Pediatric Proteinuria

Persistent proteinuria is the signal indicator of a glomerular lesion. It also may play a central role in the progression of glomerular lesions to later stages of chronic kidney disease. ^{[1, 2]} Therefore, some consider proteinuria to be nephrotoxic. The current consensus is that lessening the degree of proteinuria is an imperative of renoprotective therapy. The goal of pharmacotherapy is mitigating glomerular hyperfiltration with the use of either angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs).

This discussion focuses on proteinuria in children who appear well and in whom proteinuria is often incidentally discovered during an examination done for reasons other than an evaluation for suspected kidney disease.

The prevalence of proteinuria on a single test of urine is estimated to be 5-15%. Repeated tests, perhaps up to 3 times over a period of several weeks, should be performed to verify that a single instance of proteinuria is, in fact, persistent. First-voided morning specimens should be used to establish if proteinuria is persistent. The National Kidney Foundation Consensus Panel on Proteinuria, Albuminuria, Risk, Assessment, Detection, and Elimination (PARADE) reported that even after 4 tests, 10.7% of children have proteinuria in 1 of 4 specimens. ^[3] However, only 0.1% had positive protein results in all 4 specimens, emphasizing that it is the persistence of proteinuria that is significant, albeit that it is much less frequent than a positive result for the presence of protein if only a single specimen is tested.

The American Academy of Pediatrics (AAP) no longer advises routine screening of healthy children for kidney disease using urinalysis at any age. ^[4] The revised periodicity schedule may be downloaded from the AAP Web site. If this recent recommendation is widely implemented, the detection of proteinuria as an incidental finding will be markedly reduced. Although the limited cost-effectiveness of nontargeted urine screening of the well-child population has driven this revision, the impact of failing to detect significant kidney disease in an asymptomatic child remains to be determined.

The commonly used dip-and-read test strip (dipstick) mainly detects albumin among the various proteins in urine. This test is sensitive to albumin concentrations as low as 15 mg/dL. However, it is not sufficiently sensitive for detecting albumin in the range of microalbuminuria (ie, albumin excretion of 30-300 mg/d in an adult). The threshold for transition from microalbuminuria to dipstick-detectable albuminuria (300 mg albumin excreted per day in an adult) corresponds to a concentration of 15 mg/dL if the daily urine volume is 2000 mL. This level gives only a trace result with the dipstick and is not sensitive for the detection and quantitation of microalbuminuria.

A sensitive and specific assay for albumin is used for the quantitation of albuminuria in the microalbuminuric range. Specialized test strips are now available to specifically detect microalbuminuria as a marker for early kidney involvement due to hyperfiltration injury, as is observed in diabetes, hypertension, or other kidney diseases with reduced nephron mass.

Because the most widely used test for detection of proteinuria is the dipstick test, which is actually a test for albumin, the term proteinuria is used as a surrogate for albuminuria in the remainder of this discussion. However, the caveat remains that quantitative estimates of proteinuria performed at clinical chemistry laboratories reflect the sum total of several classes of proteins and yield a result greater than the actual amount of albumin in the specimen. Moreover, recent concepts of the renal handling of albumin, including its degradation within the kidney, suggest that the measurement of albumin excretion as the intact molecule is an underestimate of the actual quantity processed by the kidney subsequent to filtration.

The dipstick (see urinalysis) test is the most convenient method for routine testing and is often the test that causes proteinuria to be first identified in an otherwise asymptomatic individual. The urine should be tested as soon after voiding as possible. The color developed 60 seconds after immersion is compared to a chart on the side of the bottle. Gradations from light to dark green reflect increasing concentrations of albumin. Dilute urine, as may occur when a random urine specimen is tested in the middle of the day, may mask significant proteinuria. Conversely, highly concentrated urine may suggest clinically significant proteinuria when the actual degree of proteinuria is not severe. If highly dilute or concentrated urine is positive for proteinuria, a more reliable estimate is made by using the protein-to-creatinine ratio (see below).

A false-positive result may occur if the urine is highly alkaline (pH >8) or if a skin-disinfecting agent, such as chlorhexidine or benzalkonium chloride, contaminates the specimen. The dipstick result may be difficult to read if the urine is abnormally colored because of nitrofurantoin, riboflavin, azo-containing sulfonamide antimicrobials, or blood.

The dipstick test for protein provides a crude semiquantitative estimation of protein concentration, with results as follows:

• Trace = 5-20 mg/dL

• 1+ = 30 mg/dL

• 2+ = 100 mg/dL

• 3+ = 300 mg/dL

• 4+ = Greater than 2000 mg/dL

The dipstick color transition between negative and trace may not be easily distinguished. Although colors reflecting heavy proteinuria in the range of 3+ and 4+ are readily discerned, confirming grades 1+ and 2+ using sulfosalicylic acid reagent is advisable. The use of this reagent is also a semiquantitative test based on an estimate of the degree of turbidity. However, it has decreased specificity for albumin.

In any child with a positive dipstick result greater than trace for protein, a quantitative estimate of proteinuria should be determined. In older children and adolescents, a 24-hour collection may be performed. The usual rate of excretion of protein is somewhat higher in children than in adults, perhaps as much as 200 mg/d in older children. However, referencing 24-hour protein excretion to the patient's body size is preferable; the reference range is less than 100 mg/m²/d. In this context, protein refers to the aggregate of several different classes of protein in urine as determined by using the usual assay in the clinical chemistry laboratory. In healthy adults, albumin accounts for about 15% of the total protein in urine. Other plasma proteins account for about 35%. Approximately 50% is due to protein originating in the kidney and urinary tract, primarily Tamm-Horsfall protein (also referred to as uromodulin).

In young children, quantitatively assaying the degree of proteinuria by using a single voided specimen is most convenient and is now also widely used in older children in lieu of a 24-hour urine collection. As mentioned above, this test is best done on a first-morning specimen rather than one collected randomly later in the day.

The concentrations of protein and creatinine measured in the clinical chemistry laboratory are used to calculate the protein-to-creatinine ratio. The units of measurement must be the same. If protein is reported as grams per liter and creatinine as milligrams per deciliter, either unit should be converted to the other before the protein-to-creatinine ratio is calculated.

A reference ratio for children older than 2 years is less than 0.2 mg protein per milligram of creatinine. A reference value for infants aged 6-24 months is less than 0.5 mg protein per milligram of creatinine. A protein-creatinine ratio between the lower limit (depending on the age of the child, as mentioned above) and 2 is considered to fall within the subnephrotic range. A protein-creatinine ratio exceeding approximately 2-3 is found in individuals with the nephrotic syndrome. The ratio may be as high as 15 in typical nephrotic syndrome.

One caveat is that the commonly reported norms for protein-to-creatinine ratio are based on average muscle mass and creatinine production, which may not be the case in poorly nourished individuals. The variation in creatinine excretion as a function of body size must be factored into the reference value for the protein-to-creatinine ratio. Adolescent males have a higher muscle mass than females. It is estimated that for a male aged 14-18 years and height and weight at the 50th percentile, the upper limit of the protein-to-creatinine ratio, assuming average creatinine production, is 0.13. Just as in the instance of reference values for blood pressure, there is no one single norm for the protein-to-creatinine ratio that is uniformly applicable to the range of body sizes encountered in pediatrics.

Transient, low-grade proteinuria may occur in a child with fever or when urine is tested shortly after strenuous physical activity. In these instances, the urine should be tested again after fever subsides, or, if the urine was positive for protein shortly after sports participation, it should be tested again 2-3 days later.

Under most circumstances, urine for routine testing is collected in the physician's office.

Orthostatic proteinuria is the most common cause of a positive result for protein in pediatric patients (often tall, physically active adolescents with a slender body habitus). In this circumstance, the detection of isolated proteinuria (in the absence of hematuria) in an asymptomatic individual based on a random specimen collected during the day must be confirmed by repeating the test on a specimen collected immediately upon the patient's awakening in the morning. For this purpose, the child should not be allowed to be active after arising from recumbency until the moment of urine collection. Moreover, to ensure that no residual urine originating from the previous day is in the bladder, the child must completely empty his or her bladder before going to bed the night before the collection. Orthostatic proteinuria is not a kidney disease; it is a benign condition without clinical significance and usually resolves spontaneously. ^{[5, 6]}

A healthy child with orthostatic proteinuria may have a considerable quantity of protein in a 24-hour urine collection, perhaps up to 1000 mg, and may be falsely identified as having kidney disease. Alternatively, if a random urine sample is tested, the protein-to-creatinine ratio may even be in the nephrotic range. As mentioned above, only a first-voided morning specimen should be tested.

Although orthostatic proteinuria does not generally persist beyond the third decade of life, testing for proteinuria on an annual basis is prudent, especially because both pathologic and physiologic proteinuria (ie, the small amount of protein normally present in urine) also has an orthostatic component. If the first-voided morning specimen has a 1+ or greater reaction for protein, further studies are indicated.

Reviews of albumin processing by the kidney have brought to the forefront new concepts about the mechanism and pathologic significance of proteinuria. ^{[7, 8, 9, 10, 11]} The standard model has held that proteinuria is a consequence of increased permeability of the glomerular filtration barrier to plasma proteins. The concept of charge selectivity of the glomerular capillary wall is de-emphasized by recent data, whereas molecular size selectivity is reaffirmed. ^[12]

The role of the proximal tubule in the reclamation and conservation of albumin is of fundamental importance in the assessment of proteinuria. According to one estimate, based on the concentration of albumin in the glomerular filtrate (32 mg/L), the daily filtered load in an adult with a glomerular filtration of 180 L/d approaches 5.7 g, of which only 30 mg of intact albumin is excreted. Thus, in excess of 99.95% of filtered albumin is reabsorbed, based on the measurement of intact albumin. However, taking into account peptide fragments (molecular mass less than 10,000 Da), total albumin excretion inclusive of intact albumin and peptide fragments may approach 1500 mg in an healthy adult, suggesting that the fractional excretion of filtered albumin is actually 0.26 (or 26%) and, conversely, fractional reabsorption is 0.74.

The proximal tubular reabsorption of filtered albumin is accomplished by receptor-mediated endocytosis. A packet of filtrate is engulfed by an invagination of apical membrane at the base of the microvilli, forming an endocytic vesicle. The efficiency of this process is enhanced by the presence of a high-affinity receptor for albumin, cubilin. Cubilin is anchored to the clathrin-coated pit of the evolving vesicle by the membrane-bound protein megalin. The binding to the receptor enriches the albumin content of the vesicle by a factor of up to 40-fold, compared with the fluid phase concentration in the filtrate.

Before the albumin-carrying endosomes can be recycled to the apical membrane, albumin dissociates from cubilin as a consequence of acidification of the endocytic vesicle to a pH less than 6.5. Acidification is mediated by a vacuolar H⁺ -ATPase in electroneutral coordination with chloride influx via a chloride channel (CLC-5). Evidence also suggests a role for the apical Na⁺/H⁺ –exchanger isoform 3 (NHE3), which is incorporated into the early endosome and later contributes to the acidification of the late endosome and the dissociation of albumin from the cubilin-megalin complex. ^[13]

After the endocytic vesicle is pinched off from the apical membrane, 2 alternate pathways are available for the further processing of albumin. One is a high-capacity "rapid transtubular pathway" that shunts albumin away from the degradative pathway and returns the intact molecule to the circulation. This transcytosis of large quantities of albumin in large vesicles is currently the subject of research and some controversy. A second pathway channels albumin to the sorting endosomal compartment and is eventually delivered to the lysosomal compartment for degradation to peptides and amino acids. The latter are transported across the basolateral membrane of the proximal tubular cell.

The receptor-mediated endocytic mechanism of albumin reabsorption also depends on an intact actin cytoskeleton, which stabilizes the apical microvilli and a microtubular array, which provides for the trafficking of endosomes between the base of the microvilli and the endosomal compartment.

This mechanism for albumin reabsorption is saturable and is subject to downregulation as the filtered load of albumin increases. The increased intracellular trafficking and processing of a large albumin load may be proinflammatory. ^[14] Down-regulation is an adaptive response to mitigate the deleterious effects of protein overload, as might occur with an increase in permeability (nephrotic syndrome) or the single-nephron hyperfiltration of chronic kidney disease.

The maximal binding capacity of the apical membrane enrichment mechanism has an upper limit. Beyond the point of saturation of the receptor complex and the combined capacity of the degradative and rapid shunt pathways, overflow albuminuria is, in essence, tubular proteinuria.

A defect in chloride transport from the cytosol to the interior of the endocytic vesicle is associated with albuminuria and low molecular weight proteinuria in patients with Dent disease, an X-linked recessive disorder due to a mutation of the CLC5 gene, which encodes the CLC-5 chloride channel, which impairs acidification of the endocytic vesicle and causes dissociation of albumin from the bound complex, resulting in a diminished rate of recycling of the albumin-free endosome to the apical membrane.

The nephrotoxicity of cadmium and cisplatin is accompanied by proteinuria. Evidence suggests this is a consequence of a nephrotoxin-induced defect in endosomal acidification. One hypothesis is that defective endosomal acidification and the consequent failure to dissociate albumin results in recycling of albumin-loaded cubilin to the apical membrane and in a reduction in the availability of albumin-binding sites in the clathrin-coated pit for the next cycle of reabsorption.

The extensive proximal reabsorption of filtered albumin poses the conundrum that proteinuria may not simply reflect an increase in permeability of the glomerular filtration barrier. The facile presumption that proteinuria is exclusively of glomerular origin obscures the possible tubular contribution to proteinuria, as a consequence of impaired albumin reabsorption. This is especially the case because the glomerular lesion's disruption of the filtering membrane permeability is expected to result in an increased filtered load of albumin, which may exceed the capacity of the proximal tubule for reabsorption.

This paradigm shift implies that excreted protein represents the net effect of the interplay of glomerular permeability alterations and the saturable reabsorptive capacity of the proximal tubule. In other words, pathologic proteinuria has both a glomerular and a tubular component, and the heavy proteinuria of nephrotic syndrome may include a significant component of tubular proteinuria. This paradigm-shifting concept of filtration of albumin at nephrotic levels by the healthy kidney and the notion that nephrotic-range proteinuria of kidney disease represents, in part, an impairment of proximal tubular retrieval of albumin, rather than solely an increase in glomerular capillary wall permeability, is the subject of recent controversy. ^{[10, 11]}

Another paradigm shift has emerged in recent years as research has focused on the role of injury to the podocyte in the proteinuria of glomerular disease. It appears that the podocyte is the primary target of injury due to diverse incitants, and the loss of the integrity of the podocyte layer exceeding a critical threshold results in denudation of the epithelial surface of the glomerular membrane, triggering a sequence of events culminating in sclerosis. Data suggest that detachment of podocytes from the glomerular basement membrane (in essence, podocyturia) is a critical early step in the progression of the glomerular pathology.

Notwithstanding a possible tubular component, as mentioned above, proteinuria generally indicates an alteration in the permeability and selectivity properties of the aggregate glomerular filtration barrier, which encompasses the 3 major components of the glomerular capillary wall: the slit diaphragms between adjacent epithelial cell foot processes, glomerular basement membrane, and the fenestrated endothelial cell layer.

Until recently, the fixed negative electrostatic charge of the sialoprotein coating of the epithelial foot-process layer and glomerular basement membrane was considered an important determinant of the permselectivity of the filtration barrier, limiting delivery of serum albumin to the glomerular filtrate in the absence of disease. However, recent research suggests that molecular size, rather than electrostatic charge interaction, is the key determinant in restricting passage of protein across the filtration barrier.

Recent advances in the genetic basis of heritable kidney diseases now suggest that the ultimate filtration barrier resides in the complex sieve function of multiple proteins comprising the slit pores between interdigitating foot processes of adjacent epithelial cells (podocytes).

Although this discussion focuses on the incidental finding of pathologic proteinuria in an apparently well child, urine should always be tested for protein in any child with hematuria, edema, hypertension, azotemia, failure to thrive, or abnormal imaging of the kidneys and urinary tract.

Although grossly bloody urine commonly produces a positive result for protein, the dipstick test is relatively insensitive to free hemoglobin and does not react with intact erythrocytes. The positive reaction for protein associated with gross hematuria is due to plasma albumin that accompanies erythrocytes into the urine. The amount of plasma albumin that accompanies erythrocytes into the urine in 1 mL of whole blood in 100 mL of urine produces only a trace reaction (if none of the albumin is reabsorbed). High grades of proteinuria detected on dipstick testing of grossly bloody urine should not be ascribed to “blood” because this finding may reflect an underlying glomerular lesion.

Distinguishing nephrotic-range proteinuria from nonnephrotic (or subnephrotic) proteinuria is clinically useful. In adults, nephrotic-range proteinuria refers to excretion of more than 3-3.5 g of protein per 24 hours or a protein-to-creatinine ratio that exceeds 2.5-3 in a random specimen. ^[15] In adults, the albumin-to-creatinine ratio corresponds to the 24-hour albumin excretion in a roughly linear manner. For example, a ratio of 3 is predictive of an excretion of about 3 g of protein in 24 hours.

In children, nephrotic-range proteinuria is greater than 1000 mg/m²/d when body surface area is used as a reference. For a typical 2-year-old child with idiopathic minimal lesion nephrotic syndrome (MLNS), excretion of 500-600 mg per 24 hours constitutes nephrotic-range proteinuria. By comparison, excretion of 1000 mg of protein per day is nephrotic-range proteinuria in an average-sized child aged 9-10 years.

Proteinuria in the subnephrotic range does not distinguish a relatively benign glomerular lesion from a relatively serious type of glomerulonephritis. However, prognostic estimates based solely on the degree of proteinuria are often difficult, and kidney biopsy may be necessary for further definition. One example is immunoglobulin A (IgA) nephropathy, which often manifests as intermittent episodic synpharyngitic hematuria or with the incidental finding of microscopic hematuria. Nephrotic-range proteinuria portends an ominous prognosis. However, subnephrotic proteinuria in IgA nephropathy is of uncertain significance and renal biopsy is often needed.

When not orthostatic or transient, proteinuria always indicates glomerular pathology. Glomerular changes may be due to inflammation (any one of several forms of glomerulonephritis) or may be subtle and seen only on electron microscopy; an example is effacement of epithelial cell foot processes, as observed in the most common cause of nephrotic syndrome in children (ie, MLNS). See Nephrotic Syndrome for more information. In this instance, the earliest clinical manifestation can be fluctuating degrees of periorbital or facial edema. In many instances, allergy is diagnosed and treated with antihistamines. The urine should always be tested in any child with edema, no matter how subtle the findings are.

Nephrotic-range proteinuria may also be the harbinger of focal segmental glomerulosclerosis (FSGS), which has become increasingly common as a cause of idiopathic nephrotic syndrome. Early recognition and prompt treatment with steroids or other immunomodulator drugs may induce a remission ^{[16, 17]} ; although, in many instances, the condition is steroid resistant. It is now recognized that some patients with FSGS have a genetic basis for the lesion and steroid treatment is not appropriate. ^[18]

The distribution of types of protein in the urine varies among the glomerulonephropathies, depending on the degree of glomerular inflammation and its effect on glomerular permeability. MLNS is a prime example of selective proteinuria. Albumin accounts for much of the excreted protein to the exclusion of high molecular weight plasma proteins. Glomerular lesions with florid inflammatory changes result in nonselective proteinuria, wherein albumin-sized molecules are accompanied by larger proteins, such as immunoglobulins. However, albumin is a sensitive marker of glomerular proteinuria, and the dipstick test primarily detects this protein.

In general, the incidental finding of subnephrotic nonorthostatic proteinuria without hematuria in an apparently healthy child may be monitored in the office setting by means of periodic quantitative estimates, perhaps obtained every 4-6 months. If a trend for increasing proteinuria that exceeds 300 mg/d/m² or a protein-to-creatinine ratio of 0.5-1 in a first-voided specimen emerges, or if the threshold to the nephrotic range is crossed, renal biopsy is appropriate for histologic diagnosis, prognostic evaluation, and consideration of initiation of renoprotective therapy with an ACE inhibitor or an ARB.

Although the classic form of postinfectious (often poststreptococcal) glomerulonephritis may not be observed as frequently as in the past, it is generally a benign, self-limited condition. It is rarely accompanied by nephrotic-range proteinuria. Proteinuria in this instance may persist during the first few weeks of illness but then rapidly resolves. Periodic urine testing to establish complete resolution should be done. If low-grade proteinuria persists beyond 12 months after diagnosis, renal biopsy should be considered.

Proteinuria may originate from a unilateral diseased kidney in the presence of an apparently normal contralateral kidney, as with reflux nephropathy or with a hypoplastic or dysplastic kidney. However, if heavy proteinuria is found, evaluation of the presumably normal contralateral kidney should be considered.

Some filtration of low molecular weight proteins (eg, alpha-2 microglobulin, retinal-binding protein, small peptides) occurs. The proximal tubular cells reabsorb most of these filtered proteins. However, modest, low-grade proteinuria may occur in certain congenital metabolic tubulopathies, such as Fanconi syndrome or X-linked recessive nephrolithiasis with kidney failure that results from a mutation in the CLCN5 gene on chromosome 11 (Dent disease). A high grade of proteinuria, approaching the nephrotic range, may occur in a nonglomerular disease, as is seen in some instances of acute tubulointerstitial nephritis. Because dipstick testing is relatively specific for albumin, low molecular weight (tubular) proteinuria may not be detected. If tubular proteinuria is suspected, specific assays for the individual proteins are available in most hospital or commercial laboratories.

Proteinuria in children and adolescents with diabetes mellitus has special significance. Once established, proteinuria may herald the inevitable progression of diabetic nephropathy. Poor glycemic control, as reflected in an elevated hemoglobin A1C concentration, is a major risk factor for diabetic nephropathy. The earliest indicator of glomerular damage is microalbuminuria. This level of albumin excretion is below the threshold of detection by the usual dipstick test for proteinuria. ACE inhibitors and ARBs have come into widespread use for treatment of early stages of disease, in either type 1 or type 2 diabetes mellitus, before an overt nephrotic syndrome emerges.

Because evidence indicates that early intervention may delay or forestall progression of diabetic nephropathy (evidence derived from studies of type 1 diabetes mellitus), all children and adolescents with type 1 or type 2 diabetes mellitus should undergo annual monitoring for microalbuminuria. A person with diabetes mellitus should begin treatment with an ACE inhibitor or ARB if microalbuminuria is documented. The initiation of one of these agents as a preemptive renoprotective intervention before microalbuminuria emerges is currently practiced by some specialists, especially if the hemoglobin A1C is consistently elevated above 8%. The dilemma in this instance is that many people with diabetes mellitus may not have progressive disease, and the uncertain risk, if any, of long-term inhibitors of the renin-angiotensin system remains incompletely understood.

Microalbuminuria is not only a harbinger of kidney damage as a consequence of suboptimal glycemic control. A more expansive view is that it is a marker of endothelial cell injury in many vascular beds and is now considered a risk factor for cardiovascular disease.

The detection of persistent proteinuria (>1+ or protein-to-creatinine ratio of >0.2) in an apparently well child is a signal for potentially serious underlying kidney disease.

The next step in the evaluation includes complete history and physical examination (emphasizing blood pressure measurement and evaluation for edema, rashes, and assessment of growth status); quantitative urine protein excretion (protein-to-creatinine ratio of a first-morning urine); examination of the urine sediment for dysmorphic erythrocytes or casts; determination of blood concentrations of BUN, creatinine, electrolytes, albumin, cholesterol (see HDL cholesterol and LDL cholesterol), complement, antistreptococcal antibody,antinuclear antibody (ANA), and anti-DNA; and tests for hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) infection.

Ultrasonographic estimates of renal size, echotexture, and corticomedullary delineation are useful.

Most chronic nephropathies that appear to be primary glomerular disorders are invariably accompanied by tubulointerstitial disease, which may have a more ominous impact on prognosis than the glomerular lesion. The pathogenesis of tubulointerstitial mononuclear cell infiltration, inflammation, tubular atrophy, and fibrosis has not been clear. However, a concept has emerged that the high rate of albumin trafficking in the proximal tubule during the course of proteinuric kidney diseases results in protein overload and injury to the tubular cells. The mechanism of such injury is not clear, but generation of reactive oxygen species and consequent oxidative injury has been proposed as one explanation.

Increased production of proinflammatory cytokines or increased delivery to the renal interstitium of mediators of inflammation bound to albumin may possibly serve as chemoattractants to monocytes. The potential deleterious effect of protein overload also calls into question the widespread practice of administering intravenous albumin for the management of edema in patients with nephrotic syndrome. In this instance, the mechanism for albumin reabsorption is presumed to be saturated and, thus, overloaded because nearly all the infused albumin is recovered in urine.

Proteinuria is a marker of parenchymal injury in kidney disorders of diverse etiologies. Primary treatment of most disorders by immunomodulator medications is empiric, and a salutary effect is presumed to have occurred if a diminution of proteinuria is observed. In this sense, treatments aimed at the putative mechanism of the disorder, often immune mediated, also treat the proteinuria.

However, ACE inhibitors and ARBs have an established antiproteinuric effect that appears to be unrelated to their other diverse effects, including control of hypertension. ^[19] The conventional explanation for the mechanism of the antiproteinuric effect is that selective vasodilatation of the efferent arteriole lowers the filtration pressure and, hence, the amount of albumin in the ultrafiltrate. This explanation is based on the concept that chronic kidney disease is attended by increased intraglomerular pressure and hyperfiltration as an adaptation to a decline in the number of intact nephrons. However, this does not provide a complete explanation because other medications that do not affect intraglomerular pressure also reduce albuminuria (eg, nondihydropyridine calcium channel blockers).

On the other hand, intraglomerular hypertension has been suggested to result in increased mesangial stretch, which, in turn, may trigger release of transforming growth factor β (TGFβ) and other proinflammatory cytokines that impair the reabsorption of albumin by the proximal tubule. Data suggest that angiotensin II promotes proteinuria by a direct effect on proximal tubular cells. Another possible explanation for the antiproteinuric effect is that ACE inhibitor–induced reduction of angiotensin II and the subsequent decreased availability for binding to angiotensin type-1 receptors of proximal tubule cells results in shunting of reabsorbed albumin away from lysosomal degradation and toward the pathway of direct reclamation of intact albumin via a high-capacity rapid transtubular pathway and its return to the circulation. This mechanism also implies an increased availability of albumin-binding sites by the apical membrane.

 

Proteinuria is an essential marker of kidney disease. However, conventional assays by the clinical laboratory do not distinguish among different classes of proteins present in the urine. Research is now underway to characterize urinary protein excretion by means of proteomic analysis. Emerging data suggest that a proteomic "fingerprint" of the spectrum of urinary proteins will ultimately lead to earlier detection of a pattern of progression and provide markers for assessing pharmacotherapy interventions to mitigate progression of chronic kidney disease.

Because most forms of kidney disease with glomerular pathology can become chronic and progressive, the Kidney Disease Outcomes Quality Initiative Guidelines of the National Kidney Foundation emphasize early detection of proteinuria and initiation of therapies that preserve kidney function. Recommendations for the evaluation of proteinuria in children mentioned in this discussion are based on the consensus panel sponsored by the National Kidney Foundation. ^[3]