Rudolph's Pediatrics, 22nd Ed.

CHAPTER 467. Diagnostic Approach to Renal Disease

John W. Foreman


The symptoms and signs of childhood renal disorders vary widely. Diagnostic clues are provided from the history, which should include a description of the amount, frequency, and color of the urine. Changes in any of these may herald a renal disease. The presence of symptoms such as pain on urination (dysuria), urgency (difficulty holding urine in the bladder), incontinence, or dribbling of the urinary stream in boys are also helpful. Pain is not typical of most renal diseases. However, flank pain is common with renal stones and pyelonephritis. Pain from renal stones is excruciating and often radiates from the flank toward the groin. Loin pain may occur with acute glomerulonephritis. Recurrent episodes of dehydration occur in disorders that affect water reabsorption or sodium retention such as tubular disorders, obstructive uropathy, and renal dysplasia. A history of maternal oligohydramnios suggests that in utero renal function was impaired. The family history is sometimes informative, especially in children with heritable kidney disorders such as Alport syndrome, hypercalciuria, cystinosis, and polycystic kidney.

Renal disorders also may present with more insidious symptoms or signs. Chronic renal failure commonly presents with nonspecific symptoms such as fatigue, sleep disturbances, headaches, nausea, and anorexia. Children with severe hypertension (frequently related to renal disorders) can present with seizures and changes in mental status (see Chapter 479). Anemia may occur due to a lack of erythropoietin production by the kidney.

Physical findings of hypertension and edema are common with renal disorders. Periorbital or dependent edema is often an early symptom. The presence of an abdominal mass or genital abnormalities may suggest a renal disease. The kidneys are easily palpated in the first week of life, and renal abnormalities such as multicystic dysplasia, hydronephrosis, and agenesis can be detected by abdominal palpation.


Urinalysis is one of the most useful procedures in evaluating patients who have suspected renal disease.1 However, some abnormalities on urinalysis are transient; therefore, repeated urinalyses is often useful to avoid more extensive and expensive evaluation.


The most informative urine to examine is the first morning specimen, as this often is the most concentrated and acidified, and possible increases in urine protein associated with an upright posture will be minimized. Unfortunately, the practical aspects of collecting first-morning urine often delays the time between urine collection and examination. When obtaining a urine culture, the external genitalia should be cleansed, especially in girls, to minimize contamination by extraneous material, such as vaginal cells. The choice of cleansing agent is important. Betadine may interfere with the dipstick reagents, so the usual recommended agent is benzalkonium. Female patients should be instructed to wipe front to back, to spread the labia while voiding, and to collect the urine after some has been passed to minimize bacterial contamination. Sitting backward on a standard toilet is helpful in keeping the labia separated. Males should be instructed to retract the foreskin and clean the glans before voiding. For children unable to void on command, the urine (for urinalysis but not for culture) is obtained by placing an adherent plastic bag over the genitalia. Stroking the paraspinal area (Perez maneuver) can stimulate voiding in a prone infant. Suprapubic bladder puncture and urethral catheterization are the most accurate methods of collecting urine for culture but should almost never be used for routine examination, as either procedure can introduce blood into the urine. Both techniques are low risk in experienced hands. Suprapubic aspiration is used in children under 2 years of age, since the bladder is an abdominal organ in this age group and is easily accessible for puncture. It is best done after a period of time has elapsed from the last void or when percussion, palpation, or ultrasound demonstrates a full bladder. Urethral catheterization, especially in girls, is another relatively sterile way of obtaining urine for culture and is often more successful than suprapubic aspiration. The urine should be examined within 30 to 60 minutes of passage, because a rise in the pH, lysing of red cells, dissolution of casts, and logarithmic increases in bacterial counts occur if the urine is unrefrigerated.


Dipsticks with small pads containing various reagents that turn a specific color depending on the concentration of the substance analyzed have become a standard part of the routine urinalysis. They can identify blood; and determine the pH; specific gravity; and the concentration of protein, ketones, glucose, nitrite, leukocyte esterase, and urobilinogen in the urine. Test accuracy varies, and all must be interpreted carefully, since they are subject to interference by substances commonly found in urine. Despite these limitations, the low cost and rapid results of urine dipsticks make them useful for screening purposes.


Table 467-1 lists some of the causes of abnormal urine color. The yellow color of normal urine is mainly from urochrome. Urine typically varies in color from nearly colorless to dark amber, depending on the concentration. Other pigments such as carotene, urobilin, and bilirubin can create an orange appearance. White, milky-appearing urine from precipitated calcium-phosphate is seen in normal children, especially if the urine is refrigerated, and is rarely from chyluria. Pinkish sediment in infant urine is common secondary to precipitated urates that may also cause “brick dust” staining of the diaper. Unusual colors often come from dyes or foods but can be associated with pigments excreted in various diseases. Urine in acute glomerulonephritis typically looks like tea and is variously described as rusty to cola-colored (eFig. 467.1 ). With frank hematuria, the urine varies from a light rosé color to grossly red.


Specific gravity (the weight of 1 ml of urine compared to 1 ml H2O) can easily be measured and correlates roughly with osmolality, which measures the number of osmotically active particles in the urine. Glycosuria and heavy proteinuria increase the specific gravity out of proportion to the osmolality. The assessment of specific gravity by dipstick is not influenced by glucose or contrast media but is affected by protein. Specific gravity ranges from 1.001 to greater than 1.030. If specific gravity is above 1.030, a nonphysiological substance such as contrast media is likely to be present in the urine. Although urine osmolality is the more precise way of describing urine concentration or dilution, it requires special laboratory testing using an osmometer. In children older than 6 months of age, the urine osmolality (the number of osmotically active particles) varies from 50 to 1200 mOsm/kg H2O.

Table 467-1. Causes of Discolored Urine


Urine pH varies from 4.5 to 8 and is dependent on the diet (the higher the protein content, the lower the urine pH), the acid-base status of the child, and the time from collection to testing. Acidic urine (pH < 6) is more likely to be observed after an overnight fast than after a meal. Urine pH rises with standing, especially at room temperature. If the urine is alkaline (pH > 6) in a patient with an acid blood pH, an impairment of bicarbonate reclamation or hydrogen ion excretion may be present. The urine pH indicator commonly found on the dipstick gives only an approximation of the true urine pH. More precise measurements using a pH meter are required for the diagnosis of renal tubular acidosis. Collection of fresh urine and transport under paraffin or in a sealed syringe at 4°C is important to ensure accurate measures.


Urine normally contains a small amount of protein (< 100 mg/m2 per day). Forty percent is albumin, 15% are immunoglobulins, and 5% are other plasma proteins. The other 40% is uromodulin (or Tamm-Horsfall protein), which is the cleavage product of a glycosylphosphatidylinositol anchored to the luminal cell surface of the loop of Henle.2 Urine protein is commonly detected by a change in the color of tetrabromophenol blue impregnated on a dipstick pad and is reported as 0 to +4. This reaction is influenced by the urine concentration and pH (markedly alkaline urine will give a false-positive reaction). Chemically measuring the protein in a timed collection of urine, typically over 24 hours, is a more precise way of determining protein excretion but is difficult in young children. The urine protein-to-creatinine ratio can be used to screen for abnormal protein excretion without needing an accurately timed urine collection. Normal children under 2 years of age have a urine protein-to-creatinine (mg/mg) ratio that is less than 0.5, and older children and adults have a ratio that is less than 0.2.3,4 The urine protein-to-creatinine ratio can estimate the 24-hour urine protein excretion (24-hour urine protein excretion = 0.63 × urine protein/urine creatinine [mg/mg]) and is especially useful for following children with proteinuria in whom repetitive 24-hour urine collections are cumbersome.3

Immunochemical methods can detect concentrations of urine albumin (microalbuminuria) below the threshold of standard chemical methods.4,5 Microalbumin excretion rates on an overnight urine sample (normal < 30 μg/min or < 20 mg/g creatinine) have been used to detect early renal disease, especially that associated with diabetes mellitus.

Transient increases in urine protein excretion can be seen with fever, vigorous activity, and extreme cold.6 A positive reaction of +1 or greater is seen in healthy children transiently, especially if the urine is concentrated. Therefore, several urines should be examined for protein to confirm the persistence of proteinuria before an otherwise healthy child is further evaluated.


The presence of detectable amounts of glucose in the urine is abnormal except in the premature infant. The standard dipstick method of examining urine for glucose utilizes the glucose oxidase reaction, which is quite specific for glucose and can detect 75 to 125 mg/dL of glucose.


The nitrite test is used to detect bacteriuria (Griess test).6 Typically, nitrate but not nitrite is present in urine. If present in urine, gram-negative organisms reduce nitrate to nitrite but this process takes several hours. Therefore, a negative result does not exclude bacteriuria. A high level of ascorbic acid interferes with a positive reaction. Leukocyte esterase is used to detect pyuria.6 Contamination of the urine from a vaginal discharge will give a positive reaction that is not indicative of a UTI or pyuria. Positive reactions should be confirmed with standard urine microscopy.


Hemoglobin and myoglobin will react with the reagents impregnated on the dipstick to form a green to blue color, depending on the concentration. The pad also lyses intact RBCs to allow the intracellular hemoglobin to react with the reagents. The sensitivity of the reaction is reported as being between 5 and 20 RBCs/hpf or 0.015 mg/dL of hemoglobin. Trace reactions are very common and rarely correlated with disease. Positive reactions should be correlated with microscopy. The absence of RBCs on microscopy of the urinary sediment may indicate that the positive reaction is secondary to free hemoglobin or myoglobin but usually simply means that the urinary RBCs have lysed before the microscopic examination.


Careful microscopic examination of the urinary sediment is quite useful in the diagnosis and management of individuals with renal disease. However, routine microscopic examination of the urinary sediment from healthy individuals with a negative dipstick for blood, leukocyte esterase, and protein is of limited value.

Red and white cells in the urine may arise from anywhere in the urinary tract. Normal centrifuged urine contains fewer than three RBCs/hpf. Eumorphic red blood cells in urine resemble those in blood films, but in hypotonic urine, RBCs swell and lose their typical biconcave shape. RBCs that are dysmorphic with variations in size and, especially, blebs like “Mickey Mouse ears” on their outer cell membrane suggest a glomerular origin7 (eFig. 467.2 ). Normal urine contains fewer than five WBCs/hpf. Increased numbers of urinary WBCs may indicate infection, but pyuria can also be seen in noninfectious inflammation of both the glomerulus and the interstitium and in nonrenal disorders, including fever and dehydration.

Casts are formed in the tubule and consist of a proteinaceous matrix with or without cells. Hyaline casts are the most common; are nearly transparent; and can be present in normal urine, after exercise, with dehydration, and with proteinuria. Red cell casts (Fig. 467-1) are almost pathognomonic of glomerulonephritis, although they can be seen with renal infarction, renal trauma, and renal vein thrombosis. RBC casts can appear yellow-brown in color rather than red. WBC casts in the setting of a UTI are indicative of pyelonephritis; they are also seen in other causes of interstitial inflammation and can be difficult to distinguish from epithelial cell casts (broad brown casts), which are seen with tubule injury. Granular casts and fatty casts are observed in nephrotic syndrome, and waxy casts are seen in renal failure.

Crystals are commonly observed in urinary sediment and often have little clinical significance. Uric acid can form a variety of shapes, such as diamonds and needles. Calcium oxalate crystals are octahedrons that appear as a square with an X through the center. Triple phosphate or magnesium ammonium phosphate crystals are prisms that have been likened to “coffin lids”; these can be seen in normal urine that is alkaline but are also seen in abundance with urinary tract infection with urea-splitting organisms such as Proteus. Cystine crystals are flat hexagons and are pathognomonic for cystinuria.

Bacteria can be observed in the sediment but are very hard to distinguish from amorphous phosphates and urates without a Gram stain. Urinalysis reports commenting on the number of bacteria per hpf are usually questionable. The diagnosis of a UTI should rest on bacterial culture results and not on the urinalysis.

FIGURE 467-1. Red blood cell cast.


Routine screening of renal function in healthy children is not cost-effective and is therefore not recommended. Renal function assessment is useful in children in whom a renal disorder is suspected, in longitudinal assessment in children with known renal disease or those likely to be exposed to nephrotoxic therapies, and in calculating the dosage of specific drugs eliminated through the kidney.


A rough assessment of glomerular function is obtained by measuring serum urea and creatinine. In contrast, precise measurement of glomerular function is complicated by a variety of factors, the most important being that the normal kidney alters its glomerular function in response to the workload.8 Following protein loading, normal individuals can increase the glomerular filtration rate (GFR) by 50% to 100%. In early renal disease, unaffected nephrons increase their single-nephron GFR to compensate for diseased nephrons and can thus maintain relatively normal renal function until there is significant nephron loss, masking the severity of the renal disease. Furthermore, GFR actually increases in newly diagnosed diabetics9 and children with sickle cell disease,10 despite later renal disease.

Blood urea nitrogen (BUN) is actually a serum measurement. Levels reflect glomerular function but are influenced by numerous factors: The net balance of production from catabolism of both endogenous and dietary protein, filtration by the glomerulus, and re-absorption by the distal nephron determines the BUN level. Increased protein catabolism such as occurs with stress or corticosteroid therapy will increase BUN independent of any change in renal function. Tubular reabsorption of urea is altered by changes other than glomerular filtration, so it is not a reliable marker of glomerular function. Dehydration alone can raise BUN. Since dietary protein intake alters BUN, the BUN may decrease in children with renal failure who are placed on low-protein diets despite any real change in renal function. Furthermore, a rise in BUN with declining GFR is curvilinear, so that only small changes in BUN occur until a 50% to 60% decline in renal function happens, making it an insensitive and unreliable marker of glomerular function.

Creatinine is the nonenzymatic end product of creatine metabolism. It is freely filtered by the glomerulus and is secreted by the tubule in a concentration-dependent manner such that about 5% is excreted by tubular secretion when the creatinine is normal and as much as 50% when the serum creatinine is 10 mg/dL. Serum levels are essentially independent of the diet, making it a better marker of GFR than BUN. However, creatinine levels correlate to lean body mass, because creatinine is generated from muscle creatine. Muscle wasting lowers serum creati-nine levels independent of renal function. Because of this association with muscle mass, serum levels rise with age. After the age of 4 years, boys have a higher serum creatinine level than girls, although this difference is not significant until after puberty.

Newborns, especially premature infants, have higher creatinine levels than older children, and these levels are inversely correlated to gestational and postnatal age (see Table 467-2). Serum creatinine levels fall rapidly over the first weeks of life as GFR increases postnatally. Like BUN, serum creatinine rises in an exponential curvilinear, rather than a linear, pattern with a decline in GFR; therefore, only minimal increases are observed until 50% to 60% of function is lost. The serum creatinine doubles for each halving of GFR, so a serum creatinine of 0.8 mg/dL that increases to 1.6 mg/dL would indicate that GFR had decreased by 50%.

Cystatin C, a low-molecular-weight protein produced by all nucleated cells, can also be used as a marker of GFR.11 Cystatin C levels are independent of gender and body composition. They are highest in preterm infants and decline to adult values by age 1.5 years (Table 467-2). Some studies suggest that cystatin C levels can show a decrease in GFR before serum creatinine. Cystatin C is not cleared by the placenta; thus, it is a more accurate indicator of renal dysfunction in fetuses12 and newborn infants with renal malformations.13 Several formulas have been devised to estimate GFR from serum cystatin C levels, but most are quite complex, limiting their application in clinical medicine.

Clearance is the classical method of describing glomerular renal function and is the volume of plasma completely cleared of a given substance per unit of time. Mathematically, clearance is the excretion rate of that substance divided by its plasma or serum concentration:

Cx = (UxV)/Px

where Ux is the urine concentration of x, V is the urine flow rate, and Px is the plasma concentration. Substances that are freely filtered across the glomerular capillary wall and are not reabsorbed or secreted by the renal tubule can be used to determine the glomerular filtration rate (GFR). Traditionally, inulin, a polymer of fructose, has been the reference method for measuring GFR. However, inulin clearance measurements are difficult and are performed only in specialized renal units.

Table 467-2. Normal Values for Serum Creatinine, Cystatin C, and Creatinine Clearance by Age

Creatinine clearance (Ccr) is the most widely used method to estimate GFR, but because creatinine is secreted by the tubule, Ccr overestimates the GFR, and this overestimate increases with decreasing GFR. At normal levels of GFR, the Ccr is about 10% to 20% above the actual GFR, but at a GFR below 10 mL/min, the creati-nine clearance is nearly twice the inulin clearance, although this usually does not alter management. Ccr requires a complete collection of urine over 24 hours to minimize collection and timing errors. Obtaining a complete urine collection is often problematic and can be assessed by comparing the measured creatinine excretion with the expected excretion of urinary creatinine (10 to 20 mg/kg per day, or in postpubertal girls, 1 g/d and in postpubertal boys, 2 g/d). Because of the difficulties in performing timed urine collections, estimates of Ccr have been devised based on the child’s height, which is better correlated with creatinine excretion than weight, and serum creatinine. One such formula for estimating creatinine clearance is

Ccr(mL/min/1.73m2) = k × Ht (cm)/Scr(mg/dl)

where k = 0.55 for children and adolescent girls,0.7 for adolescent boys, 0.45 in term infants, and 0.33 in low-birth-weight infants.14 Scr is serum creatinine concentration. Despite limitations, in the clinical setting in which glomerular filtration rate (GFR) is being followed over time in the same patient, an estimate of GFR based upon creatinine clearance is both practical and helpful in tracking the course of renal function. Single-injection techniques provide an alternative for measuring GFR without collecting urine. The radioisotope 99m technetium diethylenetriaminepentaacetic acid (DTPA) is not metabolized and is eliminated only by glomerular filtration, so the disappearance of the DTPA from the plasma is related to the GFR. This test is readily available in most nuclear medicine laboratories and is therefore quite useful.

The GFR rises rapidly and curvilinearly over the first year of life and then increases gradually until puberty. After 2 years of age, the GFR or creatinine clearance, when expressed per unit surface area (typically 1.73 m2), is relatively constant. Before 2 years of age, knowledge of the different values for GFR for each conceptual and gestation age is necessary (see Table 467-2).


Although glomerular function can simply be described in terms of the GFR, tubular function and its assessment is more complex. The tubule can be divided into the proximal and distal portions, although this is a gross oversimplification.

Tubular function is usually described in terms of the clearance of a solute that is handled by a specific segment of the nephron or in terms of the overall clearance of a solute that is handled in several sites along the nephron, which is the case for most solutes. Another way of describing tubular function is to compare the clearance of a solute to the GFR, usually estimated by the creatinine clearance. This is termed the fractional excretion (FE) of that solute. The FE of any solute x can be determined by the ratio of the urine concentration of x to the plasma concentration of x, divided by the ratio of urine creatinine concentration to the plasma concentration:

Ux/Px ÷ Ucr/Pcr

This is usually multiplied by 100% to generate the percent fractional excretion. Subtracting the %FE from 100% will give the percent tubule reabsorption.

Disorders of the proximal tubule vary from excess loss of a single solute, such as renal glucosuria, to global loss of virtually all solutes reabsorbed in the proximal nephron, as observed in the Fanconi syndrome. The distal nephron has many functions, but the ability to concentrate and acidify the urine are most often used to assess distal nephron function. The maximal urine-concentrating ability is determined by measuring the urine concentration after an overnight fast. A normal response is for urine specific gravity to exceed 1.020 or a urine osmolality to exceed 800 mOsm/kg. This test should be done only in a closely monitored setting if the child typically drinks fluid during the night or if there is a strong possibility of diabetes insipidus (see Chapter 525). A urine pH of less than 5.5, either spontaneously or after an acid load, indicates that the distal nephron can generate acid urine, ruling out the diagnosis of type I distal RTA. Other methods of testing the distal nephron acidification mechanisms are measuring the urinary titratable acid excretion, ammonium excretion, and the concentration of CO2 in alkaline urine. A positive urinary ion gap,

UCl – (UNa + UK)

can be used to infer intact ammonium excretion; a negative urinary ion gap during acidosis suggests inadequate ammonium generation.15 Subjects with normal distal nephron hydrogen ion pumps are able to raise the urine pCO2above 60 mm Hg, as measured with a standard blood gas instrument. This test requires an excess of urinary bicarbonate. Individuals with absent or impaired H+ion pumps cannot raise the urinary pCO2.15



IVP is the classic method of imaging the kidneys, ureters, and bladder, but it does require the intravenous injection of radiocontrast. Poorly functioning kidneys will not be visible, because sufficient contrast will not accumulate. Thus, one limitation of the IVP is the need for a moderate amount of renal function in order to obtain adequate images. The contrast also can cause allergic reactions and is potentially nephrotoxic. In addition, the patient receives some gonadal irradiation in the course of the study. These limitations have led to other modalities replacing this test.


VCUG is useful for imaging the urethra and bladder and is the only reliable method of determining the presence of vesicoureteral reflux (VUR). Using radiocontrast allows imaging of the urethra, which is especially important in boys, as urethral abnormalities are much more common in this group.


This test has largely supplanted the IVP for imaging the kidneys and bladder. The advantages of renal ultrasonography compared to IVP are that it does not require any renal function to image a kidney, is not painful, involves no ionizing radiation, and is not associated with allergic or toxic reactions. Renal size, position, and pelvic dilatation can be easily determined by an experienced ultrasonographer. Increased sound wave return, termed increased echogenicity, indicates abnormalities of the renal tissue, such as dysplasia or inflammation. Tumors, cysts, and stones are easily identified. Color Doppler techniques allow identification of renal vessels and characterization of vascular flow quality. Abnormalities of the bladder, bladder wall thickness, and postvoid residual volumes can also be determined using ultrasonography. Ureters, unless dilated, are not routinely seen.


Technetium-99m mercaptoacetyltriglycine (MAG3) and dimercaptosuccinic acid (DMSA). MAG3 provides a dynamic image of the kidneys. The first seconds reflect blood flow to each kidney, followed by extraction of the nuclide by the glomerulus and proximal tubule, and subsequently the excretion of the nuclide from the kidney. Thus, MAG3 provides valuable information on renal function. DMSA gives a static but clearer image of the kidneys, because it binds to renal tissue. It is not useful for imaging the ureters or bladder. DMSA is be useful for imaging renal scars and acute renal infections.


CT provides excellent images of the genitourinary system, especially when performed with intravenous radiocontrast. CT scanning is the modality of choice for renal trauma and often for renal tumors. This technique is also useful for detecting nephrocalcinosis and small renal stones. Spiral CT scanning with computer-enhanced reconstruction of the arterial phase of renal perfusion after an intravenous bolus injection of radiocontrast also provides a relatively good image of the renal arteries, avoiding aortic catheterization. Spiral CT has been used to evaluate patients with suspected renal artery stenosis and to evaluate kidney transplant donors. MRI is increasingly being used for renal imaging.16 It also defines renal anatomy, especially in the setting of complex anomalies and tumors but does so without exposure to ionizing radiation. The renal arteries can be imaged with the rapid injection of gadolinium. Assessment of renal transit time; differential renal function; and, in some centers, estimation of GFR can be obtained with the injection of gadolinium in conjunction with MRI. The disadvantage of MRI is the need to remain motionless for significant periods of time, which often requires sedation in young children. Gadolinium may also cause nephrogenic fibrosing dermopathy when used in patients with renal failure.


Renal arteriography is reserved for patients in whom precise definition of the renal arterial system, such as those with renal artery stenosis or renal tumors, is necessary. Balloon dilatation of the stenotic renal artery can often be done at the time of arteriography, thus avoiding the need for surgical correction. Renal arteriography may also be useful in localizing a site of renal bleeding.


Percutaneous renal biopsy is usually accomplished using a spring-loaded biopsy needle guided with ultrasonography. In older children, the procedure can be done with sedation, but young and uncooperative children may require general anesthesia. The procedure is relatively safe in experienced hands, although rarely, life-threatening bleeding can occur. The tissue obtained is processed for histopathology using standard histochemical stains and is examined by light microscopy; immunofluorescent staining with antibodies to human γ-globulin and complement components provides information on the presence of these immune reactants. Electron microscopy is also routinely performed to examine ultrastructure and to detect electron-dense deposits. Biopsy is often required to allow a specific pathological diagnosis and to evaluate the severity and chronicity of the disease process. The usual indications for renal biopsy in childhood are (1) steroid-resistant nephrotic syndrome, (2) heavy proteinuria without the nephrotic syndrome, (3) glomerulonephritis other than poststreptococcal, (4) recurrent gross hematuria with significant proteinuria, (5) reduced renal function unexplained by renal imaging or the patient’s history, and (6) a family history of progressive nephropathy.


The diagnosis of several heritable renal diseases can be made by genetic testing without the need for invasive procedures. Genetic testing also allows the prenatal diagnosis of certain renal diseases in a fetus at risk or allows identification of a potential problem before it becomes manifest.