Nephritic Syndrome Teresa M. Bane-Terakubo, MD
A 7 year old male presents to his primary care physician with the chief complaint of dark "cola
colored" urine, facial puffiness and abdominal pain for the past 2 days. He had been in his usual
state of good health until 14 days ago when he had a sore throat and fever. His sore throat and
fever resolved. He was not seen by a physician at that time. Over the past 2 days facial puffiness
has been noted, but no swelling of his hands or feet. He has had some nonspecific abdominal pain
that comes and goes which does not seem to be related to eating or bowel movements. There is no
nausea or vomiting. His urine is dark brown and he has not been voiding as much as usual, only 2
times in the past 24 hrs. There is no urinary frequency, urgency, dysuria or foul smell to the urine.
His appetite has been poor although he is still drinking fluids well. He is also complaining of
some back pain in the flank area that he describes as a dull pain that comes and goes and does not
seem to be related to activity. His energy level is down and he has not felt up to going to school
for the past 2 days. He is also complaining of a dull generalized headache that has not been
relieved with acetaminophen.
Review of systems is negative for recent skin infection, skin rash, cough, rhinorrhea, seizure
activity, fever, arthralgia or weight loss. His past medical history, family history and social
history are unremarkable.
Exam: VS T 37, P 100, RR 20, BP 120/75, oxygen saturation 100% in RA. Height and weight at
50th %tile. He is tired appearing but in no acute distress. Pupils are equal and reactive. Optic disc
margins are sharp. Sclera are white and conjunctiva are clear. Mild periorbital is edema noted.
TMs are normal. Throat, oral mucosa and nose are normal. His neck is supple without
lymphadenopathy. Heart is regular without murmurs. Lungs are clear. Abdomen is diffusely
tender (mild), without guarding or rebound. Bowel sounds are normal. No organomegaly is noted.
Mild CVA tenderness is present. His extremities are warm, with strong pulses. Capillary refill is
less than 2 seconds. No edema is noted in his legs, feet or hands. No skin rashes or impetigo scars
are noted. His genitalia are normal. No scrotal edema is present. Neurologic exam is normal.
Lab: His urine is tea colored. UA shows an increased specific gravity. A dipstick is positive for a
large amount of blood and moderate protein. RBCs are too numerous to count. 5-10 WBCs per
HPF. RBC casts are present. CBC with diff is normal. Throat swab is sent for culture. ASO titer
is elevated. Serum complement C3 level is low. Serum electrolytes are normal. BUN 23 and Cr
0.8.
Clinical Course: He is diagnosed with acute poststreptococcal glomerulonephritis. He is initially
hospitalized for treatment of oliguria/volume overload with furosemide, and monitoring of his
modest hypertension. He has a good urine output with the furosemide, however he later requires a
calcium channel blocker to control worsening hypertension. He is placed on a fluid and sodium
restricted diet. His throat culture later returns positive for group A beta hemolytic streptococci
(GABHS), so he is given a course of penicillin. He is discharged after 3 days of hospitalization.
His hypertension resolves over the next 2 weeks. He is followed closely by his primary physician
and his proteinuria and gross hematuria resolve early. His C3 level normalizes two months after
the onset of illness. Microscopic hematuria is expected to persist for months so this will be
rechecked in 3 to 6 months. He does not develop any long term complications.
Acute glomerulonephritis (GN) presents with hematuria, oliguria, hypertension and volume
overload (edema), which are the findings of the classic "nephritic syndrome". Acute GN (AGN)
is associated with inflammation and proliferation of the glomerular tuft. Most AGN is
immunologically mediated. In acute poststreptococcal glomerulonephritis (APSGN), immune
complexes form with streptococcal antigens, localize on the glomerular wall, activate the
complement system, and initiate a proliferative and inflammatory response. AGN may be rapidly
progressive (RPGN). Chronic GN (CGN) implies that permanent damage has occurred.
Acute poststreptococcal glomerulonephritis (APSGN) is the most common form of
glomerulonephritis in children. APSGN can occur in all ages but is most frequent in males
between 5 and 15 years. APSGN can occur after either an upper respiratory tract or skin infection
due to GABHS. It is more common after an infection of the throat. CGN occurs more often in
teenagers and adults. There are genetic predispositions for familial GN (Alport, X-linked) and
autoimmune etiologies (e.g., SLE-lupus nephritis). Goodpasture's disease (anti-basement
membrane autoantibodies) also presents with a classic nephritic syndrome in conjunction with
hemoptysis, but this condition is rare.
Important questions to ask the patient/caregiver include history of macroscopic (gross) hematuria
(tea or cola colored urine, or red colored urine), sore throat, impetigo, prior URI at least 1 week
previously or skin sores (impetigo) in the preceding 3-4 weeks (suggestive of APSGN), URI in
the preceding few days (suggestive of IgA nephropathy), reduced urine output, dyspnea, fatigue,
lethargy, headache or seizures (hypertensive encephalopathy). Also, symptoms of a systemic
disease such as fever, vasculitic rash (especially on the buttocks and legs posteriorly), arthralgia
and weight loss may be present. On physical exam, pay particular attention to hypertension,
pallor, signs of volume overload (edema, jugular venous distention, hepatomegaly, crackles in the
lung bases), impetigo and rash. For PSGN, edema (specifically, facial edema involving the
periorbital area) is the most frequent presenting symptom. Dark colored or bloody urine is
frequently not noticed by patients because the abnormal color is only visible when the urine is
collected in a cup. The abnormal color is not noticeable in a urine stream unless the urine color is
very dark.
Many patients with APSGN are asymptomatic and do not seek medical care. Mild hypertension is
often asymptomatic. The classic dark urine is often not noticed. Screening urinalysis may often
identify persistent microhematuria which eventually resolves months later. Many of these cases
are felt to be resolving APSGN cases which never presented for medical attention during the
acute nephritis phase.
Throat culture for GABHS will be positive in 15-20% of patients with APSGN. CBC is normal in
AGN and with chronic renal insufficiency a normocytic normochromic or hypochromic
microcytic anemia will usually be found. Serum chemistries will reflect the degree of renal failure
(BUN, creatinine, potassium and phosphate are all elevated, while calcium is decreased), which is
usually mild. The ASO titer will be positive in 60% of patients with APSGN. The complement
C3 serum level will be low in APSGN and in other causes of GN described below. Urine
microscopy shows RBC casts and crenated RBCs in AGN. EKG, CXR and renal ultrasound are
other tests that should be considered. RBC casts indicate the presence of acute nephritis. WBC
casts can also be seen in APSGN, interstitial nephritis and pyelonephritis.
During convalescence from APSGN, complement C3 levels return to normal within 6-8 weeks.
Persistently low C3 levels indicate an etiology other than APSGN. Gross hematuria will generally
resolve within 1 to 2 weeks. Microscopic hematuria may persist for a year or more.
The differential diagnosis for glomerulonephritis includes infectious etiologies such as GABHS,
pneumococcus, mycoplasma, mumps and EBV. Glomerulonephritis may also be related to
hepatitis B and C as well as syphilis infections. IgA nephropathy, membranoproliferative GN,
autoimmune GN, familial GN, acute interstitial nephritis, hemolytic uremic syndrome and
pyelonephritis should all be on your differential diagnosis list. One way to sort out the etiology of
the glomerulonephritis is to look at the complement level and whether evidence of systemic or
renal disease is present. For a patient with low serum complement level and systemic disease
consider vasculitis and autoimmune disease (SLE), subacute bacterial endocarditis, shunt
nephritis and cryoglobulinemia. For a patient with low serum complement level and evidence of
renal disease consider APSGN and membranoproliferative glomerulonephritis (types 1,2, and 3).
In a patient with normal serum complement level and evidence of systemic disease consider
polyarteritis nodosum, Wegener vasculitis, Henoch-Schonlein purpura and hypersensitivity
vasculitis. In a patient with normal serum complement and evidence of renal disease consider IgA
nephropathy, idiopathic RPGN and immune complex disease. A renal tumor (e.g., Wilms) will
occasionally present with gross hematuria so an imaging study may be indicated to rule this out.
APSGN is a self-limiting disease. Treatment is symptomatic. Restricted fluid and sodium diets
are initially beneficial. Potassium and phosphate may also need to be restricted. Medication may
be required for management. Loop diuretics (e.g., furosemide) are the first choice for volume
overload, hypertension and hyperkalemia control. Vasodilators such as calcium channel blockers
are also used to manage hypertension. IV antihypertensives may also be required to treat severe
refractory hypertension. In severe hyperkalemia serum potassium lowering agents and IV calcium
may be needed. Immunosuppressive agents are used in the treatment of vasculitis associated GN,
membranoproliferative GN and RPGN. Plasmapheresis may be used to treat RPGN.
Most patients with APSGN do not need hospitalization. Indications for hospitalization include: an
uncertain diagnosis, significant hypertension, anticipated poor follow-up, cardiovascular or
cerebrovascular compromise, etc. The diagnosis can usually be firmly established as an
outpatient. An imaging study may be necessary to rule out a Wilms tumor. If the patient's blood
pressure is normal or only mildly elevated, most parents can be taught to measure the child's
blood pressure at home using an automated blood pressure measurement device which is easily
available at most stores. Parents must notify the physician when the blood pressure exceeds the
parameters given by the physician. If the parents are deemed to be unreliable, or are not capable
of measuring the child's blood pressure, then hospitalization should be considered.
Prognosis is excellent for APSGN and variable for other causes of GN in children. Complications
of AGN include acute renal failure, hyperkalemia, hypertension, volume overload (congestive
heart failure, pulmonary edema, hypertension) and chronic renal failure.
Nephrotic Syndrome Paul J. Eakin, MD
A previously well 5 year old male presents to your office with the chief complaint of facial
puffiness. His mother noticed this a few days ago and it seems to be worsening. He has no other
symptoms, but about two weeks ago had "a bad cold."
Exam: VS T 37, HR 90, RR 20, BP 92/55. He is alert and cooperative with the examination. His
face shows moderate periorbital edema. His eyes are non-injected, his conjunctiva are not
edematous and his throat is not red. His heart is regular without murmurs. Heart sounds are
normal. His lung exam shows good aeration, with no crackles or rhonchi. Abdomen is soft, nontender, non-distended and without masses or shifting dullness. No hepatosplenomegaly. He has
normal male genitalia with no scrotal edema. The dorsal surfaces of his hands and feet have mild
pitting edema. He has brisk capillary refill and 2+ pulses. No rashes are noted.
Urinalysis shows 4+ protein, and a specific gravity of 1.030. His chemistry panel is remarkable
for protein of 2 g/dL, serum albumin of 1.4 g/dL and cholesterol of 350 mg/dL. BUN and
creatinine are normal.
He is not ill enough to require hospitalization. He is started on oral prednisone BID. He is
followed as an outpatient clinically and by daily urine dipsticks. His edema and proteinuria
gradually resolve with treatment. His corticosteroids are tapered off and he remains stable.
Nephrotic syndrome describes the collection of clinical and laboratory findings secondary to
glomerular dysfunction, resulting in proteinuria. The diagnostic criteria are marked proteinuria,
generalized edema, hypoalbuminemia, and hyperlipidemia (with hypercholesterolemia). The
proteinuria in nephrotic syndrome is severe, exceeding 50 mg of excreted protein for every
kilogram of body weight over 24 hours. Primary nephrotic syndrome refers to diseases limited to
the kidney, whereas secondary nephrotic syndrome indicates systemic diseases that include
kidney involvement (e.g., diabetic nephropathy).
In healthy children (less than 18 years of age), the annual incidence of nephrotic syndrome is 2-7
new cases per 100,000. The prevalence is approximately 16 cases per 100,000 children, making
nephrotic syndrome one of the most frequent reasons for referral to a pediatric nephrologist. Also,
the most common type of nephrotic syndrome is recurrent to some degree, so cases will often
manifest repeatedly over time. The peak age for the onset of nephrotic syndrome is 2-3 years of
age. In early childhood, males outnumber females about 2:1 for new cases of nephrotic syndrome.
In adolescence and adults, the gender distribution is more equal. Primary nephrotic syndrome is
more common in children less than six years of age, while secondary nephrotic syndrome
predominates for patients older than six. The disease inheritance is usually sporadic, although
there is a congenital form of nephrotic syndrome, called Finnish type congenital nephrosis, which
is inherited in an autosomal recessive manner. This abnormality has been mapped to a defect in
the nephrin gene on chromosome 19q13.1 that codes for a protein in the glomerular basement
membrane.
The main pathogenic abnormality in nephrotic syndrome is an increase in glomerular capillary
wall permeability, resulting in pronounced proteinuria. The normal glomerular wall is remarkably
selective for retaining protein in the serum. Once this selectivity is lost, the excretion of large
amounts of protein will follow. This increase in permeability is related to the loss of negatively
charged glycoproteins within the capillary wall that usually repel negatively charged proteins.
The predominant protein lost is albumin, although immunoglobulins are also excreted. The
pathophysiology for the formation of edema is incompletely understood. A simplification of the
predominant theory is that after the plasma albumin concentration drops, secondary to protein
excretion, the plasma oncotic pressure drops. With the decrease in oncotic pressure, fluid moves
from the intravascular space to the interstitial space causing edema. The liver has a very large
capacity to synthesize protein, so the persistent hypoalbuminemia is likely not due entirely to
increased losses. Reduction of the intravascular volume results in activation of the reninangiotensin-aldosterone system. Sodium and water are retained, which further increases the
edema. There are likely other factors involved in the formation of edema, because some patients
with nephrotic syndrome have normal or increased intravascular volume.
The hyperlipidemia in nephrotic syndrome is characterized by elevated triglycerides and
cholesterol and is possibly secondary to two factors. The hypoproteinemia is thought to stimulate
protein synthesis in the liver, including the overproduction of lipoproteins. Also lipid catabolism
is decreased due to lower levels of lipoprotein lipase, the main enzyme involved in lipoprotein
breakdown.
More than 90% of children with primary nephrotic syndrome have idiopathic nephrotic syndrome
and this will be the focus of this chapter. The etiology of this condition remains largely unknown,
but some have postulated an immunologic mechanism. Supporting evidence for this theory
include the characteristic response to corticosteroids and cytotoxic agents, an observed increased
incidence of concurrent allergic conditions, and spontaneous remissions with natural measles
infections (known to induce suppression of cell-mediated immunity). Evidence against an
immunologic etiology is a failure to identify immune reactants or inflammation in kidney
biopsies.
There are three morphological patterns of idiopathic nephrotic syndrome, with minimal change
disease (also called "nil disease") making up 80-85% of the cases. In this condition, the glomeruli
appear normal or have a minimal increase in the mesangial cells or matrix. As well as being the
most common form of primary nephrotic syndrome, minimal change disease also has the mildest
clinical course. The rest of this chapter will focus on this disease entity after briefly describing the
other forms of primary nephrotic syndrome as well as secondary nephrotic syndrome. The less
commonly seen types of primary idiopathic nephrotic syndrome are focal segmental glomerular
sclerosis, membranous glomerulonephritis and membranoproliferative glomerulonephritis.
Focal segmental glomerular sclerosis is found in about 7-15% of patients with nephrotic
syndrome, making it the second most common primary renal lesion. It tends to have a more
severe clinical course with persistent proteinuria, progressive decline in glomerular filtration rate
and hypertension that can be unresponsive to therapy. Renal failure occurs, with dialysis or
transplant being the only treatment options. Unfortunately, the recurrence rate of focal segmental
glomerular sclerosis can be as high as 40% after renal transplant.
Membranoproliferative glomerulonephritis accounts for roughly 7% of primary idiopathic
nephrotic syndrome. These patients often have hematuria, hypertension and mild azotemia.
Another characteristic finding is persistently depressed C3 levels. The clinical course is variable
with only a small percentage of patients going into remission.
Membranous glomerulopathy is rare in the pediatric age group, but becomes more common into
adolescence and adulthood. It is often associated with infections, with hepatitis B being the most
common. The clinical course is variable, but the overall prognosis is good, with spontaneous
remission of proteinuria occurring in 50-60% of cases.
There are many different causes of secondary nephrotic syndrome in children. These include
multisystemic diseases such as systemic lupus erythematosus and Henoch-Schonlein purpura,
malignancies such as Hodgkin disease or leukemia, drug or toxin exposures such as mercury,
gold, penicillamine or bee sting, and infectious etiologies such as Epstein-Barr virus,
cytomegalovirus and tuberculosis.
Children with idiopathic nephrotic syndrome secondary to minimal change disease usually
present with edema. Clinically apparent edema usually is not seen until albumin levels drop
below 2 g/dL. The edema is initially noted around the eyes and in the lower extremities. Over the
course of a day, the edema often distributes from the eyes to more dependent areas. After time,
the edema becomes more pronounced, generalizes and there can be weight gain. Patients or
parents may notice tighter fit of clothes, belts and shoes and scrotal or labial edema often occurs.
As the edema accumulates, pleural effusions, ascites and decreased urine output may develop. In
manycases,thereisahistoryofprecedingupperrespiratorysymptoms.
Anorexia,abdominalpainanddiarrheamaybeseen,possibly secondary to the formation of ascites.
Blood pressure and renal function are usually normal.
The hallmark of nephrotic syndrome is severe proteinuria, most reliably diagnosed using a 24hour urine collection. Spot urinalysis is also informative and reveals +3 to +4 proteinuria (300 to
1000 mg/dL), with a specific gravity usually greater than 1.020. Gross hematuria is not common.
Blood samples show decreased albumin levels usually less than 2.0 mg/dL and elevated
triglyceride and cholesterol levels. Because of the hypoalbuminemia, hypocalcemia is often seen,
with calcium levels less than 9.0 mg/dL. Usually the ionized calcium will be normal.
Hyponatremia and hyperkalemia can be seen, with hyperkalemia developing in patients who are
oliguric. Serum C3 levels are normal in cases of minimal change disease.
Renal biopsy is not necessary for the child with newly diagnosed nephrotic syndrome and the
initial treatment will be the same, regardless of the cause. How the disease responds to
corticosteroids may help dictate the need for biopsy. If the response is good and renal function is
normal, the diagnosis of minimal change disease may be presumed. If relapses respond to
corticosteroids and there is no proteinuria during disease free periods, this diagnosis is
strengthened. Biopsy is generally obtained in cases where there is poor or no response to
corticosteroids, the patient is less than 1 year old (high likelihood of congenital nephrotic
syndrome) or over 10 years old, secondary nephrotic syndrome is suspected, there is
corticosteroid toxicity, or the use of a cytotoxic agent is being considered. Patients with low
serum complement levels or hypertension on presentation may require biopsy since these
conditions are not characteristic of minimal change disease and may indicate other renal lesions.
The treatment of primary idiopathic nephrotic syndrome of childhood is corticosteroid therapy
and supportive care. Steroid therapy will be discussed below. Many patients may be treated on an
outpatient basis, although the newly diagnosed patient is sometimes admitted for diagnostic and
educational purposes. Edema is managed with sodium restriction (the "no added salt diet") and
diuretics such as hydrochlorothiazide. If hypokalemia develops, an oral potassium supplement or
spironolactone may be added. Aggressive use of loop diuretics may be harmful since most
patients initially presenting with nephrosis are hypovolemic. The use of diuretics necessitates
close monitoring of patients. Patients need to monitor their weight closely and consume adequate
amounts of protein.
Conditions that require immediate attention and hospitalization are severe scrotal edema,
dehydration (more than 10% dehydrated), respiratory compromise due to pulmonary edema or
pleural effusions, and peritonitis or suspected bacterial infection. Despite their edematous
appearance, most patients have decreased intravascular volumes. Therapy is aimed at the
restoration of intravascular volume and preventing volume overload. Intravenous fluids are used,
sometimes with the infusion of albumin to increase the serum oncotic pressure. The albumin must
be given slowly, over 8-12 hours, to prevent fluid overload from rapid intravascular volume
expansion. There is some debate over the use of albumin, since the effect seems to be transient
and it is presumably excreted rapidly (1). Electrolyte levels and renal function must be closely
monitored. Once the intravascular volume is restored, diuretic therapy is used to mobilize the
fluid and prevent volume overload. Paracentesis is performed if there is respiratory compromise
secondary to severe ascites. Antibiotic therapy to cover for the most common pathogens should
be started if there is evidence of bacterial infection (discussed below).
Minimal change disease is characteristically responsive to corticosteroid therapy and once the
diagnosis is confirmed with laboratory testing, steroid therapy should be started. Prednisone is
initiated with a dose of 60 mg/sq-meter/day or 2 mg/kg/day divided in 2-3 doses. The daily dose
is continued until the proteinuria resolves, usually in 2-3 weeks. Some sources suggest continuing
the daily dose for 4-6 weeks (1). Regardless, the corticosteroids are continued and then tapered
over the course of 3-6 months. In patients with minimal change nephrotic syndrome,
approximately 98% will eventually have satisfactory therapeutic responses. This disease is one of
frequent relapse, with two thirds of patients having a single relapse and roughly one third
experiencing repeated relapses over many years. Most patients with steroid-responsive nephrotic
syndrome will continue to have relapses until they are in their late teens. Relapses are treated the
same as the initial presentation. With repeated relapses or severe steroid toxicity (growth
retardation, elevated blood pressure), cytotoxic agents such as cyclophosphamide are added to a
lower corticosteroid dose. This agent has been shown to prevent relapses and to increase the
duration of remission. Chlorambucil and less commonly cyclosporine have also been used for
remission induction. Another regimen for patients refractory to corticosteroids is indomethacin
and an angiotensin-converting enzyme (ACE) inhibitor.
The most common complications of nephrotic syndrome are bacterial infection and
thromboembolism. There are also complications secondary to medications such as the gastric
irritation and insulin resistance seen with corticosteroids or the hemorrhagic cystitis, sterility and
leukopenia seen with cyclophosphamide. The tendency to develop infections, especially "primary
peritonitis" (a type of pneumococcal sepsis), is thought to be due to IgG excretion, decreased
complement function, and diminished splanchnic blood flow. The organisms causing peritonitis
are most commonly Streptococcus pneumoniae and Escherichia coli. Peritonitis should always be
considered in a patient who has nephrotic syndrome and abdominal pain or fever. Antibiotics
such as ampicillin or vancomycin with a third generation cephalosporin or an aminoglycoside
would provide good empiric coverage. Other infections such as sepsis, cellulitis, pneumonia and
urinary tract infection are also seen. The signs of infection may be masked if the patient is
currently on corticosteroid therapy. Any child with nephrotic syndrome and a fever must be
thought of as having an infection until proven otherwise, since they are at high risk for sepsis,
similar to splenectomy patients. Because of their predilection for S. pneumoniae infection,
polyvalent pneumococcal vaccine should be administered to children over two years of age.
Another complication, thromboembolism is thought to be more common secondary to increased
platelet aggregation, increased fibrinogen concentration, decreased antithrombin III
concentrations, increased blood viscosity and decreased blood flow. Venous thrombosis is most
common, especially in the renal vein, pulmonary artery, and deep vessels of the extremities. In
patients with refractory nephrosis, low dose anticoagulants are sometimes used.
The prognosis for children with minimal change nephrotic syndrome is good, with most patients
ultimately becoming disease free and living a normal life. Mortality is approximately 2% with the
majority of deaths being secondary to complications such as peritonitis or thromboembolic
disease.
Cystic Kidneys Miki E. Shirakawa
A one month old female is brought to her pediatrician with a chief complaint of an abdominal
mass. Her mother noticed the mass earlier in the week and immediately made an appointment to
see the pediatrician. The mother also notes that the infant has been frequently wetting her diapers,
although there is no history of fever, vomiting or diarrhea. The infant's perinatal and birth history
are unremarkable (spontaneous vaginal delivery at term with a birth weight of 2750 grams).
There is a family history of cystic kidneys in the infant's 14 year old brother. The infant's four
other brothers and sisters do not have any renal disease and both parents do not have a history of
renal disease.
Exam: VS T 37.5, P 110, R 26, BP 115/85, Weight 3.32 kg (10th percentile). She is alert and
active, in no distress. Her physical exam is unremarkable except for a nontender 7 cm by 8 cm
left-sided abdominal mass.
Urinalysis reveals cloudy urine, positive for leukocyte esterase and nitrites. A renal ultrasound is
ordered and reveals bilateral enlargement of her kidneys with diffuse echogenicity and
microcysts. A hepatic ultrasound reveals periportal fibrosis. The infant is diagnosed with
autosomal-recessive polycystic kidney disease and a possible urinary tract infection. She is
hospitalized for antibiotic treatment and further evaluation. She improves and is discharged from
the hospital. Her renal function is sufficient, but it is anticipated that it will worsen as she grows.
Cystic kidneys in children and adolescents present in various forms and can range from a single
cyst to multiple bilateral cysts. In this chapter, a few of the more common disease conditions will
be discussed: multicystic dysplastic kidneys, autosomal recessive polycystic kidney disease and
autosomal dominant polycystic kidney disease. Other cystic kidney diseases that will not be
discussed include nephronophthisis (a common genetic cause of chronic renal insufficiency in
children which presents with polyuria and polydipsia, anemia and growth retardation), medullary
cystic disease (autosomal dominant disease in which young adults develop renal failure),
medullary sponge kidney (dilated intrapapillary collecting ducts and multiple small cysts that
usually presents in adulthood), glomerulocystic kidney disease (seen in a variety of inherited
syndromes), simple renal cysts (incidental findings that generally do not impair renal function),
multilocular cysts (unilateral benign tumor), acquired cystic kidney disease (occurs in patients
with renal failure), and syndromes with cystic kidneys (such as tuberous sclerosis, Meckel
syndrome, and von Hippel-Lindau disease).
Multicystic dysplastic kidney (MCDK) is usually a benign unilateral disorder of small to large
renal cysts separated by dysplastic parenchyma. The shape of the kidney is irregular and normal
renal architecture is lost. There are two types of MCDK: the classic type and the hydronephrotic
type (1). The classic type contains multiple cysts of various size, with an abnormal renal shape
and an atretic proximal ureter. The hydronephrotic type is rarer and consists of peripheral cysts
that communicate with a large central cyst with a dilated pelvis and calyces (1).
MCDK is the most common type of renal cystic disease, comprising 10% of fetal uropathies (1).
The most recent studies estimate that the incidence is 1 in 2400 livebirths, and it is more common
in males (1,2). The disease usually occurs unilaterally, but can be seen bilaterally in as many as
20% of cases (2). MCDK is generally considered to be nonhereditary and sporadic, although rare
cases have shown an autosomal dominant inheritance (2,3). Two theories stand out as the most
probable causes of MCDK. The first proposes that abnormal induction of the metanephric
blastema leads to dysplasia of the renal parenchyma that is non-uniform, resulting in cysts that
increase in size and eventually compress normal renal tissue (1). The second theory suggests that
MCDK is due to obstruction of the ureter that results in cyst formation (1,3). This theory was
exhibited in Beck's experiments of fetal lamb ureter ligations, which resulted in cyst formation in
the lambs (1). Urine is usually present in the cysts and causes the cysts to enlarge. In unilateral
cases, there is a compensatory hypertrophy in the contralateral kidney.
The most common presentation of MCDK is on prenatal ultrasonography (71% of cases), viewed
as early as 16 weeks gestation (1). MCDK usually presents in newborns as a unilateral flank
mass, but can occasionally cause vomiting, anorexia and failure to thrive secondary to
compressive effects (2). Other possible but rare presentations include urinary tract infection,
abdominal pain, hematuria, hypertension, and compromised respiratory function (1,2). MCDK is
associated with other anomalies of the urinary tract in half of cases and 15-28% show
vesicoureteral reflux in the contralateral kidney (1). There is also an association with contralateral
ureteropelvic junction obstruction (1). Other major anomalies can be seen in the cardiac,
respiratory and gastrointestinal systems (1). Bilateral cystic kidneys are usually not compatible
with life due to oligohydramnios and result in either stillborn babies or newborns requiring
dialysis at birth (2). MCDK is diagnosed with ultrasonography but also requires radionuclide
imaging to determine functioning of the kidney after 1 month of age (1).
The differential diagnosis for MCDK includes hydronephrosis as well as the other cystic kidney
diseases, and may be distinguishable by ultrasound. Hydronephrosis usually retains a reniform
shape and shows apparent renal parenchyma around a central cyst (1). Hydronephrosis also
retains communication of the cysts with the collecting systems (2). A radionuclide study may
need to be performed when distinguishing hydronephrosis from the hydronephrotic type of
MCDK. Autosomal dominant polycystic kidneys are usually bilaterally enlarged while autosomal
recessive polycystic kidneys are generally small with a hyperechoic pattern.
The management of MCDK is controversial because it is not clear that nephrectomy results in a
better outcome. It is recommended to obtain sonography and perform a voiding cystourethrogram
within the first 48 hours of life. Radionuclide studies are also performed after 1 month of age to
determine renal functioning. Since most cases are asymptomatic, nephrectomy is not always
performed and instead close follow-up is maintained. Ultrasound is performed every 3 months up
to 1 year of age and then every 6 months up to 5 years of age. Blood pressure is also monitored.
Nephrectomy is usually performed only if the child is symptomatic or the parents choose surgery
after understanding the benefits and risks.
Unilateral MCDK has an excellent prognosis, especially if there is an absence of other anomalies.
In 73% of cases, the cysts decrease in size, with a 40% complete resolution rate (1). However, in
13% of cases, the cysts increase in size and may cause symptoms (1). Uncommonly, children may
have pain, infection, or hypertension and even rarer is the possibility of malignant degeneration
into a Wilms tumor (1). In the 5% to 17% of cases that are bilateral, newborns generally do not
survive and if they do, they require dialysis immediately (1).
Autosomal-recessive polycystic kidney disease (ARPKD) is a recessively inherited disorder that
results in bilateral cystic dilation of renal collecting ducts and hepatic fibrosis. The kidneys are
enlarged, while retaining their normal shape and have a spongy appearance.
The incidence of ARPKD is believed to be 1 in 6000 to 1 in 55,000 livebirths (4). A single
defective gene on chromosome 6p causes ARPKD and is inherited as a typical autosomal
recessive disorder (5). Heterozygotes are unaffected. There is a 25% chance of recurrence with
subsequent pregnancies. Males and females are equally affected.
Three factors have been shown to contribute to the formation of renal cysts and their subsequent
enlargement. The first factor is that tubular hyperplasia is present in all cystic diseases and
contributes to cystic expansion (5). Second, secretion of tubular fluid leads to the accumulation of
intratubular fluid and progressive enlargement (5). Third, abnormalities in extracellular matrix
interactions appear to have an effect on cell growth and can lead to abnormal epithelial
hyperplasia and secretion (5).
ARPKD may present with various features but is usually seen within the first year of life (4).
Many cases are seen prenatally on ultrasound with oligohydramnios and large renal masses (5).
Other presentations include enlarging abdominal masses, respiratory problems due to limited
diaphragm mobility (or pulmonary hypoplasia), failure to thrive due to enlarged kidneys,
proteinuria, pyuria, hypertension due to fluid overload, and urinary tract infections due to
vesicoureteral reflux (4). Children eventually develop chronic renal failure and end-stage renal
disease with associated electrolyte imbalances of hyperkalemia and hyperphosphatemia (4). Liver
abnormalities may present as signs of portal hypertension such as esophageal varies,
hepatomegaly, and spider nevi.
The diagnosis of ARPKD is suspected in children with bilaterally enlarged kidneys and is highly
suspected if siblings also have a history of ARPKD. Ultrasound is the diagnostic test of choice,
although an intravenous pyelogram will also show enlarged kidneys (4). On renal ultrasound,
there is increased echogenicity with a possible hypoechoic rim (4). It is important to rule out
autosomal-dominant polycystic kidney disease (ADPKD), nephroblastomatosis and bilateral
Wilms' tumor (4). ADPKD usually does not have associated liver abnormalities and the
inheritance pattern is dominant instead of recessive (4).
Management of ARPKD involves ventilatory support for respiratory problems due to pulmonary
hypoplasia and diaphragmatic compression. Hypertension should be treated with medications,
although it may be difficult to control. Urinary tract infections should be properly diagnosed and
treated with antibiotics. Chronic renal failure and end-stage renal disease are treated by managing
electrolyte abnormalities, anemia, and renal osteodystrophy, with eventual dialysis and
transplantation (4). Nephrectomy may be an option if there are respiratory problems and/or
feeding problems due to compression (4).
Improvements in technology continue to increase the survival rates of ARPKD. Studies show that
about 46% are alive at 15 years of age and those that survive through the first year of life have an
even higher survival rate (79% alive at 15 years) (5). Renal failure is the most common cause of
death and ARPKD continues to have significant long-term morbidity (4).
Autosomal-dominant polycystic kidney disease (ADPKD) rarely presents in children but
occasionally exhibits a severe course in childhood. It is characterized by renal cysts in various
locations and extrarenal manifestations in the gastrointestinal and cardiovascular systems. As the
disease progresses, renal fibrosis and glomerulosclerosis increase (4). ADPKD is the most
common inherited renal disease, occurring between 1 in 500 to 1 in 1000 livebirths (4). Mutations
in any one of three genetic loci (PKD1, PKD2, PKD3) result in ADPKD. PKD1 is located on
chromosome 16p and encodes the protein polycystin, a transmembrane protein (4). PKD2 is
found on chromosome 4q and encodes for polycystin-2, another transmembrane protein that
interacts with polycystin (4). There is not much known about PKD3 (4). The variability in cyst
formation and disease severity depends on the locus affected and how much protein is being
made.
The clinical presentation of ADPKD depends on the age of presentation. Most often, children are
asymptomatic and are only diagnosed because of a positive family history and subsequent CT or
sonogram. Symptomatic children typically present in late childhood or adolescence with any of
the following: hematuria, hypertension, abdominal or flank pain, abdominal mass, urinary tract
infection, or proteinuria (4). Symptoms in childhood usually correlate with greater than 10 cysts
present (4). The third pediatric presentation is severe neonatal disease that is frequently fatal.
These neonates usually die from respiratory failure but they may also die of renal failure during
the first year of life (4). Extrarenal manifestations are not common in children but are common in
adults. These extrarenal problems include mitral valve prolapse, hypertension, extrarenal cysts,
aortic aneurysms, intracranial aneurysms, hernias, colonic diverticula, cholangiocarcinoma, and
congenital hepatic fibrosis (4). Intracranial aneurysms are a significant cause of mortality when
they rupture (4).
ADPKD is diagnosed with sonogram or CT scan as macroscopic renal cysts. As children age, the
number and size of cysts increases and therefore, the sensitivity and specificity of diagnosis by
ultrasound increases as children become older (4). ADPKD can often be distinguished from other
cystic kidney diseases through family history. Ultrasound can also be used to distinguish ARPKD
from ADPKD. ARPKD shows bilaterally enlarged kidneys with microcysts as well as hepatic
periportal fibrosis, while ADPKD will show enlarged kidneys with macrocysts as well as
extrarenal cysts (4,5).
Management of ADPKD includes physical examination, urinalysis and blood pressure monitoring
every 6-12 months (4). Ultrasound should also be performed every 2-3 years (4). Presenting
problems of ADPKD should be treated with standard therapy. Chronic renal insufficiency is
monitored carefully, especially with respect to its effects on nutrition and growth (4).
Hypertension is treated with antihypertensives and urinary tract infections are treated
appropriately. Screening for intracranial aneurysms should be performed in teenagers with a
family history of intracranial aneurysms due to the serious consequences of rupture (4,5).
Since most children with ADPKD are asymptomatic, the prognosis throughout childhood is
generally good. One study showed that 80% of children diagnosed maintained normal renal
function throughout childhood (5). As adults, disease progression is variable and unpredictable.
Potter syndrome is variably defined as including congenital renal failure or cystic kidneys
associated with oligohydramnios, abnormal facies and hypoplastic lungs. If the fetal kidneys are
non-functional or minimally functional, oligohydramnios results since the source of amniotic
fluid is fetal urine. Oligohydramnios results in the abnormal facies due to the compression of the
developing face against the inner uterine wall. Pulmonary hypoplasia results from large kidneys
(due to one of the cystic kidney conditions) compressing the diaphragms, preventing fetal lung
development. Congenital bilateral renal agenesis is also included in Potter syndrome. Potter
syndrome is generally incompatible with life due to congenital renal failure and pulmonary
hypoplasia.
Dialysis James H.E. Ireland, MD Julie Won Ireland, MD
A 16 year old girl with a past medical history of systemic lupus erythematosus (SLE) presents
with intractable nausea and vomiting, increasing edema and no urine output for two days. She had
been diagnosed with SLE at age 14. A biopsy of her kidney at that time revealed a diffuse
proliferative glomerulonephritis with prominent crescents and minimal fibrosis. Her creatinine at
that time was 1.5, and she was started on cyclophosphamide, prednisone and furosemide.
Exam: VS T 36.5, P 110, RR 18, BP 180/110, weight 75 kilograms. She is very nauseated and
actively vomiting. She responds to verbal commands and is slightly somnolent, but oriented. She
has pale conjunctiva and no oral lesions or thrush. Her lungs are clear. She is tachycardic and has
a rub. Her abdomen is soft and nontender and her upper and lower extremities have 1-2+ edema.
Her CBC is significant for a low hemoglobin of 7.5 g/dl with an MCV of 92. Her chemistries
show an elevated potassium at 5.7; a low bicarbonate at 13 and a markedly elevated BUN at 119
and a creatinine of 14. Her ANA is elevated at 160 and her TSH is normal. A renal ultrasound
shows small echogenic kidneys with no hydronephrosis, masses or stones. A chest x-ray shows
engorged pulmonary vessels (fluid overload) and an enlarged heart. An echocardiogram reveals a
moderate pericardial effusion, but is otherwise normal. Emergent vascular access is obtained, and
she is taken to hemodialysis. She receives dialysis daily and within a week, her symptoms
resolve. A follow-up echocardiogram demonstrates a reduction in the pericardial effusion.
The above case illustrates the use of acute hemodialysis for a patient with uremia secondary to
chronic renal failure in the setting of SLE. There are a number of indications for acute
hemodialysis (HD). One is renal failure (creatinine clearance less than 10) as manifested by a
urea nitrogen over 150 mg/dL or a serum creatinine elevated 10-fold over normal, or signs and
symptoms of uremia. This may include nausea and vomiting, altered mental status, seizures,
pericarditis or bleeding diathesis (platelets become progressively dysfunctional in the setting of
uremia). Other indications for HD include uncontrolled hyperkalemia, refractory fluid overload,
severe metabolic acidosis, tumor lysis syndrome, certain inborn errors of metabolism, and certain
acute poisonings/overdoses.
When a teenager needs HD, vascular access must be obtained prior to initiating therapy. In the
acute or emergent setting, a double- lumen catheter (such as a Vas-Cath) can be placed in a large
vein. The internal jugular or femoral vein is preferred, but sometimes the subclavian vein is used.
This vascular access device has large lumens to permit optimal blood flow. As with any central
venous line, there is a risk of pneumothorax if the internal jugular or subclavian sites are used; a
risk of bleeding (especially in the uremic patient) and a risk of infection. Although placed with
sterile technique, the risk of infection increases the longer the line is kept in place. If kept in for
an extended period, infection is one of the drawbacks to having this type of vascular access;
however, it can be used immediately and is ideal when dialysis needs to be done quickly.
If chronic, "maintenance" dialysis is planned for some future time (as with chronic renal failure),
more permanent vascular access should be established. One method involves connecting a vein to
an artery to create an AV fistula. It is usually done in the non-dominant arm, in case ischemia or
other complications occur. Once it is decided that permanent vascular access is needed, the
patient and nurses should be instructed to make that limb "off-limits" for blood draws,
intravenous lines or arterial punctures. This is done to minimize any potential trauma to the blood
vessels prior to fistula surgery. As a reminder, a large sign is usually placed above the patient's
hospital bed stating "No Draws: Left Arm." A number of artery-vein anastomoses are possible,
but the two most common are the wrist radiocephalic and the elbow brachiocephalic. After
surgery, the fistula needs about 6 weeks to mature and cannot be used during this time.
Maturation is the histologic process of venous thickening and dilating, essentially taking on some
of the characteristics of the attached artery. These changes enable the venous portion of the graft
to accept the repeated insertion of the dialysis needle. If the patient is already requiring dialysis, a
temporary percutaneous double lumen catheter can be used until the fistula is mature and usable.
After surgery, the fistula should have a palpable thrill and audible bruit. This should be checked
at least daily as an assessment of patency.
If an AV fistula is not anatomically possible, another type of permanent access is an arterialvenous (AV) graft. This involves the use of a synthetic tube to connect the artery and the vein.
Common sites for AV grafts include the radial artery to the basilic vein, the brachial artery to the
basilic vein and the brachial artery to the axillary vein. Maturity is faster than the fistula, usually
occurring in 2-3 weeks. The major drawback of the AV graft is it is much more likely to clot and
occlude than the native fistula, due to intimal hyperplasia in the native vein to which the graft is
attached. If this should occur, medical therapy (thrombolysis) or a surgical procedure can be done
to salvage the graft (interventional procedures or thrombectomy). Both AV fistulas and AV grafts
have a number of long-term complications. This includes edema or ischemia of the hand,
pseudoaneurysm at the graft or fistula site, infection, thrombosis and congestive heart failure. If a
hemodialysis patient has a fever or positive blood cultures and fistula or graft infection is
suspected, a nuclear WBC scan can be done to help confirm the diagnosis. Staphylococcus is a
frequent infecting organism, but gram negative rods and enterococcus infections can also occur.
Empiric therapy should be directed at these organisms, and may require vancomycin coverage for
methicillin-resistant Staphylococcus aureus (MRSA). Species of Candida can also infect these
sites.
Vascular access in infants and small children is more complicated than in older children and
teenagers. In neonates, an umbilical vein may be used. Some hemodialysis machines permit a
single lumen or needle to be used. For permanent access, AV grafts may be necessary if native
blood vessels are too small to create a fistula.
Once vascular access is established, blood leaves the body via tubing into the dialysis unit. It
passes along a semipermeable membrane with a dialysis solution (dialysate) flowing along the
other side of the membrane. Solute particles from the blood then pass down their concentration
gradient into the dialysate for removal. The mechanism of dialysis can be simplified based on
standard diffusion: where particles (solutes) of high concentration (in the blood) move down their
concentration gradient to an area of low concentration (the dialysate). The movement is across a
semipermeable membrane, so larger particles will cross more slowly or not at all. Thus the
smallest particles will be removed the fastest. Also, the steeper the concentration gradient, the
quicker the removal. Blood and dialysate run through a filter in opposite directions, with the
membrane separating them. This countercurrent flow maximizes the concentration gradients for
solute removal. The blood is then returned to the body. Other aspects of the dialysis prescription
include the type of membrane, flow rate of blood and dialysate, temperature, length of time on
dialysis, and composition of the dialysate. Modern machines can monitor these functions and
monitor for potential air emboli and blood leaks in the dialyzer as well.
The dialysate is purified water with precise amounts of various ions and glucose. For example, a
typical solution would contain: Na+ 145 mEq/L; K+ 3.5 mEq/L; Ca++ 3.5 mEq/L; Mg++ 0.75
mEq/L; and dextrose 200 mg/L. Different ionic concentrations can be used for different clinical
situations. For example, if a stable patient needs routine dialysis, and her pre-dialysis potassium is
usually 5.0, a dialysate with 3.0 mEq/L of potassium would be used. If the same patient had a
viral gastroenteritis and her pre-dialysis potassium was 3.0 then a dialysate with 4.0 mEq/L of
potassium would be used. If that same person was feeling fine and ate some high potassium foods
such as fruit the day before dialysis and her pre-HD potassium was 7.0, a dialysate with zero
potassium would be used.
Besides normalizing ionic concentrations and removing waste, another function of dialysis is to
remove accumulated water. Water moves across the membrane under hydrostatic forces and this
is known as ultrafiltration. The degree of that force determines the amount of net water
movement. Small particles within the water are also removed during this process, which is called
convection. Particles larger than the dialysis membrane pore size will be left behind in the blood.
Major complications of hemodialysis are unusual. These can include: seizures, hypotension and
hypothermia. The seizures are a severe manifestation of the dysequilibrium syndrome. The
syndrome has a characteristic EEG tracing and in mild cases can be associated with headaches,
nausea and vomiting. More severe manifestations include seizures and coma. The cause of the
syndrome is unknown, but it may have to do with osmotic shifts in the brain. It can occur during
or after hemodialysis. Preventative measures include limiting the flow and the total time on
hemodialysis for the first few sessions to prevent large fluxes.
Hypotension is another common complication during hemodialysis. If significant, it can be
treated with volume replacement. If fluid removal is necessary, however, more frequent dialysis
sessions with smaller volumes removed per session may be required. Additionally, some patients
tolerate fluid removal better if dialysate sodium concentrations are increased, something known
as sodium modeling. If large changes in fluid status are avoided, hypotension during the session
is minimized. Finally, hypothermia can be a problem, as removed blood can be cooled in the
tubing and machinery. This is prevented by heating units in the dialysis machine to keep the
temperature constant.
As mentioned, hemodialysis can be associated with large fluid shifts that can result in
hypotension. When patients are unable to tolerate such a drop in blood pressure or are already on
vasopressor support (for example, in septic shock) another form of dialysis may be required. This
typically is known as continuous renal replacement therapy (CRRT) or slow continuous therapies.
When done via a Vas- Cath, it may also be called continuous veno-venous hemofiltration (CVVH). This form of dialysis is done continuously (compared to three times a week for 4-5 hours in
standard hemodialysis). It is used almost exclusively in the intensive care unit for critically ill
patients. This type of therapy is also better than standard hemodialysis for clearing elevated
phosphorus seen in tumor lysis syndrome in leukemia or lymphoma, in part because a different
and more porous membrane is used.
Another method of dialysis is peritoneal dialysis (PD). In this method, an indwelling catheter is
placed in the abdomen, usually under general anesthesia in children, and the PD solution (another
form of dialysate) is circulated through the peritoneal cavity. This is the most common method of
chronic dialysis for pediatric patients. PD can also be used in the acute setting, but it is not
efficient in correcting hyperkalemia, hyperphosphatemia or hyperammonemia and if these values
are critical, another dialysis modality should be used. The advantages are that vascular access is
not needed; no complicated machinery is required; it does not cause large volume shifts; and it
can be performed at home after fairly brief training. In PD, the peritoneum acts as a biological
dialysis membrane and solutes cross this from the blood to the dialysate. Fluid can be changed
manually every six hours or changed through an automated cycling machine (such as during
sleep.) The major complication of this method is peritonitis. Other drawbacks include the
presence of an external catheter from the abdomen, which may make children self-conscious.
Long term complications of chronic renal failure in children include growth failure, anemia,
hypertension, acidosis and renal osteodystrophy. The etiology of the growth failure is
multifactorial. Children may respond to exogenous recombinant human growth hormone.
Erythropoietin deficiency accompanies renal failure and results in anemia. Folic acid is usually
added as a supplement and ferrous sulfate can be started if iron stores are low. If anemia persists,
exogenous erythropoietin can be initiated. Hypertension may be due to dietary indiscretion,
inadequate fluid removal during dialysis, or the renin-angiotensin axis. If these cannot be
remedied, anti- hypertensive medications are used. Acidosis can interfere with growth hormone
function and should be treated with exogenous alkali (calcium carbonate, sodium bicarbonate) to
maintain a serum bicarbonate levels of 22 mEq/L or higher.
Renal osteodystrophy can be minimized with careful control of calcium and phosphate
metabolism. As the kidney fails, phosphate excretion is impaired and the serum levels rise and a
concurrent fall in serum calcium. The lower serum calcium levels stimulate parathyroid hormone
production which acts on bone to release calcium. This can cause bone pain, deformities and
growth retardation. Radiographically, osteopenia, epiphyseal slipping and subperiosteal
resorption may be present. Laboratory findings can include elevated PTH and alkaline
phosphatase with low levels of active vitamin D (1,25-dihydroxy-vitamin-D3). Vitamin D
undergoes final hydroxylation and activation in the kidney, which is hampered in chronic renal
failure. The reduction in active metabolites of vitamin D results in calcium malabsorption in the
intestines and further exacerbates osteodystrophy, and in children with open epiphyses can lead to
what is known as "renal rickets". Therapy should reduce excess phosphate by limiting dietary
phosphorus to 1 gram per day, and if levels remain high, treatment with binders (calcium
carbonate, calcium acetate, or sevelamer) should be initiated. These are given with meals to bind
dietary phosphate and prevent absorption. Additionally, calcium and active vitamin D
replacement should be optimized and PTH levels should be monitored for hyperparathyroidism.
In summary, dialysis can be a life-saving therapy for acute renal failure, certain poisonings and in
severe electrolyte disturbances seen in the tumor lysis syndrome. It can also substitute for native
kidneys in patients with end stage renal disease, although children do not thrive as well as they do
with a functioning renal transplant. Ideally, dialysis can act as bridge until normal renal function
returns or the patient is able to receive a kidney transplant.
Hemolytic Uremic Syndrome Jonathan K. Marr, MD
This is a 3 year old male who is brought to the ED by his mother when she noted bloody diarrhea
earlier in the day. There is no fever, ill contacts, or recent exposures to children with diarrhea. He
is noted to be pale. His family had attended a birthday party 7 days prior where the child had
consumed hot dogs and hamburgers.
Exam: VS T 37.7, P 150, R 28, BP 100/45, oxygen saturation 100% in RA. Weight 17 kg
(75%ile). He is alert but fussy, pale, and non-toxic appearing. His conjunctiva are pale. His TMs
are normal. He has no nasal flaring or palatal petechiae. His oral mucosa is moist and his tongue
is pale. His neck is supple without adenopathy. His heart has a regular rhythm with tachycardia
and a grade III/VI vibratory systolic ejection murmur at the left sternal border without radiation.
No heaves, lifts, thrills, rubs, or gallops are present. His lungs are clear with good aeration. His
abdomen is flat, soft, and non-tender, with the liver edge palpable 3cm below the RCM. The
spleen is non-palpable. His genitalia and anus are normal (no rectal prolapse). His pulses and
perfusion are good. There are is no edema, rash, or petechiae.
Labs: CBC: WBC 16,000 with 56% segs, 12% bands, 27% lymphs, 3% eos, 2% basos,
hemoglobin 8 mg/dL, hematocrit 24.6, platelet count 75,000; peripheral smear shows
schistocytes, helmet cells, and polychromasia. Na 133, K 5.9, Cl 96, bicarbonate 16, BUN 45,
creatinine 1.3, glucose 145 mg/dL, Ca 7.8, PO4 7.1, uric acid 7.3, and LDH 300. Coagulation
studies are normal.
Hemolytic uremic syndrome (HUS) is a heterogeneous group of similar entities that has been
recognized for over 45 years and has been reported from most parts of the world. It is one of the
most common causes of acute renal failure in childhood and is defined by a combination of
microangiopathic hemolytic anemia, variable degrees of thrombocytopenia, and renal failure (1).
Other systems, such as the CNS may be involved.
HUS can be classified in a number of ways, but the most common is the diarrhea-associated (D+
HUS) versus atypical (D- HUS) HUS without diarrhea. The D+ HUS is characterized by a sudden
onset of hemolytic anemia, thrombocytopenia, and acute renal failure after prodromal
gastrointestinal enteritis. The atypical (D- HUS) is rare in childhood, portends a worse prognosis,
is more likely to relapse, and may be associated with a family history of HUS disease. It appears
to be associated with certain chemotherapy drugs (cyclosporin and tacrolimus), oral
contraceptives, cancer, bone marrow transplantation, Streptococcus pneumoniae infections, and
vasculitic diseases (1).
Another common classification used is Shiga-like toxin-associated HUS (Stx HUS), since D+
HUS has been strongly associated with a toxin-producing strain of Escherichia coli O157:H7
(1,2). Historically, Shigatoxin (Stx) is an exotoxin produced by Shigella dysenteriae type I and
the term verotoxin is derived from the use of vero (monkey) cells as a cytotoxic assay for the
Shigatoxins produced by E. coli O157:H7 (1). Human verotoxin producing E. coli (VTEC) strains
produce one or both of the toxins Stx-1 and Stx-2 and are established causes of HUS associated
with bloody diarrhea. Other strains of E. coli besides O157:H7 produce shiga toxins; they include
E. coli O111, O26:H11, and O103:H2, although they are less commonly found in HUS cases,
since their assays are not routinely commercially available (1,2).
Epidemiologically, the most common form of the HUS syndrome (D+ HUS) occurs
predominantly in healthy children 6 months to 5 years of age, and has seasonal variation with
peaks in the summer and fall (1). Most cases of D+ HUS occurring during epidemics are due to
ingestion of contaminated, usually undercooked, ground beef. Approximately 1% of beef cattle in
the United States harbor intestinal E. coli O157:H7. The organisms become incorporated during
the processing of ground beef that mixes meat from multiple cattle such that one infected animal
can contaminate large quantities of ground beef. E. coli O157:H7 can also be acquired by
consuming fruits or vegetables contaminated by manure, drinking unpasteurized milk, swimming
in contaminated lakes, and person-to-person contact (1).
Stx produced by VTEC is most specifically toxic to cells containing a specialized glycolipid
receptor called glycosphingolipid globotriosyl ceramide (Gb3) (2). Glomerular epithelial cells in
the renal cortex contain large quantities of Gb3. This explains the predilection for renal cortex
lesions and acute renal failure (1). Other areas that contain Gb3 include the CNS and the
pancreas.
VTEC also releases lipopolysaccharide (LPS), stimulating WBCs to release inflammatory
mediators (TNF-alpha, IL-1, and elastase) that cause endothelial cell detachment, increased
procoagulant activity, and release of free radicals causing oxidative cell membrane injury (1). The
injury to endothelial cells in renal microvessels results in local intravascular coagulation and a
microangiopathic hemolytic anemia with mechanical destruction of erythrocytes and platelets by
fibrin strands in narrow vessels (1). Platelet adherence contributes to microthrombi and platelets
are consumed when platelet-fibrin thrombi are formed in these injured areas. The capillary lumina
are narrowed by endothelial swelling and occlusive thrombi, effectively decreasing blood flow to
the glomeruli leading to renal insufficiency and eventually progressing to renal failure.
Clinically, HUS presents with abdominal pain, vomiting, and bloody, mucoid diarrhea. The
prodromal phase of the illness varies from 1-15 days before the onset of HUS. Pallor and
petechiae occurs within 5-7 days after the onset of the bloody diarrhea. Other signs that may be
noted include oliguria, personality changes, and drowsiness. The oliguria found in 60% of
patients lasts an average of one week; however 50% of patients, are anuric for an average of 3
days. Most patients are irritable and somnolent. Other findings include behavioral changes,
ataxia, dizziness, tremors, and twitching. With progression of the disease, anuria, coma,
hemiparesis, cranial nerve dysfunction, cerebral infarcts, seizures, and death can occur. Seizures
are reported in 3-5% of cases (2). Active bleeding other than the bloody diarrhea is rare.
Hypertension is a common feature of HUS and occurs in 50% of all affected individuals. Possible
etiologies for this include fluid overload and increased renin activity (1). Pancreatic insufficiency
manifested as transient diabetes mellitus occurs in 4- 15% of patients (1,2). Mortality has
declined and is between 5-10% during the acute phase. Predictive features associated with poorer
long-term outcomes include: severe gastrointestinal prodrome (colitis with rectal prolapse),
prolonged duration of anuria, extended duration of dialysis, coma on admission, and high
leukocyte count (1). Generalized seizures during the acute phase of the disease are not predictive
of death or poor neurological sequelae (1). Age and gender have no consistent correlations on
outcome.
The differential diagnosis of early HUS includes: ulcerative colitis, Crohn's disease, appendicitis,
intussusception, idiopathic rectal prolapse, gastroenteritis, or acute bacterial endocarditis.
Thrombotic thrombocytopenic purpura (TTP), also known as Moschcowitz's syndrome is similar
to HUS with the features of: microangiopathic hemolytic anemia, thrombocytopenia, renal
dysfunction, fever, and neurological disturbances (4). It is probable that TTP and HUS represent a
similar pathological process, except that TTP is the more serious multisystem disorder with a
higher mortality (30-40% within 3 months). The pathophysiologic events involved with TTP are
not fully understood but probably involve abnormalities in endothelial composition and unusually
large von Willebrand Factor (vWF) multimers in the circulation causing platelet activation with
resultant platelet thrombi formation.
Laboratory findings in HUS include a negative Coombs test, normochromic, normocytic anemia
with helmet cells, schistocytes, and polychromatophilia on blood smear indicative of hemolysis.
Other evidence for hemolysis is an elevated LDH and low serum haptoglobin. An unconjugated
hyperbilirubinemia is usually present. The mean hemoglobin is 8 mg/dL. The platelet count is
moderately depressed to 50,000, but can be as low as 5,000. Neither the severity nor the duration
of the thrombocytopenia correlates with the overall severity of disease. The duration of the
thrombocytopenia lasts from 2-3 weeks and there are usually no signs of active bleeding other
than the bloody diarrhea. The half-life of infused platelets are shorter, as they are likely taken up
by the liver and spleen; furthermore, circulating platelets are dysfunctional. Leukocytosis is
present and is nonspecific diagnostically; a recent study, however, found the risk of developing
HUS proportional to the initial WBC count (3). Coagulation tests are normal and fibrin split
products may be positive.
Signs of renal dysfunction include elevated serum levels of creatinine, potassium, phosphorus,
and uric acid which result from decreased glomerular filtration, hemolysis, and transcellular
cation shifts (1). Elevations in BUN and creatinine may initially reflect volume depletion because
of the diarrhea, but may later be the result of renal failure. Sodium, calcium, and albumin may be
low from initial diarrhea losses and later from volume overload because of renal failure.
Pancreatic insufficiency is manifested by elevations in amylase and lipase or glucose intolerance.
Histopathology on renal biopsy (not always done unless clinically indicated) demonstrates
glomerular lesions of endothelial cell swelling and a widened subendothelial space filled with
fibrin-like substances and lipids (1). This results in a thickened capillary wall and reduced
capillary lumen. The glomerular basement membrane is intact. Occasionally there may be
crescents and signs of necrosis and the glomeruli may be lobulated and resemble
membranoproliferative glomerulonephritis (1). Thrombi may occlude arteriolar lumens and there
may be tubulointerstitial disease. Fibrin, fibronectin, IgM, and C3 are found by
immunofluorescent microscopy along capillary walls, mesangium, and in the subendothelial
spaces of capillaries and arterioles (1).
Treatment for HUS is supportive. Dehydration should be corrected, but over hydration should be
avoided if oliguric renal failure occurs. Fluids must be limited to insensible losses plus the
volume of urine output. Hyperkalemia, hyperphosphatemia, and severe metabolic acidosis may be
managed medically. Dialysis is indicated if this fails. Packed red blood cells should be transfused
if the hemoglobin falls below 6g/dL or for symptomatic anemia. Platelet transfusions are rarely
administered since generalized bleeding is not common; however, they may be indicated before
surgical procedures (i.e. catheter placement for hemodialysis or peritoneal dialysis) or active
bleeding. Hypertension should be treated to prevent encephalopathy or congestive heart failure.
Calcium-channel blockers (nifedipine) or nitroprusside are the medications often recommended to
control hypertension.
Peritoneal or hemodialysis should be considered when fluid and electrolyte imbalances cannot be
corrected by medical management, or when fluid overload compromises cardiac or pulmonary
function. In general, when the BUN exceeds 100 mg/dL, dialysis should be considered even in
the absence of fluid and electrolyte imbalances (2). Non-oliguric patients generally do not need
dialysis.
Antiplatelet drugs, intravenous immune globulin, anticoagulants, thrombolytic agents,
prostacyclin, and corticosteroids have not been found to be beneficial (1,2). Plasma infusion or
exchange therapy found to be beneficial in patients with TTP, has not been found to be
advantageous in patients with HUS. Plasmapheresis has been of benefit in atypical HUS (D-)
when neurological involvement is present(1). Fresh frozen plasma administration may be harmful
in patients with HUS (1). Antibiotic therapy during D+ HUS is controversial, after a recent report
suggested that the risk of developing HUS may be increased after antibiotic therapy (sulfacontaining and beta-lactam) for E. coli O157:H7 (3). Currently, a chemically synthesized
trisaccharide (Synsorb-Pk), was found to bind with high affinity to Stx-1 and Stx-2, and is
undergoing human trials in Canada in assessing its value in preventing D+ HUS (1).
Prevention of D+ HUS is most effective by cooking ground beef until the inside is no longer
pink. The Food and Drug Administration recommends a minimum internal temperature of 155
degrees F for cooked hamburger. The most effective means of preventing person-to-person
spread is supervised handwashing. Infected children must be excluded from day care centers,
until they have documented negative stool cultures for E. coli O157:H7.
Prognosis for HUS has improved with the introduction of dialysis. Previously, children with HUS
died from fluid overload, metabolic derangements, and uremia. The acute fatality rate ranges
from 4-12% and another 5% develop acute renal failure and anuria. End-stage renal disease or
chronic renal failure develops in 10-15% of HUS patients (2). 65-85% recover completely,
however, a significant number of patients develop renal sequelae (proteinuria, hypertension, and
low creatinine clearance) during long-term follow up studies (1).
Urinary Tract Infection Janet M. Berreman, MD
This is a 4 month old female who presents to the office with a chief complaint of fever, vomiting,
and loose stools. She has had tactile fever for 3 days, and had 5-6 episodes of emesis on the first
day of illness. Stools were liquid on the first and second days of illness. She was seen at an
emergency room 2 days ago, where the impression was gastroenteritis. No labs or x-rays were
done in the emergency department. She returns to the office now because of persistent fever.
Vomiting and diarrhea have resolved, but she is breast-feeding less well than usual. Her mother
notes that her urine seems "strong" and that she is not as playful as usual. She has had no known
ill contacts. She has no cough, URI symptoms, or rash. Past history is unremarkable and she is on
no medications.
Exam: VS T 38.9, P164, R40, Wt. 5.3kg (15%ile, and 150gm below her pre-illness weight). She
is alert, smiling, active, not toxic, and in no distress. Her anterior fontanelle is soft and flat. Her
eyes and ENT exams are normal. Her oral mucosa is moist. Her neck is supple. Heart rate is
regular without murmurs. Lungs are clear and her respirations are non-labored. Her abdomen is
flat, soft, non- tender, without hepatosplenomegaly or masses. Her external genitalia are normal.
Her skin is warm and well perfused, with no rash. Her back exam reveals no deformities or
cutaneous defects. Her neurologic exam shows normal tone, strength, and activity.
A urine specimen obtained by transurethral catheterization yields a small amount of cloudy urine,
which is positive for leukocyte esterase and nitrite tests. This is sent for culture. Her CBC shows
a WBC 9.4, H/H 9.3/27.5, platelets 389,000, 51% neutrophils, 44% lymphocytes, 3% monocytes,
2% eosinophils. She is given 250mg of ceftriaxone intramuscularly and is scheduled for recheck
in the office the next morning.
At follow-up the next day, she is smiling and non-irritable, and shows a 250 gm weight gain. She
fed well overnight and continued to have a low grade fever. Urine culture is positive for greater
than 100,000 colonies/ml of a non-lactose fermenting organism, with identification and
sensitivities pending. Ceftriaxone is repeated at the same dose. The following day, she is afebrile
and her parents feel that she is entirely back to normal. Urine culture result identifies E. coli,
sensitive to all antibiotics tested. She is started on oral trimethoprim-sulfamethoxazole (TMPSMZ) to complete 10 days of antibiotic therapy. She remains well on oral antibiotics. Following
10 days of therapy, she is changed to a prophylactic dose of TMP-SMZ and a renal ultrasound
and voiding cystourethrogram (VCUG) are scheduled. Both studies are normal. Repeat urine
cultures on day 3 of antibiotics, and again at the time of VCUG are negative. Antibiotics are
discontinued. She has done well without recurrent episodes of UTI.
Urinary tract infections (UTIs) are a common, potentially serious, and (especially in young
children) often occult bacterial infection of childhood. During childhood, UTI occurs in
approximately 3-5% of girls and 1% of boys. Most of the UTIs in boys occur in the first year of
life, whereas the age of the first diagnosed UTI in girls is highly variable. After 2 years of age,
UTI in females exceeds that in males by a factor of 10:1 (1). Uncircumcised males less than one
year old are more likely to be affected than circumcised males (2,3). The prevalence of UTI in a
febrile child 2-24 months of age, without other source of infection, is 5% (4). After 6 years of
age, and before the onset of sexual activity, incidence of UTI falls dramatically in both sexes.
Many factors may predispose a child to UTI, including abnormalities of the urinary tract such as
vesicoureteral reflux (VUR), renal anomalies with hydronephrosis or obstruction, neurogenic
bladder, or nephrolithiasis; functional abnormalities such as constipation, fecal incontinence, or
incomplete bladder emptying; and environmental factors such as bubble baths, poor perineal
hygiene, pinworms, or sexual activity, including sexual abuse. Labial adhesions in girls and
phimosis in boys also contribute to an increased risk of UTI.
UTI causes acute morbidity as well as long term sequelae including hypertension and impaired
renal function. Accurate diagnosis of UTI is important both to facilitate appropriate management
of the acute illness, and to insure appropriate evaluation and follow-up. Equally important is
accurately ruling out a UTI to avoid unnecessary, costly, and potentially harmful treatment and
evaluation.
The clinical presentation of UTI varies greatly, primarily with the age of the child. In general, the
older the child, the more clearly signs and symptoms point to the urinary tract. Thus older
children (over 6 years) and adolescents are likely to present with dysuria, urgency, or frequency,
and may have associated fever, chills, flank pain, enuresis, or hematuria. Younger children (2-6
years) can have any of these same signs and symptoms, but they may show more nonspecific
signs such as abdominal pain, altered voiding pattern, decreased appetite, or general malaise (5).
From infancy to 2 years of age, fever alone is the most common presentation of UTI (6). There
may be associated vomiting, diarrhea, constipation, poor feeding, irritability, or late-onset
jaundice, but these features do not aid in distinguishing UTI from other causes of fever. Vomiting
and diarrhea are frequently attributed to gastroenteritis, when in fact it is a UTI. A history of
malodorous urine or crying with urination is helpful when present, but absence of these
complaints does not rule out UTI. In this age group, UTI should also be considered in the
differential diagnosis of failure to thrive. The possibility of UTI should be considered in any
febrile (temp greater than 39 degrees C, 102.2 degrees F) child under 24 months of age, keeping
in mind that girls under 24 months of age, and boys under 6 months of age are at highest risk.
The diagnosis of UTI depends upon: first, maintaining a high index of suspicion for the condition,
especially in young children and infants; and second, performing appropriate diagnostic studies.
Physical examination of the child with suspected UTI focuses first on assessing the overall degree
of illness severity (relatively stable or possibly toxic and septic) of the child, including hydration
status, level of alertness and comfort or discomfort, and perfusion state. Vital signs must be
evaluated, especially for fever, hypertension (as a sign of renal impairment), signs of shock, and
weight (for chronic failure to thrive or acute weight loss suggestive of dehydration). The
abdomen should be carefully examined for any masses or tenderness, including costovertebral
angle (CVA) tenderness. Genitalia should be examined for signs of trauma, urethral or vaginal
discharge, labial adhesion, or phimosis. Rectal examination may provide further assessment of
any intra-abdominal masses or tenderness, and assessment of rectal tone may aid in ruling out a
neurologic abnormality which could contribute to UTI susceptibility. Visual inspection of the
sacral spine for skin dimples or other cutaneous abnormalities may similarly lead the clinician to
further evaluate the child for spinal cord abnormalities associated with a neurogenic bladder.
The diagnosis of UTI requires culture of a properly collected urine specimen (7). In children less
than 2 years of age, a properly collected urine specimen requires an invasive procedure: either
suprapubic aspiration or transurethral catheterization. As children advance in age and toileting
abilities, it becomes possible to obtain a clean catch mid-stream voided urine specimen and thus
avoid invasive collection techniques. A clean catch mid-stream urine sample means that the
urethral meatus and surrounding area should be clean, and that the urine collected should be from
the middle of the stream: i.e., the first few drops of urine should not be collected. For girls,
cleaning involves separating the labia and cleaning the area (usually with a series of 3 premoistened antiseptic towelettes). For circumcised boys, the glans of the penis should be similarly
cleansed. For uncircumcised boys the foreskin is gently retracted prior to cleaning. After
cleaning, the child voids over the toilet, with the parent "catching" the urine in a clean specimen
cup after the first few drops are passed. In girls this is often more easily accomplished by having
the child sit facing backwards on the toilet, so the parent can easily catch the urine stream from
behind the child.
Urinalysis (UA) is helpful in evaluating the likelihood of UTI, but cannot definitively rule it in or
out. The most readily available and useful components of the UA in this context are the leukocyte
esterase test, nitrite test, and microscopy. Sensitivity is markedly
improvedwhenallthreeareused,althoughspecificityislower.
ApositiveleukocyteesteraseorpositivenitritetestissuggestiveofUTI, as are more than 5 WBC per
HPF (high power field) of a spun urine specimen, or bacteria present on a gram stain of an
unspun urine (a test not done by most labs unless specifically requested).
Urine culture results are expressed quantitatively, indicating the colony-forming units (CFU or
colony count) of bacterial growth. The significance of a positive culture depends upon the method
of specimen collection and the number of colonies of a single organism (8). In general, a colony
count of greater than or equal to 100,000 is considered positive on any properly obtained urine
specimen. Colony counts of greater than or equal to 10,000 on a catheterized specimen are also
considered positive. Colony counts of 1,000 to 10,000 on a catheterized specimen are suspicious
and should be repeated. A specimen obtained by suprapubic aspiration should be sterile, so any
growth of gram negative bacilli or any more than a few thousand gram positive cocci is
considered a positive culture.
Urine specimens obtained from young children by means of a bag applied to the perineum have a
high rate of contamination. A negative culture of a bag-collected urine does rule out a UTI;
however, a positive culture obtained in this way is not a definitive diagnostic test. In fact, positive
culture results from such a specimen are estimated to be falsely positives as much as 85% of the
time (7).
The most common causative agents of UTI are gram negative colonic bacteria, with Escherichia
coli being the cause of most acute UTIs (1,8). Klebsiella, Proteus, and Enterobacter species are
other common gram negative causes of UTI. Gram positive organisms include Staphylococcus
species and Enterococcus species. Cystitis may be viral, usually caused by adenovirus (1,9).
UTIs are divided into two major classifications: those that involve the lower urinary tract
(cystitis) and those that involve the upper urinary tract (pyelonephritis). Lower tract disease
typically does not cause fever, and does not result in renal damage. Upper tract disease classically
causes fever, abdominal or flank pain, and in younger children and infants the nonspecific signs
of irritability, poor feeding, malaise, failure to thrive, or vomiting and diarrhea. The
differentiation of upper tract disease from lower tract is primarily a clinical one, with supporting
evidence provided by technetium (Tc 99m) dimercaptosuccinic acid (DMSA) scanning (10) and
by elevated C-reactive protein (CRP) values (9).
The differential diagnosis of UTI varies with the age and presenting complaints of the patient.
The nonspecific signs associated with UTI in infancy and toddlerhood may be associated with
bacterial sepsis originating in any site, as well as with gastroenteritis, hepatitis, or viral infection.
Signs of cystitis in older children or adolescents raise the possibility of chlamydial or gonorrheal
urethritis. The presenting complaints of pyelonephritis must be differentiated from acute
appendicitis, hepatitis, gall bladder disease, pelvic inflammatory disease, and other causes of
acute abdominal pain.
Treatment of UTI depends upon assessment of the likelihood of the diagnosis of UTI and the
clinical severity of the illness. These assessments will guide the clinician to: await culture results
before initiating antibiotic therapy; initiate empiric oral antibiotic therapy; initiate empiric
parenteral outpatient therapy; or hospitalize for empiric parenteral therapy. Initial treatment
decisions are made before culture results are available, and are therefore empiric. The goals of
prompt treatment are eradication of the acute infection, symptom resolution, prevention of
progression of disease (e.g., to pyelonephritis, abscess, or sepsis), and reduction of the risk of
renal scarring and its long term sequelae (7,11).
When therapy is initiated empirically, the clinical condition of the child is the primary factor
considered. In every case, an adequate urine specimen for culture must be obtained prior to
initiating therapy. The younger and/or more clinically ill the child with probable UTI is, the more
aggressive initial therapy needs to be. In the non-toxic appearing, usually older child, in whom
there is a relatively low suspicion of UTI, and no concern of upper tract disease, treatment may be
deferred until urine culture results are available. A non-toxic child, who is feeding well, is wellhydrated, and for whom compliance and follow-up are not problematic, is appropriately managed
with oral antibiotics and close outpatient follow-up.
At any age, a child with signs of urosepsis, severe clinical illness, or significant dehydration
should be hospitalized for parenteral antibiotic therapy and close clinical monitoring and
supportive care. High risk children, such as those with immunologic impairment or known
urologic abnormalities, may also need hospitalization. Inpatient therapy traditionally has been
recommended for all children with suspected pyelonephritis as well as for infants less than 1 year
of age with UTI. Some of these children may be managed with outpatient parenteral antibiotics,
or even with oral antibiotics (7,11,12), if compliance and close daily follow-up can be assured.
Children who are vomiting, or otherwise unable to reliably take oral medications, or for whom
compliance is a concern, should be treated parenterally (either as inpatients or outpatients) until
these issues are resolved (7,13).
The initial choice of antimicrobials is guided by the chosen route of administration, known
uropathogens, and any compromise of renal function of the patient. It is adjusted based on clinical
response and results of culture and sensitivity testing. Initial oral therapy may be with a
sulfonamide (TMP-SMZ or sulfisoxazole) or with a cephalosporin (cephalexin or cefixime are
commonly used). Parenteral therapy may be with a cephalosporin (ceftriaxone, cefotaxime) or
ampicillin and/or an aminoglycoside (used with caution in the setting of impaired renal function).
The oral drug nitrofurantoin is excreted in the urine, but it does not reach therapeutic
concentrations in blood or tissues. It therefore should not be used to treat febrile UTIs in infants,
or to treat pyelonephritis.
The choice of initial oral empiric therapy involves consideration of spectrum, side effects,
allergies, palatability, dosage schedule, and price. TMP-SMZ is often considered the drug of
choice. It is, however, associated with some risk of Stevens-Johnson syndrome, and can
precipitate hemolysis in patients with undiagnosed G6PD deficiency. Cephalexin is the most
palatable of the three, and the least expensive, but usually dosed QID. Cefixime is the most
expensive, but offers the advantage of once a day dosage. TMP-SMZ is intermediate in price, and
dosed BID. All three have excellent coverage for the usual pathogens. Any of these drugs is an
acceptable first choice. Amoxicillin should no longer be considered a first line drug for empiric
therapy, due to increasing resistance of E. coli to amoxicillin/ampicillin.
Clinical response to therapy is generally prompt, with improvement evident within 24-48 hours of
initiating antimicrobial therapy. If clinical improvement is seen, and culture results indicate that
the uropathogen involved is sensitive to the antimicrobial being used, routine repeat culturing of
the urine after two days of therapy is not necessary. However, if sensitivities are unavailable, are
intermediate or resistant, or the expected clinical improvement is lacking, repeat culture should be
obtained.
Children started on parenteral antibiotics may be changed to an oral antibiotic when they are
clinically well enough to do so. That is,whentheyarenon-toxic,wellhydrated,afebrile,andtoleratingoralintake. Again,oralantibioticchoiceisguidedbytheresultsof initial
culture and sensitivity testing of the urine.
Duration of therapy varies somewhat, again based on age and degree of illness of the child. Any
child or infant with a febrile UTI needs a total of 7-14 days of antibiotic therapy, with 10-14 days
preferred for those with clinical evidence of pyelonephritis (7). Short course therapy (3 days or
less) is reserved for adolescent females with uncomplicated cystitis (11).
The management of UTI does not end with the successful treatment of the acute infection. Rather,
it continues with the evaluation for renal anomalies or VUR, monitoring for recurrence of UTI,
short or long term antibiotic prophylaxis to prevent recurrence, and medical or surgical
management of any underlying predisposing conditions.
Children with VUR are at increased risk of renal damage from UTIs, as are children with other
anomalies of the urinary tract. Therefore, all children (with the exception of adolescent females
with uncomplicated cystitis) with a documented UTI should be investigated with a renal
ultrasound and VCUG (14,15). These studies may be performed as soon after the diagnosis of
UTI as is convenient. Delaying studies for 3-6 weeks after the acute infection (as previously
recommended) does not alter the detection of VUR, but does substantially decrease the likelihood
that the studies will be completed (16).
If studies are delayed until after completion of 7-14 days of antimicrobial therapy, the child
should remain on antimicrobial prophylaxis until the studies are completed. Drugs of choice
include TMP-SMZ, sulfisoxazole, and nitrofurantoin, in doses adjusted for prophylaxis rather
than therapy (7,17).
The child with VUR needs long term follow-up with antibiotic prophylaxis, periodic monitoring
of urine cultures, repeat imaging of the urinary tract, and possible surgical consultation (for
persistent VUR, high grade VUR, or recurrent UTIs despite prophylaxis) (14,18). DMSA
scanning is helpful in determining the presence of renal scarring in children with VUR and thus
can assist in management decisions.
Prognosis after UTI in childhood depends on: 1) whether the infection was limited to the lower
tract (cystitis) or involved the upper tract (pyelonephritis), 2) the presence or absence of VUR,
and 3) the presence or absence of other urinary tract anomalies, especially those with obstructive
uropathy.
Uncomplicated infections without associated VUR or obstruction respond well to antimicrobial
therapy. However, as many as one third of these patients may experience recurrence of UTI
within the first year after acute infection (19). Follow-up urine cultures (generally monthly for 3
months, then at 3 month intervals X 3, and then at 6 month intervals X 2) are therefore
recommended.
VUR is present in 30-50% of children with UTI (20). Its severity is graded on a scale of I, II, III,
IV, V (14). While pyelonephritis and renal scarring can occur in the absence of VUR, the severity
of renal scarring correlates with the degree of reflux (20). The natural history of low grade reflux
is toward spontaneous resolution, whereas high grade reflux is less likely to resolve without
surgical intervention. The combination of renal parenchymal infection (especially repeated
infections) and VUR or obstructive nephropathy puts children at risk for renal scarring which
may progress to chronic renal insufficiency, hypertension, reflux nephropathy, and end stage
renal disease (9,14,20). Early diagnosis and treatment of UTI and VUR or obstruction may
diminish the incidence of these long term complications (21).
In summary, appropriate management of UTI hinges on three essential factors, all of which are
the responsibility of the clinician: 1) Maintaining a high index of suspicion for the diagnosis,
especially in infants and toddlers who rarely have specific symptoms, 2) Properly obtaining an
adequate urine specimen for culture before initiating antimicrobial therapy, 3) Following through
on the patient's clinical response, culture and sensitivity results, and the results of imaging studies
and follow-up cultures. Careful attention to all of these points will optimize the diagnosis,
treatment, management, and outcome of the child with UTI.
Enuresis Potenciano Reynoso Paredes, MD
This is a 4.5 year old male who presents to the office with his mother with a chief complaint of
bed-wetting twice a week. Essentially he is healthy except for an occasional cough and fever that
the mother attributes to exposure to other children with colds. Urinary discharge occurs at night
only and he therefore has to wear diapers to bed. His mother is worried since his brothers and
sisters were all toilet trained by this age. There is no history of dysuria, intermittent daytime
wetness, polyuria, or polydipsia.
His past medical history is unremarkable. Family history is significant for his father being a bedwetter. His child development is normal.
Exam: VS T 37, P 110, R 20, BP 107/64, Ht 102 cm (25th percentile), Wt 16.2 kg (25th
percentile). He is alert and active, in no distress. His appearance is non-toxic. HEENT and neck
exams are negative. His lungs are clear bilaterally. His heart has a normal rate and rhythm,
normal S1and S2, and no murmurs or rubs. No masses, organomegaly, or tenderness are
appreciated on exam of his abdomen. Bowel sounds are present. He has no inguinal hernias. He
has a circumcised penis of normal size. The meatus is normally placed, without discharge. No
phimosis is present. His testes are descended bilaterally and are of normal size (Tanner stage 1).
His back is straight with normal posture with no scoliosis or tenderness, or midline defects. His
extremities and muscle tone are normal. His gait is normal. He is able to hop, skip, and stand on
each foot for 5 seconds, copy a square and get dressed without help. His speech and behavior are
age appropriate.
You reassure his mother that bladder control is usually attained between the ages of 1 and 5 years
and bed-wetting becomes less frequent with each passing year. You recommend that she be
supportive of her son's dry nights and avoid criticism of wet nights. You also recommend
avoiding excessive fluid intake two hours before bedtime and emptying his bladder at bedtime.
He returns to your office after 6 months and his mother feels that the bed-wetting problem has
improved significantly. On his next appointment (4 months later) his mother reports the
resolution of his bed-wetting problems.
Enuresis, commonly known as bed-wetting, is the most common childhood urologic complaint
encountered by pediatricians. Nocturnal enuresis (NE) is defined as involuntary passage of urine
during sleep beyond the age of expected continence which is approximately 5 years of age. There
are two types of NE. Primary is when a child never stopped wetting for any lengthy period,
whereas secondary is acquired enuresis after being dry for at least 6 months. Primary enuresis
affects the large majority of children with enuresis.
Since urinary continence is reached earlier in girls than in boys, NE is 2-3 times more frequent in
boys. At age 5, 20% have NE at least once a month, with 5% of boys nightly and less than 1% of
the girls nightly. Since most NE is due to maturational delay, there is a significant resolution or
improvement as the child gets older. Approximately 15% resolve each year. Interestingly, family
studies show a strong genetic predisposition for enuresis. More recently studies suggest a genetic
linkage of primary nocturnal enuresis to the short arm of chromosome 13.
Organic causes of bed-wetting account for less than 5% of all cases; with most being urinary tract
infections. Other organic problems include: diabetes mellitus, diabetes insipidus, nocturnal
seizures, genitourinary anomalies, nocturnal ADH deficiency, hyposthenuria (constant secretion
of dilute urine) associated with sickle cell disease, medications, or emotional stress. These
children need to be recognized and treated. Some children with severe constipation may compress
the bladder and present with bed-wetting. Other theories suggest reduced bladder capacity or
sleep disturbance.
The office evaluation of NE must exclude any organic causes. A careful history is taken which
should include pattern of wetting, developmental milestones, fevers, polydipsia, polyuria, and
prior urinary infections. Questioning about sickle cell disease, food allergy, and constipation is
occasionally helpful. Attention should also be paid to family dynamics and stresses that may
uncover psychological factors.
Physical examination should focus on the neurological, genital, bladder and bowel exams. Back
examination should include a search for neurological involvement such as a midline defect or
suggestions of an occult spinal dysraphism. A neurological examination that includes gait, muscle
tone, strength, and perineal sensation should be done. Examination of external genitalia for
abnormalities such as labial adhesions, meatitis, epispadias, and hypospadias should also be done.
If possible, and the urine stream sounds abnormal by history, physicians should watch children
void. The abdomen should be assessed for evidence of fecal impaction, organomegaly, or bladder
distention.
Thepurposeofinitiallaboratorytestsisusuallylimitedtorulingoutinfectionasthesourceoftheproblem.
Aspecificgravityof 1.015 or greater rules out diabetes insipidus and the absence of glycosuria
rules out diabetes mellitus. In cases in which urinary tract obstruction or neurogenic bladder are
suspected, a voiding cystourethrogram may be warranted.
Atpresentthereisnotreatmentmodalitythatis100%successful.
Again,parentsneedtoberemindedthatamajorityofbed- wetting is due to maturational delay and not
under conscious control. Therefore, the most important aspects of treatment are reassurance and
protection of the child's self esteem. It is important that bed-wetting not be perceived as a bad
behavior since punishment not only lowers the child self esteem, but also does nothing to
improving symptoms. Early education of the parents in regards to maturational delay, role of
genetics and the importance of a supportive toilet training practice may ease the difficult period.
Remember that there is a 15% spontaneous remission every year so many advocate an approach
of reassurance and watchful waiting. Some simple life adjustments such as improving access to
the toilet, avoiding excessive fluid just before bedtime and emptying the bladder at bedtime may
be tried initially.
To some families, this conservative approach (which requires patience) can lead to suffering and
frustration. Instead, a comprehensive method of treatment that includes bladder training,
pharmacologic therapy and behavior modification with an alarm system can be implemented.
Treatment can begin with positive reinforcement such as keeping a calendar and rewarding dry
nights. Another treatment is bladder training consisting of different methods such as holding urine
as long as possible then when the child does urinate he/she is suppose to stop
andstarttheurineflowfrequently.
Anothermethodisgoingtothebathroomseveraltimesanight,orhavingtheparentswakethechild several
times during the night and subsequently lengthening the time interval between waking. The
objective is to increase the muscle strength of the urethra as well as give the child confidence that
he or she can control urine flow and link the feeling of a full bladder with the need to go to the
bathroom. Average bladder capacity in children can be approximated by the formula: volume in
ounces (30 ml per ounce) = 2 + age in years. Adult bladder capacity is about 250 to 400 ml.
Pharmacologic therapy consists of tricyclic antidepressants (imipramine) or desmopressin acetate
(DDAVP). Each has advantages and disadvantages. Imipramine has anticholinergic effects on
bladder capacity and noradrenergic effects which decrease bladder detrusor excitability. 10-60%
respond favorably to imipramine treatment, but more than 90% relapse. Imipramine is also
potentially lethal with acute overdose (especially cardiac toxicity). DDAVP is a synthetic analog
of vasopressin stimulating water retention and urine concentration, thereby reducing urine
volume. DDAVP is available in two forms, tablets and nasal spray. The oral form is often used on
children with nasal congestion such as colds and allergies. The drawback is the cost and rare mild
side effects of DDAVP. DDAVP is useful in certain situations such as a child going to overnight
camp. There is a 25-50% success rate with DDAVP, but a relapse rate of 94%.
In recent years, enuresis alarms have been shown to be the most effective treatment for bedwetting. Urination acts as a stimulus for the alarm and wakes the patient from sleep. The cure rate
is 60-80% and it has the lowest relapse rate of 10-40% when compared to other treatments. The
only drawback is that the child and family must be highly motivated to stay committed to these
conditioning methods.
Acute Scrotum Robert G. Carlile, MD
A 10 year old male presents with a chief complaint of acute onset of left scrotal pain 3 hours
earlier, which awoke him from sleep. The pain is constant and does not change with position.
There is no history of trauma. He has no dysuria, fever, chills, nausea or vomiting.
Exam: He is afebrile in moderate distress secondary to left scrotal pain. The left hemiscrotum is
edematous and erythematous. The left testicle has a transverse lie, with marked tenderness to
palpation. The cremasteric reflex is absent on the left. The right hemiscrotum and testicle are
normal on exam. The circumcised penis is normal, with no urethral discharge present.
A CBC and urinalysis are normal (this results in an unnecessary delay of one hour). Color
Doppler ultrasound scanning of the scrotum demonstrates the absence of blood flow to the left
testicle and epididymis. Normal blood flow to the right testicle is present. No testicular masses
are noted.
An emergent urological consultation is obtained. Scrotal exploration, under anesthesia, reveals a
720 degree torsion of the left spermatic cord, an ischemic testicle, and a "bell-clapper" deformity.
With detorsion, the left testicle's normal color returns. The left testicle is then "fixed" to the
scrotal wall to prevent retorsion. The right testicle is also fixed to the scrotal wall. Postoperatively, his pain was markedly relieved with the detorsion of the left testicle, and the
remainder of his recovery is unremarkable.
The acute scrotum is a true urologic emergency. The window of opportunity to salvage a torsed,
ischemic testicle is only 6 hours (1). Acute scrotal swelling should be considered testicular
torsion until proven otherwise.
Puberty is the most common age at which testicular torsion occurs, with the newborn period
being the second most common. The incidence is 1 in 4000 males younger than 25 years (2).
Testicular torsion can be classified into two types, relative to the tunica vaginalis' relationship to
the area of the spermatic cord that twists: extravaginal and intravaginal. Extravaginal torsions
occur perinatally, during testicular descent and prior to testicular fixation in the scrotum (2). This
incomplete fixation of the gubernaculum (the fibrous cord extending from the fetal testis to the
fetal scrotum which occupies the potential inguinal canal and guides the testis in its descent) to
the scrotal wall allows the entire testes and tunica free rotation within the scrotum (3). The
rotation of the cord is "extravaginal" because the rotation of the cord is proximal to the
attachment of the tunica vaginalis that encloses the testes. These comprise 5% of all testicular
torsions (4).
Intravaginal torsion occurs in the remaining 95% of all testicular torsions (4). A congenital high
attachment of the tunica vaginalis on the spermatic cord allows the testes to rotate on the cord,
within the tunica vaginalis. This is the "bell-clapper" deformity which is a horizontal lie of the
testicle instead of the normal vertical lie. It is called a bell clapper deformity because the testicle
resembles a horizontal oval hanging from a cord at its midpoint (like the clapper in a bell) as
opposed to the normal testicle which resembles the letter "b" or "d" with the testicle positioned
vertically attached to the cord on its side. This deformity is commonly bilateral, which places the
contralateral testicle at risk for torsion also (3). As viewed from below, the testes rotate inward or
medially during a torsion; the right clockwise and the left counter clockwise.
The acute onset of severe testicular pain with associated nausea and vomiting is very suggestive
of testicular torsion, especially in the adolescent. Fever and dysuria are not common in testicular
torsion. Intermittent testicular torsion is suspected when brief episodes of acute testicular pain
occur recurrently. Torsion of a testicular or epididymal appendage (appendix testis or appendix
epididymis) usually presents in mid childhood with mild discomfort of a few days duration (2).
Epididymitis and/or orchitis, on the other hand, may be associated with fever, dysuria, and a more
gradual onset of scrotal pain, usually over several days. A history of urethral strictures, posterior
urethral valves, myelodysplasia with neurogenic bladder, and severe hypospadias with utricular
enlargement may predispose to urinary tract infection, with secondary reflux into the ejaculatory
ducts causing epididymitis (2). A history of scrotal pain and swelling associated with fever and
parotid gland swelling suggest mumps orchitis.
Inguinal hernia and/or hydroceles may present with similar symptoms to acute testicular torsion.
A history of constipation or upper respiratory infection, both causing increases in intraabdominal
pressure may be present.
Henoch-Schonlein purpura, an uncommon cause of acute scrotal swelling (usually bilateral), is
associated with a history of vasculitis and associated onset of a cutaneous purpuric scrotal rash
(2).
Trauma, even minor, may be a cause of testicular pain and should be sought in the history
(straddle injury, wrestling, sports). A history of trauma may suggest a traumatic etiology of pain
and swelling, but this does not necessarily rule out the presence of testicular torsion.
The physical exam should be begun in conjunction with the history taking. The level of distress is
noted along with vital signs and examination of the abdomen. There should be a specific notation
of the presence or absence of inguinal and scrotal swelling, urethral discharge, scrotal or perineal
ecchymoses or rashes, and lastly the appearance of the testes and area of pain and/or tenderness.
The absence of a cremasteric reflex, in conjunction with testicular tenderness, is commonly
associated with testicular torsion (5). This reflex is usually present in epididymitis. It is elicited
by gently stroking the skin of the inner thigh: the presence of the cremasteric muscle results in
movement of the testicle in the ipsilateral hemiscrotum.
Acute testicular torsion should be considered the leading diagnosis until it is ruled out. The acute
onset of severe unilateral unrelenting pain, tenderness, high riding testicle, with absent
cremasteric reflex and no change in pain in response to testicular elevation (Prehn's sign), highly
suggest testicular torsion. In testicular torsion, the affected testicle may be more cephalad than
normal and it may lie transversely(horizontally). A change in position is not seen in
epididymitisororchitis.
If one is able to palpate the testicle separate from the epididymis, one can distinguish between
testicular torsion, epididymitis, and testicular appendage torsion. The affected testicle is
exquisitely tender in testicular torsion, and the epididymis may not be palpable, but is also tender
if palpable. In epididymitis/orchitis, the testicle itself is not tender, but the epididymis is palpable
and tender. Epididymitis has a more gradual onset, with tenderness being present. A cremasteric
reflex is usually present, and the pain may be relieved with testicular elevation. Fever, pyuria, and
dysuria may be present.
A torsion of a testicular appendage may present in a fashion similar to that of acute testicular
torsion. The tenderness may be well localized to the upper part of the testes and a characteristic
"blue dot" sign in the skin of the scrotum may be applicable. This blue dot is due to venous
congestion of the appendix testis of the torsed appendage.
Color Doppler ultrasound scanning has great utility in differentiating between the above
diagnoses and ruling out testicular torsion (6). Absence of blood flow to the affected testicle is
noted in testicular torsion, whereas increased blood flow is noted in epididymitis/orchitis. Flow to
the testicle will be present in appendage torsion. Of course, these findings should be combined
with the signs and symptoms, and not taken in isolation. Testicular anatomy is also appreciated
with ultrasound, helping to evaluate for testicular rupture, hematomas, and tumors.
Nuclear scintigraphy is not commonly used today in the evaluation of the acute scrotum. CBC
and urinalysis are helpful in evaluating infectious etiologies, but waiting for these results should
not delay a Doppler ultrasound study. A hernia or hydrocele or varicocele can be distinguished on
exam.
Acute testicular torsion requires emergent scrotal exploration, detorsion of the affected testicle,
with orchiectomy if testicular ischemia and necrosis persists, or testicular fixation if blood flow
and testicular viability is restored with detorsion. In either case, the contralateral testicle should
be explored and testicular fixation performed with permanent suture.
Epididymitis/orchitis can be treated with antibiotic and anti-inflammatory drugs. Occasionally
"sepsis" may result from severe cases, requiring hospitalization with intravenous antibiotics. The
majority can be treated with outpatient antibiotics. Activity should be limited.
Acute testicular appendage torsion may be observed, with analgesics/anti-inflammatories if the
diagnosis is firm. No testicular fixation is necessary as these are not commonly associated with
abnormalities of the attachments. If the diagnosis is in doubt, emergent scrotal exploration is
indicated.
Trauma with rupture of the tunica albuginea of the testes requires exploration emergently, with
debridement and repair. An isolated hematoma may be observed. Henoch-Schonlein purpuric
scrotal swelling may be managed medically. Neonatal torsion may require exploration, if the
diagnosis is made early enough, but unfortunately, the majority are diagnosed too late for testicle
viability. Hernias and hydroceles should be repaired, emergently if incarcerated, electively if not.
The salvageability of a testicle within 6 hours of torsion is very good. Greater than 6 hours is
more worrisome, but exploration should be performed to remove a necrotic testicle, even with a
late presentation, as diminished fertility may result from leaving in an infarcted testicle (2).
Epididymitis responds well to rest and antibiotic therapy. Any predisposing factors should be
corrected.
Ambiguous Genitalia Robert G. Carlile, MD
This is a term infant noted to have atypical genitalia with perineoscrotal hypospadias and a
marked ventral chordee. This could be a penis or an enlarged clitoris. Gonads are nonpalpable
bilaterally on examination of the labioscrotal folds. The parents aren't sure whether their child is
male or female and this constitutes a neonatal (social) emergency. Further evaluation is
commenced immediately. An ultrasound reveals a normal uterus and ovaries, as well as normal
kidneys and bladder. Chromosomal analysis shows a 46XX karyotype. A genitogram reveals a
short distal common urethrovaginal confluence, a vagina with a normal cervical impression, and a
normal urethra.
At two weeks of age, this infant is admitted to the ICU with hypovolemic shock, and found to
have hyponatremia and hyperkalemia. Plasma 17-hydroxy-progesterone levels are markedly
elevated and plasma cortisol levels are low. Hydrocortisone and mineralocorticoid replacement
are administered, along with intravenous fluids and electrolyte replacements, with a good
response. She is diagnosed with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase
deficiency.
A feminizing genitoplasty is performed at one year of age. This includes clitoral reduction and a
flap vaginoplasty. In her mid- teens, the patient undergoes a vaginoplasty revision for introital
stenosis.
Ambiguous genitalia are uncommon in a primary care pediatrician's practice, but their diagnosis
and prompt treatment require urgent medical attention. Any delay may result in death in early
infancy from an uncorrected metabolic disorder, if present. Quickly establishing a definitive
diagnosis and appropriate treatment plan will minimize medical, social and psychological
complications.
It is important to understand normal sexual differentiation in order to understand the development
of intersex (ambiguous genitalia and sex determination) disorders. Up until six weeks of
gestational age, the internal and external genitalia of the male and female fetuses are
indistinguishable. The indifferent gonad is located on the urogenital ridge, with the Wolffian and
Mullerian ducts nearby, which are destined to form the male and female internal ducts,
respectively. The external genitalia in both sexes are represented by the genital tubercle, the
urethral folds, and the labioscrotal swellings that surround the cloacal membrane (1). These
primordial structures have the potential to produce either male or female genitalia.
The SRY gene, on the short arm of the Y chromosome, initiates male sexual differentiation (2).
The SRY influences the undifferentiated gonad to form a testes, which produces the hormonal
milieu that results in male sexual differentiation. Testosterone stimulates the Wolffian structures
(epididymis, vas deferens, and seminal vesicles), and anti-Mullerian hormone suppresses the
development of the Mullerian structures (fallopian tubes, uterus, and upper vagina). Testosterone
converts to dihydrotestosterone in the skin of the external genitalia and masculinizes the external
genital structures. By 12 weeks most of this male differentiation has occurred, after which the
penis grows and the testes descend into the scrotum (3).
In the absence of these genetic (SRY gene) and hormonal influences (testosterone, anti-Mullerian
hormone), the fetus will develop as a female. Intersex conditions arise because of an error along
the male pathway that interferes with complete masculinization, or, in the case of a genetic
female, some virilizing influence that acts on the developing embryo (3).
Infants whose genitalia are obviously indeterminate and ambiguous are investigated so that sex of
rearing can be assigned. However, appearance can be deceptive. An apparent male may be a
severely virilized female with congenital adrenal hyperplasia (CAH). An apparent female infant
with only mild clitoral hypertrophy may be a male with severe androgen insensitivity.
Clinical findings in a newborn infant that raise the possibility of intersexuality (1,3) in an
apparent male: Bilateral nonpalpable testes in a full-term infant.
Hypospadias associated with
clefting of the scrotal sacs.
Undescended testes with hypospadias.
Clinical findings in a newborn infant that raise the possibility of intersexuality (1,3) in an
apparent female: Clitoral hypertrophy.
Foreshortened vagina with single opening (instead of a urethral meatus and vaginal introitus
noted separate from one another, there is just a single opening at the introitus and no separate
urethral meatus visible).
Inguinal hernia containing a gonad.
Also, as noted above, those in whom the external genitalia are clearly ambiguous so that the sex
cannot be immediately decided should be investigated.
A small number of children will only come to light in adolescence because of amenorrhea,
inappropriate breast development, virilization, or the onset of cyclic "hematuria" (gross hematuria
that occurs every 28 days, as a menstrual cycle would).
A careful history should be taken. An obstetric history should include any evidence of endocrine
disturbance during pregnancy (mother with a Cushingoid or virilized appearance), and any
medications taken during pregnancy (particularly any treatment for recurrent
abortionortheuseofhormonalcontraceptives).
Asmanyintersexstatesarerecessivelyinheritedfamilialdisorders,afamilyhistorymay reveal genital
anomalies, unexplained neonatal deaths, abnormal pubertal development, or infertility.
The physical exam starts with a search for evidence of a malformation syndrome. The genitalia
are examined with the size of the phallus noted (a normal newborn stretched penile length should
be greater than 2 cm and a normal clitoris is less than 7mm), and the position of the urethral
meatus noted. Any penile chordee should be noted. The labioscrotal folds are evaluated for
fullness, symmetry, rugosity and the presence or absence of a gonad (If a gonad is palpable in a
female infant, then congenital adrenal hyperplasia is not present, as the CAH infant would have
normal ovaries in the abdominal cavity). The position of the urethral meatus helps to determine
the extent to which the urogenital sinus has closed (a separate urethral meatus and vaginal
opening shows complete closure of the urogenital sinus while a single orifice suggests the
persistence of a common urogenital sinus with the vagina and urethra connected distally). Areolar
and labioscrotal hyperpigmentation associated with high levels of ACTH suggest congenital
adrenal hyperplasia. The palpation of a uterus or cervix may be noted on rectal exam.
Since the appearances of the external genitalia vary so widely among patients who have the same
condition, it is unwise to attempt a definitive diagnosis from the physical findings alone (1,3).
Page - 470
A chromosomal karyotype should be done in all patients. Since congenital adrenal hyperplasia is
the most common cause of ambiguous genitalia in the newborn, serum 17-hydroxy-progesterone
and deoxycorticosterone levels should be checked along with serum electrolytes and glucose in
the infant with symmetrical masculinization and nonpalpable gonads (3,4).
A pelvic ultrasound will delineate the uterine anatomy, if present. It should normally be located
posterior to the bladder. The kidneys and ureters should also be imaged. A genitogram will
delineate the anatomy of the vagina, the uterine canal, one or two fallopian tubes, and/or the vasa
deferentia, as well as the level at which the vagina enters into the urogenital sinus, if present
(1,3). It is performed by injecting contrast retrograde through the common urogenital sinus (or the
urethra and vagina if the urogenital sinus has closed), under fluoroscopy.
Further biochemical profiles may be necessary to identify a block in testosterone biosynthesis,
decreased 5-alpha-reductase activity or androgen insensitivity (3).
Gonadal inspection and biopsy are necessary and can be done laparoscopically in many cases by
an experienced pediatric urologist or pediatric surgeon. This will not be necessary in established
cases of congenital adrenal hyperplasia and Turner syndrome. Cystovaginoscopy provides
valuable information because it augments the genitogram's findings and aids in treatment
planning.
The classification of intersex disorders are most conveniently divided into four main groups
based on gonadal histology: 1) Female pseudohermaphrodites (two normal ovaries present). 2)
Male pseudohermaphrodites (two normal testes present). 3) True hermaphrodites (both ovarian
and testicular tissue are is found in the same patient). 4) Gonadal dysgenesis conditions (the
gonads are histologically disordered; e.g., streak gonads) (1,3,5).
Female pseudohermaphrodism is a disorder in which a chromosomal female (46XX), with normal
ovaries and mullerian derivatives and normal fertility potential, has virilized external genitalia
(enlargement of the phallus and labioscrotal fusion are present to varying degrees). This
virilization of the female fetus is secondary to androgens from either the maternal circulation or
the fetal adrenal gland.
Congenital adrenal hyperplasia (CAH) is the most common cause of female
pseudohermaphrodism, as well as the most common intersex disorder. The adrenal glands, in
CAH, overproduce testosterone because an enzyme defect in intermediate metabolism results in
decreased cortisol synthesis, which leads to an increase in circulating adrenocorticotropic
hormone (ACTH), and thus to hyperstimulation of the adrenals (5). Because some forms of CAH
are associated with salt-wasting, prompt monitoring and correction of electrolytes and
corticosteroid/mineralocorticoid replacement are crucial. CAH is an autosomal recessive disorder
that occurs in 1 of 15,000 births in the United States (6).
21-hydroxylase deficiency is the most common (95% of the cases) enzyme defect that causes
CAH, with salt-losing a feature of a complete deficiency. 11-beta-hydroxylase deficiency is a rare
form of CAH, which results in an accumulation of deoxycorticosterone, a potent
mineralocorticoid. This results in salt retention and hypertension.
21-hydroxylase deficiency is suspected in a masculinized infant without palpable gonads and with
Mullerian derivatives (female internal pelvic organs) evident on pelvic ultrasound. A 50 to 100
fold increase in serum 17-hydroxyprogesterone and a 46XX karyotype confirms the diagnosis.
Salt wasting occurs in 75 percent of patients with classical disease, and is evident within the first
two weeks of life, with resultant hyponatremia, hypokalemia, and inappropriate sodium wasting
(high urine sodium despite hyponatremia) due to low serum aldosterone and elevated plasma
renin activity (7). It is crucial to recognize this potentially life-threatening condition in the
newborn period and institute replacement of cortisol and mineralocorticoid as necessary.
Other causes of female pseudohermaphrodism are maternal progesterone ingestion (with
androgenic side effects) administered during pregnancy to prevent abortion, a virilizing ovarian
or adrenal tumor in the mother, or idiopathic causes.
Male pseudohermaphrodism results from inadequate virilization of the male embryo.
Chromosomal males (46XY) possess testes, but the male anatomic genital development is
abnormal. Cellular testosterone sensitivity is abnormal in 80 percent of cases, and testosterone
production is deficient in the remaining 20 percent. The causes include androgen insensitivity,
gonadotropic failure, Leydig cell agenesis, bilateral vanishing testes syndrome, persistent
mullerian duct syndrome, testosterone biosynthesis defects and 5-alpha- reductase deficiency (5).
Patients may have abnormal male genitalia, ambiguous genitalia, or female genitalia with
palpable or nonpalpable testes, depending on the completeness and nature of the defect and the
extent of gonadotropin oversecretion.
Androgen insensitivity is the most common (1 in 20,000 male births) cause of male
pseudohermaphrodism and results from dysfunction or reduction of the androgen receptor. For
complete testicular feminization, the androgen receptor is absent or completely nonfunctional.
The pituitary and hypothalamus are insensitive to testosterone and thus secrete large amounts of
gonadotropins, which results in the oversecretion of testosterone and estrogen (5). Breast
development, general body habitus, and distribution of body fat are female in character. The
clitoris is normal or small, and the vagina is short with a blind ending, but the external genitalia
are female in appearance. All internal genitalia are absent (no uterus or ovaries) except for the
gonads, which have the histologic appearance of undescended testes (6). Because of increased
tumor risk in the undescended testes (5% to 10%), gonadectomy is recommended after puberty.
Patients with complete androgen insensitivity syndromes (testicular feminization) are normal
phenotypic females who present during childhood with one or both testes palpable in an inguinal
hernia, or with amenorrhea at puberty. A few are diagnosed based on discrepancy between
prenatal karyotype and phenotype at birth (i.e., a 46XY karyotype with female external genitalia
at birth). The diagnosis is based on clinical and family history, endocrine studies and, if indicated,
androgen binding analysis in genital skin fibroblasts (5).
In the 17-beta-hydroxysteroid dehydrogenase deficiency (the most common biochemical defect
causing deficient testosterone biosynthesis without CAH, which causes male
pseudohermaphrodism), males have feminine external genitalia with mild to moderate degrees of
clitoral hypertrophy, but with a separate urethra and blind ending vaginal pouch. Testes are
usually inguinal. The diagnosis is often made at puberty, when progressive virilization associated
with penile growth, attainment of male secondary sex characteristics, testicular descent, and a
change in gender identity may occur (5).
5-alpha-reductase deficiency (pseudovaginal perineoscrotal hypospadias) is an autosomal
recessive disorder associated with failure of dihydrotestosterone (DHT) formation, resulting in
normal male internal Wolffian duct derivatives, but the external genitalia fail to virilize in utero
(DHT is necessary for the external genitalia to masculinize while the internal genitalia
masculinize in the presence of testosterone). The internal male genitalia are normal, and the testes
are located in the labioscrotal pouch. The external genitalia typically show severe perineoscrotal
hypospadias and a blind vaginal pouch opening into the urogenital sinus or urethra. At puberty,
normal levels of luteinizing hormone and testosterone result in masculinization of the external
genitalia, and breasts do not develop (5,6).
True hermaphrodism is a rare condition in which ovarian and testicular tissue exist in the same
individual. 70 percent are 46XX (but they possess the SRY gene), 10% are 46XY, and the
remainder show either mosaicism or chimerism (evidence of development from two zygotes).
Patients most commonly have ambiguous genitalia, but near-normal female and male genitalia
may be present. A unicornuate or bicornuate uterus is usually present, and the differentiation of
the genital ducts is determined by the ipsilateral gonad, with the ovary usually located on the left
side (5). The most common gonad found is the ovotestes (50%), followed by ovary (30%) and
testes (20%). Combinations are ovotestes/ovary (34%), bilateral ovotestes (27%), ovary and testes
(27%) and ovotestes/testes (12%). The ovarian tissue is potentially fertile, but the testes are not
(5).
A well masculinized patient may rarely present after puberty with gynecomastia, cyclical
hematuria, or scrotal pain secondary to ruptured ovarian follicles.
In most patients, the external genitalia are masculinized to some extent, and two thirds of true
hermaphrodites are raised as males. Of those raised as males, 80 percent have hypospadias and
over 50 percent have labioscrotal fusion. Of those raised as females, two thirds will have
clitoromegaly. All patients have a urogenital sinus, and in most cases, a uterus is present. The
ovary is found in a normal location, but the testes or ovotestes may be at any point along the path
of testicular descent (5). In addition to imaging studies, a gonadal biopsy is necessary to prove the
existence of both ovarian and testicular tissue.
Dysgenetic gonads (histologically disordered gonads) are noted primarily in mixed gonadal
dysgenesis, pure gonadal dysgenesis, and gonadal dysgenesis (Turner Syndrome). Mixed gonadal
dysgenesis is the second most common intersex disorder. Karyotype is usually a mosaic
45XO/46XY. A testis is usually found intraabdominally opposite a streak gonad (resembling
ovarian stroma histologically). A unicornuate (only one side of the uterus is present) uterus,
fallopian tubes and vagina are present. The genitalia are ambiguous with severe hypospadias, a
urogenital sinus, and labioscrotal fusion, with an undescended testicle. One third exhibit Turner
stigmata (short stature, shield like chest, webbed neck, multiple pigmented nevi, and cubitus
valgus) as well as cardiovascular and renal anomalies (5,6).
The incidence of gonadal tumors is 25 percent in patients with mixed gonadal dysgenesis and
may arise in the streak gonad or the undescended testes. A gonadal tumor has not been described
in a scrotal testes (8). Early bilateral gonadectomy with female rearing is appropriate in
phenotypic females. In phenotypic males with a scrotal testes, male rearing is appropriate, but the
streak gonads must be removed.
Pure gonadal dysgenesis is an abnormal differentiation of the gonads without a chromosomal
abnormality. A 46XX female has normal immature female external genitalia, intact Mullerian
duct structures and bilateral streak gonads. They have no stigmata of Turner syndrome. They
usually present as adolescent females who fail to mature and reach menarche (5).
Patients with 46XY "pure gonadal dysgenesis" also have bilateral streak gonads, intact Mullerian
structures, a female phenotype, and the absence of Turner stigmata. Some may present in the
newborn period with clitoromegaly. These patients with the Y chromosome are at high risk for
the development of gonadal tumors, so prophylactic gonadectomy is indicated (6,8).
Gonadal Dysgenesis (Turner Syndrome) is due to the loss of the second X chromosome (45XO),
with resultant bilateral streak gonads, normal Mullerian duct development, and phenotypically
female external genitalia. Mosaicism (45XO/46XX) lessens the severity of the gonadal
abnormality. As neonates do not have ambiguous genitalia, the syndrome is usually diagnosed
from investigations for other neonatal anomalies, which include: intrauterine growth retardation,
head and facial anomalies, lymphatic anomalies, cardiovascular or urinary tract malformations or
skeletal anomalies) (8). All should be raised as females, with gonadectomy indicated only in
those with virilization or with clear evidence of a Y cell-line (6,8).
A child born with ambiguous genitalia constitutes a social and medical emergency. In the
delivery room, no attempt should be made to suggest a diagnosis or assign a gender. The parents
should be told that development is incomplete and further tests will reveal the appropriate gender.
The infant should be referred to as "your baby" not "it", "he", or "she". Examination of the child
in the presence of the parents to demonstrate the precise abnormalities of genital development is
helpful, noting that the genitalia of both sexes develop from the same primordial structures, that
both incomplete development or overdevelopment of the external genitalia can occur, and that the
abnormal appearance can be corrected and the child raised as a boy or girl, as appropriate (3). A
family should never be told that their child is male, but will be made female, or vice versa.
Parents should be encouraged not to name the child or register the birth, if possible, until the sex
of rearing is established. The parents need to be included in the discussions regarding sex of
rearing decisions.
Transfer of the child to a tertiary care facility is usually necessary for optimal assessment and
treatment. A multidisciplinary medical team, with representation from neonatology,
endocrinology, urology, psychiatry and genetics services is useful. Pediatricians have a key role
in coordinating the diagnostic evaluation, helping families understand their child's medical
condition, and maintaining open communication between the family and other health care team
members. The presence of the nursing staff is also critical at meetings, for it is they who will be
spending the most time with the family and neonate.
The decision as to the appropriate sex of rearing of an infant, born with ambiguous genitalia, is
based on the fertility potential, capacity for normal sexual function, endocrine function, potential
for malignant change in a gonad, and psychosexual factors (testosterone imprinting) (3).
In female infants with CAH, exposure to maternal androgens, and rarely true hermaphrodites, can
be expected to be potentially fertile and should be raised as females. The potential for fertility in
most other intersex conditions is either reduced or absent.
Phallic size and its potential to develop at puberty into a sexually functional organ, are very
important when male sex of rearing is considered. Testosterone injections may need to be given
in equivocal cases, and the infant raised as male only when there is a very good response
(especially in those with partial androgen insensitivity). The severity of the hypospadias should
not be a deciding factor in the sex of rearing, as the results of hypospadias repair, using current
techniques, are satisfactory, both functionally and cosmetically.
It is advantageous to retain a gonad appropriate to the assigned sex if it is likely to function
adequately. The ovaries of virilized genetic females can be assumed to be normal. The ovaries of
true hermaphrodites may also produce estrogen adequately. The testes of true hermaphrodites and
those of infants with mixed gonadal dysgenesis may initially show good function, that later
declines, so that testosterone supplements may be necessary from puberty onward (3).
There is potential for malignant degeneration in streak gonads, especially those with a Ychromosome-bearing cell line. Testes that show dysgenetic features on biopsy should also be
excised. Histologically, normal undescended testes have an increased incidence of tumor
development, but can be preserved in a sex assigned male, with an orchiopexy, and the patient
kept under long-term observation. Gonadectomy is considered when the risk of malignancy
exists, or when gonadal tissue inappropriate to the assigned gender has been identified.
In the past, it was assumed that sexual identity was largely a result of rearing. However, in the
past decade it has become apparent that testosterone imprinting of the fetal brain may play a role
in determining male sexual orientation. Some girls with CAH engage in more typically male-like
behavior patterns than their unaffected peers. Despite these findings, extreme caution should be
exercised when a recommendation is made that the sex of the rearing should be different than the
chromosomal sex (3).
Genital reconstruction is necessary in the majority of patients with ambiguous genitalia and
intersex disorders once the multidisciplinary team, in conjunction with the family, have decided
on the appropriate gender assignment.
Male reconstruction may require hypospadias repair (usually done between 6 months and 1 year
of age), orchiopexy, and removal of inappropriate gonads as well as internal Mullerian structures.
Female reconstruction, also known as a feminizing genitoplasty, may involve a clitoral reduction
and a vaginoplasty. Clitoral reduction can be done in a nerve sparing fashion, so as to preserve
sensation and allow for orgasm, and is carried out as early in life as possible. Minor clitoromegaly
can be left alone, as clitoral involution will take place once the source of androgen is shut down.
Vaginoplasty in a low lying vagina (flap-vaginoplasty) can be usually done at the time of clitoral
reduction. This primarily widens the introitus. A major vaginal reconstruction for creation of a
vagina de novo (substitution vaginoplasty) is best deferred until at least one year of age, or even
until puberty.
Psychological and metabolic supports are also essential over time. Most individuals are able to
function in the normal range and are well adjusted after treatment of intersex disorders. Certain
affected individuals will have conflicts between their psychosexual orientation and their genital
appearance and function. Thus, ongoing counseling of the parents and the affected child is
advisable. Problems can be minimized when evaluation and treatment is done promptly by an
appropriately constituted intersex team.
Hypospadias Robert G. Carlile, MD
This is a term male infant who is noted to have a ventral penile chordee with mid-penile shaft
hypospadias. His testes are descended bilaterally. No circumcision is performed. He voids
normally, and at 6 months of age undergoes repair of the hypospadias and chordee using the
foreskin as a vascularized graft. Postoperatively he develops a urethrocutaneous fistula along the
suture line. This is repaired 6 months later, and he subsequently has no problems.
Hypospadias occurs in 1 of 300 males in the United States, and is the most common congenital
anomaly of the penis (1). "Hypospadias" refers to an abnormal penile configuration in which the
urethral meatus is located on the ventral surface of the penis, proximal to the end of the glans, and
anywhere from the ventral gland to the perineum. Epispadias refers to the condition in which the
meatus is located on the dorsal surface of the penis.
Penile chordee (ventral bending of the penile shaft) is often associated with hypospadias, and may
be due to tethering or dysplasia of the ventral penile shaft skin (2). A dorsal hood of incomplete
prepuce may also be present.
There is no single known cause of hypospadias. Genetic factors exist, most likely based on a
multifactorial mode of inheritance (3). Hypospadias is more common in first degree male
relatives. Fathers of affected boys have an 8 percent incidence of hypospadias; and male siblings,
14 percent. Undescended testes and inguinal hernia occur in about 9 percent of children with
hypospadias (1,3). Other anomalies do not occur with any significance in isolated hypospadias.
This is related to the fact that both are under androgenic hormonal control during development.
There is a significantly increased incidence of intersexuality when both conditions coexist (4),
and a karyotype should be considered (5).
Since urethral development occurs under the influence of dihydrotestosterone (which is converted
in peripheral tissue from testosterone by 5-alpha-reductase), the development of hypospadias can
be related either to a reduction in 5-alpha-reductase activity, to a lack of testosterone production,
or to failure of the local receptors to recognize the hormone (2).
Hypospadias should be classified based on the anatomical location of the urethral meatus after the
chordee has been released: glanular (meatus is located on the glans), coronal, distal shaft,
midshaft, penoscrotal, scrotal, or perineal. Associated chordee should be described in terms of
severity (mild, moderate, or severe). This provides the most practical classification of
hypospadias.
Anterior hypospadias (glanular and coronal types) account for 50% of all hypospadias. Middle
hypospadias (distal, midshaft, and proximal penile types) account for 30% of hypospadias cases.
Posterior hypospadias (penoscrotal, scrotal, and perineal types) account for 20% of cases (1).
An older classification system, not used by urologists anymore, but which you may encounter,
describes hypospadias by degrees. First degree with the meatus between the glans and the distal
shaft; second degree with the meatus between the midshaft and the proximal shaft; and the third
degree with the meatus being penoscrotal, scrotal or perineal. The severity of chordee is not
considered in this system (2).
The pediatrician will be the first physician to exam the genitalia after birth. The foreskin should
be examined for completeness circumferentially. Thinned ventral foreskin (a "hooded" penis) is
associated commonly with hypospadias. The meatal position should be noted if abnormal
(glanular, penile, penoscrotal, scrotal, or perineal), as well as the presence or absence of penile
chordee (mild, moderate or severe). The stretched penile length in the newborn is 3.5 cm
normally (range 2.8 cm to 4.2 cm) (3), and should be noted if abnormal.
The gonads should be palpated and any cryptorchidism (undescended testes) noted. Any scrotal
abnormalities should also be noted, such as a bifid scrotum (a deep cleft between the scrotal sacs)
or penoscrotal transposition (the penis lying in or beneath the scrotum). There is an increased
incidence of an intersex state (the expression of male and female physical and sexual
characteristics within the same
individual)inunilateralandbilateralcasesofcryptorchidismwithhypospadias,especiallyifthehypospa
diasissevere(4). Anyinguinal hernia should be noted.
If hypospadias is present, a family history of hypospadias should be noted. Any history of
maternal ingestion of hormonal medication during pregnancy should be noted. Other congenital
anomalies should also be noted (e.g., anorectal anomalies), if present.
Upper urinary tract abnormalities have been reported to be more frequent in boys with
hypospadias (3,5). However, routine screening with ultrasound, IVP, or cystograms is not
justified because the incidence of defective upper tract anomalies is low. If other associated
anomalies are present, with a known higher incidence of upper urinary tract abnormalities (e.g.,
anorectal malformation), then imaging screening studies are justified (5).
No circumcision should be done in the newborn with hypospadias or any other penile anomaly, as
the foreskin may be necessary to create a neourethra, and/or provide penile shaft skin coverage.
If the gonads are nonpalpable and the hypospadias is proximal (penoscrotal or scrotal), then the
risk of having an intersex state is high, and emergent urologic consultation is indicated, as well as
observation for salt wasting congenital adrenal hyperplasia conditions (the most common cause of
intersex states). For hypospadias, urological consultation or referral should be obtained during or
shortly after the neonatal period.
The goals of corrective surgery for hypospadias are to provide the child with a normally
appearing circumcised penis with the urethral meatus well placed at the tip of the glans. The child
should be able to stand to void and have a straight penis when erect (2). This will allow both
normal voiding as well as reproductive functionality of the penis after repair.
The hypospadias repair is best performed when the patient is between 6 and 18 months of age. At
this age, babies are amnestic of the procedure, post operative management while the patients are
still in diapers is easier and allows the procedure to be performed as outpatient surgery (1). The
child's anesthetic risk is lower after 6 months of age if a good pediatric anesthesiologist is used.
There are over 200 named surgical procedures to correct hypospadias (1), but there are general
concepts in the approach to hypospadias repair common to all. Ventral penile chordee must be
corrected first, as the urethral meatus may move proximally as the penis is straightened. Next, the
urethroplasty (urethral advancement) is performed to allow the placement of the neourethra well
into the glans (to the glans tip). The neourethra is formed from either local skin flaps, or from
foreskin flaps (the reason circumcision is not performed). A glanuloplasty to create a normal
appearing rounded glans penis may also be performed, if necessary. Penile shaft skin coverage is
then accomplished by bringing penile shaft skin, or foreskin flaps ventrally. A short, small caliber
silastic urethral catheter that drains directly into the diaper may be used to direct the urine away
from the repair, which is removed 7 to 14 days later.
Most hypospadias repairs can be done with a single stage repair. Sometimes a 2-stage repair is
necessary, especially for very long urethral defects. The chordee is corrected first, and the
prepuce spread along the ventral shaft. Six months later, the neourethra is completed in a second
stage repair.
The most common complication seen after hypospadias surgery are fistulae, strictures and
recurrent chordee, occurring approximately 10 percent of the time (1,2,5). A wait of at least 6
months is necessary to allow complete healing of the tissue, before the secondary surgery is
performed.
Although parents are usually quite distraught when their child is born with hypospadias, the
technique for hypospadias repair used by pediatric urologists today are very successful in
transforming the hypospadiac penis to a normally appearing and functioning penis, and can be
done while the child is still in infancy.