NEPHROLOGY - McGraw-Hill Specialty Board Review Pediatrics, 2nd Edition

McGraw-Hill Specialty Board Review Pediatrics, 2nd Edition

Chapter 15. NEPHROLOGY

CASE 121: A 4-DAY-OLD WITH FEEDING PROBLEMS

A 4-day-old boy has become anorexic and comes to your office for evaluation. Mom reports that he had begun to breast-feed avidly but seems much less interested in feeding today and last night. He was the product of a 38-week pregnancy. His mom is 24 years old and had prenatal care. By serology, she had no antibodies to rubella or human immunodeficiency virus (HIV). Routine nontreponemal serology for syphilis was negative. She lacked the hepatitis B surface antigen. The baby had an uneventful hospital course. The Apgar scores were 8 and 9 at 1 and 5 minutes. His birthweight was 3100 g. The physical examination reveals a generally healthy-looking male infant, with somewhat decreased spontaneous activity. His vital signs and physical examination are normal. You decide to perform some laboratory tests.

SELECT THE ONE BEST ANSWER

1. Which of the following statements is correct regarding evaluation for sepsis in this patient?

(A) a blood culture is not indicated; the patient is afebrile and fever almost always accompanies bacteremia

(B) a urine culture need not be performed unless the patient is shown to be bacteremic

(C) a lumbar puncture (LP) need not be part of an initial sepsis evaluation because all patients with neonatal meningitis are bacteremic

(D) the incidence of neonatal urinary tract infection is roughly equal for males and females

(E) a blood leukocyte count has a strong negative predictive value for neonatal bacteremia

2. Which statement is true regarding evaluation of the urine in a neonate?

(A) urine obtained in a sterile plastic bag can be sent for a clinically useful culture provided the genital area is carefully cleaned in advance

(B) a specimen should be obtained by bladder puncture or catheterization to minimize the likelihood of contamination

(C) having more than 10⁵bacteria per milliliter of urine in a “bagged” specimen is diagnostic of a urinary tract infection (UTI)

(D) A and C

(E) B and C

3. Assume that the laboratory tests in the patient in the vignette allowed the diagnosis of a UTI. Which of the following statement(s) is/are correct?

(A) an ultrasound of the kidneys and a voiding cystourethrography (VCUG) should be performed on all patients with proven neonatal UTI

(B) patients with neonatal UTI should be treated with a 14-day course of an oral sulfonamide

(C) intravenous pyelography (IVP) should be performed at the time of diagnosis because Wilms’ tumor is a common concomitant to UTI

(D) an ultrasound of the kidneys will allow adequate assessment of a male child with a UTI (but not a female)

(E) B and C

4. Which of the following is (are) true regarding uncomplicated cystitis in school-age children?

(A) fever is usually absent or low grade

(B) uncircumcised boys are at risk roughly equal to girls, although circumcised boys are at lower incidence compared with girls

(D) A and C

(E) A, B, and C

5. Which of the following is true regarding asymptomatic bacteriuria in school-age children?

(A) occurs in about 13% of healthy girls

(B) is a known predictor of end-stage pyelonephritis in later life

(D) is usually cleared spontaneously

(E) none of the above

6. Which of the following is incorrect about pyuria?

(A) it is defined by more than 5 white blood cells per high power field on urinalysis

(B) it is a sensitive marker for UTI

(D) it often occurs in Kawasaki disease

(E) it often occurs during measles infection and after intense exercise

7. The nitrite dipstick detection test is

(A) nonspecific when positive

(B) a sensitive test for UTI

(D) A and C

(E) all of the above

8. The leukocyte esterase (LE) dipstick detection test

(A) is nearly 99% sensitive in detection of UTI

(B) has relatively low specificity of about 75%

(D) is performed on the blood of patients with true pyelonephritis

(E) detects mercury when this metal is in high concentrations in the urine

9. You diagnose an Escherichia coli UTI in a 6-yearold girl with dysuria and a low-grade temperature. You decide she is not clinically toxic, nor has high fever, so you will manage her as an outpatient on oral antimicrobial therapy. You tell the parents which of the following?

(A) this infection is contagious; other children living in the same house as the index patient are at risk for infection

(B) amoxicillin is appropriate initial therapy because nearly all E coli isolates are susceptible to it

(C) trimethoprim-sulfamethoxazole in a single dose will sterilize her urinary tract and thus is now usually used for initial therapy

(D) radiologic studies are an important part of the ongoing evaluation for UTI and should be scheduled

(E) C and D

10. The mother of a 3-year-old patient with unilateral grade 3 vesicoureteral reflux demonstrated by VCUG comes to you for advice. You tell her that

(A) urgent referral to urology for ureteral reimplantation is warranted

(B) there is no convincing direct relationship between reflux and renal scarring

(C) most pediatricians advise prophylactic antimicrobials in this situation aimed at urinary antisepsis; amoxicillin is a good choice

(D) most children will grow out of this condition; reflux will usually cease within a few years

(E) B and D

11. Which of the following is (are) known to increase the incidence of UTIs in childhood?

(A) constipation

(B) frequent baths

(D) wiping after urination from back to front

(E) all of the above

12. All of the following can cause cystitis except

(A) pinworms

(B) ibuprofen

(D) cyclophosphamide therapy for cancer

(E) adenovirus

13. Management of acute pyelonephritis

(A) usually includes a third-generation cephalosporin antimicrobial such as cefotaxime

(B) usually includes a first-generation cephalosporin antimicrobial such as cefazolin

(D) usually involves initial parenteral therapy

(E) A and D

14. Which of the following is true regarding the interpretation of a urine culture performed on urine from a school-age child?

(A) The bladder is normally sterile. Any bacteria grown from a bladder puncture or uretheral catheterization is diagnostic of a UTI

(B) Recovery of several species from a clean catch urine is suggestive of a renal abscess

(D) A and C

(E) All of the above

15. Which of the following are risk factors for UTI among adolescents?

(A) ingestion of chocolate

(B) infectious mononucleosis

(D) use of a diaphragm with a spermicide

(E) all of the above

ANSWERS

1. (D) Neonates who are septic will most often be afebrile. A physician who waits for fever before initiating a septic workup and treatment has often waited too long. A urine culture (along with blood and cerebrospinal fluid [CSF] culture) should be part of the evaluation for sepsis in this age group. Meningitis can occur in the absence of bacteremia that may have been cleared by the host without therapy. Although girls of nearly every age group have UTIs at a higher frequency than boys, the singular exception is the neonate where the gender prevalence is roughly equal. The blood leukocyte count in a septic neonate may occasionally be abnormally high or low and may provide a clue as to the presence of a septic process. Most often, however, it is normal.

2. (B) Urine obtained in a sterile plastic bag is often contaminated with minute amounts of stool even after attempted cleaning. Because there are large amounts of bacteria in stool, it takes only minuscule contamination of the bagged specimen to yield a “positive” culture result. Any positive culture from this bag must be confirmed by obtaining a specimen of bladder urine before a diagnosis of UTI can be made. The best specimens are those obtained by bladder puncture or catheterization. Bladder urine should be sterile (see answer 14 for more details).

3. (A) The frequency of anatomic abnormalities of the urinary tract that may require urologic intervention or long-term antimicrobial prophylaxis is sufficiently high to warrant radiologic assessment after even the first well-documented UTI; in the neonatal period, a renal and bladder ultrasound (US) plus VCUG are obtained. Oral antimicrobial therapy in the neonatal period is generally avoided because of the few data available regarding absorption or outcomes. Sulfonamides may promote hyperbilirubinemia and are also to be avoided in this age group. The less invasive ultrasound has replaced IVP for evaluation of the upper urinary tract but offers no genderspecific advantage.

4. (A) Dysuria is frequent, perhaps the most frequent, clinical symptom. Uncircumcised boys are at increased risk compared with circumcised boys, but all boys are at substantially less risk than females in this age group. Fever is usually absent or low grade. High fever accompanied by symptoms and signs of UTI implies pyelonephritis.

5. (D) Asymptomatic bacteriuria occurs in about 1% of healthy school girls. The link between it and endstage pyelonephritis has never been convincingly established. Most experts do not believe antimicrobials should be routinely prescribed when asymptomatic bacteriuria is discovered. Careful questioning should be performed, however, to ensure that the patient is truly asymptomatic. Asymptomatic bacteriuria is often cleared spontaneously.

6. (C) The traditional definition of pyuria has been more than 5 white blood cells/high power field on centrifuged urine, although modifications have been suggested that can improve the sensitivity and specificity of the test. However, for all ages and for all methods, most children with symptomatic UTI have pyuria. Pyuria is also frequent in patients with Kawasaki disease, measles, and after exercise, however.

7. (C) The nitrite dipstick test is highly specific (approximately 98%) for UTI although not reliably sensitive (approximately 50%). It depends on bacteria (gram negatives such as E coli, Klebsiella pneumoniae, and Proteus spp.) converting dietary nitrates to nitrites in the urine specimen and requires a more than 4-hour incubation in the bladder for the reaction to occur. Young children with small bladders frequently void more often. Grampositive bacteria like enterococci do not perform the chemical reaction, and thus the test will not be positive when a gram-positive species is the cause. Urine pH also may be useful in diagnosing UTIs. Urease-producing organisms (eg, Proteus mirabilis, some strains of Staphylococcus saprophyticus) degrade urea into ammonia, resulting in a high urine pH (8.0-8.5).

8. (B) LE has about 80% sensitivity depending on the clinical setting. The specificity is lower, however, because pyuria may yield a positive test (see answer 6). The test is performed only on urine and has no value in the detection of mercury.

9. (D) There is no reason to believe that anyone else in the house is at risk from the patient’s E coli UTI. Amoxicillin is a poor choice because about half of E coli isolates may be resistant. Single-dose therapy of UTI in children has been largely abandoned despite a flurry of onetime interest because the rate of recurrence is unacceptably high. Radiologic studies should be performed in children with a first well-proven UTI. In general, most practitioners perform US and VCUG in a boy of any age with a first UTI, girls younger then 3 with a first UTI, children of any age and gender with a febrile UTI, recurrent UTI, or a UTI with either symptoms referable to the kidney (poor growth, hypertension, abnormal voiding) or a family history of renal disease. A child who has a UTI with fever has a 30-50% likelihood of having underlying vesicoureteral reflux (VUR).

10. (E) There is no convincing relationship between reflux and renal scarring, but most experts advocate antimicrobial prophylaxis for patients like this. Amoxicillin is a poor choice for prophylaxis (except in neonates where its side-effect profile is preferred) because enteric organisms have unacceptably high rates of resistance and thus failures are too common. Nitrofurantoin, sulfisoxazole, and trimethoprim-sulfamethoxazole are acceptable choices; no choice will prevent all breakthroughs. Most children with mild to moderate VUR (grades I to III; see Figure 121-1) do spontaneously remit (approximately 80% within 5 years), and thus are not usually initially managed with either subureteric transurethral injection (STING procedure) or open surgical reimplantation. Results with the noninvasive, ambulatory STING procedure are good, although they drop off at higher levels of reflux (Table 121-1), which are the grades of reflux most often requiring surgical intervention. In the STING procedure, a copolymer substance is injected beneath the mucosa of the ureterovesical junction through a cystoscope.

art

FIGURE 121-1. Vesicoureteral reflux. Drawings illustrate the five grades (I-V) of vesicoureteral reflux.

TABLE 121-1


GRADE VUR	SUCCESS RATE WITH STING PROCEDURE

1, 2	79%
3	72%
4	63%
5	51%

Abbreviations: STING, subureteric transurethral injection; VUR, vesicoureteral reflux.

11. (A) Despite the widely held views that all of the choices increase the incidence of UTI, evidencebased data exist to support the relationship between constipation and increased UTI incidence only. Although the other items are frequently advocated by pediatricians, convincing data to support their etiologic relationship are lacking.

12. (B) Either by mechanical irritation or by other less well understood mechanisms, pinworms, insertion of foreign bodies into the urethra, and cyclophosphamide can all cause cystitis with symptoms of urgency, frequency, and dysuria. Ibuprofen is the exception. Although a wide variety of toxicities are associated with ibuprofen, cystitis has not been described.

13. (E) Although some experts point to the modest in vitro activity of cefazolin against gram negatives, most experts do not rely on this activity for effective therapy for serious infections such as pyelonephritis that are frequently caused by gram negatives. Pseudomonas is an unusual cause of UTI and generally not included as an initial target of pyelonephritis therapy. Thus there is no need for ceftazidime. In children, most practitioners would admit and use parenteral antibiotics (often a thirdgeneration cephalosporin). Again, local bacterial susceptibilities should guide empirical selections.

14. (D) In theory, no bacteria should be recoverable from urine from a bladder catheterization obtained by sterile technique or from a bladder aspiration. Some clinical microbiology laboratories have introduced a margin of error and use a cutoff of less than 10,000 bacteria per milliliter as a negative culture on bladder urine. Traditionally, more than 100,000 bacteria per milliliter is used as a predictor of bladder infection, although this value was derived from studies done among healthy, asymptomatic adult women. Some have argued that in a symptomatic person (ie, one with dysuria for example), a lower bacterial density (eg, 10,000-100,000) may reflect bladder colonization. Mixed bacterial cultures generally reflect urethral contamination and not any specific disease process, whereas renal and perinephric abscess can be insidious but often present similar to acute pyelonephritis with fever, flank pain, abdominal pain, dysuria, and/or frequency and may be resistant to typical attempts at treatment. See answer 2 for more detail.

15. (D) Sexual intercourse and use of a diaphragm with spermicide both increase the risk of UTIs among sexually active females. Neither ingestion of any particular food nor infectious mononucleosis have any demonstrated association with UTIs.

SUGGESTED READING

Elder JS, Diaz M, et al. Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I. Reflux resolution and urinary tract infection. J Urol. 2006;175:716-722.

Gorelick MH, Shaw KN. Screening tests for urinary tract infection in children: a meta-analysis. Pediatrics. 1999;104:E54.

Hoberman A, Charron M, Hickey RW, et al. Imaging studies after a first febrile urinary tract infection in your children. N Engl J Med. 2003;348:195-202.

Practice parameter. The diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. American Academy of Pediatrics. Committee on Quality Improvement. Subcommittee on Urinary Tract Infection. [published corrections appear in Pediatrics 105:141, 2000, 103:1052, 1999, and 104:118, 1999]. Pediatrics. 1999;103(Pt 4 1):843-852.

Report of the International Reflux Study Committee. Medical versus surgical treatment of primary vesicoureteral reflux. Pediatrics. 1981;67:392-400.

CASE 122: A 4-MONTH-OLD BOY WITH POOR WEIGHT GAIN, IRRITABILITY, AND LOW URINE OSMOLALITY

A 4-month-old male infant presents with a history of poor weight gain and irritability. He was born at term by vaginal delivery with a birthweight of 3.5 kg. He was breast-fed for 3 months and appeared to have satisfactory weight gain initially. He was then switched to formula feeds, which he has been taking well. Mom says his diapers are always soaking wet. His development has been normal and his immunizations are up to date.

On examination you find an infant who is thin with weight below the 5th percentile and height on the 25th percentile. He appears to be irritable. He has a mildly sunken anterior fontanel, an umbilical hernia, and mild bilateral tibial curvature.

Laboratory studies show the following:

Hemoglobin	10.8 g/dL
Hematocrit	32.9%
Blood urea nitrogen (BUN)	17 mg/dL
Serum creatinine	0.5 mg/dL
Serum sodium	148 mEq/L
Serum potassium	3.7 mEq/L
Serum chloride	114 mEq/dL
Serum bicarbonate	20 mEq/dL
Serum calcium	9.8 mg/dL
Serum phosphorus	5.5 mg/dL
Serum alkaline phosphatase	360 U/L
Serum magnesium	1.9 mg/dL
Serum glucose	72 mg/dL
Urine specific gravity	1005
Urine pH	6.8
Urine osmolality	198 mOsm/kg of H₂O

SELECT THE ONE BEST ANSWER

1. The serum osmolality in this patient is

(A) 296

(B) 302

(D) 300

(E) none of the above

2. The most likely cause for this infant’s failure to thrive is

(A) metabolic acidosis because of renal tubular acidosis and urinary concentration defect

(B) nephrogenic diabetes insipidus

(D) Gitelman syndrome

(E) Liddle disease

3. Other laboratory investigations that may be helpful include

(A) spot urine calcium-to-creatinine ratio

(B) serum vasopressin levels

(D) B and C

(E) A, B, and C

4. This disease is most commonly inherited as

(A) an autosomal recessive disorder

(B) an autosomal dominant disorder

(D) an X-linked dominant disorder

(E) none of the above

5. This condition is most appropriately treated with

(A) low-solute diet

(B) thiazide diuretics with amiloride and prostaglandin-synthesis inhibitors, such as indomethacin

(D) all of the above

(E) A and C

6. Urine osmolality in this patient is measured to determine

(A) urine osmolal gap

(B) urine anion gap

(D) none of the above

(E) A and B

7. Urine osmolality should be measured in the urine

(A) in all patients routinely

(B) if a urinary concentration defect is suspected

(D) all of the above

(E) B and C

8. Normal range of urine osmolality in a child is

(A) 200-1200 mOsm/kg of H₂O

(B) 100-1000 mOsm/kg of H₂O

(D) 400-800 mOsm/kg of H₂O

(E) 300-900 mOsm/kg of H₂O

9. In acquired or secondary nephrogenic diabetes insipidus

(A) aquaporin 5 expression is decreased

(B) aquaporin 2 expression is decreased

(D) aquaporin 1 expression is decreased

(E) aquaporin 4 expression is decreased

10. Secondary diabetes insipidus can be caused by

(A) analgesic nephropathy

(B) amoxicillin

(D) all of the above

(E) A and C

11. Secondary diabetes insipidus occurs with

(A) obstructive uropathy

(B) chronic renal failure

(D) all of the above

(E) A and C

12. Secondary diabetes insipidus can occur in

(A) hypokalemia

(B) hyponatremia

(D) A and C

(E) diabetes mellitus

13. Acquired nephrogenic diabetes insipidus can be caused by all of the following except

(A) sarcoidosis

(B) iron deficiency anemia

(D) nephrocalcinosis

(E) sickle cell anemia and trait

14. Nephrogenic diabetes insipidus can be all of the following except

(A) caused by unresponsiveness of renal tubules to vasopressin

(B) caused by a vasopressin deficiency

(D) an acquired disorder

(E) caused by decreased aquaporin expression

15. Infants with nephrogenic diabetes insipidus can present with all of the following except

(A) failure to thrive

(B) seizures

(D) constipation

(E) dilated ureters

16. Nephrogenic diabetes insipidus in children can cause all of the following except

(A) short stature

(B) mental retardation

(D) microcystis

(E) hyperactivity

17. Children with nephrogenic diabetes insipidus are at risk of developing dehydration with all of the following except

(A) gastroenteritis

(B) low salt intake

(D) exercise

(E) fever

ANSWERS

1. (C) Sodium is the major cation in extracellular water and accounts for most of the plasma osmolality. However, under pathologic conditions, serum urea nitrogen (as in acute renal failure) and glucose (as in diabetic ketoacidosis) can also contribute significantly to the serum osmolality. Therefore, the serum osmolality is calculated as (2 × serum sodium in mEq/L) + (serum glucose in mg/dL/18) + (BUN in mg/dL/2.8). The serum osmolality in this patient is (2 × 148) + (72/18) + (17/2.8) = 306 (normal range: 285-295).

2. (B) This infant does not have renal tubular acidosis and metabolic acidosis because the serum bicarbonate of 20 mEq/L is in the normal range for infants (20-24 mEq/L). This is one of the typical presentations of congenital nephrogenic diabetes insipidus. Urine specific gravity and osmolality are low with borderline high serum sodium. An initial diagnosis of diabetes insipidus can be made with measurement of paired urine and plasma osmolality. A high serum osmolality with low urinary osmolality (< 200 mOsm/kg H₂O) provides evidence for a renal urinary concentration defect. This infant was initially breast-fed on demand but changed to fixed intervals while on formula. Had breastfeeding on demand continued, the infant would have received enough free water to continue to gain weight because human breast milk has low salt and protein content, and therefore there is less osmolar load in the glomerular filtrate requiring less obligate water loss in the urine. Demand breastfeeding would have provided adequate fluid intake appropriate to thirst. When switched to formula feeds, however, the baby was on a fixed volume of feeds at 120-150 mL/kg per day. Cow’s milk has a higher solute and protein load that would lead to greater urinary osmolar load and greater free water losses. Weight loss and failure to thrive are the result.

Bartter syndrome is characterized by a defect in the Na-K-2Cl cotransporter in the ascending limb of the loop of Henle, leading to loss of sodium (Na), potassium (K), and chloride (Cl) in the urine and hypokalemic hypochloremic metabolic alkalosis. This infant does not have metabolic alkalosis.

Gitelman syndrome occurs in older children and is a result of a defect in the Na-Cl cotransporter in the distal convoluted tubule, leading to a loss of Na, K, and Cl in the urine and hypokalemic hypochloremic metabolic alkalosis as well as hypomagnesemia, a result of increased urinary magnesium loss.

Liddle syndrome occurs in adolescents and adults and is caused by upregulation of the epithelial sodium channel (ENaC) in the principal cell of the cortical-collecting duct. It leads to excessive sodium absorption with hypokalemia due to increased Na-K exchange and K loss in the urine. Hypertension is a result of volume expansion.

3. (D) Nephrogenic diabetes insipidus is characterized by renal tubular insensitivity to antidiuretic hormone (ADH) or arginine vasopressin (AVP); therefore vasopressin levels are normal or may even be slightly increased in these patients. A vasopressin test may be performed and consists of intranasal administration of a single dose of DDAVP (1-desamino-8-D-arginine vasopressin) followed by urine collection over the next 5¹/₂hours. Patients with nephrogenic diabetes insipidus fail to concentrate their urine and the urine osmolality remains low, usually 200 mOsm/kg H₂O or less.

4. (C) Congenital nephrogenic diabetes insipidus (NDI) is inherited, most commonly (about 90%) as an X-linked recessive disorder, and therefore unaffected female carriers transmit the disease to their sons. This usually results in episodes of hypernatremic dehydration during infancy. One common presentation is failure to thrive when an infant is switched from breast milk to formula feeds. Rare cases (about 10%) have been described that are a result of mutations in the aquaporin water channel gene as an autosomal recessive or autosomal dominant disorder. Patients with this mutation present with hypokalemia. Associated conditions include renal dysplasia, obstructive uropathy, chronic renal failure, chronic pyelonephritis, sickle cell anemia and trait, analgesic nephropathy, and persons on lithium therapy.

5. (D) Free water replacement is the most important part of the treatment of NDI. Because this can be difficult in infants, a low-solute diet to decrease obligate free water losses in the urine by decreasing the urine osmolar load is prudent.

Thiazide diuretics and dietary salt restriction can decrease the urine volume up to 50% but need supplementation of diet with K because they can cause hypokalemia. A combination of a thiazide diuretic with another diuretic like amiloride that acts on ENaCs in the principal cell of the cortical collecting duct is K sparing and effective. Thiazide diuretics have also been used in combination with prostaglandin synthesis inhibitors such as indomethacin as an effective regimen in decreasing the urine output in NDI.

6. (C) In this patient, hypernatremia with low urine specific gravity is suggestive of a urinary concentration defect, and therefore a simultaneous plasma and urine osmolality would be necessary to make the diagnosis of diabetes insipidus. Urine osmolality can also be measured to determine the urine osmolal gap. This is the measured urine osmolality minus the calculated urine osmolality (based on the formula: [2 × urine sodium in mEq/L] + [glucose in mg/dL/18] + [urea in mg/dL/2.8]). The difference should be a positive number (because the measured osmolality is higher than the calculated osmolality) and under most circumstances represents the amount of ammonium chloride being excreted in the urine. Thus this calculation measures the amount of ammonium excreted in the urine in patients who are suspected to have renal tubular acidosis. However, in this patient, we are suspecting diabetes insipidus, not renal tubular acidosis.

7. (E) Routine urinalysis does not include measurement of urine osmolality. Indications for measuring osmolality are a suspected urinary concentration defect as in diabetes insipidus or a need to calculate the urine osmolar gap as described in the answer to question 6.

8. (C) The normal range of urine osmolality in a child is 50-1400 mOsm/kg; in an infant it is 50-600 mOsm/kg H₂O.

9. (B) The aquaporin 2 (water channel) is normally present in the principal cell of the cortical collecting duct and leads to water reabsorption under the effect of vasopressin. In secondary NDI, the expression of aquaporin 2 is decreased and leads to impaired water absorption.

10. (E) Secondary NDI can be caused by lithium, colchicine, radiocontrast agents, vinblastine, analgesic nephropathy, and tetracyclines.

11. (D) Secondary NDI can occur in chronic renal disease, such as chronic renal failure, chronic pyelonephritis, polycystic kidney disease, medullary cystic disease, uric acid, or calcium nephropathy.

12. (D) Acquired or secondary NDI occurs with electrolyte disorders such as hypokalemia and hypercalcemia and is a common metabolic abnormality associated with a urinary concentration defect.

13. (B) Acquired NDI can be caused by diseases such as sickle cell anemia, adrenal insufficiency, sarcoidosis, amyloidosis, and nephrocalcinosis. It can also occur with protein starvation.

14. (B) NDI can be familial or acquired. There are 2 types of familial NDI. The most common is a mutation in the gene encoding vasopressin receptor V2 in the renal tubular cells, an X-linked recessive disorder. Less common is a mutation in the gene encoding the vasopressin-sensitive water channel aquaporin 2 (AQP 2) in the cells of the renal cortical collecting duct and can be an autosomal dominant or recessive disorder. In acquired NDI, there is usually a decrease in AQP 2 abundance. Vasopressin deficiency would be a central and not a nephrogenic cause of diabetes insipidus.

15. (C) Symptoms of NDI include poor feeding, irritability, thirst or eagerness to suck, dehydration, failure to thrive, rarely seizures because of electrolyte imbalance, and constipation. Hydronephrosis and dilated ureters, because of polyuria and consequently increased urine flow, may be present.

16. (D) NDI in children can cause poor growth with short stature. Mental retardation has been reported because of recurrent episodes of dehydration with intracranial calcifications. Polyuria leading to frequent trips to the bathroom with consequent interference with learning has been associated with short attention span, distractibility, and hyperactivity. Increased urine flow in NDI can lead to a large bladder (megacystis), not a small bladder (microcystis).

17. (B) All of these can lead to increased fluid and free water loss except for low salt intake, which is a therapeutic option for NDI. A high salt intake would lead to increased obligatory free water loss and therefore worsening of the symptoms.

SUGGESTED READING

Knoers NVAM, Monnens LAH. Nephrogenic diabetes insipidus. In: Anver ED, Harmon WE, Niaudet P, eds. Pediatric Nephrology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009.

CASE 123: AN 8-MONTH-OLD BOY WITH VOMITING AND WEIGHT LOSS

An 8-month-old male infant presents to the emergency department with vomiting and weight loss of several days’ duration. He has also had some loose stools. There is no history of fever. A systematic inquiry is noncontributory. He was born at term by normal vaginal delivery with a birthweight of 3.6 kg (50th percentile) and a length of 51 cm (>50th percentile). His development has been normal and his immunizations are reported to be up to date.

On examination you find a thin infant with mild dehydration. He is irritable. His weight now is 7.8 kg (on 5th percentile) and his height is 68 cm (just below the 25th percentile). The remainder of the examination is unremarkable.

Laboratory results are as follows:

Hemoglobin	10.8 g/dL
Hematocrit	32.5%
BUN	8 mg/dL
Serum creatinine	0.3 mg/dL
Serum sodium	137 mEq/L
Serum potassium	3.2 mEq/L
Serum chloride	110 mEq/L
Serum bicarbonate	16 mEq/L
Serum calcium	8.9 mg/dL
Serum phosphorus	4.6 mg/dL
Serum magnesium	1.9 mg/dL
Urine pH	5.4
Urine specific gravity	1.020
Urine sodium	44 mEq/L
Urine potassium	23 mEq/L
Urine chloride	47 mEq/L
Urine glucose	Negative

Arterial blood gas results:
pH	7.32
Pco₂	34
PO₂	96
BE	2
HCO₃	16

BE, base excess; HCO₃, bicarbonate; Pco₂, partial pressure of carbon dioxide; Po₂, partial pressure of oxygen.

SELECT THE ONE BEST ANSWER

1. This infant has a

(A) high anion gap metabolic acidosis

(B) non–anion gap metabolic acidosis

(D) mixed metabolic and respiratory acidosis

(E) none of the above

2. The urine anion gap is calculated as follows

(A) urine sodium (mEq/L) + urine potassium (mEq/L) − urine chloride (mEq/L)

(B) urine sodium (mEq/L) − urine chloride (mEq/L)

(D) urine sodium (mEq/L) + urine potassium (mEq/L) − urine chloride and bicarbonate (mEq/L)

(E) there is no such thing as a urine anion gap

3. The urine anion gap in this case is

(A) positive and abnormal

(B) negative and normal

(D) not possible to calculate because of insufficient data

(E) none of the above

4. This infant has

(A) non–anion gap metabolic acidosis because of gastroenteritis and dehydration (the urine anion gap is suggestive of increased urinary ammonium excretion)

(B) non–anion gap metabolic acidosis because of proximal renal tubular acidosis (the urine anion gap is suggestive of increased urinary ammonium excretion)

(D) non–anion gap metabolic acidosis because of gastroenteritis and dehydration because the urine anion gap is suggestive of decreased urinary ammonium excretion

(E) none of the above

5. Another investigation that may be helpful is

(A) spot urine protein-to-creatinine ratio

(B) radiograph of the long bones

(D) computed tomography (CT) scan of the head

(E) magnetic resonance imaging (MRI) scan of the brain

6. This child’s condition can present as

(A) an autosomal dominant disorder inheritance pattern

(B) an autosomal recessive disorder inheritance pattern

(D) all of the above

(E) none of the above

7. The long-term treatment of this child should consist of

(A) dietary sodium restriction

(B) oral sodium citrate or bicarbonate with or without potassium citrate

(D) all of the above

(E) A and B

8. All of the following are recognized types of renal tubular acidosis (RTA) except

(A) type I RTA

(B) type II RTA

(D) type IV RTA

(E) none of the above (all of the above are recognized types of RTA)

9. Which type of renal tubular acidosis causes hyperkalemia?

(A) type I RTA

(B) type II RTA

(D) type IV RTA

(E) none of the above

10. Which type(s) of renal tubular acidosis cause(s) hypokalemia?

(A) type I RTA

(B) type II RTA

(D) type IV RTA

(E) A and B only

11. Rickets can accompany

(A) type I RTA

(B) type IV RTA

(D) None of the above

(E) A and C only

12. Nephrocalcinosis occurs

(A) more commonly in type I RTA

(B) more commonly in type II RTA

(D) only in type I RTA

(E) commonly in type II and IV but never in type I RTA

13. All of the following can cause type II or proximal RTA except

(A) valproic acid

(B) penicillin

(D) mercaptopurine

(E) sulfonamides

14. All of the following can cause type I or distal RTA except

(A) analgesic abuse

(B) amphotericin B

(D) amoxicillin

(E) vitamin D intoxication

15. Type I or distal RTA can be caused by

(A) a bicarbonate reabsorption defect

(B) a proton pump failure in the cortical collecting duct

(D) all of the above

(E) B and C only

16. Type II or proximal RTA can be caused by

(A) an HCO₃⁻ reabsorption defect

(B) an aldosterone deficiency

(D) insensitivity of the renal cortical collecting duct to aldosterone

(E) proton pump failure in the cortical collecting duct

17. Type IV RTA can be caused by

(A) aldosterone deficiency

(B) a bicarbonate reabsorption defect

(D) all of the above

(E) A and C only

18. Type IV RTA in children that is caused by pseudohypoaldosteronism is best treated with

(A) mineralocorticoid-like fludrocortisone

(B) alkali supplementation

(D) diuretics such as thiazides or furosemide

(E) none of the above

19. Type IV RTA caused by hyporeninemic hypoaldosteronism is best treated with

(A) vitamin D and alkali supplements

(B) mineralocorticoid-like fludrocortisone

(D) angiotensin receptor-blocking agents

(E) none of the above

ANSWERS

1. (B) The serum anion gap is calculated as (serum sodium [cation; mEq/L] − serum chloride [anion; mEq/L] + serum bicarbonate [anion; mEq/L]). The anion gap is this case is [137 − (110 + 16)] = 11. Usually the anion gap is 10, with a normal range of 8-15. The serum chloride concentrate is also high. Therefore, this patient has a normal anion gap or hyperchloremic metabolic acidosis.

2. (A) The urine anion gap (UAG) is calculated as: urine sodium concentration (mEq/L) + urine potassium concentration (mEq/L) − urine chloride concentration (mEq/L). Under normal circumstances, there is minimal HCO₃⁻in the urine. Therefore, it is not included in the equation.

3. (A) The UAG is an indirect measure of ammonium excretion in the urine. This calculation is employed because ammonium is difficult to measure. Ammonium excretion in the urine is one of the ways kidneys excrete protons (H⁺) to maintain acid-base homeostasis. Under normal circumstances, the UAG is a negative number (ie, the sum of the Na and K concentration is less than the Cl concentration) that represents the unmeasured ammonium cation (NH₄⁺, ie, ammonium ion). Ammonium ions constitute almost all of the cations in the urine after Na and K are excluded. In this patient, the UAG is a positive number (+20). This is abnormally high and indicates no ammonium ion or the presence of another anion such as HCO₃⁻ (which has not been measured in the urine). The latter is present in excess in the urine in proximal RTA and is also not measured routinely in the urine. A positive UAG is therefore a result of decreased or impaired production of ammonium and an increased concentration of HCO₃⁻in the urine due to excessive urinary losses. Both changes occur in proximal RTA. Once the serum bicarbonate falls below the renal threshold, bicarbonaturia ceases. The urine pH can then decrease to less than 5.5 as distal acidification in the cortical collecting duct continues to be normal in proximal RTA, which is characterized by HCO₃loss in the urine.

In gastroenteritis, a hyperchloremic metabolic acidosis can also occur and there is no increased serum anion gap (SAG). As a compensatory mechanism, the kidneys, if normal, would excrete more ammonium to excrete protons (H⁺) in an attempt to correct the metabolic acidosis. In this instance, one would expect the UAG to be more negative than normal. For example, the UAG may be more negative (eg, −60 or lower), suggesting increased urinary ammonium excretion.

4. (C) The UAG in this patient is positive (+20), suggesting decreased or absent ammonium in the urine. This suggests proximal RTA because the urine pH is also lower than 5.5, lower than that occurring in distal RTA. Patients with distal RTA have a proton pump disorder in the cortical collecting duct with inability to excrete hydrogen ions, and therefore they are not able to acidify urine to a pH of less than 5.5.

If this normal anion-gap metabolic acidosis were a result of gastroenteritis with normal renal function, one would expect a more negative than normal UAG. Such a finding suggests increased urinary ammonium excretion by the kidneys as a compensatory mechanism to maintain acid-base homeostasis.

5. (C) Nephrocalcinosis occurs commonly with distal RTA and rarely with proximal RTA. In distal RTA, nephrocalcinosis is caused by persistent metabolic acidosis and buffering of the acidosis by bones. Calcium is released into the serum leading to hypercalciuria. There is also decreased citrate excretion in distal RTA. Citrate in the urine inhibits stone formation. These changes in distal RTA make nephrocalcinosis and renal calculus formation more likely in distal RTA. As mentioned, nephrocalcinosis can occur in proximal RTA as well, and therefore a renal ultrasound may be useful in detecting nephrocalcinosis.

6. (D) Proximal RTA can be primary, which includes genetically determined proximal RTA that can be autosomal recessive or dominant. Proximal RTA can also be secondary to several disorders, including metabolic disorders such as cystinosis, galactosemia, glycogen storage disease, and carbonic anhydrase deficiency. It can also be associated with drugs and toxins and heavy metal poisoning including lead toxicity. It can also occur as an isolated bicarbonate reabsorption defect with consequent HCO₃⁻loss in the urine or as a part of Fanconi syndrome, a generalized disorder of proximal tubules leading not only to bicarbonaturia but also glycosuria, aminoaciduria, and phosphaturia.

7. (E) Treatment of both proximal and distal RTA consists of alkali supplementation with either oral sodium bicarbonate or sodium citrate. Citrate is converted to bicarbonate by the liver and therefore requires normal liver function. Because both types of RTA can be associated with hypokalemia, supplementation with potassium citrate or potassium chloride may also be needed. Dietary sodium restriction helps to enhance proximal tubular reabsorption of Na and HCO₃⁻and decreases the alkali supplementation requirements. Prostaglandin synthesis inhibitors are not known to play a role in the treatment of RTA.

8. (C) Type III RTA, originally described as mixed type I and type II RTA, is no longer recognized. In young infants and premature infants there can be a transient physiologic proximal tubular immaturity leading to increased urinary HCO₃⁻losses during infancy. Children with type I RTA resulting from a hydrogen ion secretion defect thus also have increased urinary HCO₃⁻losses. Therefore the term mixed or type III RTA was used in the older literature. However, this bicarbonaturia tends to resolve as the tubules mature but the distal acidification defect persists. Therefore the patients who were first described as having mixed RTA were actually children with distal RTA and a physiologic proximal tubular immaturity that resolved with time.

9. (D) Only type IV RTA causes hyperkalemia. In children, this could be the result of pseudohypoaldosteronism (with normal or high serum aldosterone levels but insensitivity or relative lack of aldosterone receptors in the principal cell of the cortical collecting duct, hence the term pseudohypoaldosteronism) and in adults because of mineralocorticoid deficiency as a result of hyporeninemic hypoaldosteronism. Other causes of hypoaldosteronism leading to type IV RTA include Addison disease, congenital adrenal hyperplasia, and effects of drugs such as ACE inhibitors, heparin, and cyclosporine.

10. (E) Hypokalemia occurs with type I and II RTA. In type I RTA there is a proton pump disorder with failure of hydrogen ion excretion. Therefore another cation must be excreted with the anions delivered in the filtrate to the cortical collecting duct; this cation is usually K. In type II RTA there is an excess of urine anions (HCO₃⁻in this case) that have to be excreted in combination with cations like K. This leads to increased excretion of K in the cortical collecting duct and hypokalemia. Both primary type I and II RTA can have autosomal recessive or autosomal dominant inheritance. Patients with both type I and II RTA can present with vomiting, anorexia, constipation, polyuria, polydipsia, or growth retardation. Both conditions have associated hypokalemia with muscle weakness.

11. (E) Rickets can occur in both type I and type II RTA. It is not seen in type IV RTA.

12. (A) Although nephrocalcinosis can occur in both type I and type II RTA, it is much more common in type I RTA (distal RTA). This is because of the following:

1. Persistent metabolic acidosis, which is seen in type I RTA compared with type II (proximal RTA) where blood pH tends to fluctuate more than in type I RTA.

2. Increased serum calcium because of calcium released from the bone as a result of buffering of persistent metabolic acidosis by the bones.

3. Decreased citrate excretion in the urine or hypocitraturia because of the distal tubular defect in type I RTA. Citrate and magnesium in the urine are known inhibitors of stone formation. In type I RTA, the previously mentioned factors lead to an increased incidence of nephrocalcinosis.

13. (B) Penicillin does not cause type II or proximal RTA.

14. (D) All of the mentioned drugs except amoxicillin can cause type I or distal RTA.

15. (E) An HCO₃reabsorption defect occurs in type II or proximal RTA, whereas type I or distal RTA can be caused by a proton pump failure or back leak of excreted proton (hydrogen ion) into the cells of the cortical collecting duct. This back-leak phenomenon typically occurs in the RTA that occurs with amphotericin therapy.

16. (A) Type II or proximal RTA can result from an isolated defect in proximal tubular HCO₃⁻absorption, or it can be caused by a bicarbonate reabsorption defect as a part of generalized proximal tubular disorder with aminoaciduria, glycosuria, and phosphaturia (seen in Fanconi syndrome).

17. (E) Type IV or hyperkalemic RTA can result from pseudohypoaldosteronism (because of insensitivity of renal tubular cells to aldosterone), as commonly seen in children, or as a result of aldosterone deficiency from various causes in children and adults. A common associated finding in adults with hyporeninemic hypoaldosteronism is seen in elderly diabetic patients as a result of hypofunction of the juxtaglomerular apparatus and consequent hyporeninemia and hypoaldosteronism. An example of hypoaldosteronism in children is congenital adrenal hyperplasia.

18. (D) In type IV RTA secondary to pseudohypoaldosteronism, there is insensitivity of the cortical collecting duct cells to aldosterone. Serum aldosterone levels are normal or high. Therefore mineralocorticoid therapy would not help. These patients are best treated with diuretics such as loop diuretics like furosemide and/or distal tubular diuretics like thiazides. These diuretics help improve hyperkalemia by delivering an excess of Na in the filtrate to the cortical collecting duct. This increased Na concentration in the urinary filtrate with a consequent increase in the Na gradient leads to K-Na exchange in the cortical collecting duct with consequent increased K excretion in the urine.

19. (B) Hyporeninemic hypoaldosteronism occurs in elderly diabetic patients as a result of the dysfunction of juxtaglomerular apparatus, and it is best treated with mineralocorticoids like fludrocortisone.

SUGGESTED READING

Abelow B, ed. Understanding Acid-Base. Baltimore, MD: Williams and Wilkins; 1998.

Gennari FJ, ed. Medical Management of Kidney and Electrolyte Disorders. New York, NY: Marcel Dekker; 2001:201-202.

Herrin JT. Renal tubular acidosis. In: Anver ED, Harmon WE, Niaudet P, eds. Pediatric Nephrology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009.

CASE 124: A 7-YEAR-OLD WITH ENURESIS

A 7-year-old white girl has a history of bedwetting. According to Mom, her daughter was born by normal vaginal delivery at term and had an uneventful neonatal period. She was out of pull-ups during the day at 2 years of age. She currently wets the bed almost every night. However, she did have a 2-month period of dry nights with occasional wettings between 5 and 6 years of age. In the daytime, she tends to have urgency and frequency of micturition with occasional dribbling of urine on the way to the bathroom. She tends to have increased fluid intake on occasions. Mom has also noticed small round stains of urine on her underwear. There is no history of UTIs. The child’s school performance has been satisfactory. The family moved to Chicago 6 months ago, and there are no other recent significant events in the family. The family history is negative apart from a history of bedwetting in the father as a child.

Her physical examination, apart from palpable fecal masses in the left iliac fossa and suprapubic areas, is unremarkable. There is a sacral dimple with no hairy patch. Her deep tendon reflexes are normal, and there is no leg length discrepancy or wasting of muscles in either lower extremity.

The results of laboratory tests are as follows:

Urinalysis:
Specific gravity	1025
pH	5.0
Protein	Negative
Blood	Negative
Glucose	Negative
Urine C & S	Negative
Hemoglobin	12.5 g/dL
Hematocrit	37%
BUN	10 mg/dL
Creatinine	0.6 mg/dL
Serum sodium	145 mEq/L
Serum potassium	4.3 mEq/L
Serum chloride	110 mEq/L
Serum bicarbonate	23 mEq/L
Serum glucose	95 mg/dL
C & S, culture and sensitivity.

SELECT THE ONE BEST ANSWER

1. This girl has enuresis by definition because

(A) daytime bladder control is usually achieved at 5 years of age and nighttime control at 6 years of age for a girl

(B) daytime bladder control is usually achieved at 2 years of age and nighttime control at 5 years of age for a girl

(D) daytime bladder control is usually achieved at 6 years of age and nighttime control at 8 years of age for a girl

(E) daytime bladder control is usually achieved at 6 years of age and nighttime control at 2 years of age for a girl

2. This girl most likely has which of the following?

(A) secondary daytime and nighttime enuresis and constipation

(B) primary nocturnal enuresis with daytime detrusor hyperactivity and constipation

(D) nephrogenic diabetes insipidus

(E) central diabetes insipidus

3. The prevalence of this condition at this age is

(A) 6-9%

(B) 10-15%

(D) 40%

(E) 1-5%

4. The differential diagnosis of this condition in this girl includes all except

(A) new-onset diabetes mellitus

(B) obstructive sleep apnea

(D) posterior urethral valves

(E) spina bifida occulta

5. Further investigations that must be performed in this patient at this point include

(A) renal US

(B) VCUG

(D) all of the above

(E) none of the above

6. The risk of occurrence of enuresis in a child is

(A) 44% if one parent had the condition or 77% if both parents had the condition as a child

(B) 15% if one parent had the condition or 25% if both parents had the condition as a child

(D) 0% if one parent had the condition or 15% if both parents had the condition as a child

(E) 0% if one parent had the condition or 50% if both parents had the condition as a child

7. Which of the following pharmacologic agents would most likely help this child’s symptoms?

(A) oxybutynin chloride

(B) imipramine

(D) A and C only

(E) none of the above

8. All of the following nonpharmacologic methods can also be tried in this child except

(A) fluid restriction in the evenings

(B) regular punishment for every wet night

(D) voiding before bedtime

(E) acknowledging to the child that parents understand that bedwetting is not being done intentionally (demystification)

9. The most effective treatment for primary nocturnal enuresis with a pure arousal mechanism problem or monosymptomatic nocturnal enuresis is

(A) intranasal or oral DDAVP

(B) imipramine

(D) an enuresis alarm program

(E) chiropractic manipulation

10. Primary nocturnal enuresis can be associated with

(A) abnormal arousal-from-sleep mechanism

(B) nighttime wetting with daytime detrusor hyperactivity or uninhibited bladder contractions

(D) A and B only

(E) all of the above

11. Nocturnal enuresis can be inherited as an

(A) autosomal recessive disorder

(B) autosomal dominant disorder

(D) all of the above

(E) none of the above

12. An enuresis gene has been identified on

(A) chromosome 12

(B) chromosome 13

(D) all of the above

(E) there is no enuresis gene

13. Primary nocturnal enuresis can be associated with

(A) nocturnal detrusor hyperactivity

(B) nocturnal polyuria

(D) all of the above

(E) A and B

14. The spontaneous annual resolution rate of monosymptomatic nocturnal enuresis is

(A) 25%

(B) 30%

(D) 35%

(E) 40%

15. Functional bladder capacity in a normal child in ounces is usually

(A) age + 2

(B) age + 8

(D) age + 4

(E) age + 9

16. Nocturnal detrusor hyperactivity occurs in

(A) 50% of all children with nocturnal enuresis

(B) 10% of all children with nocturnal enuresis

(D) 30% of all children with nocturnal enuresis

(E) 5% of all children with nocturnal enuresis

17. Enuresis may be associated with all of the following except

(A) food allergies

(B) constipation

(D) ADHD (attention deficit hyperactivity disorder)

(E) asthma

ANSWERS

1. (B) Daytime bladder control is usually achieved by 2 years when the child learns to inhibit unwanted detrusor contractions during the day. Nighttime bladder control is usually achieved by 5 years in girls and 6 years in boys. Late achievement of nighttime control in boys is attributed to mild developmental lag in boys. Enuresis needs to be differentiated from urinary incontinence. Enuresis is defined as involuntary discharge of urine without any underlying anatomic abnormality, whereas urinary incontinence is involuntary discharge of urine associated with an underlying structural abnormality.

2. (B) Three groups of patients with primary nocturnal enuresis are now described:

1. Patients with a pure arousal mechanism problem

2. Patients with a nighttime arousal problem and daytime detrusor hyperactivity

3. Patients with a nighttime arousal problem with nighttime polyuria or nocturia

Monosymptomatic nocturnal enuresis with arousal mechanism problem is a result of failure of the locus ceruleus in the rostral pons to awaken the child in response to a full bladder. These children have normal voiding otherwise.

The term nonmonosymptomatic nocturnal enuresis refers to these same children who in addition to arousal mechanism problems have coexistent daytime symptoms of urgency or voiding dysfunction because of detrusor hyperactivity and/or nocturnal polyuria.

Enuresis is “primary” if the child has never had a more than 6-month period of dry nights and “secondary” if the child, after being dry for more than a 6-month period, starts to have bedwetting again.

3. (B) The prevalence of primary nocturnal enuresis is 10-15% at 6 years of age. There is a 10-15% spontaneous remission rate annually every year leading to a prevalence of 5% at 10 years of age and 1% at 15 years of age and beyond. Thus it is important to remember that 1% of adults continue to have the problem.

4. (D) All of these conditions can cause bedwetting in a child. However, this patient is a girl, and posterior urethral valves are seen almost exclusively in boys.

Differential diagnosis includes new-onset diabetes mellitus, diabetes insipidus, spina bifida occulta, obstructive sleep apnea, urinary tract infection, vulvovaginitis, posterior urethral valves in boys, chronic renal failure, and central nervous system tumors.

Clinical examination and history should be specifically focused on looking for evidence of constipation, abdominal masses, palpable bladder, high plantar arch, or hammer toes with asymmetric atrophy of lower extremities suggestive of spina bifida occulta, as well as examination of spine and genitalia.

5. (E) In this patient the history is very suggestive of primary nocturnal enuresis with daytime detrusor hyperactivity and there is no history of UTIs. Therefore, none of these investigations are indicated. Generally a urinalysis, urine culture, complete blood count, and assessment of renal function with serum BUN, creatinine, and an electrolyte determination is sufficient to rule out UTI and renal functional impairment. The sacral dimple without a hairy patch may be a normal finding in such a patient. However, a sacral dimple with a hairy patch may also be associated with spina bifida occulta, which could potentially cause bladder dysfunction as a result of a tethering of the spinal cord with consequent enuresis. A sacral dimple with a hairy patch should be investigated with an MRI to look for spina bifida occulta.

6. (A) In primary enuresis, if one parent had enuresis as a child, the risk of the offspring having enuresis is 43% if the father was affected or 44% if the mother was affected as a child. The risk is 77% if both parents were affected during childhood. Enuresis is more common in boys and first-born children.

Multiple factors including genetic factors may be responsible for primary nocturnal enuresis. Evidence of genetic susceptibility comes from studies of familial incidence, twin studies, and molecular genetics with linkage analysis. Twin studies show 70% concordance for monozygotic twins and 31% concordance for dizygotic twins. Molecular genetics with linkage analysis has revealed a polymorphism with localization of genes for enuresis on several different chromosomes. Earlier studies localized the gene to the long arm of chromosome 13 (D13S 291 and D13S 263) and the long arm of chromosome 12 (D12S 80 and D12S 43) in 2 different families.

7. (D) Both oxybutynin and tolterodine are anticholinergic drugs that help inhibit unwanted detrusor contractions and increase urethral sphincter tone. Therefore they can potentially help this child’s symptoms. It is important to keep in mind that this child’s constipation should also be treated because both oxybutynin and tolterodine, due to their anticholinergic effect, can make constipation worse. Imipramine has been used to treat primary nocturnal enuresis. It is reported to work through its effect on the arousal mechanism, a decrease in nighttime urinary sodium excretion, a consequent decrease in nocturia, and a weak anticholinergic effect. However its use is limited because of possible significant side effects and a high relapse rate of enuresis once the treatment is stopped. In this patient who has symptoms of detrusor hyperactivity, imipramine would not be a treatment of choice.

8. (B) Surprisingly, punishment is still used by a fair number of parents for wetting the bed and has obvious negative consequences. Demystification in the presence of the child with the explanation to the parents that the child is not intentionally wetting the bed has a 15-25% therapeutic effect on the child’s enuresis. Fluid restriction and voiding before going to bed may help augment the effect of other therapeutic modalities. In this patient an enuresis alarm in combination with oxybutynin could prove to be effective provided the child and the parents are motivated to try the enuresis alarm program. A behavioral program is used with the alarm.

9. (D) The enuresis alarm program is the most effective treatment for a child with primary nocturnal enuresis caused by pure arousal mechanism problem with a success rate higher than 90% and a low incidence of relapse compared with pharmacologic therapies. Imipramine, which is seldom used now, has a response rate of 50% with a relapse rate of almost 100% after discontinuation; DDAVP has a response rate of 76% but a relapse rate of 60-100% after discontinuation.

10. (E) As mentioned, primary nocturnal enuresis can be divided into these 3 groups.

11. (B) Primary nocturnal enuresis can be inherited as an autosomal dominant disorder.

12. (D) Genes mediating enuresis have been reported at several loci. Initial molecular genetic methods such as linkage analysis showed foci on chromosomes 13 and 12 in different families. Other studies subsequently showed enuresis gene loci on chromosomes 8 and 22 in other families.

13. (D) Primary nocturnal enuresis is now classified into monosymptomatic nocturnal enuresis with an isolated arousal disorder or non-monosymptomatic nocturnal enuresis where an arousal disorder may be associated with reduced bladder capacity or nocturnal detrusor hyperactivity and/or nocturnal polyuria.

14. (C) Monosymptomatic nocturnal enuresis has an annual spontaneous resolution rate of 15%. Thus for any treatment to be proven effective for enuresis, the rate of resolution of symptoms with the treatment must be higher than this background rate.

15. (A) One formula to estimate bladder capacity in children was described by Berger and coworkers and Koff: Bladder capacity (in ounces) = Age (yr) + 2, up to 15 years of age when the adult bladder capacity is achieved.

16. (D) Nocturnal detrusor hyperactivity is reported to occur in 30% of patients with nocturnal enuresis and is one reason for failure to respond to vasopressin. These patients may need other pharmacologic agents such as oxybutynin or tolterodine to treat detrusor hyperactivity and to improve bladder capacity.

17. (E) Food allergies have been reported to lead to enuresis in 10% of affected patients. Some of these children are reported to benefit from elimination of certain foods from the diet, such as citrus fruit, juices, foods high in caffeine and sugar, dairy products, artificially colored drinks, and chocolate. Constipation can potentially interfere with the bladder function as a result of pressure from constipated stools in the sigmoid colon. Obstructive sleep apnea can cause enuresis (hypoxia and increased atrial natriuretic peptide secretion, leading to nocturia, are the proposed mechanisms). There is a higher incidence of enuresis in children with ADHD.

SUGGESTED READING

Cendron M. Primary nocturnal enuresis: Current concepts. J Am Fam Physician. 1999;59:1205-1214, 1219-1220.

Husmann D. Enuresis. Urology. 1996;48:184-193.

Schmitt BD. Nocturnal enuresis. Pediatr Rev. 1997;18:183-190.

CASE 125: A 6-YEAR-OLD WITH PUFFY EYELIDS AND SWOLLEN LEGS

A 6-year-old Asian American male is admitted for puffiness of the eyelids and swelling of both lower extremities. The illness started 2 weeks before admission with mild puffiness of the eyelids. The eyelid swelling worsened, and 1 week before admission, the patient developed swelling of both lower extremities. The abdomen became protuberant. There is no history of gross hematuria, fever, or anyone in the family receiving regular medications. On physical examination, he was in no acute distress. The temperature was 98.6°F (37°C), heart rate 110/minute, respiratory rate 20/minute, and blood pressure 115/75 mm Hg. The child had anasarca with pitting edema of both lower extremities. The remainder of the physical examination was unremarkable.

The urinalysis revealed a specific gravity of 1.030, pH 5, protein 4+, 5-10 RBC/HPF, 1-2 WBC/HPF, and an occasional coarse granular cast. The BUN was 29 mg/dL. The serum creatinine was 0.8 mg/dL, and the creatinine clearance was 98 mL/minute per 1.73 m². The streptolysin O antibody was less than 200 IU/mL, C₃124 mg/dL (88-155 for age). The antinuclear antibody (ANA) was negative, and the spot urine protein-to-urine creatinine ratio was 8. The blood cholesterol was 520 mg/dL; the total protein was 4.6 g/dL, and the serum albumin was 1.2 g/dL.

SELECT THE BEST ANSWER

1. The urinalysis and blood test data suggest the diagnosis of

(A) acute postinfectious glomerulonephritis

(B) focal segmental glomerulosclerosis (FSGS)

(D) minimal change nephrotic syndrome

(E) B and D

2. The specific gravity of the urine is very high because of

(A) heavy proteinuria

(B) intravascular volume depletion

(D) A and C

(E) A and B

3. Which of the following treatments is not indicated at this time?

(A) pneumococcal vaccine

(B) steroids

(D) aspirin

(E) HMG-CoA reductase inhibitor

4. After 14 days of daily prednisone the proteinuria resolved and the patient lost all evidence of edema. Over the next 12 months, 4 relapses of the nephrotic syndrome occurred. This patient is

(A) likely to become steroid resistant

(B) likely to outgrow the disease

(D) likely to develop premature atherosclerotic heart disease

(E) A and C

ANSWERS

1. (E) This patient has nephrotic syndrome, with heavy proteinuria, low serum albumin, edema, and elevated cholesterol. The 2 most common syndromes in childhood are minimal change nephrotic syndrome (MCNS) and FSGS. They are often clinically indistinguishable at presentation, but MCNS responds to steroids and FSGS rarely does. Responding to steroids remains the best predictor of a good long-term outcome. Twenty percent of patients with MCNS and FSGS have microscopic hematuria. In children with MCNS, 30-40% initially have an elevated serum creatinine, due in part to intravascular hypovolemia. Patients with acute postinfectious glomerulonephritis rarely develop nephrotic syndrome, and like MPGN, this disease is usually associated with a low C₃level.

2. (B) Proteins, especially albumin, have high molecular weights. Therefore heavy proteinuria does not contribute significantly to specific gravity, which is a reflection of osmolality and the contribution of osmotic particles. Patients with nephrotic syndrome have both sodium retention and low intravascular oncotic pressure (as a result of low serum albumin). Thus fluid moves from the intravascular space to the extravascular space. Intravascular volume is depleted. Because these patients may also have prerenal azotemia (volume depletion), the fractional excretion of sodium is low and the urinary sodium concentration is low. However, the release of ADH also increases water reabsorption and the specific gravity of the urine is increased.

3. (C) Prednisone is the cornerstone of treatment in MCNS. If a patient becomes proteinuria free after 2-4 weeks of daily prednisone, the long-term prognosis is excellent. The 2 most serious complications of NS are infectious, especially with Streptococcus pneumoniae and gram-negatives because of defective opsonization of bacteria, and thromboembolic (TE) phenomena that occur secondary to loss of thrombinolytic proteins in urine. So immunization with a pneumococcal vaccine is indicated if a complete PCV-13 course had not been completed earlier. Some nephrologists might consider daily low-dose aspirin (ASA), but if used, ASA is usually reserved for patients with chronic nephrotic syndrome who fail to respond to prednisone and most likely have FSGS. Further anticoagulation is reserved for patients with clinical TE events. Similarly, although hyperlipidemia and its association with cardiovascular disease is a concern, HMG-CoA reductase inhibitors are not part of the initial treatment of nephrotic syndrome but are often considered in steroid nonresponders. Diphenhydramine can help the periorbital swelling caused by allergies. However, in this case, nephrotic syndrome (NS), and not allergy, caused the periorbital swelling.

4. (B) Patients with minimal change MCNS have 1 of 3 clinical courses. A third have 1 episode of NS syndrome, approximately a third have less than 4 relapses per year, and approximately a third have more than 4 episodes per year. All 3 groups have the same favorable outcome as long as they remain steroid responsive; they all “outgrow” the disease. However, frequently relapsing patients are at increased risk of adverse events while nephrotic and from exposure to steroids and other immunosuppressant agents.

SUGGESTED READING

Brodehl J. The treatment of minimal change nephrotic syndrome: Lessons learned from multicentre cooperative studies. Eur J Pediatr. 1991;150:380-387.

Fakhouri F, Bocquet N, Taupin P, et al. Steroid-sensitive nephrotic syndrome: from childhood to adulthood. Am J Kidney Dis. 2003;41:550-557.

Koyama A, Fujisaki M, Kobayashi M, et al. A glomerular permeability factor produced human T cell hybridomas. Kidney Int. 1991;40:453-460.

Sewell RF, Short CD. Minimal-change nephropathy: how does the immune system affect that glomerulus? Nephrol Dial Transplant. 1993;8:108-112.

The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr. 1981;98:561-564.

CASE 126: A 12-YEAR-OLD GIRL WITH SMOKY-COLORED URINE

A 12-year-old girl had a sore throat. Two weeks later, she developed fever, smoky-colored urine, diffuse abdominal pain, and muscle pain. Her urine volume was about a cup for 24 hours.

On physical examination, the blood pressure was 210/130 mm Hg. There was mild facial edema, trace peripheral edema, and marked pallor. The lungs were clear to auscultation, and examination of the heart revealed normal sinus rhythm without any murmur. There was no rash.

The urinalysis revealed a grossly reddish smoky color, specific gravity 1.010, and protein 4+. The serum creatinine was 6.2 mg/dL, Na 135 mEq/L, K 6.5 mEq/L, C1 105 mEq/ L, and total HCO₃19 mmol/L. The antistreptolysin O antibody was more than 1000 IU/mL.

The C₃level was 30 mg/dL (normal: >90 mg/dL), and the ANA was negative.

SELECT THE ONE BEST ANSWER

1. The differential diagnosis includes all except

(A) membranoproliferative glomerulonephritis (MPGN)

(B) acute poststreptococcal glomerulonephritis (APSGN)

(D) subacute bacterial endocarditis (SBE) with immune complex glomerulonephritis

(E) immune globulin (Ig)A nephropathy

2. Treatment at this time consists of all except

(A) volume reduction

(B) vasodilation

(D) dialysis

(E) no exceptions; all are correct

3. Once the blood pressure is adequately controlled and renal function improves, outpatient management includes all except

(A) repeat C₃measurement in 6 weeks

(B) penicillin prophylaxis for dental work

(D) minimize consumption of processed and fast foods

(E) all of the above

ANSWERS

1. (E) MPGN, APSGN, DPLN, and SBE are glomerulopathies associated with low C₃levels. In APSGN, C₃levels normalize without specific treatment within 6 weeks. In MPGN, DPLN, and SBE, C₃levels do not improve without treatment. In IgA nephropathy, C₃levels are normal.

2. (D) If one assumes that a patient with suspected APSGN was normotensive (119/76, 50th percentile 12-year-old girl) before the illness, then a blood pressure acutely rising to 210/130 represents a medical emergency. Blood pressure is determined by cardiac output and vascular resistance. In APSGN, glomerular filtration is reduced and patients are hypervolemic. Rational treatment is volume reduction with diuretics and fluid restriction, but this patient also needs urgent reduction in blood pressure. There is a considerable lag period between volume reduction and a decrease in the blood pressure. Therefore vasodilation is also acutely necessary. If a patient has evidence of active streptococcal infection or has not been treated, penicillin is indicated to decrease the spread of a nephritogenic strain of streptococcus. Close contacts should be evaluated for streptococcal infections as well. Penicillin treatment, however, will not alter the natural history of APSGN once it has developed. Dialysis at this point is not indicated. Most minor electrolyte imbalances can be managed conservatively. Should this patient have intractable hypervolemia with pulmonary edema, hyperkalemia, acidosis, uremia, or uncontrollable hypertension, acute dialysis is indicated.

3. (B) It is important to document that the C₃level returns to normal. This confirms the diagnosis of APSGN and rules out MPGN, DPLN, and SBE. Because only a few strains of group A betahemolytic streptococci are nephritogenic and the patient now presumably has immunity to at least one of these strains, penicillin is not continued as prophylaxis after initial treatment. In children, most cases of APSGN have an excellent prognosis. However, long-term follow-up has revealed an increased incidence of hypertension and other renal sequelae, especially if the initial presentation was associated with severe renal failure. Therefore yearly urinalysis and blood pressure determination should be performed. Avoidance of processed foods and fast foods that contain preservatives is indicated for all children, including those who have had APSGN.

SUGGESTED READING

Lewy JE, Salinas-Madrigal L, Herdson PB, et al. Clinicopathologic correlations in acute poststreptococcal glomerulonephritis: a correlation between renal functions, morphologic damage, and clinical course of 46 children with acute poststreptococcal glomerulonephritis. Medicine (Baltimore). 1971;50:453-501.

Potter EV, Lipschultz SA, Abidh S, et al. Twelve to seventeenyear follow-up of patients with poststreptococcal acute glomerulonephritis in Trinidad. N Engl J Med. 1982;307:725-729.

Tejani A, Ingulli E. Poststreptococcal glomerulonephritis. Current clinical and pathologic concepts. Nephron. 1990; 55:1-5.

CASE 127: A 5-YEAR-OLD BOY WITH BLOODY DIARRHEA AND OLIGURIA

A 5-year-old boy from Houston is vacationing with his parents and 2 siblings in Colorado. They have visited a water slide park. Two days later, the patient developed diarrhea, which turned bloody. The bloody diarrhea was associated with crampy abdominal pain and vomiting. When the vomiting started, the patient was taken to a local emergency department where he was given intravenous (IV) fluids and prescribed loperamide for diarrhea. One day later, the patient returned to the emergency department because he looked pale, became somnolent, and had not urinated for 24 hours.

On physical examination this lethargic and paleappearing 5-year-old had a temperature of 100.4°F (38°C), a pulse of 100 beats/minute, a respiratory rate of 24/minute, and a blood pressure of 128/85 mm Hg. The chest was clear to auscultation and there was mild pretibial edema. The abdominal examination was remarkable for moderate diffuse tenderness without rebound; the liver measured 3 cm below the right costal margin.

The initial laboratory investigations revealed a hemoglobin (Hgb) of 8 g/dL, leukocyte count 17,500 μL, and a platelet count of 21,000/μL; the peripheral blood smear showed 12% schistocytes. The BUN was 35 mg/dL, and the serum creatinine was 2.5 mg/dL. The serum Na was 141 mEq/L, K 5.6 mEq/L, Cl 105 mEq/L, and total HCO₃18 mmol/L. The serum calcium was 8.2 mg/dL, inorganic phosphorus 7.0 mg/dL, and glucose 310 mg/dL. C3 is normal.

During the next 24 hours, the patient’s urinary output decreased to 55 mL/24 hours, with an increase in the serum creatinine to 3.8 mg/dL. Because the patient remained severely oliguric and uremic with symptoms of nausea and vomiting, peritoneal dialysis was started. After 3 weeks of peritoneal dialysis, the urine output rose to 200 mL/24 hours and platelet count increased to 95,000/μL.

SELECT THE ONE BEST ANSWER

1. The prognosis for recovery of renal function is generally favorable. Mortality during the acute illness is less than 5% but increases in the presence of risk factors. This patient’s major risk factor was

(A) leukocytosis

(B) pancreatic involvement with glucose intolerance

(D) initial platelet count 21,000/μL

(E) B and D

2. Although found in other animals, the main vector of E coli O157: H7 is

(A) chicken

(B) dogs

(D) cattle

(E) humans

3. Early treatment of diarrhea with antibiotics in this case

(A) decreases the likelihood that siblings will develop E coli O157:H7 diarrhea

(B) decreases the likelihood that the patient will develop hemolytic-uremic syndrome (HUS)

(D) exacerbates diarrhea

(E) A and B

4. In the present case, which treatment has been shown to be most efficacious?

(A) supportive treatment

(B) plasma infusion and/or plasma exchange

(D) tissue-type plasminogen activator

(E) oral shiga toxin–binding agent

ANSWERS

1. (A) Those children who do not do well during the acute episode of diarrheal-associated hemolytic uremic syndrome (d+HUS) often have one or more risk factors. Risk factors for death in the initial phase are oligoanuria, dehydration, WBC more than 20,000/ mm³, and hematocrit more than 23%. Risk factors for long-term complications of HUS are initial anuria lasting longer than 5 days, oliguria longer than 10 days, WBC more than 20,000/mm³, or histology on biopsy showing microangiopathy of more than 50% of glomeruli, arterial microangiopathy, and/or cortical necrosis. An increased leukocyte count at presentation reflects neutrophil activation resulting from toxin-induced release from monocytes of the neutrophil chemoattractant interleukin 8; these neutrophils may then contribute to tissue damage. Older age at onset of the disease is a risk factor; up to 70% of children 3 years of age or older progress to terminal renal failure. Schistocytes are part of the diagnosis of hemolysis in the syndrome as is uremia. Atypical HUS occurs at all ages, without gastrointestinal symptoms, and often with an insidious onset. A high proportion of these patients have permanent renal sequelae and recurrence after transplant.

2. (D) Although found in other animals, cattle are the main vector of E coli O157:H7, with the bacteria present in the intestine and feces. Infection in humans occurs following ingestion of contaminated, undercooked meat, nonpasteurized milk or milk products, water, fruits, and vegetables.

3. (C) Early administration of antibiotics to children with diarrhea caused by E coli O157:H7 may promote the development of HUS, perhaps by enhancing release of shiga toxin as the bacteria are killed. A prospective study of 71 children younger than 10 years with E coli O157:H7 isolated from stool found that those receiving antibiotics were more likely to develop HUS (5 of 9 [56%] versus 5 of 62 who were untreated [8%], p = 0.002).

4. (A) Four modalities have been tried in the treatment of HUS: plasma infusion and plasma exchange; antithrombotic agents, oral shiga toxin–binding agents, and tissue-type plasminogen activator. Antithrombotic agents based on the histologic evidence of thrombus formation have not been shown to influence duration of renal failure, hemolysis, thrombocytopenia, or long-term outcome. Furthermore, hemorrhagic complications are more common in treated patients. The use of plasma infusion (to supply a missing anticoagulant factor) or plasma exchange with plasma replacement (to also remove procoagulant factors) has been successful in many adults with thrombotic thrombocytopenic purpura (TTP)/HUS, but in children with typical HUS, plasma infusion has not been shown to be beneficial in the long term. A toxin-binding oral agent did not improve clinical outcome in 145 children with HUS. Early research shows restoring or providing tissue-type plasminogen activator (ie, alteplase) may improve renal function. It is difficult to evaluate the efficacy of such treatment in a disease with such a good long-term prognosis (ie, 90% with normal glomerular filtration rate [GFR]). Finally, IV immunoglobulin, possibly by neutralizing antibodies against shiga-like toxins, has not been shown to influence the duration of hemolysis, thrombocytopenia, or acute renal failure.

SUGGESTED READING

Bergstein JM, Riley M, Bang NU. Role of plasminogen-activator inhibitor type 1 in the pathogenesis and outcome of the hemolytic uremic syndrome. N Engl J Med. 1992;327:755-759.

Georgaki-Angelaki HN, Steed DB, Chantler C, et al. Renal function following acute renal failure in childhood: a long-term follow-up study. Kidney Int. 1989;35:84-89.

Gerber A, Karch H, Allerberger F, et al. Clinical course and the role of the Shiga toxin-producing Escherichia coli infection in the hemolytic-uremic syndrome in pediatric patients, 1997-2000, in Germany and Austria: a prospective study. J Infect Dis. 2002;186:493-500.

Neuhaus TJ, Calonder S, Leumann EP. Heterogeneity of atypical hemolytic uremic syndromes. Arch Dis Child. 1997;76:518-521.

Remuzzi G, Ruggenenti P. The hemolytic uremic syndrome. Kidney Int. 1995;48:2-19.

Repetto HA. Epidemic hemolytic uremic syndrome in children. Kidney Int. 1997;52:1708-1719.

Verweyen HM, Karch H, Brandis M, et al. Enterohemorrhagic Escherichia coli infections: following transmission routes. Pediatr Nephrol. 2000;14:73-83.

CASE 128: A 4-YEAR-OLD GIRL WITH A PURPURIC RASH ON THE BUTTOCKS

A 4-year-old girl presents to the emergency department with erythematous maculopapular lesions on the buttocks that extend to the lower extremities and trunk. Initially the lesions blanched on pressure but later became purpuric. As her lower extremities became swollen and painful, her parents brought her to their primary care physician. By the time she was seen by the pediatrician, her chief complaint was severe abdominal pain.

On examination, the temperature was 99.5°F (37.5°C), the pulse was 100 beats/minute, the respiratory rate was 20/minute, and the blood pressure was 110/83 mm Hg. The patient was in moderate distress because of abdominal pain, which was diffuse and intermittent. Palpation of the abdomen revealed a slightly tender sausage-shaped mass in the right upper abdomen. The chest was clear to auscultation, and examination of the heart revealed normal sinus rhythm without a murmur. Examination of the skin over the trunk and buttocks revealed many (10-12) 0.5- to 1-cm purpuric lesions. The patient had mildly swollen ankles and knees with pain on passive movements in all directions.

The urinalysis revealed: specific gravity 1.018, pH 5, protein 3+, 10-20 RBC/HPF, and 5-6 WBC/HPF. The urinary protein-to-creatinine ratio was 1.8. The BUN was 31 mg/dL, the serum creatinine was 0.6 mg/dL, and the Hgb was 11.4 g/dL. The total protein was 6.4 g/dL, the albumin was 3.7 g/dL, and the cholesterol was 151 mg/dL. The C₃was 115 mg/dL, the antistreptolysin O antibody less than 200 IU/ mL, and the ANA 1:40.

SELECT THE ONE BEST ANSWER

1. The first consults to be requested are

(A) intensive care unit (ICU) team

(B) surgery

(D) oncology

(E) nephrology for acute dialysis

2. The renal prognosis in this case

(A) depends on the persistence of hematuria

(B) is excellent because renal function is normal

(D) is guarded because of the presence of hematuria/ proteinuria

(E) is extremely poor (the patient will likely require a kidney transplant)

3. Treatment for significant renal involvement in Henoch-Schönlein purpura (HSP) includes

(A) IV and oral corticosteroids

(B) cyclophosphamide

(D) IV immune globulin

(E) all of the above

ANSWERS

1. (B) HSP is a systemic vasculitis with a prominent cutaneous component. The clinical manifestations include a classic tetrad that can occur in any order and at any time over a period of several days to several weeks: rash, arthralgias, abdominal pain, and renal disease (Table 128-1). The disease is selflimited with an excellent long-term prognosis for most children. Long-term outcome usually depends on the degree of renal involvement. GI symptoms are present in most patients with HSP; initial renal involvement is evident in 20-56% of patients. Treatment is usually supportive, but for severe abdominal pain requiring hospitalization or limiting oral intake, oral steroids are usually tried. For joint involvement, nonsteroidal anti-inflammatory drugs (NSAIDs) are often used, providing there is not renal impairment.

Most concerning in this presentation is the sausage shaped-mass in the right upper quadrant (RUQ) that could represent an intussusception. Intussusception, usually ilio-ilial, is a medical emergency that requires a surgical consult before a diagnostic/therapeutic corrective attempt is performed, if possible, by radiology. There are no indications for an ICU admission or acute dialysis.

TABLE 128-1


CLINICAL FEATURES OF HSP IN CHILDREN (N)	TAIWAN % (261)	ITALY % (150)	UNITED STATES % (100)

Purpura	100	100	100
Arthralgia/arthritis	43	74	82
Abdominal pain	58	51	63
GI bleeding	18	27	33
Intussusception	0.4%	0.6%	NR
Renal involvement	20	56	40
Edema/NS	0.7% NS	52 E, 0.6 NS	3 NS
CNS involvement	1	3	2
Orchitis (% of males)	NR	13	9

Abbreviations: E, edema; NR, not reported; NS, nephrotic syndrome

2. (C) If renal disease will manifest, it is usually noted within a few days to 4 weeks after the onset of systemic symptoms. The urinalysis in affected patients reveals mild proteinuria with an active urinary sediment characterized by microscopic (or gross) hematuria with red cell and other cellular casts. Most patients have relatively mild disease characterized by asymptomatic hematuria and proteinuria with a normal or only slightly elevated creatinine level. However, more marked findings may occur including the NS, hypertension, and acute renal failure. There is a general but not absolute correlation between the severity of the clinical manifestations and the findings on renal biopsy. Patients with HSP and asymptomatic hematuria usually are not biopsied, but, when done, they only have focal mesangial proliferation. However, if protein excretion is in the nephrotic range, there frequently is crescent formation; thus patients with heavy proteinuria or significant azotemia are usually biopsied. The percent of glomeruli showing crescents seems to be the most important prognostic finding. In general, HSP is characterized by tissue deposition of IgA-containing immune complexes. The pathogenesis of this disorder may be similar to that of IgA nephropathy, which is associated with identical histologic findings in the kidney. The description of the simultaneous occurrence of HSP and IgA nephropathy in twins after an adenoviral infection is further evidence in support of a common pathogenesis. IgA deposition is prominent in both HSP and IgA nephropathy.

3. (E) In cases of HSP with severe renal involvement, several therapies have been tried, most frequently increased immunosuppression with corticosteroids or other agents. However, there have been no adequately powered therapeutic trials and because spontaneous recovery is often observed in patients with crescent formation, it remains uncertain whether these regimens are superior to less aggressive therapy or no therapy at all. Similarly, plasmapheresis and IVIG have been tried, but, again, efficacy is uncertain and cases often have concurrent administration of immunosuppression.

SUGGESTED READING

Blanco R, Martinez-Taboada VM, Rodriguez-Valverde V, et al. Henoch-Schönlein purpura in adulthood and childhood: two different expressions of the same syndrome. Arthritis Rheum. 1997;40:859-864.

Cameron JS. Henoch-Schönlein purpura: clinical presentation. Contrib Nephrol. 1984;40:246-249.

Chang WL, Yang YH, Wang LC, Lin YT, Chiang BL. Renal manifestations in Henoch-Schonlein purpura: a 10-year clinical study. Pediatric Nephrol. 2005;20;1269-1272.

Gardner-Medwin JM, Dolezalova P, Cummins C, Southwood TR. Incidence of Henoch-Schönlein purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins. Lancet. 2002;360:1197-1202.

Habib R, Niaudet P, Levy M. Henoch-Schönlein purpura nephritis and IgA nephropathy. In: Tisher CC, Brenner BM, eds. Renal Pathology with Clinical and Functional Correlations. Philadelphia, PA: Lippincott; 1993:472.

Kauffmann RH, Herrmann WA, Meyer CJ, et al. Circulating IgAimmune complexes in Henoch-Schönlein purpura. A longitudinal study of their relationship to disease activity and vascular deposition of IgA. Am J Med. 1980;69:859-866.

Levy M, Broyer M, Arsan A, Levy-Bentolila D, Habib R. Anaphylactoid purpura nephritis in childhood: natural history and immunopathology. Adv Nephrol Necker Hosp. 1976;6: 183-228.

Meadow SR. Henoch-Schönlein syndrome. In: Edelmann CM, ed. Pediatric Nephrology. 2nd ed. Boston, MA: Little, Brown; 1992:1525.

Saulsbury FT. Henoch-Schönlein purpura in children. Report of 100 patients and review of the literature. Medicine (Baltimore). 1999;78:395-409.

Trapani S, Micheli A, et al. Henoch Schonlein purpura in childhood: epidemiological and clinical analysis of 150 cases over a 5-year period and review of literature. Semin Arthritis Rheum. 2005;35:135-137.

CASE 129: A 10-YEAR-OLD GIRL WITH BED-WETTING AND PROTEINURIA

A 10-year-old African American girl is being evaluated for bedwetting. She had been dry during the day since age 2 years but is wet every night. A urinalysis was performed as part of the evaluation for enuresis. It demonstrated 3+ proteinuria with an occasional RBC/HPF.

She denied symptoms of periorbital, pedal, or pretibial edema; there was no history of arthralgias, headaches, dizziness, UTI, or rash. Her father was known to have proteinuria and is being evaluated for it.

On physical examination this healthy-appearing 10-year-old weighed 46.3 kg, measured 61.3 cm in length, and had blood pressure 122/78 mm Hg. The chest was clear to auscultation, and there was no evidence of peripheral edema. The abdominal evaluation was normal. There was no rash.

The laboratory examination reveals a urinalysis with specific gravity 1.018, pH 6.5, protein 3+, 3-5 WBC/HPF, and occasional RBC/HPF. The urinary protein-to-creatinine ratio is 3.5. The BUN is 10 mg/ dL, serum creatinine 0.7 mg/dL, total protein 6.7 g/ dL, albumin 3.7 g/dL, and cholesterol 158 mg/dL. The C₃level is 110 mg/dL and the ANA is less than 1:40.

SELECT THE ONE BEST ANSWER

1. Regarding her proteinuria, the next test that should be ordered is

(A) renal ultrasound

(B) creatinine clearance

(D) first voided sample for protein-to-creatinine ratio

(E) a renal biopsy

2. The morning urinary protein-to-creatinine ratio was 3.0 (normal is <0.2). A likely cause of asymptomatic fixed proteinuria in a 9- to 10-year-old girl with enuresis is

(A) minimal change nephrotic syndrome

(B) reflux nephropathy

(D) membranoproliferative glomerulonephritis

(E) nephrogenic diabetes insipidus

3. The renal ultrasound and voiding cystourethrogram are normal. The pediatric nephrologist performs a percutaneous renal biopsy. The most likely tissue diagnosis is

(A) focal segmental glomerulosclerosis

(B) minimal change nephrotic syndrome

(D) membranous nephropathy

(E) normal

ANSWERS

1. (D) Although this patient with asymptomatic proteinuria had a random protein-to-creatinine ratio of 3.5, one should always exclude orthostatic proteinuria before proceeding to a more complicated evaluation. The long-term prognosis for orthostatic proteinuria is excellent. The urinary protein-to-creatinine ratio is commonly used in pediatrics because it is difficult to collect an accurately timed specimen. Also, 24-hour collections may yield an increased protein concentration even in orthostatic proteinuria. Because creatinine is a byproduct of muscle metabolism that is produced and excreted at a constant rate, the ratio of total protein (or any other substance) to creatinine is constant and reproducible regardless of whether the urine is concentrated or dilute.

2. (B) Reflux nephropathy can be diagnosed with a renal ultrasound that shows irregular contours and thinned cortex, along with frequently dilated ureters. A VCUG most likely will demonstrate vesicoureteral reflux (see Case 119). The natural history of low grade reflux is that it improves with time, but if reflux is severe enough to cause nephropathy, it will likely persist. Hypertension is often present with reflux nephropathy. Minimal change, focal segmental glomerulosclerosis, and membranoproliferative glomerulonephritis often present with heavy proteinuria but patients with these disorders usually have less primary nocturnal enuresis. All require percutaneous renal biopsy for diagnosis. Nephrogenic diabetes insipidus does reflect an inability of the kidney to concentrate the urine in response to DDAVP but is not usually associated with proteinuria.

3. (A) Focal segmental glomerulosclerosis is the most common finding on biopsy in such patients, especially African Americans, who have asymptomatic, isolated, fixed proteinuria. Minimal change and membranous nephropathy present with symptomatic nephrotic syndrome. Membranoproliferative glomerulonephritis may or may not be associated with the nephrotic syndrome but is associated with hematuria and low complement. FSGS in the context of asymptomatic proteinuria has a much better prognosis than in patients who have steroidresistant nephrotic syndrome and biopsy-proven FSGS. This patient with only moderate proteinuria and FSGS was successfully treated with cyclosporine, and the protein-to-creatinine ratio decreased to 0.56.

SUGGESTED READING

Hogg RJ, Portman RJ, Milliner D, et al. Evaluation and management of proteinuria and nephrotic syndrome in children: recommendations from a pediatric nephrology panel established at the National Kidney Foundation Conference on Proteinuria, Albuminuria, Risk, Assessment, Detection and Elimination (PARADE). Pediatrics. 2000;105:1242-1249.

Houser MT, Jahn MF, Kobayashi A, Walburn J. Assessment of urinary protein excretion in the adolescent: effect of body position and exercise. J Pediatr. 1986;109:556-561.

Roy S 3rd, Stapleton FB. Focal segmental glomerulosclerosis in children: comparison of nonedematous and edematous patients. Pediatr Nephrol. 1987;1:281-285.

Rytand DA, Spreiter S. Prognosis in postural (orthostatic) proteinuria: forty to fifty-year follow-up of six patients after diagnosis by Thomas Addis. N Engl J Med. 1981;305:618-621.

Vehaskari V, Rapola J. Isolated proteinuria: analysis of a schoolage population. J Pediatr. 1982;101:661-668.

CASE 130: A 15-YEAR-OLD BOY WITH FLANK PAIN AND BLOODY URINE

A 15-year-old Asian American adolescent boy presented to the emergency department with right flank pain and otherwise painless gross hematuria. The patient is adopted, and his adoptive parents were unaware of any family history of renal disease or nephrolithiasis. The past medical history was unremarkable except for seasonal allergies.

On physical examination this healthy-appearing 15-year-old weighed 61.5 kg, measured 169 cm in height, and had a blood pressure of 140/90 mm Hg. The chest was clear to auscultation, and there was no evidence of peripheral edema. The abdominal examination was normal. The laboratory tests revealed a urinalysis with a specific gravity 1.010, pH 8, 3+ proteinuria, 10-20 WBC/HPF, and more than 20 RBC/HPF. The urinary protein-tocreatinine ratio was 0.23 (normal <0.2) and the calciumto-creatinine ratio was 0.09 (normal < 0.21). The urine culture was negative.

The BUN was 13 mg/dL, serum creatinine 0.9 mg/ dL, and Hgb 16.1 g/dL. The serum C3 level was 131 mg/dL (83-177 for adults), C₄44 mg/dL (15-45 for adults), and the antistreptolysin O antibody less than 200 IU/mL. The patient was referred to the pediatric renal clinic after acute nephrolithiasis was ruled out on imaging.

SELECT THE ONE BEST ANSWER

1. In the evaluation of hematuria with absent or minimal proteinuria, the most important part of the evaluation is

(A) history

(B) physical examination

(D) CT scan

(E) renal biopsy

2. Which is the least common cause of isolated microscopic hematuria?

(A) benign familial hematuria/thin basement membrane disease

(B) idiopathic hypercalciuria

(D) IgA nephropathy

(E) exercise

3. If the urinary calcium/creatinine ratio was 0.45 and reconfirmed, the patient should be

(A) encouraged to drink more than 2 L of fluids in 24 hours

(B) placed on a low-sodium, normal-calcium diet

(D) none of the above

(E) all of the above

4. Gross hematuria persisted for 7 days. A renal ultrasound was ordered that showed enlargement of both kidneys with multiple cysts bilaterally consistent with autosomal dominant polycystic kidney disease (ADPKD). The next test that should be ordered is

(A) magnetic resonance angiography (MRA) of brain

(B) US of abdomen

(D) genetic testing for PKD1 and PKD2

(E) sweat chloride test

5. This 15-year-old boy with ADPKD may demonstrate which of these clinical manifestations during childhood?

(A) pain

(B) hematuria

(D) renal insufficiency

(E) A, B, and C

ANSWERS

1. (A) There are many causes of microscopic hematuria without significant proteinuria, some benign and some serious. Truly asymptomatic microscopic hematuria is present in 3-4% of school-age children, most of whom have no significant clinical disease. Thus the most important part of the initial evaluation is a careful history. The history of present illness should confirm that the patient is truly asymptomatic—that there is no history of trauma, lower urinary tract symptoms, no edema, or no history of granular urine. The past medical history is important to exclude a relevant illness such as lupus or sickle cell disease. Also, the family history is important. Inquiries should be made about hematuria, renal failure, deafness, and nephrolithiasis. A physical examination is important, including a blood pressure measurement. Because some causes are transient, as in recovering postinfectious GN or after exercise, it is important to make sure the finding persists over time and to check for hematuria when the patient has not been exercising. When hematuria is persistent, a CT is occasionally done; an US is usually done to rule out hydronephrosis, obstruction, stone, and renal malignancy. A calcium-to-creatinine spot ratio is usually sent, and if history, imaging, or this ratio is suggestive of nephrolithiasis, a more complete workup is usually done, as indicated. A biopsy is usually reserved for significant or worsening proteinuria or renal impairment.

2. (C) Alport syndrome is a rare condition, usually X-linked, and thus worse in males than carrier females. It consists of hereditary nephritis accompanied by neurosensory hearing loss. Benign familial hematuria is a common syndrome associated with hematuria that is diagnosed by screening first-degree relatives. On biopsy, the basement membrane of the glomerular filtration barrier is thinned. Increasing evidence indicates some of these patients are heterozygous carriers for collagen defects that are found in autosomal recessive Alport syndrome. Idiopathic hypercalciuria is also a common cause of hematuria. It is diagnosed if the urinary calcium-to-creatinine is more than 0.21. IgA nephropathy is a strong consideration. It is often characterized by 1-2 days of gross hematuria during an upper respiratory tract infection. Between episodes of gross hematuria there is microscopic hematuria, and occasionally proteinuria or renal insufficiency. Diagnosis is made by renal biopsy showing deposition of IgA on immunofluorescence. After significant exercise, microscopic hematuria is often present.

3. (D) Idiopathic hypercalciuria is a common syndrome associated with microscopic hematuria in childhood. There is disagreement as to whether hypercalciuria leads to renal stones. Thus treatment is reserved for patients who have previously had nephrolithiasis, have calcifications on US, or patients with a strong family history of hypercalciuria and nephrolithiasis. Increased fluid intake, restricted sodium, ample intake of calcium (>1200 mg/day), and thiazide treatment are helpful in preventing recurrent nephrolithiasis. In adults, protein restriction is sometimes also recommended, but in children the need for growth must also be considered, and protein is not usually restricted.

4. (B) ADPKD occurs in 1 in 400-1000 live births. In ADPKD, renal involvement is characterized by cystic dilations in all parts of the nephron including Bowman space. In the early stages there may only be a few irregularly distributed macrocysts. Later, both kidneys are enlarged and large cysts are present in the cortex and medulla. Cysts in the liver, pancreas, and other organs are common in patients with ADPKD, but congenital hepatic fibrosis is rare. Cerebral vessel malformations have been described, and a ruptured cerebral aneurysm is the most serious complication of PKD. An MRA (or CTA) of the brain should be performed to exclude cerebral aneurysms in those at high risk (including previous rupture, warning symptoms, high-risk occupation or positive family history of aneurysm or bleed), but the role of screening all patients with ADPKD is currently unresolved. This is due to the risk of complications following elective aneurysm surgery and the high frequency of finding small aneurysms at low risk for rupture. A VCUG is not part of the workup for a patient with ADPKD unless there is a UTI or hydronephrosis. Genetic testing is now available that can find a molecular change in about 70% of affected patients because about 85% of patients with ADPKD have a mutation in the PKD1 locus, and the rest have a different defect in the PKD2 locus. Thus screening can be used for counseling, but it can be expensive and its role in children who are at risk is debatable because there can be adverse effects of a presymptomatic positive finding. A sweat chloride test is used to diagnose cystic fibrosis.

5. (E) Manifestations of disease such as pain, hematuria, and hypertension are associated with large or enlarging kidneys. The GFR does not deteriorate in this population of children. Renal insufficiency often develops in later decades with less than 2% of patients progressing to end-stage renal disease (ESRD) before age 40. However, 75% have ESRD by age 75. There is marked interfamilial heterogeneity and even intrafamilial variability regarding prognosis. Specific therapies are being evaluated, but typically blood pressure is well controlled usually with ACE inhibitors and receptor blockers.

SUGGESTED READING

Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002; 346:77-84.

Dodge WF, West EF, Smith EH, et al. Proteinuria and hematuria in schoolchildren: epidemiology and early natural history. J Pediatr. 1976;88:327-347.

Feld LG, Meyers KE, Kaplan BS, et al. Limited evaluation of microscopic hematuria in pediatrics. Pediatrics. 1998;102: E42.

Ingelfinger JR, Davis AE, Grupe WE. Frequency and etiology of gross hematuria in a general pediatric setting. Pediatrics. 1977;59:557-561.

Jais PJ, Knebelmann B, Giatras I, et al. X-linked Alport syndrome: natural history in 195 families and genotype-phenotype correlations in males. J Am Soc Nephrol. 2000;11:649-657.

Kaplan BS, Kaplan P, Rosenberg HK, et al. Polycystic kidney diseases in childhood. J Pediatr. 1989;115:867-880.

Kissane JM. Renal cysts in pediatric patients: a classification and overview. Pediatr Nephrol. 1990;4:69-77.

Shaikewitz ST, Chapman A. Autosomal recessive polycystic kidney disease: issues regarding the variability of clinical presentation. J Am Soc Nephrol. 1993;3:1858-1862.

Stapleton FB. Idiopathic hypercalciuria: association with isolated hematuria and risk for urolithiasis in children. The Southwest Pediatric Nephrology Study Group. Kidney Int. 1990;37:807-811.

Vehaskari VM, Rapola J, Koskimies O, et al. Microscopic hematuria in school children: epidemiology and clinicopathologic evaluation. J Pediatr. 1979;95(5 Pt 1):676-684.

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