diseases in children have several etiologies, and they
commonly present in specific age ranges (Box 21.3).
Nephrotic Syndrome
Nephrotic syndrome is a constellation of clinical findings common
to a number of glomerular diseases. These features include proteinuria
greater than 40 mg/m2/h or a urinary protein-to-creatinine ratio
greater than 2.0 mg/mg, hypoalbuminemia, and hyperlipidemia.
The reason for the increased hepatic production of lipoproteins
during the nephrotic state is not entirely understood, but it appears
to be associated with low plasma oncotic pressure and alterations
in lipoprotein metabolism. Although nephrotic syndrome may
present as a feature of glomerular nephritis, it presents more
commonly in children in isolation.
Nephrotic syndrome of childhood has been divided into three
broad groups: congenital/infantile, primary (inherited or idiopathic),
and secondary. Approximately 10% of children have an identifiable
secondary cause of nephrotic syndrome. The histologic lesions that are
associated with secondary causes of nephrotic syndrome are frequently
indistinguishable from the idiopathic lesions, but the treatment is
targeted to the primary underlying cause in these cases. Over the past
two decades, mutations in nearly 30 genes have been identified in
either inherited or sporadic primary nephrotic syndrome.
Primary nephrotic syndrome is the occurrence of the constellation
of clinical findings that define NS in the absence of an identifiable
causative agent or disease. Primary NS is classified into four categories
based on histologic findings: minimal change nephrotic syndrome
(MCNS), mesangial proliferation (MES), focal segmental glomeru-
losclerosis (FSGS), and membranous nephropathy (MN). Nephrotic
syndrome is classified by responsiveness to steroid therapy and
histopathologic features if a biopsy is performed.

Steroid-sensitive nephrotic syndrome (SSNS) typically presents
with dependent edema with variable swelling of the eyelids, scrotum,
and labia. Hypertension is not typical. Microscopic hematuria is
seen in approximately 20% of patients. Macroscopic hematuria is
unusual.
Corticosteroids will induce a remission in the vast majority
of children with nephrotic syndrome. Therefore, for those with a
typical clinical presentation, a kidney biopsy is not indicated before
initiating steroid therapy. Atypical features that may require a kidney
biopsy before treatment include age younger than 1 year at presenta-
tion, macroscopic hematuria, hypertension, hypocomplementemia,
and extrarenal symptoms such as a rash or arthritis.
Edema is mild in most patients and can be managed with dietary
restriction (Teoh et al., 2015). The current standard of care is to treat
these children with corticosteroids. Most children receive initial
treatment with prednisone (60 mg/m2/day or 2 mg/kg/day). The
current definition of steroid responsiveness is a resolution of pro-
teinuria within 8 weeks of starting steroid therapy. Once the urine
become negative for protein, the prednisone is switched to alternate
days and tapered over 6 weeks or longer. Almost 50% of children
with SSNS will experience multiple relapses (Teeninga et al., 2012).
Frequently-relapsing nephrotic syndrome (FRNS) is defined as
two or more relapses within 6 months of initial response to steroid
therapy or four or more relapses within any 12-month period. In
this setting, the potential adverse effects of the cumulative steroid
doses required to achieve sustained remission begin to exceed the
benefits of maintaining nephrotic syndrome remission. Steroid-
sparing strategies have also been developed to treat FRNS including
alkylating agents such as oral cyclophosphamide, mycophenolate
mofetil (MMF), B-cell depletion with rituximab, and calcineurin
inhibitors (CNIs).
Steroid-dependent nephrotic syndrome (SDNS) is defined when
a child with NS develops two consecutive relapses during steroid
therapy or when the ability to achieve and/or remain in remission
from nephrotic syndrome requires continuous administration of
corticosteroids. Steroid-sparing strategies in this population include
low-dose alternative-day corticosteroids, MMF, B-cell depletion with
rituximab, and CNIs. Children with SDNS tend not to respond as
well to alkylating agents as the FRNS subgroup.
Steroid-resistant nephrotic syndrome (SRNS) is seen in 15%
to 20% of children with idiopathic NS and in a small subset of
patients who were initially steroid responsive. It is defined as a
failure to achieve remission after 6 to 8 weeks of full-dose daily
prednisone. A biopsy is often recommended for steroid-resistant
patients before initiating alternative therapies as there is a much
higher prevalence of FSGS in this subset of patients (Lovric et al.,
2015). A wide range of therapies has been utilized in patients with
SRNS, with varying degrees of efficacy including intravenous pulse
steroids, combined treatment with high-dose corticosteroids and
alkylating agents, and cyclosporine or tacrolimus (Büscher et al.,
2016). Patients who achieve remission with CNIs are reported to
have a high frequency of relapse when these agents are discontinued.
Patients who are refractory to steroids and CNIs rarely respond to
other therapies.
Congenital nephrotic syndrome (CNS) is defined as nephrotic
syndrome presenting within 3 months after birth. CNS can be caused
by either genetic defects or perinatal infections. Proteinuria often
begins in utero and can be detectable in the first urine sample after
birth. In cases of CNS, immunosuppressive therapy is not recom-
mended as patients have been shown to be nonresponsive to these
agents. Conservative management of edema consists of sodium and
fluid restriction and intermittent intravenous albumin and loop
diuretics. The management of these patients also includes a hyper-
caloric diet, thyroid hormone replacement, monitoring for thrombotic
episodes, and aggressive management of infectious complications.
Minimal change nephrotic syndrome (MCNS) is the most
common cause of nephrotic syndrome in childhood, accounting
for 90% of patients presenting before 10 years of age and 70% to
80% of all pediatric patients with nephrotic syndrome. MCNS is
characterized by response to corticosteroids and often a chronic
relapsing course. Most patients have an excellent long-term prognosis.
Chapter 21  Urologic Aspects of Pediatric Nephrology 345
The peak incidence is in preschool children, with a median age of
2.5 years. MCNS is usually idiopathic in childhood, although there
is a wide range of secondary causes of MCNS and an increasing
number of genetic mutations linked to MCNS. The cornerstone of
therapy for MCNS is corticosteroids, which will induce remission
in nearly 90% of children. Up to 85% of patients achieve long-lasting
remission. However, a subset of patients will continue to experience
relapses into adulthood.
Focal segmental glomerulosclerosis (FSGS) is seen in the majority
of children with SRNS. FSGS may be primary or secondary. As opposed
to MCNS, less than 25% of patients with FSGS respond to steroid
therapy. In children, primary FSGS typically presents between 2 and
7 years of age, with a higher incidence among African-Americans,
Hispanics, and Asians. Genetic etiologies of steroid-resistant FSGS
have been identified with increasing frequency. The vast majority of
children with idiopathic FSGS present with nephrotic syndrome that
is indistinguishable from SSNS. Definitive diagnosis requires kidney
biopsy. Current guidelines recommend initial treatment of primary
FSGS with high-dose prednisone for durations of 4 to 16 weeks or
until complete remission. CNIs are often recommended for patients
who are resistant or intolerant to corticosteroids. FSGS can recur
after kidney transplantation. Treatment with plasmapheresis, B-cell
depletion, and CNIs has been reported to be effective in some patients.
However, many will lose their graft and return to dialysis.
Membranous nephropathy (MN) is a rare cause of nephrotic
syndrome in childhood. The majority of childhood cases of MN are
secondary to an underlying disorder; autoantibodies to phospholipase
A2 receptor (aPLA2R) are frequently seen in children and adolescents
with primary MN (Cossey et al., 2013). Hepatitis serology, serum
complement levels, and ANA testing should be obtained. A kidney
biopsy is required to establish a diagnosis. On biopsy, MN is character-
ized by the presence of subepithelial immune deposits. There are no
universally accepted treatment guidelines for children with MN. The
use of ACE inhibitor or angiotensin receptor blocker (ARB) therapy
and a low-sodium diet are recommended. Corticosteroids alone can
decrease proteinuria, but rarely leads to long-term remission when
used in isolation. For this reason, corticosteroids are often used
combined with an alkylating agent. CNIs are also commonly used.
Recent data suggest that MMF and rituximab may be efficacious in
MN secondary to PLA2R-AB. MN is typically a slowly progressive
disease, with 5% of children developing ESRD 5 years after diagnosis.
Persistence of nephrotic syndrome is associated with significant
morbidity and even mortality. Because nephrotic syndrome frequently
follows a chronic relapsing course, children are at risk for several
recognized long-term complications. Spontaneous bacterial peritonitis
occurs in 2% to 6% of these children and is typically caused by
Streptococcus pneumoniae or gram-negative organisms. Thromboem-
bolism is one of the most serious complications of nephrotic
syndrome. Virtually all nephrotic patients are in a hypercoagulable
state, and as many as 20% experience thrombotic events. Mortality,
although rare, is most frequently caused by infectious complications
and less commonly by thromboembolic events.
Glomerulonephritis
As opposed to isolated nephrotic syndrome, glomerulonephritis
classically presents with hematuria (gross or microscopic), pro-
teinuria, hypertension, and acute kidney injury. Inflammation
leads to decreased renal function and retention of salt and water
with ensuing hypertension and edema. Urinary features typically
include “tea-colored” or “cola-colored” urine, with a urine sediment
characterized by dysmorphic erythrocytes and red blood cell casts
(Kidney Disease Improving Global Outcomes [KDIGO], 2012).
Although glomerular diseases can occur in almost any age group,
most have a characteristic age range for disease onset. A number of
systemic diseases may have their initial presentation with glomeru-
lonephritis, so a careful examination for signs and symptoms of
multisystem disease should be sought. It is essential to recognize
that many patients with chronic glomerulonephritis may be
asymptomatic in the early stages of disease progression. Therefore
it is essential to determine if there is evidence of chronic kidney
346 PART III  Pediatric Urology
disease (CKD) at the time of initial evaluation. Features of CKD
include anemia, growth failure, and the hallmarks of chronic kidney
disease/mineral bone disease (CKD/MBD): hyperparathyroidism,
hypocalcemia, and hyperphosphatemia. Initial laboratory evaluation
of children with glomerulonephritis is focused on defining the severity
of acute kidney injury, any metabolic derangements associated with
decreased renal function, and whether the child has evidence of
hypocomplementemia which, if present, significantly narrows the
differential diagnosis. Hypocomplementemia, defined by a low C3
level when combined with normal C4 levels, is strongly supportive
of a diagnosis of acute postinfectious glomerulonephritis or C3
glomerulopathy, and a low C3 level and a low C4 level focuses the
diagnosis on either lupus nephritis or membranoproliferative glo-
merulonephritis. Normocomplementemia is a feature of the other
common forms of glomerulonephritis that are seen in the pediatric
population.
Acute poststreptococcal glomerulonephritis is the most common
form of post-infectious glomerulonephritis (PIGN) in childhood.
However, many other bacterial, viral, and parasitic pathogens are
also associated with PIGN. Typically the child has a history of
pharyngitis or pyoderma that precedes the presentation of glomeru-
lonephritis by several weeks. Acute poststreptococcal glomerulone-
phritis is primarily a disease of school-age children. It is rare before
3 years of age and may occur as a sporadic or epidemic disease.
Clinical symptoms begin abruptly, with most patients presenting
with edema and gross hematuria. Proteinuria is typically mild; however
some patients can present with features of nephrotic syndrome. Mild
to moderate hypertension is common, although some patients with
severe disease present with hypertensive urgency or emergency. Acute
kidney injury is typically mild, although in severe cases, rapidly
progressive glomerulonephritis (RPGN) can occur, necessitating renal
replacement therapy (RRT). Laboratory testing supportive of a
diagnosis of PIGN includes a serum C3 level usually below 50% of
normal levels, and an elevated ASO or DNase B titer. In the vast
majority of cases, with conservative management, spontaneous
improvement typically begins within 1 week, with resolution of the
edema occurring in 5 to 10 days, and resolution of the hypertension
occurring in 2 to 3 weeks. In the majority of patients, the clinical
presentation and laboratory testing that includes complement levels
is usually sufficient to make the diagnosis of PIGN, and there is no
indication to perform a kidney biopsy to confirm the diagnosis. C3
levels typically return to normal within 8 to 12 weeks after presenta-
tion. However, if a child has persistently low C3 levels or has an
atypical clinical course, a kidney biopsy may be indicated. Residual
proteinuria may be present of up to 6 months after the acute injury,
and microscopic hematuria may persist for more than 1 year.
Two other forms of hypocomplementemic nephritis, although
rare, can present in childhood: Membranoproliferative glomeru-
lonephritis (MPGN) and C3 glomerulopathy (C3G), which is further
subdivided into dense deposit disease and C3-dominant glomeru-
lonephritis (C3GN). These diseases typically present in late childhood
and are rare before 5 years of age. The presentation of MPGN/C3G
is varied and includes asymptomatic hematuria or proteinuria,
nephrotic syndrome, and features that initially mimic PIGN, including
low serum C3 levels in the remainder (Pickering et al., 2013). The
presence of nephrotic syndrome and a depressed serum C4 level are
early clues that differentiate MPGN from PIGN. Persistent hypo-
complementemia in a patient with suspected PIGN is highly unusual
and is suggestive of either G3G or MPGN. Although many MPGN
patients have evidence of activation of the classical complement
cascade with low serum C3 levels and low C4 levels, and patients
with C3G patients commonly have signs of alternative pathway
activation with persistently low C3 and normal C4 levels, these
distinctions are not absolute and a kidney biopsy is required to
establish the diagnosis of MPGN/C3G.
The final form of hypocomplementemic nephritis that presents
in childhood is systemic lupus erythematosus (SLE) and should
be considered a likely diagnosis in any child with evidence of
systemic disease, glomerulonephritis, and low C3 and C4 levels
(Hiraki et al., 2012). The clinical presentation of SLE ranges from
asymptomatic microscopic hematuria or proteinuria to rapidly
progressive glomerulonephritis. Usually other systemic manifestations
of SLE are apparent. The presence of 4 out of 11 American College
of Rheumatology classification criteria for SLE confers a 96% sensitivity
and specificity for the diagnosis of SLE. Almost all patients have
hypocomplementemia, positive antinuclear antibodies, and anti–
double-stranded DNA titers. No combination of serologic markers
effectively predicts the histologic type or severity of kidney involve-
ment. The treatment of patients with mild renal disease (classes I
and II) should be determined by the extrarenal manifestations and
typically have a favorable renal prognosis. However, children with
more extensive renal involvement (class III and IV) can have more
progressive renal dysfunction if left untreated. Consensus treatment
recommendations developed for children with SLE include the use
of corticosteroids combined with immunosuppressive drugs in this
patient population (Mina et al., 2012). However, only 80% of patients
with class IV achieve sustained remission, and up to 50% of patients
will experience at least one relapse.
Normocomplementemic Glomerulonephritis
Immunoglobulin A (IgA) nephropathy is the most common primary
cause of glomerulonephritis throughout the world including in
the pediatric population. Patients with this condition commonly
present in the second and third decades of life, and it is rare in the
first decade of life. The true incidence of IgA nephropathy is uncertain,
as there are no reliable serologic markers, and a renal biopsy is the
only way to definitively make the diagnosis. IgA nephropathy is
defined by the presence of dominant IgA deposits in the glomerulus.
These deposits are polymeric IgA1 with aberrant glycosylation patterns
in the hinge region of the antibody (Kiryluk et al., 2011).
Most commonly, these patients present with recurrent episodes
of painless macroscopic hematuria. The onset of gross hematuria is
often concurrent with or immediately proceeded by an upper respira-
tory tract infection. The latency period between the onset of infectious
symptoms and gross hematuria is considerably shorter in IgA
nephropathy than that seen in patients with PIGN. The gross
hematuria episodes typically resolve within a few days, but microscopic
hematuria and variable degrees of proteinuria may persist. Occasion-
ally there are complaints of flank or loin pain associated with the
gross hematuria. Many patients will also present with incidental
findings of microscopic hematuria and mild proteinuria. Less com-
monly, patients will present with isolated nephrotic syndrome. Most
of the acute episodes resolve without specific therapy, and the
long-term prognosis remains relatively good. There are currently no
diagnostic markers for IgA nephropathy. A renal biopsy for suspected
IgA nephropathy may be considered in patients who have impaired
kidney function, hypertension, or significant proteinuria, as these
individuals are at increased risk for developing ESRD. IgA nephropathy
is a disease with a highly variable outcome. For patients with self-
limited episodes of recurrent gross hematuria who do not develop
significant proteinuria, the long-term outcome is quite good. Risk
factors for progressive disease include persistent and significant degrees
of proteinuria, hypertension, and an elevated serum creatinine. In
the high-risk patient population, kidney function slowly deteriorates.
Current data suggest that up to 20% to 30% of this population will
develop ESRD and another 20% have progressive CKD.
Henoch-Schönlein purpura (HSP) is a self-limited systemic
vasculitis syndrome of childhood characterized by symptoms that
may occur asynchronously over a period of several days to weeks.
These features include a purpuric rash, arthralgia, abdominal pain,
and glomerulonephritis. Nephritis rarely, if ever, precedes the onset
of purpura. Histologically, the glomerulonephritis in HSP is indis-
tinguishable from idiopathic IgA nephropathy. Whereas IgA
nephropathy is exclusively a renal disorder, HSP is characterized by
its extrarenal manifestations. The pathophysiology is similar in its
involvement of glomerular deposition of polymeric IgA1 immune
complexes (Kiryluk et al., 2011). Most patients with HSP nephritis
present with asymptomatic hematuria and mild proteinuria, although
up to one-fourth of these patients develop gross hematuria. A small
subset of patients will present with an acute nephritis and/or nephrotic
syndrome, and presentation with RPGN is rare. HSP remains a clinical

diagnosis as there are no specific diagnostic markers for this condition.
Kidney biopsy is not necessary for diagnosis but can be helpful in
making treatment decisions when patients develop nephrotic syn-
drome or RPGN. HSP usually spontaneously resolves within 1 to 2
weeks, but recurrent episodes occur fairly commonly for the first 4
months. Ultimately the vast majority of patients achieve full clinical
remission (Dudley et al., 2013). Persistent urinary abnormalities,
low-grade proteinuria, and microscopic hematuria is commonly seen
for up to 3 months after presentation and for up to 2 years in 10%
to 20% of children. A rapidly progressive clinical course with ensuing
ESRD can be seen in a small percentage of patients. Patients with
persistent heavy proteinuria may see progression over a period of
several years. In a long-term follow-up study of patients with HSP,
44% of patients with nephrotic syndrome or acute nephritis at
presentation developed hypertension or progressive CKD, compared
with normal renal function in 82% of patients who presented with
isolated hematuria.
Alport syndrome is a genetic disorder of the collagen type IV
α3, α4, or α5 chains that form the mature glomerular basement
membrane. The primary presenting clinical finding in all forms of
Alport syndrome is persistent microscopic hematuria. Intermittent
gross hematuria is also commonly seen. Sensorineural deafness is
a common feature that distinguishes Alport syndrome from other
forms of glomerular disease. Hearing deficits typically occur in late
childhood, are bilateral, and initially involves high-frequency hearing
loss that gradually worsens over time. A family history of kidney
failure or deafness in a child with hematuria is highly suggestive of
Alport syndrome. Ocular anomalies may develop later in childhood,
including macular disease and anterior lenticonus. Other rare associa-
tions include leiomyomata of the esophagus, trachea, and the external
genitalia in females. Alport syndrome has X-linked, autosomal
dominant, and recessive forms of inheritance (Savige et al., 2016).
The majority of patients have X-linked mutations in COL4A5, the
gene encoding the α5 chain of collagen type IV. Autosomal disease
is caused by mutations in COL4A3 or COL4A4. Heterozygous muta-
tions in COL4A3 or COL4A4 are inherited in a dominant fashion,
and patients with mutations in both alleles present in a recessive
manner. Kidney function is usually well preserved during the first
decade of life in males with X-linked Alport syndrome. Frank pro-
teinuria frequently appears during late childhood or early adolescence
and is followed by development of hypertension and renal insuf-
ficiency (Savige et al., 2013). About 50% of males with X-linked
disease reach ESRD by 25 years of age. Patients with autosomal
recessive disease follow a course similar to males with X-linked
Alport syndrome. There are no disease-specific treatments for Alport
syndrome, and therapy is focused on reducing the rate of progression
with RAAS inhibition to reduce proteinuric renal injury and to control
hypertension (Kashtan et al., 2013).
Antineutrophilic cytoplasmic antibody (ANCA)-associated
glomerulonephritis is a rare disease in childhood. Two target ANCA
antigens have been identified: proteinase-3, or cANCA, and myelo-
peroxidase, or pANCA. ANCA-associated glomerulonephritis in
childhood is divided into two small-vessel vasculitic syndromes:
microscopic polyangiitis (MPA) and granulomatosis with polyangiitis
(GPA) (Cabral et al., 2016). Eosinophilic granulomatosis with
polyangiitis (Churg-Strauss syndrome) is extremely rare in childhood.
Although ANCA-associated glomerulonephritis occurs primarily in
adults, it can present in adolescence and occasionally during child-
hood. Nephritis is seen in 70% to 80% of children with either GPA
or MPA. The features of GPA and MPA overlap where both typically
present with a flulike prodrome and systemic symptoms such as
fever, anorexia, malaise, weight loss, myalgias, arthritis and/or
arthralgias, and skin lesions (purpura or urticaria). Lung disease
occurs in both syndromes and can include life-threatening pulmonary
hemorrhage. Granulomatous involvement of the upper airway, sinuses,
nasal passages, and ears is present in many patients with GPA but
not in MPA. A small subset of patients present with renal-limited
vasculitis. Histologically, the principal finding is pauci-immune focal
necrotizing glomerulonephritis, which is similar in both GPA and
MPA and is often severe. All patients with nephritis have hematuria,
most have proteinuria, and more than 70% have decreased renal
Chapter 21  Urologic Aspects of Pediatric Nephrology 347
function at diagnosis. Some patients present with RPGN. ANCA are
detected in 85% to 95% of patients with active GPA (PR3-cANCA)
and 70% with MPA (MPO-pANCA). ANCA-associated systemic
vasculitis is an aggressive disease. Without treatment, mortality rates
are 90% within 2 years. Patient and kidney survival have improved
dramatically with intensive immunosuppressive therapy, however
relapses are common. CKD persists in as many as one-half of patients,
with nearly one-fourth of patients eventually developing ESRD.
Antiglomerular basement membrane (Anti-GBM) disease is an
aggressive form of glomerulonephritis that is rarely seen in childhood.
It is mediated by antibodies to the glomerular basement membrane.
Known as Goodpasture syndrome when associated with pulmonary
hemorrhage, it is rare in the first decade of life but has been reported
in children as young as 2 years of age. Anti-GBM nephritis may occur
as a rare complication after extracorporeal shock wave lithotripsy
(ESWL), membranous nephropathy, or minimal-change disease.
Anti-GBM nephritis may also occur in a small subset of patients
with Alport syndrome after kidney transplantation. The Goodpasture
target antigen is the carboxy-terminal region (NC1 domain) of the
α3 chain of collagen type IV, the structural component of glomerular
and pulmonary basement membranes. Patients present with acute
nephritis or less commonly with symptoms of CKD. Pulmonary
hemorrhage presenting as hemoptysis often precedes or accompanies
the onset of nephritis; these episodes of hemoptysis may be life-
threatening. More than 90% of patients have anti-GBM antibodies
at the time of clinical presentation. Progression to irreversible kidney
injury can occur within weeks. The mainstay of therapy is plasma-
pheresis to remove the circulating antibody combined with
immunosuppressive therapy to reduce new antibody production.
The kidney disease is unlikely to be reversible unless treatment is
started early. Patients who recover from the acute disease generally
do well, and disease relapses are extremely rare.
RPGN is a rare disorder in childhood that is traditionally divided
into three groups; anti-GBM nephritis, immune complex nephritis,
and pauci-immune disease associated with ANCA. Less commonly,
other forms of proliferative glomerulonephritis may present as severe
crescentic disease. This clinical syndrome is characterized by sudden
onset and rapid decline in kidney function. It typically presents with
gross hematuria, edema, anemia, and hypertension. Isolated nephrotic
syndrome is uncommon. Pulmonary hemorrhage suggests a diagnosis
of anti-GBM nephritis or ANCA vasculitis and may be fatal if treatment
is delayed. Serologic studies including a C3, C4, ANA, ANCA, and
anti-GBM antibodies should be obtained; however, a biopsy confirma-
tion is essential and establishes the diagnosis in most patients. The
renal biopsy commonly shows extensive crescent formation. Therapy
is directed to the specific disease entity. Spontaneous resolution of
RPGN is extremely unlikely. The prognosis is poor unless aggressive
therapy is started early in the course of the disease.
Hemolytic uremic syndrome (HUS) is a common cause of severe
acute kidney injury in a previously healthy young child. The majority
of children with HUS have an antecedent diarrheal illness caused
by Shiga toxin–producing Escherichia coli (STEC). Approximately
10% of HUS cases are not associated with STEC infections and are
referred to as atypical HUS (aHUS). HUS, aHUS, and thrombotic
thrombocytopenic purpura (TTP) are classified as forms of thrombotic
microangiopathy (TMA), however the triggers, primary target organs,
response to treatment, and clinical outcomes are distinct. HUS occurs
in both sporadic and epidemic patterns. More than 70% of children
in the United States with STEC-positive HUS have been infected
with E. coli 0157:H7. The primary reservoir for E. coli 0157:H7 is
farm animals, although contamination of fruits, juices, and vegetables
is also common. HUS is initiated by damage to the endothelium
with microthrombi formation, leading to the diagnostic triad of
microangiopathic hemolytic anemia, thrombocytopenia, and acute
kidney injury. In patients with aHUS, defects in regulation of the
alternative complement pathway are commonly found (Loirat et al.,
2015). These include mutations in complement factor H, factor I,
membrane cofactor protein, C3, complement factor B, and autoan-
tibodies against complement factor H and factor I. In young children,
aHUS can occur as a complication of S. pneumoniae infection. Unlike
other patients with HUS, these patients have a positive Coombs
348 PART III  Pediatric Urology
anemia. Of note, the use of fresh-frozen plasma is contraindicated
in patients with pneumococcal-associated HUS.
After ingestion of E. coli–contaminated food, most affected children
develop abdominal pain and bloody diarrhea. The colitis is usually
self-limited, but complications may occur, including rectal prolapse,
toxic megacolon, bowel wall necrosis, and bowel perforation. The
onset of HUS is usually abrupt, occurring within 1 week after the
onset of the diarrhea. The presenting symptoms are often caused by
acute kidney injury. The severity of the acute kidney injury is highly
variable, but one-half will develop oligoanuria and require dialysis.
Hypertension is variable but may be severe. The mean duration of
the acute kidney injury is 2 weeks. In aHUS, the antecedent illness
is more nonspecific, often associated with fever, upper respiratory
symptoms, and vomiting. Sometimes a prodromal illness is not
apparent. Neurologic involvement is common and can mimic TTP.
Most patients are very irritable and somnolent, and seizures and
coma can occur in 10% of children. Virtually any organ can become
damaged by the microvascular thrombi. Anemia is characterized by
the presence of schistocytes, negative Coombs test, elevated reticu-
locytosis and lactose dehydrogenase levels, and a low serum hapto-
globin. The prothrombin and partial thromboplastin time are usually
normal. Serum C3 level and CH50 may be depressed in both
STEC-positive HUS and aHUS but is more common in those with
aHUS; an abnormal serum C3 level does not rule out the possibility
of a genetic complement deficiency. In patients with clinical features
suggestive of STEC-positive HUS, confirmation of a Shiga toxin–
producing E. coli either by culture or the presence of the Shiga toxin
is recommended. When aHUS is a consideration, it is important to
measure ADAMT13 activity and inhibitor testing to rule out TTP
and to evaluate the complement system by protein and genetic testing.
For STEC-positive HUS, supportive medical care is by far the most
important aspect of treatment. Meticulous attention must be paid
to fluid and electrolyte management. Severe acute kidney injury
requiring dialysis still develops in nearly one-half of patients.
Packed red blood cell transfusions should be reserved for patients
with clinical indications of severe anemia. Platelet transfusions should
be avoided unless the patient is actively bleeding or the platelets
are needed in preparation for an invasive procedure. During the
prodromal phase of colitis, antimotility drugs are contraindicated,
and antibiotics should be avoided as they have been reported to
increase the probability of developing HUS. For patients with aHUS,
Eculizumab, a monoclonal antibody to the complement component
C5, is the therapy of choice. It has been shown to be highly effective
in patients with complement dysregulation. Acute mortality in
STEC-positive HUS is related to severe complications such as neu-
rologic disease, cardiac failure, and multiorgan involvement. Kidney
function typically improves spontaneously, and almost all patients
are able to discontinue dialysis. However, long-term follow-up studies
suggest that 5% to 25% of patients will develop CKD. aHUS generally
follows a more severe clinical course and is more likely to relapse
in the absence of chronic complement inhibition. Recurrent disease
in either native kidneys or after kidney transplant is extremely rare
in STEC-positive HUS but is quite common in aHUS. Eculizumab
treatment is also recommended for aHUS patients undergoing kidney
transplantation.
KEY POINTS
• Corticosteroids will induce a remission in the vast majority
of children with nephrotic syndrome.
• Focal segmental glomerulosclerosis is seen in the majority
of children with steroid-resistant nephrotic syndrome.
• Minimal change nephrotic syndrome is the most common
cause of nephrotic syndrome in childhood.
• IgA nephropathy is the most common primary cause of
glomerulonephritis throughout the world.
• Hemolytic uremic syndrome is a common cause of severe
acute kidney injury in a previously healthy young child.
TUBULOPATHIES
Renal tubular disorders frequently present during routine laboratory
investigation of children with failure to thrive. Tubular diseases can
be isolated defects as in the case of distal renal tubular acidosis
(RTA), or generalized defects as seen in Fanconi syndrome, and are
primary or secondary in nature (Batlle and Haque, 2012). Tubu-
lopathies such as renal glycosuria can result in solute wasting, and
others such as Gordon syndrome result in excess solute reabsorption
(O’Shaughnessy, 2015). Evaluation of patients with suspected tubular
dysfunction begins with a careful history and physical examination
focusing on a family history of renal or metabolic disease, and signs
of failure to thrive, poor feeding, recurrent vomiting, dehydration,
irritability, tetany, seizures, or icterus. The initial evaluation of patients
with suspected tubular disease should include a complete blood
count; a comprehensive metabolic panel including electrolytes, renal
function, calcium, magnesium, and phosphorus; a venous or arterial
blood gas; and urine for quantitative assessment of urine potassium,
sodium, calcium, phosphorus, and magnesium excretion. In patients
with suspected RTA, a metered urine pH should be obtained and
urine sodium, potassium, and chloride concentrations to measure
the urine anion gap. Additional testing including genetic testing
should be based on the history and physical examination in combina-
tion with underlying metabolic disturbances. RTA is defined as an
inappropriately elevated urine pH in the setting of metabolic acidosis.
The hallmark of RTA is hyperchloremic metabolic acidosis (normal
anion gap acidosis); the presence of metabolic acidosis must be
confirmed by measurement of venous or arterial pH. In the setting
of normal anion gap metabolic acidosis, a urine pH greater than
5.5 and an elevated urine anion gap are highly supportive of RTA
(Carlisle et al., 1991).
Proximal RTA is defined by a decrease in the proximal tubule
bicarbonate reabsorptive capacity, resulting in a low bicarbonate
threshold with ensuing bicarbonate loss. Patients present with
failure to thrive and hyperchloremic metabolic acidosis. However,
patients with proximal RTA can reabsorb filtered bicarbonate below
the lower resorption threshold. Thus patients with proximal RTA
can maintain their serum bicarbonate level, although at a lower
level than normal (typically 14 to 17 mEq/L). Because the distal
tubule is intact, when the serum bicarbonate level is at or below
the absorptive threshold of the proximal tubule, patients with proximal
RTA can excrete urine with a pH less than 5.5. Isolated proximal
RTA is rare and is more commonly seen in conjunction with Fanconi
syndrome. Isolated proximal RTA can be caused by autosomal recessive
mutations in the sodium bicarbonate cotransporter. Patients with
this disorder usually have ocular defects, short stature, and intellectual
impairment. Treatment of proximal RTA is challenging when exog-
enous alkali is not absorbed by the proximal tubule. Therefore,
patients commonly require 10 to 15 mEq/kg/day of alkali with only
modest improvement in serum bicarbonate levels.
Fanconi syndrome is a generalized disorder of the proximal tubule.
Patients with Fanconi syndrome typically present with failure to
thrive, hyperchloremic metabolic acidosis with hypophosphatemia,
and hypokalemia (Moe et al., 2009). Typical urinary findings include
glucosuria, aminoaciduria, and phosphaturia. Cystinosis is a common
cause of Fanconi syndrome in children. It is an autosomal recessive
disorder resulting in accumulation of free cysteine in intracellular
lysosomes (Nesterova and Gahl, 2013). Presenting clinical features
typically include polydipsia, polyuria, constipation, and failure to
thrive. Many patients have evidence of rickets caused by renal
phosphate wasting. Treatment of Fanconi syndrome is twofold;
initially, the treatment of the underlying primary disease, if possible,
and secondly, the replacement of urinary solute losses and the cor-
rection of acidosis.
Children with distal RTA present with short stature and failure
to thrive, and they often have rickets. Classically, they have hyper-
chloremic metabolic acidosis, hypokalemia, hypercalciuria, and
nephrocalcinosis. If the hypokalemia is severe, they may present
with muscle weakness, cramps, and paralysis. The chronic metabolic
acidosis results in bone demineralization. Patients with distal RTA are
unable to excrete urine with a pH less than 5.5. Distal RTA may be

either a primary or a secondary disorder. Primary distal RTA has been
linked to autosomal dominant or autosomal recessive mutations in the
basolateral Cl–/HCO3– exchanger and autosomal recessive mutations
in H+-ATPase that are also associated with hearing loss. Secondary
causes of distal RTA include medications and rheumatologic disorders.
Distal RTA is treated by providing alkali equivalent to the amount of
H+ ion normally secreted by the distal nephron. Typically 3 to 5 mEq/
kg/day of alkali is sufficient in most children to normalize the serum
bicarbonate levels and correct the associated metabolic disturbances.
RTA associated with hyperkalemia is also known as type 4 RTA. It
is associated with a number of disorders of either mineralocorticoid
deficiency or mineralocorticoid resistance. Decreased mineralocorti-
coid production is seen most commonly with 21-hydroxylase deficiency
because Addison disease is rare in children. Angiotensin-converting
enzyme inhibitor use can also result in functional hypoaldosteronism.
Hyporeninemic hyperaldosteronism in children can be the result of
drugs such as calcineurin inhibitors, nonsteroidal anti-inflammatory
drugs (NSAIDs), and tubulointerstitial disease. Other common causes
of type 4 RTA in children include obstructive uropathy and interstitial
renal disease. In these disorders, aldosterone secretion is normal, but
damage to the cortical collecting tubule results in functional resistance
to aldosterone. Typically the degree of hyperkalemia is out of proportion
to the severity of the renal insufficiency. Evaluation and management
of type 4 RTA should be focused on defining the underlying etiology
and treating the primary disease. Patients with glucocorticoid and
mineralocorticoid deficiency should receive replacement therapy. Most
cases of type 4 RTA caused by obstructive uropathy need urologic
evaluation and surgery.
Dent disease is an X-linked recessive disorder characterized by
low-molecular-weight proteinuria, nephrocalcinosis, recurrent
urolithiasis, and progressive renal insufficiency. Dent disease results
from a defect in the renal proximal tubule Cl–/H+ exchanger designated
as CLC-5 (Devuyst et al., 2010). Patients with Dent disease have
low–molecular weight proteinuria, not glomerular proteinuria (i.e.,
albumin). Treatment is directed at preventing renal calculi. Patients
should have adequate fluid intake and eat a low-sodium diet. A
thiazide diuretic may be helpful to decrease renal calcium excretion.
ESRD usually occurs between the third and fifth decade of life.
Bartter syndrome is an autosomal recessive disorder, which usually
presents in the first year of life with failure to thrive. Typically, patients
have a prenatal history of polyhydramnios and prematurity, and
polydipsia and polyuria as infants and young children. A history of
constipation, salt craving, and muscle cramps are also quite common.
Hypokalemic metabolic alkalosis is the defining feature of Bartter
syndrome (Seyberth and Schlingmann, 2011). Blood pressure is
typically normal, but plasma renin and aldosterone levels are elevated
as a result of volume depletion. Bartter syndrome is commonly
caused by mutations in the Na/K/2Cl cotransporter or in Barttin,
which is associated with sensory neural deafness. Treatment of patients
with Bartter syndrome is centered on replacement of urinary solute
loss and management of polyuria.
Gitelman syndrome is an autosomal recessive disorder that also
presents with hypokalemic alkalosis and can be confused with Bartter
syndrome (Seyberth and Schlingmann, 2011). Patients with Gitelman
syndrome typically do not have failure to thrive, and there is no
antenatal history of polyhydramnios. Hypomagnesemia is nearly
universal in Gitelman syndrome, and urinary calcium excretion is
low in Gitelman syndrome as opposed to Bartter syndrome, in which
urinary calcium excretion is elevated. Many patients with Gitelman
syndrome have a history of tetany and muscle cramps secondary to
hypomagnesemia, which is an uncommon feature of Bartter syndrome.
Gitelman syndrome is caused by mutations in the thiazide-sensitive
NaCl cotransporter (NCC) found in the distal convoluted tubule.
The keystone of treatment for Gitelman syndrome is magnesium
and potassium supplementation to replace urinary loss.
CYSTIC RENAL DISEASE
Cystic renal diseases are a common cause of both CKD and eventually
ESRD in the pediatric population. Clinical presentation of these
Chapter 21  Urologic Aspects of Pediatric Nephrology 349
KEY POINTS
• The hallmark of RTA is hyperchloremic metabolic acidosis
(normal anion gap acidosis).
• Children with distal RTA classically have hyperchloremic
metabolic acidosis, hypokalemia, hypercalciuria, and
nephrocalcinosis.
• Hypokalemic metabolic alkalosis is the defining feature of
Bartter syndrome.
• RTA associated with hyperkalemia is also known as type
4 RTA.
heterogeneous disorders is varied. Many patients are diagnosed
prenatally or during the evaluation of hypertension, gross or micro-
scopic hematuria, abnormal renal function, polyuria, or incidentally
as part of an evaluation of abdominal pain or constipation. Often
a specific diagnosis can be determined by imaging alone or by family
history. However, genetic testing to achieve a definitive diagnosis is
preferred. Currently there are no disease-specific treatment options
that can alter disease progression or correct the underlying disorders.
Therefore, therapy is conservative in nature and focused on manage-
ment of complications that might accelerate CKD progression.
Multicystic dysplastic kidney (MCDK) disease appears on
ultrasonography as a large reniform mass with noncommunicat-
ing cysts. The MCDK is nonfunctional and is usually unilateral;
although rare, if MCDK is bilateral, neonatal mortality is nearly
universal. Urologic anomalies are seen in up to 25% of patients with
MCDK, including renal hypoplasia/dysplasia, vesicoureteral reflux,
and ureteropelvic junction obstruction. Typically there is gradual
reduction in the size of an MCDK with eventual involution over a
period of months to years. The contralateral kidney typically shows
compensatory hypertrophy. Because of the association of MCDK
with VUR, voiding cystourethrography (VCUG) is recommended,
particularly in patients with hydronephrosis and/or hydroureter.
Serial monitoring of renal function, blood pressure, and renal
ultrasonography is generally recommended at an interval of 3 months
for the first year of life and then every 6 months up to involution,
or at least up to 5 years. There is emerging data that patients with
unilateral MCDK are at risk for development of early-onset hyper-
tension and possible CKD. As a result, there is growing consensus
that these patients should be monitored annually until well into
adulthood.
Autosomal recessive polycystic kidney disease (ARPKD) is caused
by a mutation in the PKHD1 gene and occurs in approximately
1 : 40,000 live births (Bergmann et al., 2004). The kidneys are
bilaterally enlarged as a result of fusiform cysts arising from the
collecting ducts. The principal extrarenal manifestation of ARPKD
is congenital hepatic fibrosis; over time, cystic dilation of the biliary
tree develops with ensuing portal hypertension and liver failure. In
addition to complications related to CKD, patients with ARPKD are
at risk for ascending cholangitis, recurrent urinary tract infections,
hypertension, nephrolithiasis, and bleeding from esophageal varices.
Neonatal presentation with oligohydramnios/anhydramnios has a
reported mortality rate of 25% to 50%. Over 75% of patients with
ARPKD progress to ESRD by 5 years of age.
Autosomal dominant polycystic kidney disease (ADPKD) is
caused by mutations in the polycystin-1 (PKD-1) or polycystin-2
(PKD2) gene, and it has a prevalence of roughly 1 : 1000 (Igarashi
and Somlo, 2002; Torres et al., 2007). ADPKD usually presents in
adulthood but can lead to clinical symptoms in older children and
young adults. ARPKD is often identified in childhood either because
of a positive family history, as an incidental finding on imaging for
abdominal complaints (pain or constipation), or as part of an
evaluation for hypertension or urinary tract infections. Similar to
ARPKD, there is no disease-specific therapy approved in children.
However, hypertension and urinary tract infections should be treated
aggressively to limit disease progression. In patients with a family
history of cerebral aneurysm, routine screening is currently not
350 PART III  Pediatric Urology
recommended in the pediatric population unless there are clinical
signs or symptoms that warrant imaging.
Nephronophthisis in distinction to ARPKD or ADPKD is
characterized by cyst formation at the corticomedullary junction,
but the kidney size is typically normal. Most patients with neph-
ronophthisis have a history of polyuria, polydipsia, anemia, and
growth retardation, and eventually reach ESRD by early adolescence.
Many forms of recessive nephronophthisis are syndromic in nature,
and extrarenal manifestations are common; these include retinitis
pigmentosa in Senior-Løken syndrome; cerebellar vermis aplasia
and colobomas in Joubert syndrome; obesity, diabetes mellitus, and
polydactyly in Bardet-Biedl syndrome; and skeletal dysplasias in
Juene and Ellis-van Creveld syndromes. In patients with suspected
recessive nephronophthisis, comprehensive genetic analysis is war-
ranted as this can help to predict both complications and disease
progression, and importantly can help with caregiver education.
Currently there are more than 100 distinct genes that have been
associated with nephronophthisis.
Other types of cystic kidney disease include medullary cystic
kidney disease, which is an autosomal dominant disorder associated
with hyperuricemia, gout, and ESRD in adults. Mutations in the
gene encoding uromodulin/Tamm-Horsfall protein have been linked
with one of the two types of medullary cystic kidney disease (type
2). In addition, glomerulocystic kidney disease is characterized by
multiple small cortical cysts that result from cystic dilation of the
Bowman space; the lack of tubular involvement distinguishes it from
other forms of cystic disease. And medullary sponge kidney is a rare
congenital cystic disorder in which there is ectasia of cortical ducts
within the inner medulla of the kidney, resulting in a spongelike
appearance on radiograph and is associated with nephrolithiasis
and urinary tract infection.
KEY POINTS
• Urologic anomalies are seen in up to 25% of patients with
MCDK, including renal hypoplasia/dysplasia, VUR, and
ureteropelvic junction obstruction.
• Autosomal recessive polycystic kidney disease (ARPKD) is
caused by a mutation in the PKHD1 gene.
• ADPKD is caused by a mutation in the polycystin-1
(PKD-1) or polycystin-2 (PKD2) gene.
UROLITHIASIS: MEDICAL MANAGEMENT
Accurate data on the incidence and prevalence of urolithiasis in the
pediatric population in the United States are not readily available.
Although not as common as in the adult population, it is estimated that
nephrolithiasis accounts for between 1 in 600 and 1 in 800 pediatric
hospital admissions in the United States. Recent data suggest that the
incidence of urolithiasis in the adolescent population has increased
significantly over the past 10 years from roughly 20 per 100,000 in
the late 1980s to more than 50 per 100,000 in 2014; this number is
likely to be an underestimate as urolithiasis remains under-diagnosed
because many children are asymptomatic at the time of diagnosis
(Braun et al., 2016; Sas, 2011). Concurrent with the increase in the
frequency of stone disease has been a shift in the types of stones seen
at presentation. There has been a marked drop in the incidence of
infectious stones from more than 60% before the 1980s to now less
than 20%; there are similar reported reductions in the frequency of
uric acid and ammonium acid urate stones. The calcium stones are
now the most prevalent. The reasons behind these shifts are not
clear, however in the United States, it has been proposed that changes
in dietary practices, changes in types of fluids used for hydration,
and the obesity epidemic underlie the rise in pediatric stone disease.
Reported rates for stone recurrence in the pediatric population are
variable, ranging from 15% to 20%, but may be as high as 30% in
individuals with underlying metabolic disorders.
The clinical presentation of nephrolithiasis in children is varied
and includes microscopic or gross hematuria, urgency, dysuria,
frequency, hesitancy, and nonspecific abdominal or flank pain.
Although increasingly less common in the United States, stones may
be identified as part of the evaluation of urinary tract infections. It
is not unusual for nephrolithiasis to be noted incidentally as part
of a diagnostic evaluation for nonspecific complaints such as recurrent
abdominal pain or failure to thrive. Children rarely present with
the typical “renal colic” described in adults. In the United States,
the majority of stones are found in the kidney, and presentation
with bladder stones is more common in those with underlying
urologic abnormalities.
Hypercalciuria is the most common risk factor identified in
children with urolithiasis, and the vast majority have idiopathic
hypercalciuria. Systemic hypercalcemia is less common and is
associated with hyperparathyroidism, immobilization hypercalcemia,
thyroid disease, idiopathic hypervitaminosis D, corticosteroid use,
Williams syndrome, and rarely, mutation of the calcium-sensing
receptor. Children with hypercalciuria are much more commonly
normocalcemic, and with the exception of those on loop diuretics,
most will have idiopathic hypercalciuria. There is, however, an
increasing understanding of the genetic underpinnings of tubular
dysfunction as a cause of hypercalciuria. Examples of this include
mutations in CLCN5 or ORCL1 seen in Dent disease; mutations in
SLC12A1, KCNJ1, CLCNKB, BSND, or CASR seen in Bartter syndrome;
and mutations in CLDN16 or CLDN19 with familial hypomagnesemia
with hypercalciuria and nephrocalcinosis.
Hyperoxaluria is a less common cause of urolithiasis and can be
either primary or secondary. Secondary causes include enteric
hyperoxaluria, excess vitamin C intake, and oxalate-rich diets. Primary
hyperoxaluria (PH) is rare autosomal recessive disorder of oxalate
metabolism of which there are three subtypes (Nazzal et al., 2016).
PH type 1, which is the most common and most severe, is caused
by aniline/glyoxylate aminotransferase (AGT) deficiency leading to
increased systemic levels and excretion of glycolate and oxalate. PH
type 2 is less common and is caused by mutations of glyoxylate
reductase, leading to increased excretion of L-glycerate and oxalate.
The clinical course of PH type 2 is usually less severe than in PH
type 1. PH type 3 is the rarest and least severe form and is caused
by mutations in HOGA1. Uric acid stones caused by hyperuricosuria
can be either a primary disorder seen with inborn errors of purine
metabolism (Lesch-Nyhan syndrome) or, more commonly, a second-
ary process associated with hematologic malignancies, gout, high
purine intake, tubular disorders, or diabetes mellitus.
Other rare causes of pediatric urolithiasis include cystinuria and
adenine phosphoribosyltransferase (APRT) deficiency. Cystinuria is
a rare autosomal recessive disorder caused by mutations in either
SCL3A1 or SLC7A9, which result in decreased tubular reabsorption
of cystine and other dibasic amino acids (ornithine, arginine, and
lysine), leading to excessive excretion of cystine and stone formation.
APRT deficiency is a rare autosomal recessive inborn error of adenine
metabolism that results in the generation and urinary excretion of
large amounts of poorly soluble 2,8-dihydroxyadenine with ensuing
stone formation.
The evaluation of nephrolithiasis should begin with a history
focused on symptoms associated with stones and predisposing factors
including recurrent urinary tract infection, familial history of neph-
rolithiasis, gout, and conditions that increase enteric oxalate absorption:
inflammatory bowel disease, short gut syndrome, or cystic fibrosis
(Edvardsson et al., 2013). A through dietary history should be taken
including sodium, calcium, fluid intake, and vitamin supplementation.
Initial screening studies should focus on identifying a metabolic etiology
for the kidney stones and should include serum electrolytes, blood
urea nitrogen (BUN), creatinine, calcium, phosphorus, uric acid, and
a venous blood gas (for evaluation of possible RTA). In the presence
of hypercalciuria, hypercalcemia, or hypophosphatemia, serum
parathyroid hormone and vitamin D levels should be obtained. Urine
microscopy can be quite useful, particularly in the diagnosis of cystinuria
or ARPT deficiency as the urinary crystals seen in these conditions
are disease-specific. If the stone is available, it should be sent for
analysis by infrared spectroscopy or radiographic diffraction. A urine
culture should be done to rule out the presence of infection. Timed
urine collections for calcium, oxalate, urate, citrate, and sodium should

be performed for any child with stones if possible. For children in
whom 24-hour urine collections are not feasible, spot ratios of urine
solute to urine creatinine can be substituted. It is important to remember
that normative data for urinary solute excretion vary with age. For
example, a normal urine calcium-to-creatinine ratio for a 2-month-old
child is in the 0.4 to 0.5 mg/mg range, and a ratio of 0.2 mg/mg is
the upper limit of normal for a 5-year-old child. One of the primary
goals of the initial evaluation is to identify patients with underlying
metabolic disease for whom specific therapies will be beneficial and
to determine which individuals are at risk for recurrent disease. In
terms of imaging, to limit radiation exposure, ultrasonography is
commonly employed in children for initial screening (Smith-Bindman
et al., 2014). In patients with a nondiagnostic ultrasound examination,
nonenhanced helical CT is highly sensitive and specific for the diagnosis
of nephrolithiasis. Standard abdominal radiographs remain useful
to determine stone burden and for longitudinal assessment of response
to therapy. Genetic testing is an increasingly important part of the
evaluation of pediatric stone disease, as monogenic disorders may
underlie urolithiasis or nephrocalcinosis in 20% of children.
Medical therapy should be directed toward the underlying meta-
bolic cause, if one has been identified, to prevent recurrence and
growth of existing stones (Hernandez et al., 2015). Increasing fluid
intake with a minimum of 2 L/1.73 m2/day should be encouraged
to decrease the chance of crystallization and growth of calculi.
With hypercalciuria, salt restriction will reduce urinary calcium
losses by promoting reabsorption of sodium and calcium. Avoiding
excessive protein intake to reduce the acid load is also recommended
in recurrent stone formers. A thiazide diuretic can be used in the
normocalcemic hypercalciuric patient to increase distal tubular
reabsorption of calcium.
For primary hyperoxaluria, the goal of therapy is to decrease
oxalate production, increase urine calcium oxalate solubility, and
decrease crystal deposition in the kidney. Potassium citrate, ortho-
phosphate, or magnesium citrate formulations are used to decrease
urinary calcium oxalate supersaturation. A trial of pyridoxine should
be given in PH type 1. About 20% of patients with PH type 1 will
respond to pyridoxine treatment with normalization of urine oxalate
concentration, and about 30% will have a partial response. However,
pyridoxine is not effective in PH types 2 and 3 (Ben-Shalom and
Frishberg, 2015). Therefore, only successful liver transplantation
can offer a potential cure for PH type 1.
In individuals with hypocitraturia, a diet rich in fruits and veg-
etables, and/or supplemental potassium citrate is recommended.
Sodium citrate should be avoided because the excess salt may increase
hypercalciuria. In cystinuria, alkalization of the urine to a pH greater
than 7.5 with potassium citrate will decrease cystine supersaturation.
If stone formation continues despite high fluid intake and alkaliniza-
tion of the urine, D-penicillamine or tiopronin can also be used.
However, these medications are not always well tolerated. In
hyperuricosuria, allopurinol, alkalinization of urine, and avoidance
of protein excess are recommended. Struvite calculi often require
surgical removal and prolonged treatment with antibiotics.
For children who present with acute renal colic, analgesia and
adequate hydration with appropriate monitoring of fluid and
electrolyte status are the mainstays of therapy. Radiologic evaluation
should be performed, and in the setting of urinary obstruction,
infection, acute kidney injury, or incontrollable pain, urologic
intervention may be needed. For small ureteral stones (< 10 mm),
management with observation with or without medical expulsive
therapy is recommended. Urologic interventions such as ESWL,
percutaneous nephrolithotripsy, ureteroscopy, and open surgery have
all been successful therapies in children with urolithiasis. The choice
of intervention is typically guided by stone size, composition, and
location. Complete removal is important in children as residual
small fragments are associated with regrowth and adverse outcomes.
Medical expulsive therapy with an α-blocker has been successful in
the management of small ureteral stones. ESWL is often employed
for intermediate-size stones (10 to 20 mm) within the ureter or
collecting system. Percutaneous nephrolithotomy is the recommended
treatment for large renal pelvic or caliceal stones (>20 mm). Ure-
teroscopy is increasingly becoming a first-line procedure of choice,
Chapter 21  Urologic Aspects of Pediatric Nephrology 351
especially for distal ureteral stones greater than 10 mm. Open surgery
is usually reserved for very young children with complex stones,
children with orthopedic issues that limit positioning, or those who
have failed primary therapy.
Urolithiasis has a high rate of recurrence, especially if an underlying
metabolic disorder exists. Prevention with appropriate medical therapy
and high fluid intake should be encouraged to limit morbidity.
Long-term follow up is advisable as some children may develop
CKD and progress to ESRD.
KEY POINTS
• Urolithiasis remains underdiagnosed because many
children are asymptomatic at the time of diagnosis.
• Calcium stones are now the most prevalent stones in
children.
• Cystinuria results in decreased tubular reabsorption of
cystine, ornithine, arginine, and lysine.
HYPERTENSION
Hypertension in the pediatric population is defined as blood pressure
on repeat measurements greater than the 95th percentile for age,
gender, and height in comparison to normative population-based
data. The estimated prevalence of hypertension in children is
much lower than the prevalence seen in the adult population;
however, data suggests the increase in the prevalence in hyperten-
sion seen in the pediatric population in recent years is closely
linked to increasing obesity rates in children (Din-Dzietham et al.,
2007, Falkner, 2010; Muntner, 2004). Weight-related disorders such
as hypertension are now increasingly common in pediatric patients
and are likely to account for the rise in the prevalence of hypertension
from 2.7% noted in the early 1990s to 3.7% seen in the 2000s, with
elevated blood pressures (previously known as prehypertension)
observed in approximately 10% of children and adolescents.
An accurate measurement of blood pressure is essential to the
diagnosis of hypertension (National High Blood Pressure Education
Program, 2004). Accurate blood pressure measurement requires a cuff
that is appropriate to the size of the child’s upper arm; the bladder
width should be at least 40% of the mid-arm circumference with a
cuff length that covers at least two-thirds of the upper arm. Systolic
blood pressure is defined by the first Korotkoff sound, with the disap-
pearance of the Korotkoff sounds defining diastolic blood pressure. As
accurate auscultatory measurement of blood pressure is often difficult
in infants and young children, the use of automated (oscillometric)
blood pressure measurement devices is now widespread; however
it should be noted that pediatric normative blood pressure data is
based on auscultatory and not oscillometric standards.
A recent clinical practice guidelines for management of hyperten-
sion in children and adolescents (Flynn et al., 2017) that was
published by the American Academy of Pediatrics (AAP) update and
refine reference data from the 4th Report of the National Institutes
of Health Working Group for the management of blood pressure
in children (2004). A major focus of this report was improving the
recognition of hypertension by simplifying the initial screening blood
pressure table. Furthermore, normative data by age, gender, and
height have been revised, including only those children with a normal
BMI. The blood pressure classification scheme has also been revised
to align the classification system for adolescents with the absolute
blood pressure values used in adult blood pressures guidelines
(Redwine et al., 2012). Current AAP guidelines now distinguish
between children 1 to 13 years of age and adolescents older than
13 years of age, with normal blood pressure defined as less than
the 90th percentile for children and less than 120/80 mmHg for
adolescents (Flynn et al., 2017). The term prehypertension has been
abandoned and replaced with elevated blood pressures to be consistent
with the adult guidelines.
Staging of hypertension is useful in determining which children
require more immediate attention for diagnostic evaluation and
management. In addition, staging can also predict the presence of
352 PART III  Pediatric Urology
end-organ damage from hypertension. Two other clinically relevant
designations for severity of hypertension are important: (1) hyper-
tensive emergency, when a patient has end-organ injury such as
encephalopathy, pulmonary edema, or cerebral hemorrhage or clinical
symptoms like blurred vision, headache, or nausea, which can be
associated with severely elevated blood pressure; and (2) hypertensive
urgency, when blood pressure is severely elevated without clear
evidence of end-organ involvement or overt symptoms.
It also should be recognized that not every child with elevated
blood pressure readings in the office setting has true hypertension.
Up to one-fourth of such patients have normal blood pressures
outside of the office setting and are classified as having “white
coat” hypertension. The recent AAP care guidelines promote the
use of 24-hour ambulatory blood pressure monitoring (ABPM)
in the evaluation of children and adolescents with suspected
hypertension. ABPM is not only useful in identifying patients with
“white-coat” hypertension, but also it can identify individuals with
so called “masked” hypertension: those with normal blood pres-
sure readings in the office setting, but who are truly hypertensive.
Furthermore, ABPM data is extremely useful in accessing effectiveness
of antihypertensive regimens. Unfortunately, access to 24-hour ABPM
is often limited and may require referral to pediatric subspecialists.
The causes of hypertension are classified as either primary
(essential) or secondary when a specific etiology is identified.
Historically, secondary causes of hypertension have been thought to
predominate in the pediatric population (Vehaskari, 2009). However,
with the rising rates of childhood obesity, the AAP guidelines have
recognized that primary (essential) hypertension is now the most
common cause of hypertension in obese children older than 6
years of age with a positive family history of hypertension.
Secondary causes of hypertension vary with age. In infants younger
than 1 year of age, the majority of cases are caused by either coarctation
of the aorta or renovascular disease. Renovascular disease may also
present later in childhood. In school-age children, the dominant
secondary causes of hypertension are renal parenchymal diseases
including reflux nephropathy. Malignancy-associated hypertension,
primarily with Wilms tumor and nephroblastoma, typically presents
in infancy and early childhood, and pheochromocytoma is seen
more frequently in the adolescent population. Secondary causes of
hypertension should still be sought in adolescents, however, this
population, much like adults, is far more likely to have primary
(essential) hypertension.
Although hypertension is becoming more common in children,
the differential diagnosis of childhood hypertension is quite broad.
Features from the history, the physical, the age of the patient, and
even the blood pressure values themselves can narrow the diagnostic
focus. A secondary cause for hypertension should always be sought
in infants younger than 1 year of age, and secondary causes should
also be investigated thoroughly in preadolescent children as renal
disease is the most common secondary cause of hypertension in
this age group. The new AAP guidelines recognize that the impact
of obesity extends even into the early school-age population as
the previous guidelines recommended only a limited investigation
into secondary causes of hypertension in patients older than 6 years
of age with obesity, a strong family history of essential hypertension,
and an unrevealing history and physical examination. Review of the
patient’s history should be focused on two areas; firstly, the presence
of symptoms suggestive of hypertensive injury such as headaches,
dizziness, diplopia, or vomiting; and secondly, information that
provides insight into underlying causes of hypertension including
neonatal history, urinary tract infections or unexplained fevers, signs
and symptoms of renal or cardiac disease, chronic illness, medications,
and family history of hypertension, kidney disease, early-onset
cardiovascular disease, and diabetes.
The patient’s weight, height, and growth percentiles should be
defined. Ideally blood pressure measurements should be obtained
in both upper extremities and in at least one lower extremity. The
physical examination should focus on identifying signs of underlying
disorders that are associated with hypertension.
Recommended initial diagnostic testing in all patients with
confirmed hypertension includes a urinalysis, electrolytes, BUN,
creatinine, and a lipid profile. Although commonly utilized, the current
AAP guidelines do not recommend screening renal ultrasonography
for patients older than 6 years of age unless there is an abnormal
urinalysis or abnormal renal function. Additional testing such as
renin and aldosterone levels; catecholamines; cortisol levels; genetic
testing for forms of monogenic hypertension; or advanced imaging
studies including VCUG, dimercaptosuccinic acid (DMSA) renal
scans, CT angiography, magnetic resonance angiography (MRA), or
angiography are often required based on an individual patient’s
clinical findings, initial screening studies, and the severity of the
hypertension. Echocardiograms are no longer recommended as part
of the initial screening of patients with confirmed hypertension.
However, baseline echocardiography is now recommended at the
initiation of pharmacologic therapy for all patients regardless of the
etiology of their hypertension.
For patients with stage 1 hypertension or those with primary
(essential) hypertension without end-organ damage, therapeutic
lifestyle changes are the initial intervention of choice (Lurbe et al.,
2009). There is clear data that support dietary modification (DASH
diet), weight loss, and exercise in reducing blood pressure in children
and adolescents. However, like all behavioral interventions, the
long-term success of therapeutic lifestyle changes requires engagement
not only of the patient, but of family members as well.
Pharmacologic therapy should be considered in patients with
primary (essential) hypertension who do not have improvement in
their blood pressure after a trial of therapeutic lifestyle changes, or
in patients with stage 2 hypertension, evidence of end-organ damage,
symptomatic hypertension, or secondary hypertension (Flynn and
Daniels, 2006). Unlike adult hypertension guidelines, there are no
data or evidence-based guidelines regarding which drug to select
when initiating pharmacologic therapy. Acceptable first-line agents
include diuretics, β-blockers, ACE inhibitors, ARBs, and calcium
channel blockers. Rather than standardized approaches to pharma-
cologic therapy, most practitioners individualize therapy with the
underlying renal, cardiac, or endocrine conditions guiding the choice
of the initial agent. This would include the use of RAAS blockage
for those with glomerulonephritis and other forms of CKD because
of the additional benefit in terms of preventing CKD progression.
Along similar lines is the use of RAAS inhibition in patients with
type 1 or type 2 diabetes mellitus as these agents may slow or prevent
the development of diabetic nephropathy. Conversely, the use of
β-blockers in patients with asthma is not recommended. Adverse
effects of each agent and available formulations need to be considered,
because many standard adult hypertensive medications are not
available in liquid formulations or are in fixed ratios that are not
suitable for the pediatric population. Patients and families should
be counseled about the potential side effects of the medications
before initiation of therapy; this is especially important for adolescents
who are engaged in organized sports and may be at risk for dehydra-
tion and acute kidney injury while on RAAS or diuretic therapy, and
for sexually active adolescents on RAAS therapy regarding the potential
for ACE fetopathy. Once therapy is initiated, blood pressure should
be monitored closely, including laboratory monitoring, both for
efficacy of the antihypertensive medication and for potential side
effects. The goals of therapy for patients without diabetes or CKD
have also been revised in the current AAP guidelines. Based on data
suggesting that end-organ damage is present in patients with blood
pressures greater than the 90th percentile but less than the 95th
KEY POINTS
• The increase in prevalence of pediatric hypertension in
recent years is closely linked to increasing obesity rates in
children.
• Up to one-fourth of patients have normal blood pressures
outside of the office setting (“white coat” hypertension).
• Therapeutic lifestyle changes are the initial intervention of
choice for patients with primary hypertension without
end-organ damage.

TABLE 21.1  KDIGO Criteria for Acute Kidney Injury
SERUM CREATININE URINE OUTPUT
STAGE CHANGES CHANGES
I SCr increase ≥0.3 mg/dL in <0.5 mL/kg/h for
48 h or 6–12 h
1.5–1.9 times baseline
II SCr increase 2.0–2.9 times <0.5 mL/kg/h for
baseline 12 h
III SCr ≥3.0 increase or < 0.5 mL/kg/h
SCr >4.0 mg/dL or for 24 h or
If <18 years of age, estimated <0.3 mL/kg/h for
creatinine clearance 12 h
<35 mL/min/1.73 m2
h, Hour; KDIGO, Kidney Disease Improvng Global Outcomes; SCr, serum
creatinine.
Modified from Kellum JA, Lameire N; KDIGO AKI Guideline Work Group.
Diagnosis, evaluation, and management of acute kidney injury: a KDIGO
summary (Part 1). Crit Care 17(1):204, 2013.
percentile, the current guidelines recommend a target blood pressure
goal of less than 90%, or less than 130/80 for adolescents. Lower
target goals are recommended for patients with CKD or diabetes
mellitus (<50th percentile).
ACUTE KIDNEY INJURY
Acute kidney injury (AKI) is currently defined as an abrupt reduc-
tion in kidney function characterized by an absolute increase in
serum creatinine of more than 0.3 mg/dL, a relative increase in
serum creatinine of 50% from baseline, or 6 hours or more of
oliguria (< 0.5 mL/kg/h of urine output). This precise definition
is a result of a large body of work that recognized that AKI is a
continuum renal injury wherein reductions in renal function are
linked to adverse outcomes (Table 21.1 and Box 21.4) and shifts the
focus to earlier detection and treatment of AKI before the development
of significant morbidity, as noted in KDIGO staging table (Devarajan,
2013; Mehta et al., 2016; Selewski et al., 2014). Recent data suggest
that the incidence of AKI is roughly 4 cases per 1000 pediatric hospital
admissions, where as AKI is seen in up to one-third of all children
admitted to intensive care units and one-half of pediatric patients
with shock (Lameire et al., 2017). Patients with AKI have been
reported to have a nearly 15-fold increased mortality risk compared
with patients without AKI (15% vs. 0.6%) (Fitzgerald et al., 2016;
Kaddourah et al., 2017). The estimated incidence of AKI requiring
dialysis ranges from 1% to 2% in critically ill children (Slater et al.,
2016; Sutherland et al., 2013). AKI can result from ischemic, toxic,
or inflammatory mechanisms and can be further classified as caused
by renal hypoperfusion (prerenal), structural injury to the kidneys
(intrinsic), or urinary tract obstruction (postrenal). Primary renal
disease is no longer the predominate cause of intrinsic AKI and has
been supplanted by a heterogeneous mix of pathologic conditions
including multiple organ failure, renal ischemia, nephrotoxic injury,
congenital heart disease, bone marrow transplantation, and sepsis.
The diagnosis of AKI is dependent on increases in serum creatinine
compared with baseline levels. As opposed to the adult population,
normal serum creatinine levels vary in the pediatric population based
on age, muscle mass, and body size; therefore there is no absolute
creatinine level that defines pediatric AKI. Typically renal function
needs to decrease by 50% before a change in serum creatinine can
be measured, and changes in creatinine commonly lag behind the
reduction in renal function (GFR) by 24 to 72 hours. This lack of
sensitivity and delayed response has presented challenges to early
identification of patients with AKI. A number of biomarkers to
identify early AKI have been developed; these include neutrophil
gelatinase-associated lipocalin (NGAL), kidney injury molecule-1
Chapter 21  Urologic Aspects of Pediatric Nephrology 353
BOX 21.4  Causes of Acute Kidney Injury
Decreased true intravascular volume
• Third-space losses: sepsis, trauma, burns, nephrotic
syndrome
• Gastrointestinal losses
• Salt wasting: renal or adrenal
• Diabetes insipidus: central or renal
Decreased apparent intravascular volume: congestive heart
failure
Acute tubular necrosis/cortical necrosis
• Hypoxic-ischemic insults
• Medications: aminoglycosides, intravenous contrast
agents, nonsteroidal anti-inflammatory drugs,
chemotherapeutics
• Exogenous toxins: ethylene glycol, methanol
• Endogenous toxins: hemoglobin, myoglobin
Tumor lysis syndrome and uric acid nephropathy
Interstitial nephritis
• Medication induced: anticonvulsants, antibiotics
• Idiopathic
Glomerulonephritis: all causes
Vascular disorders
• Hemolytic uremic syndrome
• Renal artery or vein thrombosis
Infection
• Pyelonephritis
• Sepsis
Obstructive lesions
• Obstructed single kidney
• Bilateral ureteral obstruction
• Urethral obstruction
(KIM-1), and interleukin-18. Although there is substantial data
in the adult population regarding the sensitivity and specificity of
these biomarkers, and although there are emerging pediatric data,
these biomarkers have not yet entered widespread clinical use, and
the application of the data from adult studies is challenging in the
pediatric population.
Differentiating between functional and intrinsic AKI is essential.
Functional AKI is a sodium-avid state with maximal reabsorption
of solutes and water by the intact proximal tubule; on the other
hand, the tubular damage typical of intrinsic AKI results in impaired
reabsorptive capacity of the proximal tubule. Functional AKI is
typically characterized by fractional excretion of sodium (FENa) less
than 1%, and greater than 3% is characteristic of intrinsic AKI.
However, the use of FENa in patients on diuretic therapy is unreliable.
In this setting, the fractional excretion of urea (FEUrea) is very useful,
with FEUrea less than 35% being indicative of prerenal AKI.
AKI results in the disruption of normal electrolyte and fluid
homeostasis. Common complications include hyponatremia caused
by excessive free water retention, hypernatremia from sodium
administration, hyperkalemia caused by reduction in glomerular
filtration and tubular potassium secretion, anion gap metabolic
acidosis secondary to impaired renal hydrogen ion excretion and
concurrent impairment of bicarbonate reabsorption and regeneration,
hyperphosphatemia caused by reduced renal excretion, and hypo-
calcemia secondary to increased serum phosphate and impaired
vitamin D metabolism. Fluid overload in patients with AKI is chal-
lenging as adequate fluid resuscitation is essential for tissue perfusion
in patients with prerenal AKI. However, there is a clear association
between excessive fluid accumulation and adverse outcomes in the
pediatric population.
Prerenal AKI requires prompt and vigorous fluid resuscitation
with isotonic fluids. The use of potassium-containing fluids should
be avoided until urine output is established and the severity of AKI
354 PART III  Pediatric Urology
is defined. If oliguria is present, conservative fluid management
should be instituted. Fluid intake should therefore be limited to
match output including insensible fluid loss with replacement of
output. If patients are fluid overloaded, then urine output should
not be replaced, and diuretics are likely indicated. If adequate urine
output cannot be achieved with diuretic therapy, RRT may be required.
In addition, aggressive nutritional support is essential for all patients
with AKI (Kyle et al., 2013). Adequate calories should be provided
that meet maintenance requirements and to limit or prevent excessive
catabolism. Protein intake should not be restricted. If adequate
nutrition cannot be achieved because of fluid restriction, early
institution of RRT should be considered. Nephrotoxic agents should
be avoided in AKI, as they may worsen the injury or delay recovery
of function. Medications should be adjusted based on residual renal
function. Importantly, patients in the early phase of AKI should be
assumed to have a GFR of less than 15 mL/min/1.73 m2, regardless
of the absolute value of the serum creatinine.
Indications for initiating RRT in AKI typically include fluid overload
that is unresponsive to diuretics, the need to deliver adequate nutri-
tion, or to address hyperkalemia or metabolic disturbances that are
refractory to medical therapy, and symptomatic uremia. RRT options
include hemodialysis, peritoneal dialysis, and continuous renal
replacement therapy (CRRT). The choice of dialysis modality depends
on the patient’s clinical status, the available clinical expertise, and
the availability of appropriate resources. Hemodialysis provides the
most efficient and rapid correction of fluid and electrolyte distur-
bances; however hemodialysis can be poorly tolerated in patients
with hemodynamic instability. Therefore, CRRT via hemodialysis
has become the standard of care as it delivers slow continuous
correction of fluid overload and electrolyte imbalances. Peritoneal
dialysis is also a CRRT modality and has been preferred in neonates
and small infants when central venous access can prove challenging.
The advantages of peritoneal dialysis include ease of performance
and avoiding the requirement for specialized equipment, personnel,
or anticoagulation. In critically ill children with respiratory failure,
dwell volumes in the peritoneal cavity may be poorly tolerated, and
previous abdominal surgery with compromise of the peritoneum,
intra-abdominal infection, and ostomy placement can limit the
application of peritoneal dialysis.
Data suggest that children who have recovered from an episode
of AKI are at significant risk for CKD, as more than one-third have
been reported to have either reduced kidney function or were dialysis-
dependent on hospital discharge. Furthermore, nearly two-thirds of
the patients with long-term follow-up had evidence of CKD. These
data suggest that long-term follow-up is warranted for children who
survive an AKI episode.
KEY POINTS
• Hospitalized pediatric patients with AKI have a nearly
15-fold increased mortality risk compared with patients
without AKI.
• Prerenal AKI requires prompt and vigorous fluid
resuscitation with isotonic fluids.
• CRRT via hemodialysis has become the standard of care as
it delivers slow continuous correction of fluid overload
and electrolyte imbalances.
CHRONIC KIDNEY DISEASE
CKD is defined by the persistence of structural or functional abnor-
malities of the kidney for more than 3 months. The primary marker of
kidney damage using the Kidney Disease Outcomes Quality Initiative
(KDOQI) staging system is a decrease in GFR. This staging system
was developed to stratify the severity of CKD and to guide clinical
management, as the complications of CKD commonly develop at
specific GFR levels irrespective of the etiology of CKD. There are a
number of caveats with respect to applying this system to pediatrics.
First, the staging of CKD excludes patients younger than 2 years
TABLE 21.2 Classification of Chronic Kidney Disease
for Children Older Than 2 Years of Age
STAGE DEFINITION GFR (mL/min/1.73 m2)
I Normal or ↓ GFR (with ≥90
kidney damage)
II Mild ↓ GFR (with 60–89
kidney damage)
III Moderate ↓ GFR 30–59
IV Severe ↓ GFR 15–29
V Kidney failure <15 or dialysis
GFR, Glomerular filtration rate.
of age. A normal term infant has a GFR of approximately 40 mL/
min/1.73 m2, and, as part of normal renal developmental processes,
GFR does not reach final adult levels until nearly 2 years of age, thus
GFR increases during the first 2 years of life can make definitive CKD
staging in patients younger than 2 years of age problematic. Secondly,
the requirement for renal abnormalities to persist for more than 3
months to meet the criterion for CKD makes this staging system
inapplicable to newborns and infants younger than 3 months of age.
Causes of CKD in children are very different from those in
adults and vary by age group within the pediatric population. In
younger children, the most common causes are CAKUT: renal
hypoplasia/dysplasia and obstructive lesions such as posterior urethral
valves and prune belly syndrome. Renal cystic diseases, including
multicystic kidneys, cystic renal dysplasia, juvenile nephronophthisis,
and autosomal recessive polycystic kidney disease, are also common
causes of CKD during childhood. Glomerular diseases such as
nephrotic syndrome, focal segmental glomerulosclerosis, hemolytic
uremic syndrome, membranoproliferative glomerulonephritis,
membranous nephropathy, and lupus nephritis are uncommon causes
of CKD in early childhood, but by late childhood and early adoles-
cence, they become the predominant causes of CKD. Although the
prevalence of ESRD, including renal transplantation and chronic
dialysis, is well-defined, no incidence or prevalence data for pediatric
CKD are available from North American registries.
The frequency and severity of the complications of CKD increase
as CKD progresses. The classification of CKD is based on five stages
(Table 21.2), and stage-based care guidelines for the management
of these complications are detailed in consensus recommendation
by the KDOQI and KDIGO initiatives (Inker et al., 2014; KDIGO,
2009; KDOQI, 2009).
Protein malnutrition is seen in up to 20% of pediatric patients
with any stage of CKD and is more common in advanced CKD and
in infants and younger children. In younger children, the key factor
contributing to malnutrition is inadequate intake. Although the
underlying cause of malnutrition in children with CKD is often
multifactorial, it is extremely important that this be recognized and
treated promptly and aggressively, as malnutrition has been strongly
associated with mortality. Children with CKD often have an impaired
appetite, and this can be further complicated by nausea and vomiting.
They may also require the restriction of specific dietary components,
especially potassium and phosphate. Specialized formulas and diets
designed for children with CKD are often required. A pediatric dietitian
with experience in CKD/ESRD is essential to optimize caloric intake,
which is the overriding treatment goal for malnutrition in children
with CKD.
Growth impairment is a common complication in children with
CKD and can have a major psychological impact on a child while
negatively affecting their quality of life (QoL). Children with CKD
are approximately 1.5 standard deviations below normal for height,
and this height deficit is greatest in the youngest children. With
aggressive treatment of nutritional deficiencies and renal osteodys-
trophy, a normal growth pattern is usually reestablished until the
child reaches ESRD (CKD stage V). The causes of growth delay in

children with CKD include malnutrition/protein-energy wasting,
chronic acidosis, severe renal osteodystrophy, sodium depletion,
and growth hormone resistance. Where possible, treatment should
be directed to correction of these metabolic disturbances before the
introduction of growth hormone (Haffner et al., 2000). Children
with CKD are not growth hormone deficient, but rather have
abnormalities along the growth hormone activation pathway including
reduced production of insulin-like growth factor-1 (IGF-1), increased
circulating levels of IGF-binding proteins that reduce IGF-1 activity,
and resistance of bone to growth hormone activity. Despite the
consensus recommendations for children with growth impairment
and CKD, only about 1 in 4 children are prescribed recombinant
growth hormone.
CKD/mineral bone disease, a term now employed to replace renal
osteodystrophy, is a systemic disorder characterized by alterations in
mineral metabolism, bone deformities, and calcific cardiovascular
abnormalities in CKD. Insufficiency of 1,25(OH)2 vitamin D in CKD
can be a result of deficient activation of cholecalciferol to the active
form of 1,25-dihydrocholecalciferol in the kidney or a result of low
cholecalciferol levels as a result of dietary insufficiency. In the later
stages of CKD, retention of phosphate worsens as renal function
declines. Both the elevation of phosphate levels in plasma and a
fall in plasma calcium values stimulate parathyroid hormone secretion;
the parathyroid hormone then increases phosphate excretion by the
suppression of tubular phosphate reabsorption, thereby returning
phosphate values to normal but at the expense of persistently elevated
parathyroid hormone values. It has been shown that skeletal min-
eralization defects start in pediatric patients as early as CKD stage
II, even before defects of bone turnover or any biochemical abnormal-
ity, except for an increase in circulating FGF-23 levels. The effects of
metabolic bone disease on the epiphysis are unique to children with
CKD and include growth failure, slipped epiphysis, and rickets.
There are a number of therapeutic approaches to prevent and
treat renal bone disease in patients with CKD. Initially, if plasma
levels of 25-OH vitamin D are low, then vitamin D3 (cholecalciferol)
supplements should be prescribed. Calcitriol (Rocaltrol), active 1,25
vitamin D, is typically prescribed if the parathyroid hormone levels
exceeds the recommended limits and the calcium level is not elevated.
In the presence of elevated plasma phosphate values, if dietary
phosphate restriction is ineffective, phosphate binders such as calcium
carbonate, calcium acetate, or sevelamer should be prescribed.
Calcium-containing compounds are available in liquid formulations
and, therefore, are most easily used in young children. However,
excessive total calcium ingestion may lead to hypercalcemia, which
has been associated with vascular calcification, even in children.
Multiple studies have evaluated QoL and social behavior in children
with CKD and have shown lower health-related QoL scores when
compared with healthy controls and other children with chronic
medical conditions; in fact, patients with CKD/ESRD have lower
QoL scores than children with cancer. Children with CKD are also
at risk for neurocognitive impairment. Developmental problems
have been reported in as many as 25% of infants with renal disease
and correlates with the severity of renal dysfunction. Cognitive deficits
are also noted in older children, and the overall IQ of school-age
children with CKD is lower than the normal population.
Anemia is nearly universal in advanced CKD. The most common
cause of anemia with CKD is a deficiency of erythropoietin.
However, erythropoietin deficiency in CKD is often confounded by
other causes of anemia including iron deficiency, blood loss associated
with surgical procedures, and frequent phlebotomy. Erythropoietin-
stimulating agents are essential for the management of the anemia
in all CKD patients and especially in pediatric CKD patients (Kliger
et al., 2013). Either epogen or darbepoetin can be used to successfully
treat anemia in the vast majority of children with CKD. Iron therapy
is also required for nearly all children with CKD, however iron
therapy is affected by gastrointestinal side effects, and there is
decreased absorption with concomitant use of phosphate-binding
agents or proton pump inhibitors.
Children with CKD are in the highest risk category for cardio-
vascular disease, and registry data indicates that cardiovascular disease
accounts for nearly one-half of all deaths of children on dialysis.
Chapter 21  Urologic Aspects of Pediatric Nephrology 355
Contributing risk factors include chronic hypertension, dyslipidemia,
and abnormal mineral metabolism. Hypertension has been reported
in more than one-half of children with CKD, and, even with anti-
hypertensive medications, less than 50% were well controlled (ESCAPE
Trial Group et al., 2009; Mitsnefes, 2012; Taler et al., 2013). Left
ventricular hypertrophy is common in children with CKD, with
nearly 60% to 80% of children who are initiating dialysis having
left ventricular hypertrophy as well. Dyslipidemia is also seen in
approximately 39% to 65% of children with CKD. The most common
abnormality is hypertriglyceridemia, followed by elevated non-HDL
cholesterol and lower HDL cholesterol levels. It is estimated that
one-fourth of children have more than one lipid abnormality. Initial
treatment options usually involve nutrition and dietary modification
(Sarnak et al., 2015).
Electrolyte abnormalities in children with CKD are very common
and include metabolic acidosis from renal tubular dysfunction
and/or progressive uremia with ensuing retention of phosphate
or sulfate anions. Treatment consists of correction of the acidosis
with supplemental bicarbonate or citrate solutions and is particularly
important for growth and bone health. Hyponatremia may also
occur as a result of urinary sodium wasting and is commonly seen
in the setting of CKD associated with CAKUT. Hyperkalemia is
frequently seen as a result of impaired renal potassium excretion
and can be aggravated by concurrent metabolic acidosis; potassium
control is often focused on dietary restriction and modification.
The natural course of CKD is gradual deterioration of kidney
function. This decline does not occur in a linear fashion as the
later stages of CKD are associated with a more rapid progression.
Although there are no clear therapeutic interventions to prevent or
reverse progression of CKD, several factors have been identified that
may slow progression. In adults, intake of a reduced protein diet
may reduce proteinuria and slow the decline of kidney function.
However pediatric trials have shown that lower protein intake does
not provide any benefit as measured by the rate of decline in creatinine
clearance over a 2-year period. Therefore, it is not recommended to
restrict protein intake in pediatric patients with CKD unless evaluation
of an individual’s diet or laboratory values suggests that their protein
intake is clearly excessive. Strict blood pressure control is the only
intervention that has been shown to decrease progression of CKD
in children. Based on this, KDIGO guidelines recommend that the
target blood pressure for children should be the 50th percentile for
age, gender, and height, and particularly if children have proteinuria.
Children with obstructive uropathies, particularly those with inad-
equate bladder emptying including those who require intermittent
catheterization, as well as increasing hydronephrosis, which may
indicate partial lower tract obstruction, should be dealt with promptly
by a pediatric urologist. Similarly, for those with repeated urinary
tract infections, efforts should be focused on prevention either by
assuring appropriate bladder drainage or by using prophylactic daily
antibiotics.
KEY POINTS
• Causes of CKD in children are very different from those in
adults and vary by age group within the pediatric
population.
• The most common cause of anemia with CKD is a
deficiency of erythropoietin.
• With CKD, kidney function declines in a nonlinear
fashion as the later stages are associated with a more rapid
progression.
END-STAGE RENAL DISEASE: DIALYSIS AND
RENAL TRANSPLANTATION
ESRD is defined by the need for either chronic dialysis or kidney
transplantation to sustain life. There is no absolute creatinine or
BUN level that mandates the initiation of chronic dialysis. Typically
initiation of dialysis is considered in children who have reached
356 PART III  Pediatric Urology
CKD stage V (GFR <15 mL/min/1.73 m2) or when CKD is com-
plicated by uncontrolled hypertension, volume overload, metabolic
derangements, poor growth, or complications of uremia (Green-
baum and Shaefer, 2012). There are two chronic dialytic modalities
available for infants, children, and adolescents: peritoneal dialysis
and hemodialysis (Chand et al., 2017; Fischbach et al., 2005).
Selection of hemodialysis or peritoneal dialysis is dependent on a
number of factors including the needs of the patient and family,
patient size, age, lifestyle choices, and psychosocial risk.
Peritoneal dialysis is the most common initial modality for
children younger than 9 years of age and less than 20 kg, as the
treatment is provided at home and does not require central venous
access. For older children, it offers the advantage of greater flexibility
in the timing of treatments and better social integration. PD can be
successfully performed in many patients with prior urologic surgeries
including vesicostomies, however the presence of omphalocele,
gastroschisis, diaphragmatic hernia, or bladder exstrophy are con-
traindications to peritoneal dialysis.
Peritoneal dialysis is performed via a process of repeated instillation
and drainage of dialysis solution both into and out of the peritoneal
space via a surgically implanted peritoneal dialysis catheter. The
dialysate solutions contain electrolyte additives in physiologic
concentrations, with the exception of potassium and phosphorus,
to facilitate correction of electrolyte abnormalities and acid-base
abnormalities. The glucose concentration in the dialysis solution
creates an osmotic gradient that mediates the net movement of water
into the peritoneal cavity, which is referred to as ultrafiltration. In
peritoneal dialysis, solute clearance occurs via a process of diffusion
whereby solutes move from a compartment of higher concentration
to a compartment of lower concentration across the peritoneal
membrane and by convection whereby solutes move via solvent
drag with the movement of fluid between the blood and dialysate
compartments. Peritoneal dialysis is typically performed overnight
for 8 to 12 hours and thus achieves more steady metabolic and
blood pressure control than hemodialysis. Peritoneal dialysis can
be prescribed either manually (continuous ambulatory peritoneal
dialysis) or using an automated machine (continuous cycling
peritoneal dialysis). Continuous cycling peritoneal dialysis is pre-
scribed for the majority of pediatric patients in the United States.
The peritoneal dialysis prescription, including volumes, dwell times,
and dextrose concentration, is tailored to each child’s specific needs.
Infections, such as peritonitis and tunnel infections, are the
most common complications of peritoneal dialysis (Warady
et al., 2012). Peritonitis typically occurs more frequently in younger
children. Peritonitis typically presents with acute onset of abdominal
pain and cloudy dialysis fluid, and fluid with a white blood cell
count greater than 100/mm3 and at least 50% neutrophils meet
the presumptive criteria for peritonitis. Gram-positive organisms are
the most common cause of peritonitis in the pediatric population,
followed by culture-negative, and then gram-negative organisms.
Fungal peritonitis, although rare, can require discontinuation of
peritoneal dialysis, and transition to hemodialysis. Peritonitis can lead
to the development of intra-abdominal adhesions, and ultimately
peritoneal membrane failure. Peritoneal dialysis catheter exit site and
tunnel infections are also important risk factors for peritonitis and
can require catheter removal if persistent or recurrent. Noninfectious
complications of peritoneal dialysis include the development of
dialysate leak, abdominal hernias, hydrothorax, or hemoperitoneum.
In children older than 10 years of age, hemodialysis is the
predominant chronic dialysis modality in the United States. As
opposed to peritoneal dialysis, hemodialysis requires chronic central
venous access. The ability to maintain hemodialysis access in infants
and smaller children presents a major challenge for pediatric ESRD
care. Options for hemodialysis access include arteriovenous fistula;
arteriovenous graft, which uses a synthetic material to create a conduit
between an artery and a vein; and central venous hemodialysis
catheters. Arteriovenous fistulas have better survival rates and lower
rates of infection compared with arteriovenous grafts or hemodialysis
catheters and are recommended for children greater than 20 kg for
whom renal transplantation is not eminent (Ma et al., 2013). However
arteriovenous fistulas are not always technically possible, particularly
in younger children for whom a central hemodialysis catheter may
be necessary. Hemodialysis catheters are preferentially placed in the
internal jugular veins; the subclavian veins should be avoided because
of the risk for subclavian stenosis.
Hemodialysis removes metabolic waste products, solutes, and
excess fluid via diffusion, convection, and ultrafiltration. Diffusion
characterizes the solute movement across the semipermeable dialysis
membrane against a concentration gradient. Convection is the
movement of solutes with plasma water; it is determined by the
amount of ultrafiltration and characteristics of the dialysis membrane.
Ultrafiltration is the movement of water across the dialysis membrane
by convective flow caused by a pressure or osmotic gradient. Hemo-
dialysis fluid removal is determined by the transmembrane pressure
gradient across the dialysis membrane and the permeability of a
given dialysis membrane to water, and the dialysate solution contains
electrolytes in physiologic concentrations to normalize electrolytes
and correct acid-base abnormalities. Typically, pediatric patients
receive in-center hemodialysis 3 to 4 times per week for 4 hours at
a time to achieve adequate metabolic control and fluid balance.
Home hemodialysis is also an option for select patients and caregivers;
similar to peritoneal dialysis, home hemodialysis is provided daily
at night to provide more consistent metabolic control and fluid
balance than achieved with the thrice-weekly in-center hemodialysis
treatments (Hothi et al., 2016).
For the vast majority of pediatric patients with ESRD, the
ultimate treatment goal is renal transplantation, not long-term
dialysis. Pediatric patients younger than 18 years of age account for
less than 5% of all kidney transplantations performed in the United
States (Dharnidharka et al., 2014; Lau et al., 2012; United States
Renal Data System [USRDS], 2016). Of the approximately 900 annual
pediatric kidney transplants, about two-thirds are from deceased
donors and one-third are from living donors (primarily parents).
For patients with an identified living related donor, a preemptive
transplant before the need for dialysis is often recommended. The
transplant community has recognized the unique benefits that renal
transplantation has for pediatric ESRD patients, including improved
growth, neurocognitive development, and QoL. Therefore, children
on the transplant waiting list for deceased-donor organs before 18
years of age receive priority compared with the average adult deceased-
donor transplantation candidate. Furthermore, children are also
preferentially allotted kidneys from younger donors in an attempt
to optimize the life of the allograft. Overall outcomes for pediatric
kidney transplants are excellent, with 50% of deceased-donor
transplants functioning 12.5 years post-transplant and 50% of living-
donor kidneys functioning 20 years post-transplant. Almost all
children with ESRD should be considered for kidney transplantation;
absolute contraindications are few but include active malignancy or
uncontrolled infections. Cognitive impairment or intellectual disability
should not automatically exclude a patient from consideration of
kidney transplantation (Goldberg et al., 2015).
There are a number of unique considerations relating to renal
transplantation in the pediatric population. In infants, because of
technical issues and the increased risk for graft thrombosis, many
centers wait until the child is at least 10 kg and 65 cm in length
before proceeding with transplantation. As CAKUT is a common
cause of ESRD in the pediatric population, urinary tract repair or
reconstruction of anomalies needs to be addressed before transplanta-
tion to optimize outcomes. Compared with adults, immune-mediated
glomerular disease and focal segmental glomerulosclerosis are
common causes of ESRD in children, thus the risk for disease recur-
rence in the allograft must be considered both in terms of pretransplant
evaluation and postoperative care. This is particularly of concern for
primary focal segmental glomerulosclerosis, membranoproliferative
glomerulonephritis, C3 glomerulopathy, and atypical hemolytic
uremic syndrome. Adequate immunization before renal transplant
is also a necessity. Surgical removal of native kidneys is often con-
sidered in the peritransplant period; indications for nephrectomy
include chronic or recurrent pyelonephritis, hypertension refractory
to medical therapy, and uncontrolled nephrotic syndrome.
For most children less than 20 kg, the allograft is placed intra-
abdominally and anastomosed to the aorta and the inferior vena

cava. For children more than 20 kg, a retroperitoneal approach is used
with the allograft placed in the iliac fossa and vascular anastomoses
to the common or external iliac vessels. An antirefluxing anastomosis
for the donor ureter into the recipient bladder is common as this
will reduce the risk for vesicoureteral reflux into the allograft. The
use of ureteral stents at the time of transplantation to reduce the
risk for ureteral obstruction appears to be largely center-specific.
In the immediate post-transplant period, primary graft dysfunc-
tion is reported to occur in less than 3% of pediatric kidney
allografts, with delayed graft function requiring dialysis being
reported in 5% of pediatric related living-donor allografts and
15% of pediatric deceased-donor allografts.
Immunosuppression, both in terms of induction at the time of
transplantation and chronic maintenance therapy, are needed for
long-term function of the allograft. Most pediatric transplant centers
now use antibody-based agents such as thymoglobulin or basiliximab
at the time of transplantation for induction therapy. Thereafter,
children are typically maintained on long-term immunosuppression
with a calcineurin inhibitor (tacrolimus or cyclosporine) and an
antiproliferative agent such as mycophenolate mofetil. In the past
decade, there has been a reduction in the use of steroids as part
of maintenance therapy, with many centers adopting steroid-free
maintenance immunosuppression for children thought to be at lower
immunologic risk for rejection.
Infectious complications are a concern in all transplant recipients,
particularly in younger children who may not yet have acquired native
immunity to cytomegalovirus (CMV), Epstein-Barr virus, or the BK
virus. Transplant centers commonly use valganciclovir as prophylaxis
to reduce the risk for CMV disease. Trimethoprim-sulfamethoxazole is
often used for prophylaxis against Pneumocystis carinii pneumonia early
in the post-transplant period. However, chronic immunosuppression
also increases the risk for renal cell carcinoma, thyroid carcinoma, and
cutaneous malignancies by nearly sevenfold in transplant recipients
compared with the general pediatric population.
In the pediatric renal transplant population, the risk for acute
cellular rejection in the first year post-transplant is less than 10%
in living-donor transplants and approximately 15% in deceased-
donor transplants. Generally the rates of acute rejection decrease
over the life of a renal allograft. Although most rejection episodes
are reversible, rejection episodes negatively affect long-term graft
function. Antibody-mediated rejection is increasingly being recognized
as a cause of allograft dysfunction. The impact on antibody-mediated
rejection on long-term allograft function and the treatment strategies
for antibody-mediated rejection are areas of ongoing investigation;
many centers are now using a combination of therapies for antibody-
mediated rejection including intravenous immunoglobulin, rituximab,
and/or apheresis. Over time, all transplants will lose substantial
function as a result of a process-labeled chronic allograft nephropathy
for which there is no current therapeutic intervention. With this
progressive decline in allograft function, nearly all pediatric renal
transplant recipients will eventually require either retransplantation
or a return to dialysis.
KEY POINTS
• Peritoneal dialysis is the most common initial modality
for dialysis in children younger than 9 years of age and
less than 20 kg.
• The unique benefits of renal transplantation include
improved growth, neurocognitive development, and QoL.
• The risk for acute cellular rejection in the first year after
pediatric renal transplantation is less than 10% in living-
donor transplants.
• The risk for acute cellular rejection in the first year
post-transplant is approximately 15% in deceased-donor
transplants.
Chapter 21  Urologic Aspects of Pediatric Nephrology 357
SUMMARY
Effective partnership between pediatric urologists and pediatric
nephrologists is needed for the optimal care of pediatric patients
with kidney and urinary tract abnormalities. Although differences in
opinion regarding best approaches may exist, a careful appreciation of
the expertise of both specialties is needed, as both have expert teams
of health care providers that can provide the full spectrum of care for
these complex issues. As a result of these specialties working closely
together, the management of these disorders has clearly improved
to provide future generations of children with improved health and
less burden from their kidney and urinary tract diseases.
SUGGESTED READINGS
Batlle D, Haque SK: Genetic causes and mechanisms of distal renal tubular
acidosis, Nephrol Dial Transplant 27(10):3691–3704, 2012.
Ben-Shalom E, Frishberg Y: Primary hyperoxalurias: diagnosis and treatment,
Pediatr Nephrol 30(10):1781–1791, 2015.
Chand D, Swartz S, Tuchman S, et al: Dialysis in children and adolescents:
the pediatric nephrology perspective, Am J Kidney Dis 69(2):278–286,
2017.
Dharnidharka VR, Fiorina P, Harmon WE: Kidney transplantation in children,
N Engl J Med 371(6):549–558, 2014.
Dodge WF, West EF, Smith EH, et al: Proteinuria and hematuria in school-
children: epidemiology and early natural history, J Pediatr 88(2):327–347,
1976.
Edvardsson VO, Goldfarb DS, Lieske JC, et al: Hereditary causes of kidney
stones and chronic kidney disease, Pediatr Nephrol 28(10):1923–1942,
2013.
ESCAPE Trial Group, Wühl E, Trivelli A, et al: Strict blood-pressure control
and progression of renal failure in children, N Engl J Med 361(17):1639–1650,
2009.
Falkner B: Hypertension in children and adolescents: epidemiology and
natural history, Pediatr Nephrol 25(7):1219–1224, 2010.
Flynn JT, Kaelber DC, Baker-Smith CM, et al: Clinical practice guideline for
screening and management of high blood pressure in children and
adolescents, Pediatrics 140(3):e20171904, 2017.
Hernandez JD, Ellison JS, Lendvay TS: Current trends, evaluation, and
management of pediatric nephrolithiasis, JAMA Pediatr 169(10):964–970,
2015.
Inker LA, Astor BC, Fox CH, et al: KDOQI US commentary on the 2012
KDIGO clinical practice guideline for the evaluation and management of
CKD, Am J Kidney Dis 63(5):713–735, 2014.
Kaddourah A, Basu RK, Bagshaw SM, et al: Epidemiology of acute kidney
injury in critically ill children and young adults, N Engl J Med 376(1):11–20,
2017.
Little MH, McMahon AP: Mammalian kidney development: principles, progress,
and projections, Cold Spring Harb Perspect Biol 4(5):a008300, 2012.
Savige J, Gregory M, Gross O, et al: Expert guidelines for the management
of Alport syndrome and thin basement membrane nephropathy, J Am Soc
Nephrol 24(3):364–375, 2013.
Torres VE, Harris PC, Pirson Y: Autosomal dominant polycystic kidney disease,
Lancet 369(9569):1287–1301, 2007.
REFERENCES
The complete reference list is available online at ExpertConsult.com.

REFERENCES
Abitbol C, Zilleruelo G, Freundlich M, et al: Quantitation of proteinuria
with urinary protein/creatinine ratios and random testing with dipsticks
in nephrotic children, J Pediatr 116(2):243–247, 1990.
Batlle D, Haque SK: Genetic causes and mechanisms of distal renal tubular
acidosis, Nephrol Dial Transplant 27(10):3691–3704, 2012.
Ben-Shalom E, Frishberg Y: Primary hyperoxalurias: diagnosis and treatment,
Pediatr Nephrol 30(10):1781–1791, 2015.
Bergmann C, Senderek J, Schneider F, et al: PKHD1 mutations in autosomal
recessive polycystic kidney disease (ARPKD), Hum Mutat 23(5):453–463,
2004.
Braun DA, Lawson JA, Gee HY, et al: Prevalence of monogenic causes in
pediatric patients with nephrolithiasis or nephrocalcinosis, Clin J Am Soc
Nephrol 11(4):664–672, 2016.
Büscher AK, Beck BB, Melk A, et al: Rapid response to cyclosporin A and
favorable renal outcome in nongenetic versus genetic steroid-resistant
nephrotic syndrome, Clin J Am Soc Nephrol 11(2):245–253, 2016.
Cabral DA, Canter DL, Muscal E, et al: Comparing presenting clinical features
of 48 children with microscopic polyangiitis against 183 having granulo-
matosis with polyangiitis. An ARChiVe cohort study, Arthritis Rheumatol
68(10):2514–2526, 2016.
Carlisle EJF, Donnelly SM, Halprin ML: Renal tubular acidosis (RTA): recognize
the ammonium defect and pHorget the urine pH, Pediatr Nephrol
5(2):242–248, 1991.
Chand D, Swartz S, Tuchman S, et al: Dialysis in children and adolescents:
the pediatric nephrology perspective, Am J Kidney Dis 69(2):278–286,
2017.
Combes AN, Davies JA, Little MH: Cell-cell interactions driving kidney
morphogenesis, Curr Top Dev Biol 112:467–508, 2015.
Cossey LN, Walker PD, Larsen CP: Phospholipase A2 receptor staining in
pediatric idiopathic membranous glomerulopathy, Pediatr Nephrol
28(12):2307–2311, 2013.
Devarajan P: Pediatric acute kidney injury: different from acute renal failure
but how and why?, Curr Pediatr Rep 1(1):34–40, 2013.
Devuyst O, Thakker RV: Dent’s disease, Orphanet J Rare Dis 5:28, 2010.
Dharnidharka VR, Fiorina P, Harmon WE: Kidney transplantation in children,
N Engl J Med 371(6):549–558, 2014.
Din-Dzietham R, Liu Y, Bielo MV, et al: High blood pressure trends in children
and adolescents in national surveys, 1963 to 2002, Circulation 116(13):1488–
1496, 2007.
Dodge WF, West EF, Smith EH, et al: Proteinuria and hematuria in school-
children: epidemiology and early natural history, J Pediatr 88(2):327–347,
1976.
Dudley J, Smith G, Llewelyn-Edwards A, et al: Randomized, double-blind,
placebo-controlled trial to determine whether steroids reduce the incidence
and severity of nephropathy in Henoch-Schönlein purpura, Arch Dis Child
98(10):756–763, 2013.
Edvardsson VO, Goldfarb DS, Lieske JC, et al: Hereditary causes of kidney
stones and chronic kidney disease, Pediatr Nephrol 28(10):1923–1942,
2013.
ESCAPE Trial Group, Wühl E, Trivelli A, et al: Strict blood-pressure control
and progression of renal failure in children, N Engl J Med 361(17):1639–
1650, 2009.
Falkner B: Hypertension in children and adolescents: epidemiology and
natural history, Pediatr Nephrol 25(7):1219–1224, 2010.
Fischbach M, Edefonti A, Schröder C, et al: European Pediatric Dialysis Working
Group. Hemodialysis in children: general practical guidelines, Pediatr
Nephrol 20(8):1054–1066, 2005.
Fitzgerald JC, Basu RK, Akcan-Arikan A, et al: Acute kidney injury in pediatric
severe sepsis: an independent risk factor for death and new disability, Crit
Care Med 44(12):2241–2250, 2016.
Flynn JT, Daniels SR: Pharmacologic treatment of hypertension in children
and adolescents, J Pediatr 149(6):746–754, 2006.
Flynn JT, Kaelber DC, Baker-Smith CM, et al: Clinical practice guideline for
screening and management of high blood pressure in children and
adolescents, Pediatrics 140(3):e20171904, 2017.
Gattineni J, Baum M: Developmental changes in renal tubular transport - an
overview, Pediatr Nephrol 30(12):2085–2098, 2015.
Gleason CA: Prostaglandins and the developing kidney, Semin Perinatol
11(1):12–21, 1987.
Goldberg AM, Amaral S, Moudgil A: Developing a framework for evaluating
kidney transplantation candidacy in children with multiple comorbidities,
Pediatr Nephrol 30(1):5–13, 2015.
Greenbaum LA, Shaefer F: The decision to initiate dialysis in a pediatric
patient. In Warady BA, Schaefer F, Alexander SR, editors: Pediatric dialysis,
New York, NY, 2012, Springer, pp 85–100.
Haffner D, Schaefer F, Nissel R, et al: Effect of growth hormone treatment
on the adult height of children with chronic renal failure. German Study
Chapter 21  Urologic Aspects of Pediatric Nephrology 357.e1
Group for Growth Hormone Treatment in Chronic Renal Failure, N Engl
J Med 343(13):923–930, 2000.
Hernandez JD, Ellison JS, Lendvay TS: Current trends, evaluation, and
management of pediatric nephrolithiasis, JAMA Pediatr 169(10):964–970,
2015.
Hiraki LT, Feldman CH, Liu J, et al: Prevalence, incidence, and demo- graphics
of systemic lupus erythematosus and lupus nephritis from 2000 to 2004
among children in the US Medicaid beneficiary population, Arthritis Rheum
64(8):2669–2676, 2012.
Hogg RJ, Portman RJ, Milliner D, et al: Evaluation and management of
proteinuria and nephritic syndrome in children: recommendation from
a pediatric nephrology panel established at the National Kidney Foundation
Conference on proteinuria, albuminuria, risk assessment, detection, and
elimination (Parade), Pediatrics 105(6):1242–1249, 2000.
Hothi DK, Stronach L, Sinnott K: Home hemodialysis in children, Hemodial
Int 20(3):349–357, 2016.
Igarashi P, Somlo S: Genetics and pathogenesis of polycystic kidney disease,
J Am Soc Nephrol 13(9):2384–2398, 2002.
Inker LA, Astor BC, Fox CH, et al: KDOQI US commentary on the 2012
KDIGO clinical practice guideline for the evaluation and management of
CKD, Am J Kidney Dis 63(5):713–735, 2014.
Kaddourah A, Basu RK, Bagshaw SM, et al: Epidemiology of acute kidney
injury in critically ill children and young adults, N Engl J Med 376(1):11–20,
2017.
Kashtan CE, Ding J, Gregory M, et al: Clinical practice recommendations for
the treatment of Alport syndrome, Pediatr Nephrol 28(1):5–11, 2013.
Kaskal FJ, Kumar FM, Feld LG, et al: Renal reabsorption of phosphate during
development: tubular events, Pediatr Nephrol 2(1):129–134, 1988.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work
Group: KDIGO clinical practice guideline for the diagnosis, evaluation,
prevention, and treatment of chronic kidney disease–mineral and bone
disorder (CKD-MBD), Kidney Int Suppl 113:S1–S130, 2009.
Kidney Disease: Improving Global Outcomes (KDIGO): Glomerulonephritis
Work Group. KDIGO clinical practice guideline for glomerulonephritis,
Kidney Int Suppl 2(2):139–274, 2012.
Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guideline
for nutrition in children with CKD: 2008 update. Executive summary, Am
J Kidney Dis 53(3 Suppl 2):S11–S104, 2009.
Kiryluk K, Moldoveanu Z, Sanders JT, et al: Aberrant glycosylation of IgA1
is inherited in both pediatric IgA nephropathy and Henoch-Schönlein
purpura nephritis, Kidney Int 80(1):79–87, 2011.
Kliger AS, Foley RN, Goldfarb DS, et al: KDOQI US commentary on the
2012 KDIGO Clinical Practice Guideline for Anemia in CKD, Am J Kidney
Dis 62(5):849–859, 2013.
Kyle UG, Akcan-Arikan A, Orellana RA, et al: Nutrition support among critically
ill children with AKI, Clin J Am Soc Nephrol 8(4):568–574, 2013.
Lameire N, Van Biesen W, Vanholder R: Epidemiology of acute kidney injury
in children worldwide, including developing countries, Pediatr Nephrol
32(8):1301–1314, 2017.
Lau KK, Giglia L, Chan H, et al: Management of children after renal trans-
plantation: highlights for general pediatricians, Transl Pediatr 1(1):35–46,
2012.
Little MH, McMahon AP: Mammalian kidney development: principles, progress,
and projections, Cold Spring Harb Perspect Biol 4(5):a008300, 2012.
Loirat C, Fakhouri F, Ariceta G, et al: An international consensus approach
to the management of atypical hemolytic uremic syndrome in children,
Pediatr Nephrol 31(1):15–39, 2015.
Lovric S, Ashraf S, Tan W, et al: Genetic testing in steroid-resistant nephrotic
syndrome: when and how?, Nephrol Dial Transpl 31(11):1802–1813,
2015.
Lurbe E, Cifkova R, Cruickshank JK, et al: Management of high blood pressure
in children and adolescents: recommendations of the European Society
of Hypertension, J Hypertens 27(9):1719–1742, 2009.
Ma A, Schroff R, Hothi D, et al: A comparison of arteriovenous fistulas and
central venous lines for long term chronic hemodialysis, Pediatr Nephrol
28(2):321–326, 2013.
Mehta RL, Burdmann EA, Cerdá J, et al: Recognition and management of
acute kidney injury in the International Society of Nephrology 0by25
Global Snapshot: a multinational cross-sectional study, Lancet
387(10032):2017–2025, 2016.
Mina R, von Scheven E, Ardoin SP, et al: Consensus treatment plans for
induction therapy of newly diagnosed proliferative lupus nephritis in
juvenile systemic lupus erythematosus, Arthritis Care Res (Hoboken)
64(3):375–383, 2012.
Mitsnefes MM: Cardiovascular disease in children with chronic kidney disease,
J Am Soc Nephrol 23(4):578–585, 2012.
Moe OW, Seldin DW, Baum M: The Fanconi syndrome. In Lifton R, Somlo
S, Seldin DW, et al, editors: Genetic diseases of the kidney, New York, NY,
2009, Elsevier, pp 171–198.
357.e2 PART III  Pediatric Urology
Muntner P: Trends in blood pressure among children and adolescents, JAMA
291(17):2107, 2004.
National High Blood Pressure Education Program Working Group on High
Blood Pressure in Children and Adolescents: The fourth report on the
diagnosis, evaluation, and treatment of high blood pressure in children
and adolescents, Pediatrics 114(2 Suppl 4th Report):555–576, 2004.
Nazzal L, Puri S, Goldfarb DS: Enteric hyperoxaluria: an important cause of
end-stage kidney disease, Nephrol Dial Transplant 31(3):375–382, 2016.
Nesterova G, Gahl WA: Cystinosis: the evolution of a treatable disease, Pediatr
Nephrol 28(1):51–59, 2013.
O’Shaughnessy KM: Gordon syndrome: a continuing story, Pediatr Nephrol
30(11):1903–1908, 2015.
Palmer BF: Regulation of potassium homeostasis, Clin J Am Soc Nephrol
10(6):1050–1060, 2015.
Pickering MC, D’Agati VD, Nester CM, et al: C3 glomerulopathy: consensus
report, Kidney Int 84(6):1079–1089, 2013.
Quigley R, Baum M: Neonatal acid base balance and disturbances, Semin
Perinatol 28(2):97–102, 2004.
Quigley R: Developmental changes in renal function, Curr Opin Pediatr
24(2):184–190, 2012.
Redwine KM, Acosta AA, Poffenbarger T, et al: Development of hypertension
in adolescents with pre-hypertension, J Pediatr 160(1):98–103, 2012.
Sarnak MJ, Bloom R, Muntner P, et al: KDOQI US commentary on the 2013
KDIGO clinical practice guideline for lipid management in CKD, Am J
Kidney Dis 65(3):354–366, 2015.
Sas DJ: An update on the changing epidemiology and metabolic risk factors in
pediatric kidney stone disease, Clin J Am Soc Nephrol 6(8):2062–2068, 2011.
Savige J, Gregory M, Gross O, et al: Expert guidelines for the management
of Alport syndrome and thin basement membrane nephropathy, J Am Soc
Nephrol 24(3):364–375, 2013.
Savige J, Colville D, Rheault M, et al: Alport syndrome in women and girls,
Clin J Am Soc Nephrol 11(9):1713–1720, 2016.
Schell C, Wanner N, Huber TB: Glomerular development–shaping the multi-
cellular filtration unit, Semin Cell Dev Biol 36:39–49, 2014.
Schell-Feith EA, Kist-van Holthe JE, van der Heijden AJ: Nephrocalcinosis in
preterm neonates, Pediatr Nephrol 25(2):221–230, 2010.
Schwartz GJ, Muñoz A, Schneider MF, et al: New equations to estimate GFR
in children with CKD, J Am Soc Nephrol 20(3):629–637, 2009.
Selewski DT, Cornell TT, Heung M, et al: Validation of the KDIGO acute
kidney injury criteria in a pediatric critical care population, Intensive Care
Med 40(10):1481–1488, 2014.
Seyberth HW, Schlingmann KP: Bartter- and Gitelman-like syndromes: salt-
losing tubulopathies with loop or DCT defects, Pediatr Nephrol 26(10):1789–
1802, 2011.
Short KM, Smyth IM: The contribution of branching morphogenesis to kidney
development and disease, Nat Rev Nephrol 12(12):754–767, 2016.
Slater MB, Gruneir A, Rochon PA, et al: Risk factors of acute kidney injury
in critically ill children, Pediatr Crit Care Med 17(9):e391–e398, 2016.
Smith-Bindman R, Aubin C, Bailitz J, et al: Ultrasonography versus computed
tomography for suspected nephrolithiasis, N Engl J Med 371(12):1100–1110,
2014.
Sutherland SM, Ji J, Sheikhi FH, et al: AKI in hospitalized children: epidemiol-
ogy and clinical associations in a national cohort, Clin J Am Soc Nephrol
8(10):1661–1669, 2013.
Taler SJ, Agarwal R, Bakris GL, et al: KDOQI US commentary on the 2012
KDIGO clinical practice guideline for management of blood pressure in
CKD, Am J Kidney Dis 62(2):201–213, 2013.
Teeninga N, Kist-van Holthe JE, van Rijswijk N, et al: Extending prednisolone
treatment does not reduce relapses in childhood nephrotic syndrome, J
Am Soc Nephrol 24(1):149–159, 2012.
Teoh CW, Robinson LA, Noone D: Perspective on edema in childhood
nephrotic syndrome, Am J Physiol Renal Physiol 309(7):F575–F582,
2015.
Torres VE, Harris PC, Pirson Y: Autosomal dominant polycystic kidney disease,
Lancet 369(9569):1287–1301, 2007.
United States Renal Data System (USRDS): 2016 USRDS annual data report:
Epidemiology of kidney disease in the United States. Bethesda, MD: National
Institutes of Health, National Institute of Diabetes and Digestive and
Kidney Diseases, 2016.
Vehaskari VM: Heritable forms of hypertension, Pediatr Nephrol 24(10):1929–
1937, 2009.
Vehaskari VM, Rapola J: Isolated proteinuria: analysis of a school age popula-
tion, J Pediatr 101(5):661–668, 1982.
Vehaskari VM, Rapola J, Koskimies O, et al: Microscopic hematuria in school
children: epidemiology and clinicopathologic evaluation, J Pediatr 95(5
Pt 1):676–684, 1979.
Warady BA, Bakkaloglu S, Newland J, et al: ISPD guidelines/recommendations:
consensus guideline for the prevention and treatment of catheter-related
infections and peritonitis in pediatric patients receiving peritoneal dialysis,
Perit Dial Int 32(Suppl 2):S32–S86, 2012.
Zhou H, Satlin LM: Renal potassium handling in healthy and sick newborns,
Semin Perinatol 28(2):103–111, 2004.