Pediatrics_Nelson

Pediatrics_Nelson. NS may be primary or secondary (Table 162-1). A child with apparent primary NS, prior to renal biopsy, is considered to have idiopathic nephrotic syndrome. Minimal change nephrotic syndrome (MCNS) is the most common histologic form of primary NS in children. More than 80% of children less than 7 years of age with NS have MCNS. Children 7 to 16 years old with NS have a 50% chance of having MCNS. Males are affected more frequently than females (2:1). Focal segmental glomerulosclerosis (FSGS) accounts for approximately 10% to 20% of children with primary NS. It may present like MCNS or with less impressive proteinuria. FSGS may develop from MCNS or represent a separate entity. A circulating factor that increases glomerular permeability is found in some patients with FSGS. More than 35% of children with FSGS progress to renal failure.


Pediatrics_Nelson

Pediatrics_Nelson. Membranoproliferative glomerulonephritis (MPGN) is characterized by hypocomplementemia with signs of glomerular renal disease. MPGN represents 5% to 15% of children with primary NS, is typically persistent, and has a high likelihood of progression to renal failure over time. Membranous nephropathy represents less than 5% of children with primary NS. It is seen most commonly in adolescents and children with systemic infections, such as hepatitis B, syphilis, malaria, and toxoplasmosis, or on specific medications (gold, penicillamine).


Pediatrics_Nelson

Pediatrics_Nelson. Congenital NS presents during the first 2 months of life. There are two common types. The Finnish type is an autosomal recessive disorder most common in persons of Scandinavian descent and is due to a mutation in the nephrin protein component in the glomerular filtration slit. The second type is a heterogeneous group of abnormalities, including diffuse mesangial sclerosis and conditions associated with drugs or infections. Prenatal onset is supported by elevated levels of maternal alpha-fetoprotein. Secondary NS may result from many different causes in children and are listed in Table 162-1. Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Secondary NS may result from many different causes in children and are listed in Table 162-1. Available @ StudentConsult.com The sudden onset of dependent pitting edema or ascites is the most common presentation for children with NS. Anorexia, malaise, and abdominal pain are often present. Blood pressure may be elevated in up to 25% of children on presentation; acute tubular necrosis and significant hypotension may occur with sudden decline in serum albumin and significant volume depletion. Diarrhea (intestinal edema) and respiratory distress (pulmonary edema or pleural effusion) may be present. Typical MCNS is characterized by the absence of gross hematuria, renal insufficiency, hypertension (HTN), and hypocomplementemia. Proteinuria of 1+ or higher on 2 to 3 random urine specimens suggests persistent proteinuria that should be further quantified. A UPr/Cr >0.2 on a first morning specimen excludes orthostatic proteinuria. UPr/Cr >2.0 indicates nephrotic range proteinuria.


Pediatrics_Nelson

Pediatrics_Nelson. In addition to a demonstration of proteinuria, hypercholesterolemia, and hypoalbuminemia, routine testing typically includes a serum C3 complement. A low serum C3implies a lesion other than MCNS, and a renal biopsy isindicated before trial of steroid therapy. Microscopic hematuria may be present in up to 25% of cases of MCNS butdoes not predict response to steroids. Additional laboratorytests, including electrolytes, blood urea nitrogen, creatinine,total protein, and serum albumin level, are performed basedon history and physical examination features. Renal ultrasound is often useful. Biopsy is performed when MCNS isnot suspected. Transient proteinuria can be seen after vigorous exercise, fever, dehydration, seizures, and adrenergic agonist therapy. Proteinuria usually is mild (UPr/Cr<1), glomerular in origin, and always resolves within a few days. It does not indicate renal disease.


Pediatrics_Nelson

Pediatrics_Nelson. Postural (orthostatic) proteinuria is a benign condition defined by normal protein excretion while recumbent but significant proteinuria when upright. It is glomerular in nature, more common in adolescents and tall, thin individuals, and not associated with progressive renal disease. Many children with orthostatic proteinuria continue this process into adulthood. Tubular proteinuria is characterized by preponderance of low-molecular-weight proteins in the urine and is suspected with acute tubular necrosis, pyelonephritis, structural renal disorders, polycystic kidney disease, and tubular toxins such as antibiotics or chemotherapeutic agents. The combination of tubular proteinuria with evidence of tubular electrolyte wasting and glycosuria is termed Fanconi syndrome.


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Pediatrics_Nelson. Glomerular proteinuria is characterized by a combination of largeand small-molecular-weight proteins in the urine, variable levels of proteinuria, and often evidence of glomerular disease (hematuria, red blood cell casts, HTN, and renal insufficiency). Causes of glomerular proteinuria include glomerular capillary disruption (hemolytic uremic syndrome, crescentic glomerulonephritis); glomerular capillary immune complex deposition (poststreptococcal glomerulonephritis and lupus nephritis); and altered glomerular capillary permeability (MCNS, congenital NS).


Pediatrics_Nelson

Pediatrics_Nelson. Because greater than 80% of children less than 13 years of age with primary NS have steroid-responsive forms (chiefly MCNS), steroid therapy may be initiated without a renal biopsy if a child has typical features of NS. Typical therapy for MCNS is prednisone, 2 mg/kg/day (60 mg/m2/24 h, maximum 60 mg/day), provided once a day or split into multiple doses. Over 90% of children who respond to steroids do so within 4 weeks. Responders should receive steroids for 12 weeks. A renal biopsy is indicated for nonresponders because steroid resistance decreases the chance that MCNS is the underlying disease. Frequent relapses or steroid resistance may necessitate additional immunosuppressive therapy.


Pediatrics_Nelson

Pediatrics_Nelson. No clearly effective therapy for FSGS has been identified. Approximately 35% respond to steroid therapy; others may respond to immunosuppressive therapy. MPGN and membranous glomerulonephritis may improve with chronic steroid or immunosuppressive therapy but do not reliably remit with standard NS steroid therapy. Aggressive medical therapy of familial congenital NS, with early nephrectomy, dialysis, and transplantation, is the only effective approach to this syndrome.


Pediatrics_Nelson

Pediatrics_Nelson. NS edema is treated by restricting salt intake. Severe edema may require the use of loop diuretics. When these therapies do not alleviate severe edema, cautious parenteral administration of 25% albumin (0.5 to 1.0 g/kg intravenously over 1 to 2 hours) with an intravenous loop diuretic usually results in diuresis. The administered albumin is excreted rapidly, and, thus, salt restriction and diuretics must be continued. Significant pleural effusions may require drainage. Acute HTN is treated with β-blockers or calcium channel blockers. Persistent HTN usually responds to angiotensin-converting enzyme inhibitors.


Pediatrics_Nelson

Pediatrics_Nelson. An increased incidence of serious infections, particularly bacteremia and peritonitis (particularly Streptococcus pneumoniae, Escherichia coli, or Klebsiella), is due to urinary loss of immunoglobulins and complement. Side effects of steroids are most common in steroid-dependent and frequently relapsing patients. Hypovolemia may result from diarrhea or diuretic use. The loss of coagulation factors, antithrombin, and plasminogen may lead to a hypercoagulable state with a risk of thromboembolism (TE). Warfarin, Lovenox, low-dose aspirin, or dipyridamole may minimize the risk of clots in NS patients with a history of TE or high risk for TE. Hyperlipidemia promotes increased atherosclerotic vascular disease.


Pediatrics_Nelson

Pediatrics_Nelson. Most children with NS eventually go into remission. Nearly 80% of children with MCNS experience NS relapse, defined as heavy proteinuria that persists for 3 or more consecutive days. Transient (up to 3 days) proteinuria may occur with intercurrent infection in children with MCNS and is not considered a relapse. Steroid therapy is typically effective for true relapse. Steroid-responsive patients have little risk of chronic renal failure. Patients with FSGS may initially respond to steroids but later develop resistance. Many children with FSGS progress to end-stage kidney failure (see Chapter 165). Recurrence of FSGS occurs in 30% of children who undergo renal transplantation.


Pediatrics_Nelson

Pediatrics_Nelson. A child with gross hematuria may have a serious disease and requires prompt evaluation. Microscopic hematuria, defined as more than 3 to 5 red blood cells (RBCs) per high-power field on freshly voided and centrifuged urine, is often benign. Isolated asymptomatic microscopic hematuria is found in up to 4% of healthy children. In most cases this is a transient finding. Hematuria may originate from glomerular disease, tubulointerstitial processes, and lower urinary tract disorders (Table 163-1). Immune-mediated inflammation is the mechanism of glomerulonephritis (GN). Poststreptococcal glomerulonephritis (PSGN) is the most common form of acute GN, and IgA nephropathy is the most common chronic GN, but many other types of GN can occur. The most common identifiable lower urinary tract causes of hematuria include urinary tract infection (UTI), kidney stones, and hypercalciuria. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Nonpathologic (urate crystals in infants, ingested foods, medications, dyes) Pathologic (hemoglobinuria from hemolytic anemia, myoglobinuria from rhabdomyolysis) Immunologic injury (GN—e.g., PSGN, IgA nephropathy, MPGN, systemic diseases) Structural disorder (Alport syndrome, thin basement membrane disease) Toxin-mediated injury (HUS) Inflammation (interstitial nephritis, pyelonephritis) Vascular (sickle cell trait/disease, Nutcracker syndrome) Structural (cyst rupture, Wilms tumor, urinary tract obstruction, renal trauma) Inflammation (cystitis, hemorrhagic cystitis, urethritis) Injury (trauma, kidney stone) Hypercalciuria GN, Glomerulonephritis; HUS, hemolytic uremic syndrome; MPGN, membranoproliferative glomerulonephritis; PSGN, poststreptococcal glomerulonephritis.


Pediatrics_Nelson

Pediatrics_Nelson. Children with acute GN commonly present with hematuria (gross or microscopic) along with other cardinal features of glomerular injury (proteinuria, hypertension, edema, oliguria, renal insufficiency). PSGN occurs most frequently in children 2 to 12 years of age and is more common in boys. Manifestations of PSGN are typical of acute GN listed previously and develop 5 to 21 days (average 10 days) after streptococcal pharyngitis infections and 4 to 6 weeks after impetigo. Acute postinfectious GN presents in the same manner as PSGN and can occur following infections with other bacterial and viral pathogens. PSGN can develop regardless of whether the child was treated with antibiotics at the time of infection. Special attention must be paid to the blood pressure because hypertension may be severe enough to lead to complications such as heart failure, seizures, and encephalopathy.


Pediatrics_Nelson

Pediatrics_Nelson. The presentation of IgA nephropathy is more variable and may take the form of acute GN, asymptomatic microscopic hematuria, or recurrent gross hematuria concurrent with an upper respiratory infection as opposed to several days later, as with PSGN. Children with hematuria secondary to systemic disorders such as Henoch-Schönlein purpura nephritis, lupus nephritis, and vasculitis-associated GN will present with other systemic features typical of the respective disease. A special form of GN is rapidly progressive glomerulonephritis (RPGN) that presents with typical features of acute GN, but the renal insufficiency progresses more quickly and severely. Renal biopsy shows glomerular epithelial cell proliferation with crescents. RPGN may be idiopathic or secondary to any of the known types of GN. Early recognition of RPGN is crucial to prevent the progression to end-stage renal disease (ESRD) that occurs without prompt treatment.


Pediatrics_Nelson

Pediatrics_Nelson. Alport syndrome is typically caused by X-chromosome mutations in type IV collagen leading to an abnormal glomerular basement membrane (GBM) and may present with either asymptomatic microscopic or gross hematuria. Males typically History and Physical Urinalysis to confirm RBCs Directed evaluation studies based on suspected cause Cause apparent on H&P e.g. UTI, trauma, kidney stone, GN Urinalysis Cause not apparent on H&P Urine microscopy Negative for blood Positive for blood Hemolytic anemia Rhabdomyolysis Minimal RBCs RBCs confirmed Isolated microscopic hematuria Urine culture Urine calcium to creatinine ratio Urine protein to creatinine ratio Serum chemistries Serum albumin C3 and C4 complement Complete blood count Renal ultrasound Renal biopsy in selected cases RBCs confirmed Symptomatic microscopic hematuria or gross hematuria Urate crystals in infants Medications, foods, dyes


Pediatrics_Nelson

Pediatrics_Nelson. Urate crystals in infants Medications, foods, dyes Tests to consider if hematuria persistent: Urine calcium to creatinine ratio Test first degree relatives for hematuria Hgb electrophoresis to rule out sickle cell Serum chemistries Renal ultrasound Figure 163-1 Suggested algorithm for evaluation of red urine/hematuria. GN, Glomerulonephritis; H&P, history and physical; Hgb, hemoglobin; RBCs, red blood cells; UTI, urinary tract infection.


Pediatrics_Nelson

Pediatrics_Nelson. Figure 163-1 Suggested algorithm for evaluation of red urine/hematuria. GN, Glomerulonephritis; H&P, history and physical; Hgb, hemoglobin; RBCs, red blood cells; UTI, urinary tract infection. develop progressive renal failure and sensorineural hearing loss during adolescence and young adulthood. Females typically have a more benign course but usually have at least microscopic hematuria. Thin basement membrane disease (benign familial hematuria) is caused by more benign mutations leading to a thinning of the GBM. The mutation is often autosomal dominant, and therefore hematuria is often noted in first-degree relatives. As opposed to Alport syndrome, thin basement membrane disease is typically not progressive and usually has an excellent prognosis.


Pediatrics_Nelson

Pediatrics_Nelson. The presentation of nonglomerular causes of hematuria is more variable and related to the underlying etiology. Hematuria due to tubular disorders is usually only microscopic and may be associated with proteinuria, glycosuria, and polyuria. These children typically do not have hypertension and only develop renal insufficiency with more severe disease. Painless gross hematuria may be seen with sickle cell trait/disease, Wilms tumor, and strenuous exercise. Hematuria may or may not be associated with pain when due to cystic bleeding and Nutcracker syndrome. Gross hematuria following trauma may signify more severe renal or lower urinary tract injury. UTI is associated with typical symptoms such as dysuria and urinary frequency. Urolithiasis may be associated with asymptomatic hematuria or with flank or abdominal pain. Hypercalciuria can cause both gross and microscopic hematuria and may be associated with urinary tract symptoms such as dysuria and urinary frequency or may be asymptomatic.


Pediatrics_Nelson

Pediatrics_Nelson. All patients with hematuria should have a careful history and physical (including blood pressure) along with a urinalysis, including microscopic examination to identifyRBCs. Glomerular hematuria is suggested by a brownish (teaor cola-colored) appearance of the urine and the presence ofRBC casts and/or dysmorphic RBCs on urine microscopy.A urine color that is more bright red in appearance withoutRBC casts or dysmorphic RBCs is more suggestive of a lowerurinary tract source. However there may be overlap of thesefindings.


Pediatrics_Nelson

Pediatrics_Nelson. A suggested algorithm for the evaluation of hematuria is given in Figure 163-1. Gross hematuria and microscopic hematuria with associated concerning findings should have additional laboratory evaluation. The presence of low C3 complement narrows the differential diagnosis to PSGN, membranoproliferative GN, and lupus nephritis. Children with isolated asymptomatic microscopic hematuria may be observed with repeat urinalyses. If the hematuria is persistent, additional evaluation may be appropriate.


Pediatrics_Nelson

Pediatrics_Nelson. Therapy for PSGN is supportive and involves dietary sodiumrestriction, diuretics, and antihypertensive agents as needed.Although treating the streptococcal infection does not prevent PSGN, antibiotic treatment is still warranted with active streptococcal infection. Therapies for children with otherforms of GN depend on the underlying cause and severity.In some cases, anti-inflammatory therapy involving corticosteroids and/or other immunosuppressive agents may beused. Treatment with angiotensin-converting enzyme inhibitors may reduce proteinuria and glomerular hyperperfusion but should be used with caution in the setting of acutekidney injury. PSGN usually has a benign outcome. In typical cases, the gross hematuria, proteinuria, and edema decline quickly (in 5 to 10 days). Microscopic hematuria may persist for months or even years; over 95% of children recover completely with no longterm sequelae.


Pediatrics_Nelson

Pediatrics_Nelson. Children with IgA nephropathy and other forms of chronic GN have a greater risk of progression to ESRD. The prognosis for renal recovery in chronic GN and in RPGN is variable and related to the underlying disorder and disease severity. The presence of persistent, heavy proteinuria, hypertension, decreased kidney function, and severe glomerular lesions on biopsy is associated with poor outcomes. Children with idiopathic isolated asymptomatic microscopichematuria or suspected thin basement membrane disease typically have an excellent renal prognosis. Long-term follow-up,including yearly urinalysis (to rule out proteinuria) and bloodpressure, is required to exclude progressive forms of renal disease.


Pediatrics_Nelson

Pediatrics_Nelson. Hemolytic uremic syndrome (HUS) is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal injury and is an important cause of acute kidney injury in children. HUS typically occurs in children less than 5 years of age but can occur in older children. The most common type of HUS is associated with a prodromal diarrheal illness (D+HUS). Contamination of meat, fruit, vegetables, or water with verotoxin (VT)-producing Escherichia coli (most commonly E. coli O157:H7) is responsible for many outbreaks. VT may be produced by other E. coli strains as well as other bacteria such as Shigella. VT causes hemorrhagic enterocolitis of variable severity and results in HUS in 5% to 15% of affected children.


Pediatrics_Nelson

Pediatrics_Nelson. HUS presenting without a prodrome of diarrhea (atypical HUS) may occur at any age. The clinical course is usually more severe than that of D+HUS. Atypical HUS can be secondary to infection (Streptococcus pneumonia, human immunodeficiency virus), genetic and acquired defects in complement regulation, medications, malignancy, systemic lupus erythematosus, and pregnancy. Available @ StudentConsult.com Classic D+HUS begins with enterocolitis, often with bloody stools, followed in 7 to 10 days by weakness, lethargy, and Anemia Thrombocytopenia Presence of schistocytes, helmet cells, and burr cells on peripheral blood smear Increased LDH Decreased haptoglobin Increased indirect bilirubin Increased AST Elevated reticulocyte count Elevated creatinine Presence of hematuria, proteinuria, pyuria, casts on urinalysis Leukocytosis Positive stool culture for E. coli O157:H7 Positive stool test for shiga-toxin Elevated amylase/lipase


Pediatrics_Nelson

Pediatrics_Nelson. Leukocytosis Positive stool culture for E. coli O157:H7 Positive stool test for shiga-toxin Elevated amylase/lipase AST, Aspartate aminotransferase; LDH, lactate dehydrogenase. oliguria/anuria. Physical examination reveals irritability, pallor, and petechiae. Dehydration is often present; however some children have volume overload. Hypertension may be due to volume overload and/or renal injury. Central nervous system (CNS) involvement, including seizures, occurs in up to 25% of cases. Other potential organ involvement includes pancreatitis, cardiac dysfunction, and colonic perforation.


Pediatrics_Nelson

Pediatrics_Nelson. Children without evidence of a diarrheal prodrome mayhave a similar microangiopathic syndrome, identified asthrombotic thrombocytopenic purpura (TTP). Childrenwith TTP typically have predominant CNS symptoms butmay also have significant renal disease. Recurrent episodes are common. Because CNS involvement is also seen in HUS, TTP can be difficult to distinguish from HUS in some cases. Deficiencies of ADAMTS13, a von Willebrand factor-cleaving protease, have been identified in childrenaffected with TTP. Common laboratory findings in HUS are listed in Table 164-1. Peripheral blood smear reveals evidence of microangiopathic hemolysis. Coombs test is negative. The diarrhea and presence of toxin-producing E. coli may have resolved by the time HUS is diagnosed.


Pediatrics_Nelson

Pediatrics_Nelson. Therapy for HUS is supportive and includes volume repletion, control of hypertension, and managing complications of renal insufficiency, including dialysis when indicated. Red blood cell transfusions are provided as needed. Platelet transfusions should be avoided because they may add to the thrombotic microangiopathy and are indicated only by active hemorrhage or in anticipation of a procedure. Antibiotics and antidiarrheal agents may increase the risk of developing HUS. Early hydration during the diarrheal phase may lessen the severity of renal insufficiency. Most children (>95%) with D+HUS survive the acute phase and recover normal renal function, although some may have evidence of long-term morbidity.


Pediatrics_Nelson

Pediatrics_Nelson. Acute kidney injury (AKI), formerly termed acute renal failure, refers to an abrupt decrease in glomerular filtration rate (GFR) and tubular function. This may lead to decreased excretion of waste products (e.g., urea) and a disturbance in fluid and electrolyte homeostasis. Early recognition and management of AKI are crucial. AKI may be oliguric (<1 mL/kg/h in neonates and infants, <0.5 mL/kg/h in children) or nonoliguric, which is more difficult to recognize. Although urine output in nonoliguric AKI is normal or polyuric, electrolyte disturbances and uremia may become significant. The major causes of AKI may be divided into prerenal (renal hypoperfusion), intrinsic renal (tubular, glomerular, or vascular injury), and postrenal (urinary tract obstruction) categories (Table 165-1). In many cases the cause of AKI is multifactorial.


Pediatrics_Nelson

Pediatrics_Nelson. Prerenal azotemia is most commonly due to dehydration but may be secondary to other mechanisms of glomerular hypoperfusion. Tubular injury encompasses the most common causes of intrinsic AKI in children. Tubular injury may occur fromhypoxia-ischemia (acute tubular necrosis), infection (sepsis),nephrotoxic agents (medications, contrast, myoglobin) and inflammation (interstitial nephritis). Postrenal AKI may be due to either structural or functional urinary tract obstruction. Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Available @ StudentConsult.com History, physical examination, and basic studies usually allow proper classification of the child with AKI (Table 1652). Prerenal azotemia is characterized by precipitating factors and oliguria. Intrinsic tubular injury is associated with precipitating factors but urine output may be low, normal, or high, depending on the severity of the injury. Glomerular and vascular disorders may present with hematuria, edema, hypertension, and oliguria. The urine output with postrenal AKI may be low or normal and may be associated with flank masses or a distended bladder on examination. Depending on the underlying cause and severity of illness, AKI can be associated with signs of dehydration or volume overload. A urinalysis (UA) should be obtained in all children with AKI.In prerenal azotemia, the UA is unremarkable with a high specific gravity reflecting appropriate renal retention of water in thesetting of renal hypoperfusion. However neonates are not able


Pediatrics_Nelson

Pediatrics_Nelson. Urethral obstruction (stricture, posterior urethral valves) Ureteral obstruction Ureterocele Extrinsic tumor compressing bladder outlet Neurogenic bladder (myelomeningocele, spinal cord injury)


Pediatrics_Nelson

Pediatrics_Nelson. Acute tubular necrosis Nephrotoxins (medications, contrast, myoglobin) Infection (sepsis) Interstitial nephritis Glomerular injury (primary glomerulonephritis, vasculitis, hemolytic uremic syndrome) Vascular (renal vein thrombosis, arterial emboli, malignant hypertension) to concentrate urine as well. With intrinsic tubular injury andpostrenal AKI, the UA may show mild hematuria and/or proteinuria with a specific gravity of 1.015 or less. With glomerularand vascular injury, the amount of hematuria and proteinuriais usually moderate to severe. In oliguric states, differentiationbetween prerenal azotemia and acute tubular necrosis may beaided by determining the urine osmolality and fractional excretionof sodium (see Table 165-2). Renal ultrasound is often helpful in determining the AKI category (see Table 165-2). Renal biopsy is indicated in select cases only.


Pediatrics_Nelson

Pediatrics_Nelson. Common electrolyte abnormalities seen with AKI includehyperkalemia, metabolic acidosis, hypocalcemia, and hyperphosphatemia. These labs may need to be monitored frequently,depending on the initial results and clinical course. A complete blood count should be obtained as anemia is frequentlyobserved. Other studies may be obtained as clinically indicated. In some cases the underlying disorder can be treated. Examples include volume repletion in dehydration, stopping an offending nephrotoxic medication, and relieving urinary tract obstruction. In all cases efforts should be made to limit additional renal injury (e.g., ensuring adequate renal perfusion and avoiding nephrotoxic medications). Medication dosages should be adjusted for decreased renal function as appropriate.


Pediatrics_Nelson

Pediatrics_Nelson. Fluid therapy depends on the volume status and urine output. If hypovolemia is present, intravascular volume should be expanded by intravenous administration of saline. If hypervolemia is present, 1 to 2 mg/kg of furosemide and fluid restriction may be attempted. If the patient is relatively euvolemic, then the total fluid input should be adjusted to meet the total Urine output Low Low, normal, or high Low or normal Urinalysis Normal RBCs, WBCs, protein, casts Variable Urine Na+ (mEq/L) <15 <20–30 >40 >50 Variable, may be >40 FENa* (%) <1 <2.5 >2 >2.5 Variable, may be >2 Urine osmolality >500 >350 ∼300 ∼300 Variable, may be (mOsm/L) Renal ultrasound Normal Increased echogenicity, decreased Hydronephrosis corticomedullary differentiation FENa, Fractional excretion of sodium; RBCs, red blood cells; WBCs, white blood cells. *FENa (%) = [(urine sodium/plasma sodium) ÷ (urine creatinine/plasma creatinine)] × 100.


Pediatrics_Nelson

Pediatrics_Nelson. FENa, Fractional excretion of sodium; RBCs, red blood cells; WBCs, white blood cells. *FENa (%) = [(urine sodium/plasma sodium) ÷ (urine creatinine/plasma creatinine)] × 100. output, which may be higher or lower than normal, depending on the urine output. Assessment of intake and output should be augmented with serial measurements of body weight.


Pediatrics_Nelson

Pediatrics_Nelson. output, which may be higher or lower than normal, depending on the urine output. Assessment of intake and output should be augmented with serial measurements of body weight. A large part of AKI treatment involves management of itscomplications. Electrolyte disorders are treated as appropriate. Potassium intake and medications that increase potassiumshould be restricted. Intravenous calcium will lower risk of arrhythmia while measures are initiated to shift potassium intocells (bicarbonate, beta-agonists, insulin/dextrose) and hastenremoval (diuretics, sodium-potassium exchange resins, dialysis).Preferred treatment of hypocalcemia involves oral supplementation and calcitriol, and IV supplementation is reserved for severecases. Hypertension may be treated with diuretics, calcium channel blockers, and vasodilators. Angiotensin-converting enzyme(ACE) inhibitors are usually avoided in the setting of AKI.


Pediatrics_Nelson

Pediatrics_Nelson. Major indications for acute dialysis are listed in Table 165-3. Medical therapy may be attempted before initiating renalreplacement therapy. There is no set blood urea nitrogen orcreatinine level at which dialysis is started for uremia. Renal replacement options in children include peritoneal dialysis,hemodialysis, and continuous renal replacement therapy. Themode used is chosen on an individual basis. Recovery from AKI depends on the etiology, severity, availability of specific treatments, and other aspects of the patient’s course. Nonoliguric AKI usually recovers well, whereas the outcome with oliguric AKI is more variable. Even with a seemingly good recovery, history of AKI may place the child at increased risk for future renal complications, including chronic kidney disease (CKD).


Pediatrics_Nelson

Pediatrics_Nelson. Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common causes of CKD that present between birth and 10 years of age. After age 10 acquired diseases, such as focal segmental glomerulosclerosis and glomerulonephritis (GN), are more common causes of incident CKD. The risk of progression to end-stage renal disease (ESRD) is related to the underlying cause and severity of CKD. During puberty, renal function may deteriorate if the damaged kidneys are not able to grow and adapt to increased demands. CKD is staged to facilitate appropriate evaluation and monitoring (Table 165-4). The GFR can be estimated in children using the Schwartz formula (see Chapter 161). Most complications of CKD do not manifest until at least stage 3 CKD. In stage 4 CKD, the complications become more numerous and severe. Children with stage 5 CKD (ESRD) are typically treated with either dialysis or renal transplantation.


Pediatrics_Nelson

Pediatrics_Nelson. The clinical presentation of a child with CKD may be related to both the underlying diagnosis and complications of CKD. A child with CAKUT may have polyuria, polydipsia, and recurrent urinary tract infections. A child with glomerular disease may have hematuria, proteinuria, edema, and hypertension. Common complications of CKD in children are listed in Table 165-5. Most of these complications are multifactorial in etiology. For example, factors associated with growth failure include poor nutrition, renal osteodystrophy (ROD), metabolic acidosis, hormonal abnormalities, and resistance to growth hormone. Anemia results primarily from a failure to produce adequate erythropoietin and iron deficiency. ROD is usually due to secondary hyperparathyroidism as a result of diminished 1,25-dihydroxyvitamin D production in the kidney, hypocalcemia, and hyperphosphatemia (from decreased renal excretion). If prolonged and/or severe, ROD may eventually lead to rickets and bone deformities.


Pediatrics_Nelson

Pediatrics_Nelson. D production in the kidney, hypocalcemia, and hyperphosphatemia (from decreased renal excretion). If prolonged and/or severe, ROD may eventually lead to rickets and bone deformities. Hypertension and


Pediatrics_Nelson

Pediatrics_Nelson. Table 165-4 Classification of the Stages of Chronic Kidney Disease STAGE GFR (ml/min/ 1.73 m2)* DESCRIPTION >90 Minimal kidney damage 2 60–89 Kidney damage with mild reduction of GFR 3 30–59 Moderate reduction of GFR 4 15–29 Severe reduction of GFR 5 <15 (or dialysis) End-stage renal disease From National Kidney Foundation Kidney Disease Outcomes Quality Initiative. GFR, Glomerular filtration rate. *GFR ranges apply for children 2 years of age and older. 1. Poor growth Increased caloric intake, treat acidosis, treat renal osteodystrophy, recombinant GH 2. Anemia Erythropoietin, iron supplementation 3. Renal 1,25-Dihydroxyvitamin D osteodystrophy/ supplementation, calcium secondary supplementation, dietary phosphorous hyperparathyroidism restriction, phosphate binders 4. Cardiovascular 4a. Hypertension Antihypertensive medications 4b. Left ventricular Volume control hypertrophy 5.


Pediatrics_Nelson

Pediatrics_Nelson. Cardiovascular 4a. Hypertension Antihypertensive medications 4b. Left ventricular Volume control hypertrophy 5. Electrolyte abnormalities Low K diet, furosemide, sodium 5a. Hyperkalemia polystyrene sulfonate 5b. Hyponatremia Sodium supplementation 5c. Metabolic acidosis Alkali replacement CKD, Chronic kidney disease; GH, growth hormone; K, potassium. left ventricular hypertrophy are commonly seen cardiovascular complications. Delayed puberty results from altered gonadotropin secretion and feedback patterns. Learning and school performance may also be impaired in CKD.


Pediatrics_Nelson

Pediatrics_Nelson. The management of children with advanced CKD requires a multidisciplinary team of pediatric practitioners. Adequate nutrition should be provided even if this requires dietary supplements and tube feedings. In infants a low-solute formula may be indicated. Unless a child is oliguric, fluid restriction is not necessary. Many children with CAKUT require supplemental salt due to urine sodium wasting. Conversely children with GN tend to retain sodium and may become hypertensive or edematous if given excess salt. Common treatment considerations for other CKD complications are given in Table 165-5.


Pediatrics_Nelson

Pediatrics_Nelson. Measures can be taken to preserve kidney function or slow down the progression of CKD. Hypertension and proteinuria can be treated with ACE inhibitors or angiotensin receptor blockers. Potentially nephrotoxic medications should be avoided when feasible, and medication adjustment for reduced kidney function should be made as appropriate. Protein intake is typically not restricted in pediatric CKD. The optimal treatment of ESRD is renal transplantation.Both deceased and living donors can be used for renal transplantation, but living donors are preferred when available. Maintenance dialysis is effective for a child awaiting renal transplantation or for whom renal transplantation is not possible. Indications for chronic dialysis are given in Table 165-3. Peritoneal dialysis is done at home by the family. Hemodialysis is typically done three times a week at a dialysis facility.


Pediatrics_Nelson

Pediatrics_Nelson. Children with mild CKD (stages 1 and 2) may do well but needto be monitored for progressive loss of kidney function. Childrenwith stages 3 and 4 CKD have a high likelihood of progressing toESRD at some point, although the timing can vary. Children withkidney transplants generally do well but have to take immunosuppressive medications associated with a variety of side effects,including infections, nephrotoxicity, cardiovascular complications, and increased risk for certain malignancies. Unfortunatelymost transplanted kidneys fail over time but can last for severalyears. Children on maintenance dialysis have the highest morbidity and mortality, especially with longer time spent on dialysis. Thus, their primary goal is to receive a kidney transplant.


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Pediatrics_Nelson. In children, hypertension (HTN) is defined as blood pressure (BP) greater than the 95th percentile for age, gender, and height on at least three different occasions. The context of the BP measurement (e.g., cuff size, pain, anxiety) is important. The staging of HTN is given in Table 166-1. Hypertensive emergency is defined as severe elevation in BP associated with target organ damage (encephalopathy, heart failure). Pediatric HTN has many causes (Table 166-2) that are either primary (essential) or secondary. Essential HTN is the most common cause of HTN in adolescents. Obese children are more likelyto develop essential HTN. Secondary HTN should be suspectedwith younger age and more severely elevated BP. Renal disease is the most common cause of secondary HTN in children. Available @ StudentConsult.com <90th Prehypertension *90th to 95th Stage 1 hypertension 95th to (99th + 5 mm Hg) Stage 2 hypertension >99th + 5 mm Hg *If 90th % is >120/80, use 120/80 as the lower limit.


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Pediatrics_Nelson. Congenital anomalies (renal dysplasia, obstructive uropathy) Structural disorders (Wilms tumor, polycystic kidney disease) Glomerulonephritis Acquired injury (renal scarring, acute tubular necrosis) Catecholamine-secreting tumors (pheochromocytoma, neuroblastoma) Hypercortisolism (Cushing syndrome) Hyperaldosteronism Hyperthyroidism Increased sympathetic activity (stress, anxiety, pain) Dysautonomia Increased intracranial pressure Coarctation of the aorta Renal artery embolism (from umbilical artery catheter) Renal vein thrombosis Renal artery stenosis Vasculitis Obstructive sleep apnea Medications, illicit drugs


Pediatrics_Nelson

Pediatrics_Nelson. Obstructive sleep apnea Medications, illicit drugs Most children with HTN have no symptoms. Signs and symptoms associated with severe HTN include encephalopathy (headache, vomiting, seizures), heart failure, stroke, and retinopathy (blurred vision, flame hemorrhage, and cotton wool spots on retinal exam). Neonatal history (low birth weight or use of umbilical artery catheter); family history of HTN, stroke, or heart disease; and dietary history (excessive salt or caffeine, drugs) are important. Additional findings that may suggest specific causes include abdominal bruit; diminished leg pressure and weak femoral pulse (coarctation of aorta); cafe-au-lait spots (neurofibromatosis associated renal artery stenosis); flank mass (hydronephrosis, Wilms tumor); tachycardia with flushing and diaphoresis (pheochromocytoma); and truncal obesity, acne, striae, and buffalo hump (Cushing syndrome). Signs of underlying kidney disease may be present.


Pediatrics_Nelson

Pediatrics_Nelson. In addition to history and physical examination, the evaluation of children with confirmed HTN includes the following: 1. Baseline etiologic assessment (urinalysis, electrolytes, blood urea nitrogen, creatinine, and renal ultrasound) 2. Focused studies based on clinical suspicion (e.g., plasma metanephrines, thyroid studies, vascular imaging) 3. 4. Assessment of other cardiovascular risk factors (lipids, fasting glucose, uric acid)


Pediatrics_Nelson

Pediatrics_Nelson. 4. Assessment of other cardiovascular risk factors (lipids, fasting glucose, uric acid) Therapeutic lifestyle changes (diet, exercise) should be initiated for asymptomatic stage 1 HTN without target organ damage or systemic disease. Medication should be started for stage 2 or symptomatic HTN and stage 1 HTN, which fails to respond to lifestyle changes. Calcium channel blockers or angiotensin-converting enzyme inhibitors are the most frequently chosen first-line options in children. Angiotensin receptor blockers, β-blockers, or diuretics are also recommended as first-line antihypertensive agents. More than one agent may be needed. Hypertensive emergency requires prompt hospitalization and may require parenteral antihypertensive treatment with nicardipine, labetalol, esmolol, or sodium nitroprusside.


Pediatrics_Nelson

Pediatrics_Nelson. Prognosis depends on the underlying etiology and BP control. Essential HTN, when present in adolescents, is usually not associated with morbidity at presentation. Left untreated, however, even asymptomatic stage 1 HTN may increase risk for cardiovascular, central nervous system, and renal morbidity in adults. Vesicoureteral reflux (VUR) is the retrograde flow of urine from the bladder up to the ureter or even up to the kidney. Most VUR results from congenital incompetence of the ureterovesical (UV) junction, a structure that matures through early childhood. In a significant minority of children, structural UV abnormalities exist that never resolve. VUR may be familial; 30% to 40% of siblings of a child with VUR also have VUR. VUR may also be secondary to distal bladder obstruction or other urinary tract anomalies.


Pediatrics_Nelson

Pediatrics_Nelson. VUR exposes the kidney to increased hydrodynamic pressure during voiding and increases the likelihood of renal infection due to incomplete emptying of the ureter and bladder (see Chapter 114). Reflux nephropathy refers to development and progression of renal scarring. This is a particular risk if VUR is associated with a urinary tract infection (UTI) or obstruction. Although a single UTI may result in renal scarring, the incidence is higher in children with recurrent UTIs. Renal dysplasia is associated with congenital VUR. Because of increasing use of maternal-fetal ultrasonography, a number of newborns are now identified with VUR before UTI has occurred, creating opportunities for early intervention and prevention strategies. Duplication of the ureters, with or without an associated ureterocele, may obstruct the upper collecting system. Often the ureter draining the lower pole of a duplicated renal unit has VUR. Neurogenic bladder is accompanied by VUR in up to 50% of affected


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Pediatrics_Nelson. ureterocele, may obstruct the upper collecting system. Often the ureter draining the lower pole of a duplicated renal unit has VUR. Neurogenic bladder is accompanied by VUR in up to 50% of affected children. VUR may also be due to increased intravesicular pressure when the bladder outlet is obstructed from inflammation of the bladder (cystitis) or by acquired bladder obstruction.


Pediatrics_Nelson

Pediatrics_Nelson. VUR is most often identified during radiologic evaluation following a UTI (see Chapter 114). The younger the patient with UTI, the more likely VUR is present. No clinical signs reliably differentiate children with UTI with and without VUR.


Pediatrics_Nelson

Pediatrics_Nelson. An imaging study can be performed after initiation of UTI treatment with no need to wait days or weeks before performing the test. Renal ultrasound (RUS) is the best study to evaluate the urinary tract in children. A voiding cystourethrogram (VCUG) or radionuclide cystogram (NCG) is performed to detect urethral/bladder abnormalities and/or VUR. Recent American Academy of Pediatrics guidelines for infants with a first UTI between 2 and 24 months of age recommend a VCUG if an RUS reveals hydronephrosis, scarring, or other findings suggestive of either high grade VUR or obstructive uropathy and in other atypical or complex clinical circumstances. VCUG should also be performed if there is a recurrence of a febrile UTI. Although the VCUG provides additional anatomic detail, the NCG may detect more children with mild VUR and involves less radiation. An international grading system has been used to describe reflux (Fig. 167-1).The incidence of renal scarring in patients with low-grade VUR is


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Pediatrics_Nelson. children with mild VUR and involves less radiation. An international grading system has been used to describe reflux (Fig. 167-1).The incidence of renal scarring in patients with low-grade VUR is low (15%) and increases with grade IV or V reflux (65%). Grade I or II VUR is likely to resolve without surgical intervention, but VUR resolves in less than 50% grade IV or V. Nuclear renal scanning best identifies renal scars.


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Pediatrics_Nelson. Controversy remains about whether long-term prophylactic antibiotic therapy (trimethoprim-sulfamethoxazole ornitrofurantoin) is indicated in mild to moderate VUR. It isoptional in this population and may be particularly useful inchildren with high-grade VUR and/or recurrent symptomatic Figure 167-1 International classification of vesicoureteral reflux. Grade I: into a nondilated ureter; grade II: into the pelvis and calyces without dilation; grade III: mild to moderate dilation of the ureter, renal pelvis, and calyces with minimal blunting of the fornices; grade IV: moderate ureteral tortuosity and dilation of the pelvis and calyces; grade V: gross dilation of the ureter, pelvis, and calyces; loss of papillary impressions; and ureteral tortuosity. (From Wein A, Kavoussi L, Novick A, et al: Campbell-Walsh Urology, ed 9, Philadelphia, 2007, Saunders.)


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Pediatrics_Nelson. UTI. Pivotal studies are under way. Complications of reflux nephropathy are hypertension and chronic kidney disease(CKD). CKD is typically heralded by mild proteinuria andinvolves the development of focal and segmental glomerulosclerosis as well as interstitial scarring. Indications for surgical repair of VUR are controversial and have been mademore complex by the development of dextranomer/hyaluronic acid copolymer (Deflux procedure), which appears tobe a very successful minimally invasive correction of mild tomoderate VUR.


Pediatrics_Nelson

Pediatrics_Nelson. Anomalies of the urinary tract (UT) occur in up to 4% ofinfants. Bilateral renal agenesis occurs in 1 in 4000 births. Renal agenesis is a component of Potter syndrome (flatfacies, clubfoot, and pulmonary hypoplasia). Any intrauterine UT disorder that results in little fetal urine and, therefore, little amniotic fluid can lead to Potter syndrome.Unilateral renal agenesis occurs in 1 in 3000 births and is more common in infants of diabetic mothers and African Americans. It is accompanied by normal or minimallyreduced renal function. This condition can also be found with vesicoureteral reflux (VUR) and other anomalies of thegenital tract, ear, skeletal system, and cardiovascular system.Unilateral renal agenesis can be a component of the Turner syndrome, Poland syndrome, or VACTERL association (vertebral abnormalities, anal atresia, cardiac abnormalities, tracheoesophageal fistula, renal agenesis and dysplasia, andlimb defects).


Pediatrics_Nelson

Pediatrics_Nelson. Renal hypoplasia/dysplasia refers to kidneys that are congenitally small, malformed, or both. Over time many affected children progress to chronic kidney disease (CKD) because of reduced nephron number. The kidneys are often unable to fully reabsorb sodium and water, and these children require salt and water supplementation to optimize growth. Multicystic renal dysplasia (MCD) is due to abnormalnephron development that occurs in 1 in 4000 births. Thereis minimal or no functioning renal tissue in the affected kidney; bilateral disease is lethal. There is an association withVUR in the contralateral kidney. MCD often spontaneouslyinvolutes over the first few years of life and is rarely associated with hypertension (HTN) or recurrent urinary tractinfection (UTI).


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Pediatrics_Nelson. Polycystic kidney diseases (PKDs) are a group of genetic diseases affecting the kidneys and other tissues. PKD may be primary (autosomal recessive or autosomal dominant) or associated with other syndromes. Autosomal recessive PKD occurs in 1 in 10,000 to 40,000 children and is due to genetic defects in fibrocystin. Autosomal dominant PKD, due to defects in polycystin 1 or 2, occurs in 1 in 1000 individuals, making it the most common inherited kidney disease. Although there is some overlap clinically, the two conditions differ morphologically. Both may appear in infancy or in older children. Renal cysts also are observed in other inherited disorders, such as von Hippel–Lindau syndrome, tuberous sclerosis, and Bardet-Biedl syndrome.


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Pediatrics_Nelson. Urinary tract obstruction can occur at any anatomiclevel of the genitourinary system (Table 168-1). Early in gestation, severe obstruction results in renal dysplasia. Ureteralobstruction later in fetal life or after birth results in dilation of the ureter and collecting system, often with subsequentrenal parenchymal alterations. An obstructed UT is susceptible to infections, which may worsen renal injury. Posterior urethral valves are the most common cause of bladder Infundibula/pelvis Congenital, calculi, infection, trauma/ hemorrhage, tumor Ureteropelvic Congenital stenosis,* calculi, trauma/ junction hemorrhage Ureter Obstructive megaureter,* ectopic ureter, ureterocele, calculi,* inflammatory bowel disease Retroperitoneal tumor (lymphoma), retroperitoneal fibrosis, chronic granulomatous disease Bladder Neurogenic dysfunction,* tumor (rhabdomyosarcoma), diverticula, ectopic ureter


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Pediatrics_Nelson. Retroperitoneal tumor (lymphoma), retroperitoneal fibrosis, chronic granulomatous disease Bladder Neurogenic dysfunction,* tumor (rhabdomyosarcoma), diverticula, ectopic ureter Urethra Posterior valves,* diverticula, strictures, atresia, ectopic ureter, foreign body, phimosis,* priapism *Relatively common. outlet obstruction in males, present in 1 in 50,000 boys.Parents may note a poor urine stream in affected children.The valves are sail-shaped membranes that arise from the verumontanum and attach to the urethral wall. The prostaticurethra becomes dilated, VUR may be present, and hypertrophied detrusor muscle develops. Renal dilation variesin severity. Some degree of renal dysplasia is often present.Severe obstruction may be associated with oligohydramnios, resulting in lethal pulmonary hypoplasia. Intrauterinerupture of the renal pelvis produces urinary ascites, which is the most common cause of ascites in the newborn period. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Bilateral renal agenesis results in insufficient lung development and Potter syndrome. Respiratory distress is severe, pneumothoraces can occur, and severe pulmonary hypoplasia is fatal. Unilateral renal agenesis may be asymptomatic because the nonaffected kidney undergoes compensatory growth and provides normal renal function. Autosomal recessive PKD is characterized by marked bilateral renal enlargement. Interstitial fibrosis and tubular atrophy progress over time. Kidney failure usually occurs in early childhood. Hepatic fibrosis is present and may lead to portal HTN. Bile duct ectasia and biliary dysgenesis occur. Many affected infants display flank masses, hepatomegaly, pneumothorax, proteinuria, and/or hematuria.


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Pediatrics_Nelson. Autosomal dominant PKD typically presents in middle adulthood but may present in infancy or childhood. Infants may have a clinical picture similar to autosomal recessive PKD, but older children show a pattern similar to that of adults, with large isolated cysts developing over time. The defect may occur anywhere along the nephron unit. Hepatic cysts are often present, and pancreatic, splenic, and ovarian cysts can also develop. Cerebral aneurysms may develop, and the risk of hemorrhage depends on size, blood pressure, and family history of intracranial hemorrhage. UT obstruction may be silent but usually is discovered during prenatal ultrasound or with UTI or flank mass in early childhood. In a newborn, the most common type of abdominal mass is renal (most commonly ureteropelvic junction obstruction).


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Pediatrics_Nelson. Renal ultrasound (RUS) and radionuclide renography(usually with a diuretic administered) are the standard testsfor diagnosis of UT obstruction. RUS allows identificationof renal agenesis, hypoplasia, dysplasia, cysts, and UT dilation. Obstruction may be suggested but a dilated UT mayalso result from VUR, ureteral hypoplasia, or neurogenicbladder. A voiding cystourethrogram (VCUG) is also apart of the evaluation. Many boys with posterior urethralvalves are identified by prenatal ultrasound. Postnatally the diagnosis and extent of renal damage are established by RUSand VCUG. Infants and children with bilateral dysplasia often require additional sodium and water due to renal wasting. With MCD surgical removal of the kidney is rarely indicated unless severe HTN or recurrent UTI occurs. Treatment of HTN can prolong maintenance of renal function. General therapy of CKD (see Chapter 165) can improve growth and development.


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Pediatrics_Nelson. Treatment of HTN can prolong maintenance of renal function. General therapy of CKD (see Chapter 165) can improve growth and development. UT obstruction often requires drainage or surgical correction. Treatment of posterior urethral valve consists of either primary valve ablation or diversion (usually via vesicostomy) if ablation is not possible. Ectopic ureters are frequently obstructed; when this happens, surgical intervention is required. Children with neurogenic bladder are prone to UTI and renal impairment from poor urine emptying. Clean intermittent catheterization or a urinary diversion is used to help minimize these complications.


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Pediatrics_Nelson. Urinary tract calculi are called nephrolithiasis or urolithiasis. Primary bladder stones can be seen with recurrent urinarytract infections (UTIs), neurogenic bladder or bladder surgery(sutures serve as a nidus), and intestinal bladder augmentation.Renal stones can result from obstructive abnormalities or an underlying metabolic predisposition. In industrialized societies,most stones (>90%) in children arise in the urinary tract (UT)and become symptomatic with passage or if lodged (commonlyat the ureteropelvic junction or the ureterovesical junction).Metabolic causes include idiopathic familial hypercalciuria(IHC), hyperoxaluria, uric acid disorders, distal renal tubularacidosis, cystinuria, hypercalcemic hypercalciuria, and primaryhyperparathyroidism. Some children with UT abnormalitiesand stones have a concomitant metabolic predisposition.


Pediatrics_Nelson

Pediatrics_Nelson. Acute obstruction of urine flow is the cause of renal colic, a severe sharp intermittent pain in the flank or lower abdomen often radiating to the groin. Vomiting, distress, and inability to relieve pain with position changes are characteristic. In younger children, classic symptoms may not be apparent; fussiness and vomiting may be the only symptoms. Hematuria may be gross or microscopic and typically clears rapidly with passage of gravel or stone material.


Pediatrics_Nelson

Pediatrics_Nelson. Renal ultrasound may identify kidney stones in the kidney but can easily miss UT stones. Computed tomography (CT), particularly a helical CT, can identify stones throughout the UT, but stones can be obscured by oral or intravenous contrast material. Etiologic diagnosis is facilitated when stone material can be obtained and sent for analysis. Spot or 24-hour urine studies for mineral and electrolyte determinations, obtained on a typical diet for the child, are important to characterize any underlying metabolic predisposition and are valuable even when a stone is available for analysis.


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Pediatrics_Nelson. Acute treatment of urinary calculi consists of hydration and analgesia. Chronic treatment for all types of metabolic stonesinvolves vigorous fluid intake, usually twice maintenance rates.Infection-related stones require treatment of infection and oftenremoval of the stone as well as correction of any predisposinganatomic abnormality. Specific metabolic conditions require specific treatments; for IHC, normal calcium intake with low sodium and low oxalate intake is prescribed. For some children with IHC,potassium citrate or thiazides are required to minimize stonerecurrence. Lithotripsy or surgery by a pediatric urologist may berequired for children with large, infected, or obstructing stones.


Pediatrics_Nelson

Pediatrics_Nelson. Voiding difficulties are frequent in preschool age children due todelay in maturation of bladder and micturition pathways. Normal micturition and continence rely on structural UT integrity,neurologic maturation, and coordination between somatic andautonomic nervous system units, including the central nervoussystem, spinal cord pathways, nerves innervating the bladder/urinary sphincter, and the autonomic system. Daytime continence is usually achieved before nighttime continence. Mostchildren are dry, day and night, by 4 to 5 years of age. Nocturnalenuresis is the involuntary loss of urine during sleep. Childrenwith primary enuresis have never had a prolonged (usually >3months) span of nighttime continence. Up to 10% of 5-year-oldchildren have primary enuresis with 15% spontaneous resolution per year. Boys are affected more than girls with increasedincidence in families (40% at 6 years of age if one affected parent, 70% if two affected parents). Secondary enuresis involvesloss of


Pediatrics_Nelson

Pediatrics_Nelson. per year. Boys are affected more than girls with increasedincidence in families (40% at 6 years of age if one affected parent, 70% if two affected parents). Secondary enuresis involvesloss of nighttime control after an extended period of drynessand generally requires evaluation to uncover the cause.


Pediatrics_Nelson

Pediatrics_Nelson. Decision-Making Algorithm Available @ StudentConsult.com Clinical Manifestations Dysfunctional voiding (DV) may manifest as incontinence, fre- quency, urgency, hesitancy, dysuria, lower abdominal pain, or recurrent UTI. Symptoms may vary over time and be associatedwith obvious neurologic problems (spinal cord injury, encephalitis), constipation, and/or behavioral problems. DV symptomsmay vary, depending on recent UTI or changes in family orschool life/stressors. The majority of children with DV are anatomically, neurologically, and psychologically normal.


Pediatrics_Nelson

Pediatrics_Nelson. Evaluation for DV may be performed at any age, but isolatedurinary incontinence in an otherwise normal child is notusually evaluated until 5 years of age. A urinalysis and urineculture should be done to exclude occult infection and renal disease. Children with daytime incontinence should undergorenal/bladder ultrasound to exclude structural abnormalities. Urodynamic evaluation is typically reserved for childrenwith a suspicion of neurogenic bladder or known neurologicetiology.


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Pediatrics_Nelson. For children with recurrent UTI, prophylactic antibiotics may be useful. Timed voiding and anticholinergic medications are used to treat bladder hyperactivity and sensory defects. More complicated treatment regimens include biofeedback, α-blockers, and intermittent catheterization. For children with simple primary enuresis, the bed wetting alarm provides safe and effective resolution of the problem for greater than 70% of affected children; medical therapy with anticholinergics, imipramine, or DDAVP may also be used in selected children.


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Pediatrics_Nelson. Hypospadias occurs in approximately 1 in 500 newborn infants. In this condition the urethral folds fail to fuse completely over the urethral groove leaving the urethral meatus located ventrally and proximally to its normal position. The ventral foreskin is also lacking, and the dorsal portion gives the appearance of a hood. Severe hypospadias with undescended testes is a form of ambiguous genitalia. Etiologies include congenital adrenal hyperplasia with masculinization of females or androgen insensitivity. UT anomalies are uncommon in association with hypospadias. Hypospadias may occur alone, but in severe cases can be associated with a chordee (a fixed ventral curvature of the penile shaft). Rarely when the urethra opens onto the perineum, the chordee is extreme, and the scrotum is bifid and sometimes extends to the dorsal base of the penis.


Pediatrics_Nelson

Pediatrics_Nelson. In 90% of uncircumcised males, the foreskin should be retractable by adolescence. Before this age, the prepuce may normally be tight and not need treatment. After this age, the inability to retract the prepuce is termed phimosis. The condition may be congenital or the result of inflammation. Paraphimosis occurs when the prepuce has been retracted behind the coronal sulcus, cannot resume its normal position, and causes swelling of the glans or pain. The meatal opening in hypospadias may be located anteriorly (on the glans, coronal, or distal third of the shaft); on the middle third of the shaft; or posteriorly (near the scrotum). Testes are undescended in 10% of boys with hypospadias. Inguinal hernias are common. Males with hypospadias should not be circumcised, particularly if the meatus is proximal to the glans, because the foreskin may be necessary for later repair. Most pediatric urologists repair hypospadias before the patient is 18 months old.


Pediatrics_Nelson

Pediatrics_Nelson. Phimosis is rarely symptomatic. Parents should be reassured that loosening of the prepuce usually occurs during puberty. Treatment, if needed, is topical steroids. If the narrowing is severe, gentle stretching may be useful. Circumcision is reserved for the most severe cases. Paraphimosis with venous stasis and edema leads to severe pain. When paraphimosis is discovered early, reduction of the foreskin may be possible with lubrication. In some cases, emergent circumcision is needed.


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Pediatrics_Nelson. Undescended testes (cryptorchidism) are found in about 1% of boys after 1 year of age. It is more common in full-term newborns (3.4%) than in older children. In neonates, cryptorchidism is more common with shorter gestation (20% in 2000to 2500-g infants and 100% in <900-g infants). Cryptorchidism is bilateral in 30% of cases. Spontaneous testicular descent does not tend to occur after 1 year of age, but failure to find one or both testes in the scrotum does not indicate undescended testicles. Retractile testes, absent testes, and ectopic testes may resemble cryptorchidism in presentation. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com A history of maternal drug use (steroids) and family history are important in the evaluation of a child for apparent cryptorchidism. Whether the testis was ever noted in the scrotum should be asked. The true undescended testis is found along the normal embryologic path of descent, usually in the presence of a patent processus vaginalis. An undescended testis is often associated with an inguinal hernia; it is also subject to torsion. There is a high incidence of infertility in adulthood. When bilateral and untreated, infertility is uniform. There is an increased malignancy risk (five times the normal rate) with undescended testis, usually presenting between the ages of 20 and 30. The risk is greater in untreated males or those with surgical correction during or after puberty.


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Pediatrics_Nelson. Retractile testes are normal testes that retract into the inguinal canal from an exaggerated cremasteric reflex. The diagnosis of retractile testes is likely if testes are palpable inthe newborn period but not at later examination. Frequentlyparents describe seeing their son’s testes in his scrotum whenhe is in the bath and seeing one or both “disappear” when hegets cold. Available @ StudentConsult.com Torsion of the testis is an emergency requiring prompt diagnosis and treatment to save the affected testis. Torsion accounts for 40% of cases of acute scrotal pain and swelling and is the major cause of the acute scrotum in boys less than 6 years of age. It is thought to arise from abnormal fixation of the testis to the scrotum. On examination the testicle is swollen and tender, and the cremasteric reflex is absent. The absence of blood flow on nuclear scan or Doppler ultrasound is consistent with torsion.


Pediatrics_Nelson

Pediatrics_Nelson. The differential diagnosis of testicular pain includes trauma, an incarcerated hernia, and torsion of the testicular epididymal appendix. Torsion of the appendix testis is associated with point tenderness over the lesion and minimal swelling. In adolescents, the differential diagnosis of testicular torsion also must include epididymitis, the most common cause of acute scrotal pain and swelling in older adolescents. Diagnosis is aided by an antecedent history of sexual activity or UTI. Testicular torsion must be considered as the principal diagnosis when severe acute testicular pain is present.


Pediatrics_Nelson

Pediatrics_Nelson. The undescended testis is usually histologically normal at birth. Atrophy and dysplasia are found after the first year of life. Some boys have congenital dysplasia in the contralateral descended testis. Surgical correction at an early age results in greater chance of adult fertility. Administration of human chorionic gonadotropin causes testosterone release from functioning testes and may result in descent of retractile testes. Orchidopexy is usually done in the second year of life. Most extra-abdominal testes can be brought into the scrotum with correction of the associated hernia. If the testis is not palpable, ultrasound or magnetic resonance imaging may determine its location. The closer the testis is to the internal inguinal ring, the better the chance of successful orchidopexy.


Pediatrics_Nelson

Pediatrics_Nelson. Surgical correction of testicular torsion is called detorsion and fixation of the testis. If performed within 6 hours of torsion, there is greater than a 90% chance of testicular salvage. The contralateral testis usually is fixed to the scrotum to prevent possible torsion. If torsion of the appendix is found, the necrotic tissue is removed. We gratefully acknowledge the invaluable contributions of Rama Jayanthi, MD, Pediatric Urology, Nationwide Children’s Hospital, Columbus, Ohio. Brady TM: Hypertension, Pediatr Rev 33:541–552, 2012 Gipson DS, Massengil SF, Yao L, et al: Management of childhood onset nephrotic syndrome, Pediatrics 124:747–757, 2009 Massengill SF: Hematuria, Pediatr Rev 29:342–348, 2008 McKay CP: Renal stone disease, Pediatr Rev 31:179–188, 2010 Schwartz GJ, Munoz A, Schneider MF, et al: New equation to estimate GFR in children with CKD, J Am Soc Nephrol 20:629–637, 2009


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Pediatrics_Nelson. McKay CP: Renal stone disease, Pediatr Rev 31:179–188, 2010 Schwartz GJ, Munoz A, Schneider MF, et al: New equation to estimate GFR in children with CKD, J Am Soc Nephrol 20:629–637, 2009 Urinary tract infection: clinical practice guideline for the diagnosis and man agement of the initial UTI in febrile infants and children 2 to 24 months. Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management, Pediatrics 128:595–610, 2011 Whyte DA, Fine RN: Acute renal failure in children, Pediatr Rev 29:299–307, Whyte DA, Fine RN: Chronic kidney disease in children, Pediatr Rev 29:335–341, 2008 Paola A. Palma Sisto and MaryKathleen Heneghan 23


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Pediatrics_Nelson. Whyte DA, Fine RN: Chronic kidney disease in children, Pediatr Rev 29:335–341, 2008 Paola A. Palma Sisto and MaryKathleen Heneghan 23 The endocrine system regulates vital body functions by means of hormonal messengers. Hormones are defined as circulating messengers, with action at a distance from the organ (gland)of origin of the hormone. Hormones can be regulated by nerve cells; endocrine agents can serve as neural messengers. There is also a relationship between the endocrine system and the immune system; autoantibodies may cause an organ to produce an excess or deficiency of a hormone. Manifestations of an endocrine disorder are related to the response of the peripheral tissue to a hormone excess or deficiency.


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Pediatrics_Nelson. Hormone action also may be paracrine (acting on adjacent neighboring cells to the cell of origin of the hormone) or autocrine (acting on the cell of origin of the hormone itself); agents acting in these ways are called factors rather than hormones (Fig. 170-1). Hormones generally are regulated in a feedback loop so that the production of a hormone is linked to its effect or its circulating concentration. Endocrine disorders generally manifest from one of four ways: 1. By excess hormone: In Cushing syndrome, there is an excess of glucocorticoid present; if the excess is secondary to autonomous glucocorticoid secretion by the adrenal gland, the trophic hormone adrenocorticotropic hormone (ACTH) is suppressed. 2. By deficient hormone: In glucocorticoid deficiency, the level of cortisol is inadequate; if the deficiency is at the adrenal gland, the trophic hormone is elevated (ACTH). 3.


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Pediatrics_Nelson. 2. By deficient hormone: In glucocorticoid deficiency, the level of cortisol is inadequate; if the deficiency is at the adrenal gland, the trophic hormone is elevated (ACTH). 3. By an abnormal response of end organ to hormone: In pseudohypoparathyroidism, defects in the gene (GNAS1) encoding the alpha subunit of the stimulatory G protein (Gsa) is manifested by elevated PTH levels in the face of deficient PTH function (PTH resistance). 4. By gland enlargement that may have effects as a result of size rather than function: With a large nonfunctioning pituitary adenoma, abnormal visual fields and other neurologic signs and symptoms result even though no hormone is produced by the tumor.


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Pediatrics_Nelson. Peptide hormones act through specific cell membrane receptors; when the hormone is attached to the receptor, the complextriggers various intracellular second messengers that cause the biologic effects. Peptide hormone receptor number and aviditymay be regulated by hormones. Steroid hormones exert their effects by attachment to intranuclear receptors, and the hormone-receptor complex translocates to the nucleus, where itbinds with DNA, and leads to further gene activation. The interpretation of serum hormone levels must be related totheir controlling factors. For example, a given value of parathyroidhormone may be normal in a eucalcemic patient but inadequatein a hypocalcemic patient with partial hypoparathyroidism orexcessive in a hypercalcemic patient with hyperparathyroidism.


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Pediatrics_Nelson. The hypothalamus controls many endocrine systems either directly or through the pituitary gland. Higher central nervoussystem (CNS) centers control the hypothalamus. Hypothalamicreleasing or inhibiting factors travel through capillaries of the pituitary portal system to control the anterior pituitary gland,regulating the hormones specific for the factor (Fig. 170-2).The pituitary hormones enter the peripheral circulation andexert their effects on target glands, which produce other hormones that feed back to suppress their controlling hypothalamicand pituitary hormones. Insulin-like growth factor-1 (IGF-1),growth hormone (GH), cortisol, sex steroids, and thyroxine (T4)all feed back on the hypothalamic-pituitary system. Prolactin isthe only pituitary hormone that is suppressed by a hypothalamicfactor, dopamine. The hypothalamus is also the location of vasopressin-secreting axons that either terminate in the posteriorpituitary gland and exert their effect via vasopressin secretion


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Pediatrics_Nelson. Figure 170-1 Schematic representation of mechanisms of action of hormones and growth factors. Although traditional hormones are formed in endocrine glands and transported to distant sites of action through the bloodstream (endocrine mechanism), peptide growth factors may be produced locally by the target cells themselves (autocrine modality of action) or by neighboring cells (paracrine action). (From Wilson JD, Foster DW, editors: Williams Textbook of Endocrinology, ed 8, Philadelphia, 1992, WB Saunders, p 1007.) HYPOTHALAMUSPITUITARYSRIF (somatostatin) GHRH CRH GH ACTH Prolactin FSH, LH TSH Dopamine GnRH TRH Growth Cortisol Lactation T4, T3 Sex steroids Insulin-like growth factors (and binding proteins)


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Pediatrics_Nelson. HYPOTHALAMUSPITUITARYSRIF (somatostatin) GHRH CRH GH ACTH Prolactin FSH, LH TSH Dopamine GnRH TRH Growth Cortisol Lactation T4, T3 Sex steroids Insulin-like growth factors (and binding proteins) Figure 170-2 Hormonal influences of the hypothalamus and pituitary gland. Solid line represents stimulatory influence; dotted line represents inhibitory influence. ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone or CRF; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, GH-releasing hormone or GRF; GnRH, gonadotropin-releasing hormone or luteinizing hormone releasing factor, LRF or LHRH; LH, luteinizing hormone; SRIF, somatotropin release-inhibiting factor, somatostatin or SS; Inhibin TRH, thyrotropin-releasing hormone or TRF; TSH, thyroid-stimulating hormone; T3, triiodothyronine; T4, thyroxine.


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Pediatrics_Nelson. T4, thyroxine. Table 170-1 Diagnostic Evaluation for Hypopituitarism MANIFESTATION CAUSE TESTS* Growth failure, hypothyroidism, or both GH deficiency, TRH/TSH deficiency, or both Provocative GH tests, free T4, bone age, IGF-1, IGFBP3 Hypoglycemia GH deficiency, ACTH insufficiency, or both Provocative GH tests, test of ACTH secretion, IGF1, IGFBP3 Polyuria, polydipsia ADH deficiency Urine analysis (specific gravity), serum electrolytes, urine and serum osmolality, water deprivation test ADH, Antidiuretic hormone; CNS, central nervous system; E2, estradiol; FSH, follicle-stimulating hormone; GH, growth hormone; GnRH, gonadotropin-releasing hormone; IGF-1, insulin-like growth factor; IGFBP3, insulin-like growth factor-binding protein 3; LH, luteinizing hormone; MRI, magnetic resonance imaging; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone; T4, thyroxine.


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Pediatrics_Nelson. *Each patient with hypopituitarism should have CNS MRI as part of evaluation to determine the etiology of the condition. from this area or terminate in the mediobasal hypothalamus, DISORDERS OF THE from which they can exert effects on water balance, even in the HYPOTHALAMIC-PITUITARY AXIS absence of the posterior pituitary gland. The assessment of pituitary function may be determined Decision-Making Algorithms by measuring some of the specific pituitary hormone in the Available @ StudentConsult.com basal state; other assessments require the measurement after stimulation. Indirect assessment of pituitary function can be obtained by measuring serum concentrations of the target gland hormones (Table 170-1). Several tests of pituitary func- tion are listed in Table 170-2.


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Pediatrics_Nelson. Table 170-2 Anterior Pituitary Hormone Function Testing RANDOM HORMONE MEASUREMENTS PROVOCATIVE OR OTHER TESTS TARGET HORMONE MEASUREMENT GH (not useful as a random determination except in newborns, and in GH resistance or in pituitary gigantism) Arginine (a weak stimulus) L-Dopa (useful clinically) Insulin-induced hypoglycemia (a dangerous but accurate test) IGF-1, IGFBP3 (affected by malnutrition as well as GH excess) TSH* TRH FT4 LH, FSH* GnRH (difficult to interpret in prepubertal subjects) Testosterone/estradiol ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; FT4, free thyroxine; GH, growth hormone; GnRH, gonadotropin-releasing hormone; GRH, growth hormone-releasing hormone; IGF-1, insulin-like growth factor-1; IGF-BP3, insulin-like growth factor-binding protein 3; L-dopa, L-dihydroxyphenylalanine; LH, luteinizing hormone; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.


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Pediatrics_Nelson. *New supersensitive assays allow determination of abnormally low values found in hypopituitarism. Hypothalamic deficiency leads to a decrease in most pituitary hormone secretions but may lead to an increase in prolactin secretion. Destructive lesions of the pituitary glandor hypothalamus are more common in childhood thanincreased pituitary secretion of various hormones. A craniopharyngioma, a tumor of the Rathke pouch, may descendinto the sella turcica, causing erosion of the bone anddestruction of pituitary and hypothalamic tissue. Acquired hypopituitarism also may result from pituitary infections;from infiltration (Langerhans cell histiocytosis [histiocytosisX], lymphoma, and sarcoidosis); after radiation therapy or trauma to the CNS; and as a consequence of autoimmunity against the pituitary gland.


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Pediatrics_Nelson. Congenital hypopituitarism can be caused by the absenceof hypothalamic releasing factors. Without hypothalamicstimulation, the pituitary gland does not release its hormones.Congenital defects associated with hypopituitarism range from holoprosencephaly (cyclopia, cebocephaly, orbital hypotelorism), to cleft palate (6% of cases of cleft palate are associated with GH deficiency). Septo-optic dysplasia (optic nerve hypoplasia, absent septum pellucidum, or variations of both)may result in significant visual impairment with pendular(“roving”) nystagmus (inability to focus on a target) in addition to varying degrees of hypopituitarism. The magnetic resonance imaging (MRI) findings of congenital hypopituitarismmay include an ectopic posterior pituitary gland bright spot, the appearance of a pituitary stalk transection, and/or small pituitary gland.


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Pediatrics_Nelson. Diabetes mellitus (DM) is characterized by hyperglycemia andglycosuria and is an end point of a few disease processes (Table 171-1). The most common type occurring in childhood is type1 DM (DM1), which is caused by autoimmune destruction of the insulin-producing beta cells (islets) of the pancreas leadingto permanent insulin deficiency. Type 2 DM (DM2) resultsfrom insulin resistance and relative insulin deficiency, usuallyin the context of exogenous obesity. The incidence of DM1 andDM2 in the United States is increasing. Less common types ofdiabetes result from genetic defects of the insulin receptor orinherited abnormalities in sensing of ambient glucose concentration by pancreatic beta cells (see Table 171-1).


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Pediatrics_Nelson. A diagnosis of DM is made based on four glucose abnormalities that may need to be confirmed by repeat testing: (1) Fasting serum glucose concentration ≥126 mg/dL, (2) a random venous plasma glucose ≥200 mg/dL with symptoms of hyperglycemia, (3) an abnormal oral glucose tolerance test (OGTT) with a 2-hour postprandial serum glucose concentration ≥200 mg/dL, and (4) a HgbA1c ≥6.5%. A patient is considered to have impaired fasting glucoseif fasting serum glucose concentration is 100 to 125 mg/dL or impaired glucose tolerance if 2-hour plasma glucose following an OGTT is 140 to 199 mg/dL. Sporadic hyperglycemia can occur in children, usually in the setting of an intercurrent illness. When the hyperglycemic episode is clearly related to Classic type 1 Glycosuria, ketonuria, hyperglycemia, islet cell positive; genetic component Secondary Cystic fibrosis, hemochromatosis, drugs (L-asparaginase, tacrolimus)


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Pediatrics_Nelson. Classic type 1 Glycosuria, ketonuria, hyperglycemia, islet cell positive; genetic component Secondary Cystic fibrosis, hemochromatosis, drugs (L-asparaginase, tacrolimus) Adult type (classic) Associated with obesity, insulin resistance; genetic component diabetes pregnancy only, which reverts to normal postpartum; increased risk for later onset of diabetes Maturity-onset Autosomal dominant, onset before age diabetes of youth of 25 years; not associated with obesity or autoimmunity Mitochondrial Single-gene mutations include hepatocyte diabetes nuclear factors 1β,1α, 4α; glucokinase; insulin promoter factor 1 Associated with deafness and other neurologic defects, maternal transmission— mtDNA point mutations an illness or other physiologic stress, the probability of incipient diabetes is small (<5%).


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Pediatrics_Nelson. DM1 results from the autoimmune destruction of insulin-producing beta cells (islets) of the pancreas. In addition to the presence of diabetes susceptibility genes, an unknown environmental insult presumably triggers the autoimmune process. A variety of studies has produced conflicting data regarding a host of environmental factors. These include cow’s milk feeding at an early age, viral infectious agents (Coxsackie virus, cytomegalovirus, mumps, rubella), vitamin D deficiency, and perinatal factors. DM1 is thought to be primarily a T cell–mediated disease.


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Pediatrics_Nelson. Antibodies to islet cell antigens may be seen months to years before the onset of beta cell dysfunction (Fig. 171-1). These include islet cell antibodies, insulin autoantibodies, antibodies to tyrosine phosphatase IA-2, antibodies to glutamic acid decarboxylase, and others. The risk for diabetes increases with the number of antibodies detected in the serum. In individuals with one detectable antibody only, the risk is only 10% to 15%; in individuals with three or more antibodies, the risk is 55% to 90%. When 80% to 90% of the beta cell mass have been destroyed, the remaining beta cell mass is insufficient to maintain euglycemia and clinical manifestations of diabetes result (see Fig. 171-1).


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Pediatrics_Nelson. The annual incidence of DM1 is increasing steadily but with significant geographic differences. In the United States, the annual incidence is approximately 20 in 100,000. The annual incidence in children ranges from a high of 40 in 100,000 among Scandinavian populations to less than 1 in 100,000 in China. The prevalence of DM1 in the United States is highest in non-Hispanic whites followed by African Americans, Hispanic, and American Indians.


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Pediatrics_Nelson. Genetic determinants play a role in the susceptibility to DM1, although the mode of inheritance is complex and multigenic. Siblings or offspring of patients with diabetes have a risk of 2% to 8% for the development of diabetes; an identical twin has a 30% to 50% risk. The human leukocyte antigen (HLA) region on chromosome 6 provides the strongest determinant of susceptibility, accounting for approximately 40% of familial inheritance of DM1. Specific class II DR and DQ HLA alleles (HLA DR3 and HLA DR4) increase the risk of developing DM1, whereas other specific HLA alleles exert a protective effect. More than 90% of children with DM1 possess HLA DR3 alleles, HLA DR4 alleles, or both. The insulin gene region variable number tandem repeat on chromosome 11 is also linked to DM1 susceptibility. There is evidence for association, beyond HLA, of more than 100 other loci with DM1. Genetic factors do not fully account for susceptibility to DM1; environmental factors also play a role.


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Pediatrics_Nelson. Available @ StudentConsult.com Polyuria Failure to Thrive Hyperglycemia results when insulin secretory capacity becomesinadequate to enhance peripheral glucose uptake and to suppress hepatic and renal glucose production. Insulin deficiencyusually first causes postprandial hyperglycemia and then fastinghyperglycemia. Ketogenesis is a sign of more complete insulin deficiency. Lack of suppression of gluconeogenesis and glycogenolysis further exacerbates hyperglycemia while fatty acidoxidation generates the ketone bodies: β-hydroxybutyrate, acetoacetate, and acetone. Protein stores in muscle and fat stores in adipose tissue are metabolized to provide substrates for gluconeogenesis and fatty acid oxidation.


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Pediatrics_Nelson. Glycosuria occurs when the serum glucose concentrationexceeds the renal threshold for glucose reabsorption (from 160to 190 mg/dL). Glycosuria causes an osmotic diuresis (includingobligate loss of sodium, potassium, and other electrolytes), leading to dehydration. Polydipsia occurs as the patient attempts tocompensate for the excess fluid losses. Weight loss results fromthe persistent catabolic state and the loss of calories through glycosuria and ketonuria. The classic presentation of DM1 includespolyuria, polydipsia, polyphagia, and weight loss. If the clinical features of new-onset DM1 are not detected, diabetic ketoacidosis (DKA) will occur. DKA may also occur in patients with known DM1 if insulin injections are omitted 0 50 100 Beta cell mass (% of max) 0 Time (y) Progressive Impairment In Insulin Release Overt Diabetes “Honeymoon” Period Release Birth Figure 171-1 Schematic representation of the autoimmune evolution of diabetes in genetically predisposed individuals.


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Pediatrics_Nelson. or during an intercurrent illness when greater insulin requirements are unmet in the presence of elevated concentrations of the counter-regulatory and stress hormones (glucagon, growth hormone [GH], cortisol, and catecholamines). DKA can be considered to be present if (1) the arterial pH is below 7.3, (2) the serum bicarbonate level is below 15 mEq/L, and (3) ketones are elevated in serum or urine.


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Pediatrics_Nelson. In the absence of adequate insulin secretion, persistent partialhepatic oxidation of fatty acids to ketone bodies occurs. Twoof these three ketone bodies are organic acids and lead to metabolic acidosis with an elevated anion gap. Lactic acid maycontribute to the acidosis when severe dehydration results indecreased tissue perfusion. Hyperglycemia causes an osmoticdiuresis that is initially compensated for by increased fluidintake. As the hyperglycemia and diuresis worsen, most patients are unable to maintain the large fluid intake, anddehydration occurs. Vomiting, as a result of increasing acidosis, and increased insensible water losses caused by tachypneacan worsen the dehydration. Electrolyte abnormalities occurthrough a loss of electrolytes in the urine and transmembrane alterations resulting from acidosis. As hydrogen ionsaccumulate as a result of ketoacidosis, intracellular potassium is exchanged for hydrogen ions. Serum concentrationsof potassium increase initially with acidosis


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Pediatrics_Nelson. from acidosis. As hydrogen ionsaccumulate as a result of ketoacidosis, intracellular potassium is exchanged for hydrogen ions. Serum concentrationsof potassium increase initially with acidosis then decrease asserum potassium is cleared by the kidney. Depending on theduration of ketoacidosis, serum potassium concentrations at diagnosis may be increased, normal, or decreased, but intracellular potassium concentrations are depleted. A decreasedserum potassium concentration is an ominous sign of totalbody potassium depletion. Phosphate depletion also can occur as a result of the increased renal phosphate excretion required for elimination of excess hydrogen ions. Sodiumdepletion is also common ketoacidosis, resulting from renallosses of sodium caused by osmotic diuresis and from gastrointestinal losses from vomiting (Fig. 171-2).


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Pediatrics_Nelson. Available @ StudentConsult.com Patients with DKA present initially with polyuria, polydipsia, nausea, and vomiting. Abdominal pain occurs frequently and can mimic an acute abdomen. The abdomen may be tender from vomiting or distended secondary to a paralytic ileus. The presence of polyuria, despite a state of clinical dehydration, indicates osmotic diuresis and differentiates patients with DKA from patients with gastroenteritis or other gastrointestinal disorders. Respiratory compensation for acidosis results in tachypnea with deep (Küssmaul) respirations. The fruity odor of acetone frequently can be detected on the patient’s breath. An altered mental status can occur, ranging from disorientation to coma.


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Pediatrics_Nelson. Laboratory studies reveal hyperglycemia (serum glucose concentrations ranging from 200 mg/dL to >1000 mg/dL).Arterial pH is below 7.30, and the serum bicarbonate concentration is less than 15 mEq/L. Serum sodium concentrationsmay be elevated, normal, or low, depending on the balance ofsodium and free water losses. The measured serum sodium concentration is artificially low, however, because of hyperglycemia. Hyperlipidemia also contributes to the decrease inmeasured serum sodium. The level of blood urea nitrogen(BUN) can be elevated with prerenal azotemia secondary todehydration. The white blood cell count is usually elevatedand can be left-shifted without implying the presence ofinfection. Fever is unusual and should prompt a search forinfectious sources that may have triggered the episode ofDKA. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Therapy for patients with DKA involves careful replacement of fluid deficits, correction of acidosis and hyperglycemia via insulin administration, correction of electrolyte imbalances, and monitoring for complications of treatment. The optimal approach to management of DKA must strike a balance between adequate correction of fluid losses and avoidance of rapid shifts in osmolality and fluid balance. The most serious complication of DKA and its treatment is cerebral edema and cerebral herniation.


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Pediatrics_Nelson. A patient with severe DKA is assumed to be approximately 10% dehydrated. If a recent weight measurement is available, the precise extent of dehydration can be calculated. An initial intravenous (IV) fluid bolus of a glucose-free isotonic solution (normal saline, lactated Ringer solution) at 10 to 20 mL/kg should be given to restore intravascular volume and renal perfusion. The remaining fluid deficit after the initial bolus should be added to maintenance fluid requirements, and the total should be replaced slowly over 36 to 48 hours. Ongoing losses resulting from osmotic diuresis usually do not need to be replaced unless urine output is large or signs of poor perfusion are present. Osmotic diuresis is usually minimal when the serum glucose concentration decreases to less than 300 mg/dL. To avoid rapid shifts in serum osmolality, 0.9% sodium chloride can be used as the replacement fluid for the initial 4 to 6 hours, followed by 0.45% sodium chloride.


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Pediatrics_Nelson. Hyperglycemia. Fast-acting soluble insulin should be administered as a continuous IV infusion (0.1 U/kg/hour). Serum glucose concentrations should decrease at a rate no Figure 171-2 Pathophysiology of diabetic ketoacidosis. faster than 100 mg/dL/hour. When serum glucose concentrations decrease to less than 250 to 300 mg/dL, glucose should be added to the IV fluids. If serum glucose concentrations decrease to less than 200 mg/dL before correction of acidosis, the glucose concentration of the IV fluids should be increased, but the insulin infusion should not be decreased by more than half, and it should never be discontinued before resolution of acidosis.


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Pediatrics_Nelson. Acidosis. Insulin therapy decreases the production of free fatty acids and protein catabolism and enhances glucose usage in target tissues. These processes correct acidosis. Bicarbonate therapy should be avoided. Potential adverse effects of bicarbonate administration include paradoxical increases in central nervous system (CNS) acidosis caused by increased diffusion of carbon dioxide across the blood-brain barrier, potential tissue hypoxia caused by shifts in the oxyhemoglobin dissociation curve, abrupt osmotic changes, and increased risk of the development of cerebral edema. As acidosis is corrected, urine ketone concentrations may appear to rise. β-Hydroxybutyrate, which is not detected in urine ketone assays, is converted with treatment to what the assay most detects, acetoacetate. Hence minute-to-minute urine ketone concentrations are not a required index of the adequacy of therapy.


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Pediatrics_Nelson. Electrolyte imbalances. Regardless of the serum potassium concentration at presentation, total body potassium depletion is likely. Serum potassium concentrations can decrease rapidly as insulin and then glucose therapy improves acidosis, and potassium is exchanged for intracellular hydrogen ions. When adequate urine output is shown, potassium should be added to the IV fluids. Potassium replacement should be given as 50% potassium chloride and 50% potassium phosphate at a concentration of 20 to 40 mEq/L. This combination provides phosphate for replacement of deficits but avoids excess phosphate administration, which may precipitate hypocalcemia. If the serum potassium level is greater than 6 mEq/L, potassium should not be added to IV fluids until the potassium level decreases.


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Pediatrics_Nelson. Monitoring. Initial laboratory measurements should include serum glucose, sodium, potassium, chloride, bicarbonate, BUN, creatinine, calcium, phosphate and magnesium concentrations; arterial or venous pH; and a urinalysis. Serum glucose measurement should be repeated every hour during therapy; electrolyte concentrations should be repeated every 2 to 3 hours. Calcium, phosphate, and magnesium concentrations should be measured every 4 to 6 hours during therapy. Neurologic and mental status should be assessed at frequent intervals. Any complaints of headache or deterioration of mental status should prompt rapid evaluation for possible cerebral edema. Indicative symptoms include a decreased sensorium, sudden severe headache, vomiting, change in vital signs (bradycardia, hypertension, apnea), a dilated pupil, ophthalmoplegia, or seizure.


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Pediatrics_Nelson. Clinically apparent cerebral edema occurs in 1% to 5% of cases of DKA. Cerebral edema is the most serious complication of DKA, with a mortality rate of 20% to 80%. The pathogenesis of cerebral edema likely involves osmolar shift resulting in fluid accumulation in the intracellular compartment and cell swelling. Subclinical cerebral edema is common in patients with DKA, but the factors that exacerbate this process leading to symptomatic brain swelling and possible cerebral herniation are not clearly defined. Cerebral edema typically occurs 6 to 12 hours after therapy for DKA is begun, often following a period of apparent clinical improvement. Factors that correlate with increased risk for cerebral edema include higher initial BUN concentration, lower initial Pco2, failure of the serum sodium concentration to increase as glucose concentration decreases during treatment, and treatment with bicarbonate.


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Pediatrics_Nelson. Signs of advanced cerebral edema include obtundation, papilledema, pupillary dilation or inequality, hypertension, bradycardia, and apnea. Treatment involves the rapid use of IV mannitol, endotracheal intubation, and ventilation and may require the use of a subdural bolt. Other complications of DKA are intracranial thrombosis or infarction, acute tubular necrosis with acute renal failure caused by severe dehydration, pancreatitis, arrhythmias caused by electrolyte abnormalities, pulmonary edema, and bowel ischemia. Peripheral edema occurs commonly 24 to 48 hours after therapy is initiated and may be related to residual elevations in antidiuretic hormone and aldosterone. Transition to Outpatient Management


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Pediatrics_Nelson. When the acidosis has been corrected and the patient tolerates oral feedings, the IV insulin infusion can be discontinued, and a regimen of subcutaneous (SC) insulin injections can be initiated. The first SC insulin dose should be given 30 to 45 minutes before discontinuation of the IV insulin infusion. Further adjustment of the insulin dose should be made over the following 2 to 3 days. A patient already diagnosed with DM1 may be restarted on the prior doses if they were adequate. For a patient with new-onset DM1, typical starting total daily doses are approximately 0.5 to 0.7 U/kg/24 hours for prepubertal patients and approximately 0.7 to 1 U/kg/24 hours for adolescents, using any number of the available insulin combinations. The best and most common choice for making the transition to SC insulin is to begin by giving injections of fast-acting (bolus) insulin (lispro, aspart, or glulisine insulin) with each meal and long-acting (basal) insulin (glargine or detemir) at bedtime. This


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Pediatrics_Nelson. SC insulin is to begin by giving injections of fast-acting (bolus) insulin (lispro, aspart, or glulisine insulin) with each meal and long-acting (basal) insulin (glargine or detemir) at bedtime. This regimen of multiple daily injections provides the most flexibility but requires the patient to administer many injections per day and to count carbohydrates in food. An alternative is a fixed mixed split dosing regimen (neutral protamine Hagedorn [NPH] and fasting-acting insulin) with two daily injections.


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Pediatrics_Nelson. Externally worn pumps that provide a continuous SC infusion of fast-acting insulin are available, although not usually used at the very onset of DM1. Insulin pumps provide fast-acting insulin in small basal amounts continuously every hour and will provide bolus insulin when instructed. Insulin pumps may be used by all age groups who are highly motivated to achieve tight control. The absence of SC depot insulin (glargine or detemir) can increase the risk of DKA.


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Pediatrics_Nelson. Serum glucose concentrations should be assessed before each meal, at bedtime, and periodically at 2 to 3 am to provide information for adjustment of the regimen. Patients and their families should begin learning the principles of diabetes care as soon as possible. Demonstration of the ability to administer insulin injections and test glucose concentrations using a glucose meter is necessary before discharge, as is knowledge of hypoglycemia management. Meal planning is crucial to control glucose in DM1. Nutrition services must be part of the care delivered to the families from diagnosis.


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Pediatrics_Nelson. In some patients with new onset of DM1, the beta cell mass has not been completely destroyed. The remaining functionalbeta cells seem to recover function with insulin treatment. When this occurs, exogenous insulin requirements decrease.This is a period of stable blood glucose control, often with nearly normal glucose concentrations. This phase of the disease, known as the honeymoon period, usually starts in thefirst weeks of therapy, often continues for 3 to 6 months, andcan last 2 years. Management of DM1 in children requires a comprehensive approach with attention to medical, nutritional, and psychosocial issues. Therapeutic strategies should be flexible with the individual needs of each patient and the family taken into account. Optimal care involves a team of diabetes professionals, including a physician, a diabetes nurse educator, a dietitian, and a social worker or psychologist.