Healthy children normally have protein in their urine, at a rate of protein excretion <4 mg/m2/h or <100 mg/m2/d throughout childhood. The upper limit of normal protein excretion is up to 150 mg/d. Albumin, relatively small in molecular size, tends to be the dominant constituent, and Tamm-Horsfall protein, a mucoprotein produced in the distal tubule, makes up the remainder.
Proteinuria in children can be transient, orthostatic, or pathologic. Transient proteinuria (often associated with fever, stress, dehydration, or exercise) does not indicate underlying renal disease. Orthostatic proteinuria (elevated protein excretion when the subject is upright but normal protein excretion during recumbency) occurs most commonly in school-aged children and rarely exceeds 1 g/m/d. These patients do not have hematuria and have normal values of creatinine clearance and C3 complement. Pathologic proteinuria is likely if proteinuria is associated with hematuria and/or the first morning urine Pr/Cr ratio is >0.2 in older children. Nephrotic-range proteinuria is levels >40 mg/m/h in 24 hours.
Take a complete history and physical examination including blood pressure in a patient with proteinuria. In general, urinalysis showing mild proteinuria (trace to 1+) is not reliable during acute illness (unless there are other symptoms and signs pointing to renal disease). Discharge patients with mild proteinuria who have normal blood pressure and urine output and no evidence of kidney disease. For patients with moderate to severe proteinuria (3+ or 4+), obtain serum albumin, creatinine, cholesterol, electrolytes, serum C3/C4 complement, antinuclear antibody, serologies for hepatitis B and C, and human immunodeficiency virus as clinically indicated. Use renal ultrasound to exclude underlying renal disease. Consult pediatric nephrology for further evaluation if any of the studies are abnormal. Hospitalize patients with severe nephrosis, especially the first episode.
Not all proteinuria is pathologic.
Exclude hematuria when evaluating patients with proteinuria in the emergency department (ED).
Proteinuria is not an uncommon finding in children and may indicate a completely benign condition or be the first clue to a significant renal parenchymal disease (eg, nephrotic syndrome or glomerulonephritis).
Heavy proteinuria (3+ or 4+ on dipstick) is typically seen in nephrotic syndrome; mild proteinuria (trace to 1+) is typically seen with fever or dehydration.
Figure 16.1 ▪ Nephrotic Syndrome (NS) Presenting with Edema and Proteinuria.
(A, B) An 18-month-old child presented with periorbital and facial edema (A) and edema of the feet (B). Urinalysis showed 4 + proteinuria associated with hypoproteinemia. He was clinically diagnosed as Minimal change NS. (Reproduced with permission from Shah BR, Laude T: Atlas of Pediatric Clinical Diagnosis. WB Saunders, Philadelphia, 2000, p. 468.)
Figure 16.2 ▪ Nephrotic Syndrome (NS) Presenting with Edema and Proteinuria.
(A) This adolescent male with NS presented with anasarca, hypoproteinemia and heavy proteinuria. He had edema involving the scrotum, shaft, and foreskin of the penis. (B) Pitting edema is demonstrated here on the shin (edema of hypothyroidism or lymph edema is nonpitting). (Photo contributor: Mark Silverberg, MD.)
Figure 16.3 ▪ Severe Edema Associated with Heavy Proteinuria.
(A, B) Severe edema of the lower extremity and edema of the vulva are seen in an adolescent girl who had hypoalbuminemia, heavy proteinuria, microscopic hematuria, and hypertension. Renal biopsy confirmed diagnosis of focal segmental glomerulosclerosis. (Photo contributor: Binita R. Shah, MD.)
The authors acknowledge the special contributions of Binita R. Shah, MD, to prior edition.
Gross hematuria is blood in urine that can be seen with the naked eye, and major causes in children and adolescents include glomerulopathy, urinary tract infection (UTI), hypercalciuria, urolithiasis, and trauma. Less common causes include malignancy, exercise, angiomatous malformations of the collecting system, nutcracker syndrome, cystic kidney disease, and sickle hemoglobinopathies.
In patients with glomerular disease, the urine is uniformly discolored, and can be a brownish-red color or dark brown often described as being like “tea” or “Coca-Cola.” In patients with vascular bleeding or lower urinary tract bleeding, the urine appears bright red. Dysuria and urinary frequency may indicate a UTI. Viral and chemical agents can cause a hemorrhagic cystitis that may be difficult to clinically distinguish from a bacterial infection. Oliguria, edema, and hypertension suggest an acute nephritic process. The most common causes of glomerulonephritis (GN) in children are IgA nephropathy and acute poststreptococcal GN (APSGN). A history of a preceding or concurrent illness such as upper respiratory tract infections and findings such as rash (eg, impetigo) may suggest an underlying cause. Severe episodic flank or abdominal pain associated with gross hematuria strongly suggests urolithiasis.
Figure 16.4 ▪ Gross Hematuria; Hemorrhagic Cystitis.
A child with hematuria at the end of micturition (terminal hematuria) due to hemorrhagic cystitis (adenovirus is one of the common etiologies). Passage of blood clots and eumorphic erythrocytes are suggestive of a nonglomerular cause of hematuria. (Photo contributor: Anil Mongia, MD.)
Figure 16.5 ▪ Wilms Tumor (Nephroblastoma) Presenting with Hematuria.
(A, B) Longitudinal sonogram (A) of the left kidney shows a large mass (M) arising from the mid to lower pole. There is mild hydronephrosis of the upper pole portion of the collecting system (arrow). Computed tomography (CT) image (B) shows a large mass of the left kidney. Abdominal pain and vomiting were the presenting complaint of this child. Urinalysis showed hematuria, which occurs in up to 25% of patients with Wilms tumor. (C) Cut section of the tumor from the lower pole of kidney with the characteristic tan to gray color and well-circumscribed margins. (Photo contributors: John Amodio, MD [A, B] and Shella Mongia, MD [C].)
Order complete blood count (CBC), blood urea nitrogen (BUN), serum creatinine, albumin, C3 and C4, urinalysis, and urine culture as indicated clinically. If there is high suspicion for stones, order renal and bladder ultrasound or abdominal and pelvic spiral CT scans (with thinner cuts). Send any stone collected for analysis. Order abdominal CT for patients with gross hematuria and a history of abdominal trauma to assess the injury and possible need for surgery. If blood is present at the urethral meatus, obtain retrograde urethrography before catheterization to evaluate for urethral injury.
Most children with hematuria do not require hospitalization. Admit those with hematuria with hypertension, oliguria, or pulmonary edema due to APSGN, hematuria due to renal injury from trauma, hematuria due to papillary necrosis resulting from sickle cell hemoglobinopathy, or patients with urolithiasis requiring intravenous (IV) hydration (eg, vomiting and poor intake) and pain management.
Figure 16.6 ▪ Renal Papillary Cell Carcinoma Presenting with Hematuria.
(A) Intermittent history of passing “red urine” for 3 months followed by passing “red urine” daily for a week was the presenting complaint of this 11-year-old patient. His reddish urine (shown with normal urine) was loaded with red blood cells on microscopy. (B, C). Longitudinal ultrasonographic image (B) of the left kidney shows mass in midpole region (arrow). Coronal CT image (C) shows heterogeneous mass in the midpole region of the left kidney (arrow). (D). Tumor in the middle pole of kidney shows variegated appearance with areas of hemorrhage and necrosis. Pathology showed renal papillary cell carcinoma. (Photo contributors: Haamid Chamdawala, MD [A], John Amodio, MD [B, C], and Shella Mongia, MD [D].)
If history or physical examination is not suggestive of any obvious cause of hematuria, refer to a pediatric nephrologist for evaluation for possible hypercalciuria, nephrocalcinosis, benign familial hematuria, or hereditary nephritis. If persistent bleeding seems to originate from the urinary tract and no cause is identified, refer to urology for possible cystoscopy to identify unilateral bleeding from vascular malformations.
Microscopic examination of the urine is required to confirm the presence of red blood cells (RBCs). Absence of any RBCs in microscopic exam with a positive dipstick reaction suggests hemoglobinuria or myoglobinuria.
An occasional RBC on microscopic examination of the urine may be seen in most children. Further testing is required if examination reveals >5 RBCs/hpf.
Tea or cola-colored urine, RBC casts, and dysmorphic RBCs are pathognomonic for glomerular bleeding (eg, APSGN).
Figure 16.7 ▪ Gross Hematuria; Sickle Cell Disease.
Sudden onset of painless hematuria was a presenting complaint of this adolescent patient with sickle cell anemia. Hematuria, also seen in sickle cell trait and Hb-SC disease, occurs because of ischemia in the renal papillae resulting in necrosis. Treatment is supportive, including adequate hydration and pain management. (Photo contributor: Binita R. Shah, MD.)
Nephrotic Syndrome (NS) is characterized by proteinuria severe enough to cause hypoalbuminemia (serum albumin <2.5 g/dL), hypercholesterolemia, and edema. The nephrotic range of proteinuria is >40 mg/m2/h (normal: <4 mg/m2/h). Minimal change NS (MCNS) is the most common variety of primary NS. Initially, edema is often mild and variable in distribution; being periorbital in the early morning hours. More severe degrees of edema may result in ascites, pleural effusions, scrotal or vulvar edema, and skin breakdown. Children with NS are prone to develop cellulitis and spontaneous bacterial peritonitis (usually pneumococcal). Gram-negative bacilli, such as Escherichia coli, may also cause infection in such patients. Patients with NS and primary peritonitis (especially when they present with an acute abdomen) are not uncommonly misdiagnosed as having acute appendicitis. Hypercholesterolemia can be quite severe but usually resolves when the NS has been treated successfully. Although NS is usually associated with avid sodium retention, serum sodium concentrations are low in some patients and result from water retention (secondary to high antidiuretic hormone levels). Although the total serum calcium in patients with NS is often low, resulting from the low level of protein-bound calcium, the level of free ionized calcium is usually normal. Patients with NS usually demonstrate laboratory features of a hypercoagulable state. Reduced intravascular volume predisposes to thrombotic events. Venous thrombosis may be associated with pulmonary embolism. Renal vein thrombosis (uncommon) will present with a triad of abdominal pain, palpable abdominal mass, and gross hematuria.
Order CBC, BUN, and serum values of creatinine, albumin, lipid profile, C3 and C4. Urinalysis will show a high specific gravity (intravascular volume depletion), proteinuria 3+ or 4+, and lipid droplets and broad waxy casts. Microscopic hematuria can be seen (20%-25%); gross hematuria is rare. Consult pediatric nephrology for any child with suspected NS. Admit patients with evidence of acute peritonitis, or severe anasarca. Consider admission for a first episode of nephrosis (provide education about the chronic relapsing nature of the disease, home monitoring of urine by dipstick, diet, and complications related to both the disease and therapy). Therapies include oral prednisone given daily for the first 4 to 6 weeks followed by prednisone every other day for the following 4 to 6 weeks, salt and fluid restriction, and diuretics (eg, Furosemide) during periods of symptomatic edema as indicated. Diuretics are used judiciously and avoided in patients with a history of thromboembolic events. Antiplatelet drugs and/or anticoagulants are recommended for patients with thromboembolic events.
Figure 16.8 ▪ Minimal Change Nephrotic Syndrome.
A 15-month-old infant with periorbital/facial edema is seen in this photo, which was taken soon after he woke up in the morning. Facial edema is usually seen on arising in the morning and edema is gravity-dependent; thus, early morning periorbital/facial edema may not be apparent by the time the child is seen later in the day. Edema also involves dependent areas such as the feet and legs, scrotum, and sacrum. (Photo contributor: Binita R. Shah, MD.)
Heavy proteinuria is an essential element of NS. Proteinuria from other causes (eg, transient proteinuria associated with fever, dehydration or exercise) or orthostatic proteinuria rarely exceeds 1 g/24 h and is not associated with edema.
Children with periorbital edema due to NS are often misdiagnosed as having angioedema (allergic reaction) on initial presentation. Absence of itching and a positive urine dipstick for proteinuria should alert to the possibility of NS in such children.
Figure 16.10 ▪ Minimal Change Nephrotic Syndrome (MCNS).
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