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.