Chapter 468. Kidney or Urinary Tract Disorders

Hematuria is a common sign of urinary tract disease but also occurs in otherwise healthy children.1,2 Hematuria can present as either discolored red, brown, or tea-colored urine (eFig. 467.1), or it can present as yellow urine with a positive dipstick for blood. Clues to the diagnosis may be obtained from a history focused on whether the hematuria is painless, intermittent, or persistent, or microscopic or gross. A family history of hematuria or renal disease is important. Brown or tea-colored urine is common in glomerulonephritis, whereas red or obviously bloody urine suggests postglomerular bleeding. Glomerulonephritis is commonly associated with other abnormalities of the urine such as proteinuria and cellular casts as well as hypertension, edema, and reduced renal function. Table 468-1 provides a simple mnemonic for the causes of hematuria throughout the urinary tract. A diagnostic approach and differential diagnosis for discolored urine and microscopic hematuria are shown in Figure 468-1.

Microscopic hematuria, defined as the presence of a positive urine dipstick for blood and more than five RBCs/hpf on centrifuged urine, occurs in approximately 1% of school-age children on at least one urine sample. About 0.5% will continue to have hematuria on two of three samples, and a third have hematuria on three samples.1,2 Fewer than one third of patients diagnosed with hematuria demonstrate hematuria 1 year later. Only a very small number of children with microscopic hematuria had significant renal or urological disease. Microscopic hematuria can occur following vigorous exercise; thus, it is common in school-age children and in the majority of cases is benign.

Hypercalciuria, defined as more than 4 mg urinary calcium/kg per day, has been found in significant numbers of children with microscopic hematuria.3 This association is even stronger if there is a family history of stone disease or the occurrence of gross hematuria. The calcium-to-creatinine ratio can be used to screen for hypercalciuria; for children or adolescents, a urinary Ca/Cr ratio greater than 0.2 is abnormal.4

The value of urinary tract imaging in children with microscopic hematuria is controversial. The yield of routine IVP or ultrasound is low, and reported findings are frequently of little clinical significance. When microscopic hematuria persists for several months, decisions on the need for urinary tract imaging are made based on other concerns. Voiding cystourethrograms and cystoscopy are rarely helpful and are not indicated for the routine evaluation of children with either microscopic or gross hematuria.5

Gross hematuria is much less common than microscopic hematuria and warrants a more thorough investigation, as outlined in Figure 468-1. Trauma should be considered, especially if the urine contains clots. If trauma is a likely cause, the urinary tract should be promptly imaged by CT scan. Similarly, if a palpable flank mass is noted, a renal tumor must be considered. Brown- or tea-colored urine, especially with cellular casts and protein, suggests glomerulonephritis. The presence of dysuria or fever suggests hemorrhagic cystitis, which can be caused by both bacterial and viral agents. Sickle cell hemoglobinopathies are associated with recurrent gross hematuria that at times can be quite severe. Nephrolithiasis is associated with abdominal pain and nausea. Hypercalciuria, even in the absence of a demonstrable stone, is a common cause of gross hematuria. Renal cysts, especially those in Autosomal Dominant Polycystic Kidney Disease (ADPKD), occasionally rupture and cause gross hematuria. Coagulopathies are an extremely rare cause of gross hematuria and are almost always associated with bleeding elsewhere. Rare causes include obstructive uropathy, tumors, and vascular malformations.

Most children excrete urine free of protein when evaluated by the semiquantitative dipstick method.1,6 Proteinuria is not an uncommon finding in otherwise healthy children. An approach to proteinuria is shown in Figure 468-2. If the proteinuria is associated with other signs of renal disease, such as edema, hematuria, hypertension, growth failure, or elevated serum creatinine, then a more extensive evaluation is indicated. Proteinuria can be transient, orthostatic, or fixed.

Transient proteinuria, defined as disappearance of proteinuria on several occasions after a positive test, accounts for 80% of patients with isolated proteinuria and occurs in conjunction with fever, exercise, cold exposure, heat stress, and emotional distress. In an otherwise healthy child, transient proteinuria is not associated with renal disease.

Orthostatic proteinuria, defined as proteinuria only in an upright position, is the next most frequent cause and occurs commonly in adolescents. Evaluation for orthostatic proteinuria is accomplished by having the patient empty the bladder before going to bed at night and checking the first urine passed on waking. A second sample is obtained later in the day, after the patient has been upright for several hours. Urine protein is evaluated by dipstick, urine protein/creatinine ratio, or quantitative collection. If the recumbent urine is negative for protein and the upright urine has protein, the patient is considered to have orthostatic proteinuria. If dipsticks are used, this determination must be repeated over 5 to 7 days because of a 22% to 54% false-negative rate for protein. A more precise method is to measure the urine protein/creatinine ratio in the recumbent and upright urine samples or to quantify protein in each position. In orthostatic proteinuria, the recumbent ratio will be less than 0.2, but the upright sample will have an increased ratio, or the recumbent sample will have less than 100 mg protein/12 h and the upright sample will have 300 to 900 mg/12 h. If the total quantitative protein excretion exceeds 1.0 g/d, the diagnosis of orthostatic proteinuria is unlikely. Orthostatic proteinuria is usually transient, remitting after some time, but it can be persistent. Long-term studies in adults have shown orthostatic proteinuria to have a favorable outcome and not be associated with renal disease; however, strict criteria, including normal renal function, blood pressure, and serum competent levels, must be used to exclude patients with other renal diseases. Patients with orthostatic proteinuria should be seen at least yearly for several years to be certain that this is not the harbinger of more serious renal disease.

Fixed proteinuria is persistent and occurs in both upright and recumbent positions. It requires more thorough evaluation (Fig. 468-2). Protein excretion should be quantified in a timed collection, renal function assessed using serum creatinine, and a serum C3 complement level should be obtained. If the serum creatinine and C3 complement are normal and the protein excretion rate is greater than 40 mg/m2 per hour (< 3 g/d), then the patient may be followed every 6 to 12 months. If these results are abnormal, then more extensive testing should be done, likely including a renal biopsy.

The presence of both hematuria and proteinuria strongly suggests a diagnosis of more serious renal disease than either condition alone, especially if other abnormalities such as cellular casts, edema, hypertension, and azotemia are present. The approach to evaluation is shown in Figure 468-3. Serum creatinine, C3 complement, streptococcal antibody titers (usually ASO and DNase B), and possibly an ANA titer should be obtained. The urine protein excretion rate should be evaluated, and if edema is present, serum albumin should be obtained. A renal biopsy may be indicated, especially if the diagnosis of poststreptococcal glomerulonephritis is excluded. The decision to perform a renal biopsy is influenced by the magnitude of the proteinuria, the presence of other signs and symptoms, and the inability to establish a specific diagnosis. Patients who have a combined nephritic (hematuria, hypertension, azotemia) and nephrotic (proteinuria, low albumin, edema) syndrome are likely to have a systemic disease (systemic lupus erythematosus, Henoch-Schonlein purpura, vasculitis) or progressive primary glomerulonephritis. In children with proteinuria, hematuria, or both, a low C3 complement level suggests one of four diagnoses: (1) postinfectious glomerulonephritis, (2) SLE nephritis, (3) mesangiocapillary glomerulonephritis, or (4) nephritis associated with chronic infection.

The approach to evaluating edema is shown in Figure 468-4. Renal disease is the most common cause, especially when persistent. Congestive heart failure may cause edema in children, and allergic disorders occasionally cause localized edema that is usually transient and often associated with other signs such as urticaria. Hypoalbuminemia from decreased hepatic albumin synthesis or, rarely, from a protein-losing enteropathy will cause generalized edema. A careful history, physical examination, and selected laboratory tests (such as a serum albumin, urinalysis, and fecal α1-antitrypsin if the urinalysis is normal) will usually elucidate the cause of the edema.

Edema in the child with renal disease is most evident in places where tissue resistance is low, such as the periorbital area, abdomen, scrotum, and labia, or where the hydrostatic pressure is high, such as the lower extremities. Early in renal disease, the only place edema may be noticeable is in the periorbital tissue on following several hours in the recumbent position. Edema from acute glomerulonephritis is usually caused by a decreased glomerular filtration rate (GFR) with enhanced tubular reabsorption of sodium and water. In patients with nephrotic syndrome, marked proteinuria combined with hypoalbuminemia (<2.5 g/dL) leads to decreased plasma oncotic pressure, decreased sodium and water excretion, and edema. With severe or long-standing renal disease, the GFR can be reduced so much that the urine output is less than the fluid intake, even with a high fractional excretion of sodium, and edema occurs.

Pyuria is defined as more than five WBCs/hpf on centrifuged urine. The most common cause of pyuria is a urinary tract infection, which is discussed in detail. In UTI, pyuria may be associated with other signs of infection including fever and dysuria. Definitive diagnosis of a UTI is made by growth of a single organism in cultured urine of greater that 100,000 colonies/mL urine. Pyuria may also be the result of a viral, mycobacterial, or a fungal infection of the urinary tract; pelvic inflammatory disease; or peritonitis. Pyuria also occurs as a consequence of fever and dehydration. Systemic lupus erythematosus and interstitial nephritis are unusual causes of pyuria. Interstitial nephritis is often due to a drug reaction, and pyuria is often associated with the presence of eosinophils in the urine (sometimes with eosinophilia) or may be associated with uveitis, which is then known as tubular interstitial nephritis uveitis syndrome.

The first step in evaluating children with pyuria is to culture the urine for bacteria. If the urine culture is negative, then several additional urinalyses should be obtained to determine if pyuria is persistent. Transient pyuria in an otherwise healthy child requires no further evaluation. Persistent pyuria should be investigated, and the approach to investigation is based on the history, physical examination, and presence of other abnormal elements in the urinalysis such as eosinophils, casts, and proteinuria.

Children with polyuria void large volumes frequently and have polydipsia, whereas children with urinary frequency void small volumes often. (The approach to evaluating polyuria is discussed in Chapter 525.) Normal children between the ages of 5 and 12 years void about four to eight times a day. Frequency refers to a pattern of increased number of voids each day. Some children with frequency will urinate small amounts several times an hour.7 Urinary tract infections are the most common cause, especially if accompanied by dysuria and fever. Frequency may persist for weeks after resolution of the infection. Other causes include urethral irritation from vulvovaginitis in girls or meatitis in boys, trauma, foreign body, or bubble baths. Hypercalciuria has also been reported to cause frequency and dysuria.8,9 In a number of children, especially younger children, no discernible cause can be found, and the problem resolves with time. On occasion, anticholinergic agents, such as oxybutynin, are useful in reducing the number of voidings. Usually, little evaluation is necessary beyond a history, physical examination, urinalysis, and urine culture. Imaging studies of the bladder and urethra are rarely indicated.

Oliguria denotes very low urine flow, and anuria means virtually no urine flow. Oliguria is common in children and is usually related to volume contraction rather than to a renal abnormality. Oliguria is defined as a urine flow rate less than 0.5 ml/kg per hour in children or less than 1 ml/kg per hour in infants. Eight percent of healthy newborns do not void in the first 24 hours of life, but 98% do so by 48 hours.10 The average urine output in the first 2 days of life is 20 ml/day and rises to 200 ml by the end of the second week of life. Most children with oliguria do not have renal disease, but the low urine flow is a renal response to dehydration from other nonrenal sources of volume and electrolyte loss such as diarrhea or sweat (especially in cystic fibrosis) and increased insensible losses. A careful history and physical examination can usually identify the presence of dehydration as the cause for the oliguria. Laboratory clues include an elevated blood urea nitrogen compared to serum creatinine and concentrated urine. With severe dehydration, there may also be a small amount of blood and protein in the urine along with granular, but not cellular, casts. With the development of renal parenchymal injury from dehydration and hypotension (acute tubular necrosis), the kidney often loses the ability to concentrate and retain sodium, so the urine specific gravity is fixed at 1.010 to 1.012, the urine/serum creatinine ratio is less than 10, and the fraction excretion of sodium is greater than 3%.

Oliguria from acute glomerulonephritis is associated with a high specific gravity and low fractional excretion of sodium (< 1%). The presence of gross hematuria, heavy proteinuria, and cellular casts distinguishes between dehydration and acute glomerulonephritis. Disorders to the renal vasculature and obstruction to urine flow should also be considered as a cause of oliguria. A renal ultrasound with Doppler assessment of renal arterial and venous flow is useful to assess renal blood flow. The approach to the child with oliguria is diagrammed in Figure 468-5. Anuria is uncommon and should raise the suspicion of obstruction.

The first step is to evaluate for dehydration. If volume contraction is present (based on physical exam findings and vital signs), then a trial of volume expansion (20 ml/kg of normal saline) with careful monitoring is administered to determine if increased urine flow can be established. If dehydration is not present or the patient has edema, then other causes for oliguria should be considered, such as acute glomerulonephritis, nephrotoxic injury from medications, or acute obstruction. Congenital absence of the kidneys and vascular occlusions are important causes in the neonate.

Enuresis is defined as the inappropriate discharge of urine in a child who has reached the age at which bladder control would be expected. However, bladder control is a maturational event, and what constitutes “normal” is ambiguous. The average age of successful toilet training is 2.4 years, with a range of 0.75 to 5 years.11 Approximately 75% of 3 year olds and 85–90% of 5 year olds are dry at night.12 Between the ages of 5 and 9 years, 10% to 15% of children experiencing bed-wetting will achieve dryness each year. Thus, most children will become dry with time.

Enuresis may be nocturnal (bed-wetting) or diurnal (daytime wetting) or both. Nocturnal enuresis is much more common than diurnal enuresis. Approximately, 10% of children with nocturnal enuresis will have daytime wetting as well, whereas 50% of children with daytime wetting will have nocturnal enuresis.12Primary enuresis refers to children who have never achieved dryness for an extended period of time and is more common than secondary enuresis and less likely to be associated with disease. Secondary enuresis refers to the appearance of enuresis in a child who has been dry for at least a year.

Nocturnal Enuresis

This common problem occurs in 15% of 5-year-olds, 7% of 10-year-olds, and 1% of adults. The majority of children with this problem do not have either organic or functional disease. However, bed-wetting does cause significant psychosocial problems in older children. Nocturnal enuresis is commonly a familial disorder, as 74% of enuretic males and 58% of enuretic females have at least one parent with a history of enuresis. Under the age of 12 years, it is twice as common in males as females, but over the age of 12 years, this difference disappears. Primary nocturnal enuresis is thought to occur because of (1) small bladder capacity, (2) excessive urine formation during sleep, (3) a problem with sleep arousal, or (4) uninhibited detrusor contractions during deep sleep. Children with nocturnal enuresis may have a smaller functional bladder capacity such that they feel the need to void with smaller volumes than age-matched nonenuretic children; however, measurements of bladder capacity under anesthesia show no difference between enuretic and nonenuretic children. Some children with nocturnal enuresis do not have the normally expected increase in antidiuretic hormone levels at night and therefore do not decrease urine formation at night. Sleep studies have shown that nocturnal enuresis occurs randomly throughout the night and not in a particular sleep stage. Although most families report that their enuretic child is the most difficult to arouse from sleep, actual measurement of sleep arousal times does not support a problem with arousal. Finally, to remain dry throughout the night, the child must be able to centrally inhibit bladder contractions while asleep, just as he must while awake to remain dry during the day. As this is a maturational event, it is not surprising that there is a wide range of ages when this is achieved. Rare causes of enuresis are nocturnal seizures and sleep apnea.

The evaluation of children with nocturnal enuresis begins with a complete history that includes determining the number of wet nights per week, the longest period of dry nights, fluid intake in the evening, voiding pattern or difficulties, UTI symptoms, family history of nocturnal enuresis, and family or behavioral problems. The appearance of secondary enuresis should alert the physician to a possible organic cause such as UTI, diabetes mellitus, or diabetes insipidus or to a recent psychologically traumatic event in the child’s life. A careful physical examination should also be performed with attention paid to the presence of a full bladder, an abnormal urinary stream, lumbar spine or sacral abnormalities, and neurological examination of the lower extremities. A urinalysis on a first-morning void should be obtained from all children with enuresis to exclude a urine concentrating problem (normal elevation in specific gravity), diabetes mellitus (absence of glycosuria), and UTI (WBCs, a positive reaction for nitrate, or leukocyte esterase). A simple measurement of bladder capacity may also be useful (normal bladder capacity in ounces is 2 + the age in years).

A variety of treatment approaches may be helpful, but it is important to recognize that most children become dry with time no matter what approach is used.13 Educating the child and the family is the cornerstone of initial therapy. Parents must be made aware that nocturnal enuresis is not under the child’s voluntary control, so punishment is counterproductive. One treatment method addresses the small bladder capacity of many of these children by helping the child learn to awaken at night to void. This behavioral approach encourages the child to visualize the sensation of a full bladder, awakening, and going to the bathroom before falling asleep. The child is awoken several times throughout the night to void. The child must be awake and aware, not somnolent, when he is voiding. This approach requires highly motivated parents.

A variation of the self-awakening method uses bed-wetting alarms. The alarm appears to work by negative reinforcement or avoidance. It goes off and awakens the child during voiding; the child gets out of bed and finishes voiding in the toilet or holds urine until later. These are quite effective, with an initial cure rate of approximately 70% and only a 10% to 15% relapse rate.13 They also require motivated patients and parents who are willing to learn how to use the devices properly. Use for 2 to 3 months is usually required to achieve dryness. A self-awakening program should be used in conjunction with the alarm, as many children with enuresis will not awaken easily when the alarm sounds.

Exercises to increase bladder capacity have also been shown to be effective. These are accomplished by having the child delay the interval between voids for as long as possible during the daytime, which appears to increase the functional bladder capacity. Voluntarily contraction of the pelvic floor musculature (Kegel exercise) inhibits bladder detrusor contractions. A program of practicing with 10 contractions three times a day improves about half of children with both nighttime and daytime wetting.

Pharmacological treatment options may also be useful. Imipramine has been used extensively for enuresis and combines an anticholinergic effect for increasing functional bladder capacity with a noradrenergic effect to decrease detrusor contractions. The starting dose is 25 mg at night with an increase to a maximum of 50 mg in children less than 12 years of age and 75 mg in adolescents. The cure rate is between 10% to 60%, with a high relapse rate.14 The relapse rate can be improved if administered for 3 to 4 months and then gradually tapered over 3 to 4 weeks. Imipramine does have the potential for serious toxicity and therefore should be used only with appropriate warnings regarding risks of overdose and other complications.

Desmopressin (DDAVP), as a nasal spray or as a tablet, is quite effective in reducing the number of wet nights in most children and allowing many to be completely dry.13 Treatment using the nasal spray is initiated with 10 mcg given at bedtime, one half of the dose in each nostril. If necessary, the dosage can be increased to 20 mcg and then 40 mcg at bedtime. The 0.2-mg tablet is taken at bedtime; if necessary, the dose can be titrated to 0.6 mg. Desmopressin is especially useful for older children with high nighttime-to-daytime urine-volume ratios, suggesting suppression of the expected increase in ADH secretion at night. However, it is quite expensive, and relapse exceeds 80% when treatment is stopped. Complications include headache, nasal irritation, and nosebleeds. It can be used intermittently to allow enuretic children to participate in sleepovers and camp.

Diurnal Enuresis

Diurnal wetting problems arise as a consequence of the transition from an infantile voiding pattern to an adult pattern. In the infant, the bladder fills and reflexively empties when a set volume is reached. Adults are able to cortically inhibit these reflex bladder contractions until there is a convenient time and place to void. Problems in making this transition in bladder control lead to most daytime enuresis. Organic causes of daytime wetting include bladder outlet obstruction, neurogenic bladder, ectopic ureter, and urinary tract infections. Vaginal reflux of urine that seeps out upon rising from the toilet is a common physiological cause in girls. Giggle incontinence (the sudden involuntary emptying of the bladder with giggling) is a rare cause of daytime wetting that predominantly occurs in girls and is often associated with a family history. Sudden fright will cause involuntary voiding in young children. Other associated behavioral issues that may establish a daytime wetting pattern include constant anxiety, such as the loss of a parent, marital discord, or an abusive home environment. Some children, usually boys, are resistive to toilet training and have a history of toilet avoidance that prevents achievement of daytime dryness. Some children either do not recognize the sensation of a full bladder or ignore it and continue playing. Some children appear to have an unstable bladder, detrusor instability, and persistence of an infantile bladder that manifests as having difficulty cortically inhibiting the spontaneous bladder contractions that occur at lesser bladder volumes. These children withhold voiding by tightening their external sphincter. They frequently are fidgety and use external compression to avoid wetting their pants, such as pressing the heel against the perineum (girls) or grabbing the penis (boys). This behavior can interfere with normal relaxation of the perineum with voiding and can lead to incomplete bladder emptying.

UTIs may initiate these problems, which can persist following treatment. Severe problems with perineal relaxation result in the Hinman syndrome14 (non-neurogenic neurogenic bladder) and renal damage. A staccato pattern of voiding is a clue to this problem. Constipation is often associated with voiding problems, and its correction often leads to less wetting. It is unclear whether the constipation directly causes the wetting or may be a reflection of problems with perineal relaxation that is necessary for complete emptying of both the bowel and the bladder.

Only a limited evaluation is generally indicated for children with daytime enuresis. The history should focus on the pattern of voiding, toilet training, problems with urinary stream in boys, symptoms of urinary tract infection or history of a UTI, presence of constipation, and the family’s response to wetting accidents. The physical exam should evaluate for a distended bladder and possible spinal defects. The urinary stream in boys should be observed. It is more useful to listen to the sound of voiding in girls; normally, there is a smooth rise and fall in the force, but a forceful, intermittent stream (staccato voider) or abrupt cessation of voiding suggests problems with relaxation of the perineum. A urinalysis and possibly a urine culture are the only laboratory tests that are usually useful. Radiographic studies are indicated only if there are problems with the urinary stream in the male, presence or history of a urinary tract infection, constant dampness from a possible ectopic ureter, or physical signs suggestive of a neurogenic bladder.