PEDIATRICS Vol. 105 No. 6 June 2000, pp. 1242-1249

Evaluation and Management of Proteinuria and Nephrotic Syndrome in Children: Recommendations From a Pediatric Nephrology Panel Established at the National Kidney Foundation Conference on Proteinuria, Albuminuria, Risk, Assessment, Detection, and Elimination (PARADE)

Ronald J. Hogg, MD^*, Ronald J. Portman, MD, Dawn Milliner, MD^§, Kevin V. Lemley, MD, PhD, Allison Eddy, MD^¶, and Julie Ingelfinger, MD^#

From ^* North Texas Hospital for Children at Medical City Dallas, Dallas, Texas;  University of Texas Health Science Center, Houston, Texas; ^§ Mayo Clinic, Rochester, Minnesota;  Stanford University Medical Center, Stanford, California; ^¶ Children's Hospital and Medical Center, Seattle, Washington; and ^# Massachusetts General Hospital, Boston, Massachusetts.

	ABSTRACT

Top Abstract Conclusion References

Objective.  The development of this review article evolved from a National Kidney Foundation consensus conference on recent advances in the importance of evaluating and treating proteinuria. From this conference, a series of recommendations for the evaluation of adults with proteinuria was published. Because specific pediatric aspects of the problem were outside the scope of the original National Kidney Foundation publication, an ad hoc committee of 6 pediatric nephrologists who were active participants in the National Kidney Foundation conference was established to provide primary care physicians with a concise, up-to-date reference on this subject.

Methods.  The recommendations that are given represent the consensus opinions of the authors. These are based on data from controlled studies in children when available, but many of the opinions are, by necessity, based on uncontrolled series in children or controlled trials performed in adults, because controlled trials in children have not been performed to evaluate many of the treatments described.

Results and Conclusions.  These recommendations are intended to provide primary care physicians with a useful reference when they are faced with a young child or teenager who presents with proteinuria, whether this is mild and asymptomatic or more severe, leading to nephrotic syndrome.  Key words:  proteinuria, children, adolescents, nephrotic, nephrosis.

The fact that proteinuria is associated with progressive renal disease is well-established.^1,2 Recent reports have further implicated proteinuria as an effector mechanism in the development of renal injury^3-5 and as a risk factor for cardiovascular disease.^6-8 To review these studies and make the information more available to the public and the medical profession, the National Kidney Foundation held a conference entitled, "Proteinuria, Albuminuria, Risk, Assessment, Detection, and Elimination" in Nashville, Tennessee, on March 25 to 26, 1998. Recommendations for adults with proteinuria were published in the May 1999 issue of the American Journal of Kidney Disease.⁹ The current article provides some specific comments and recommendations regarding risks associated with proteinuria in children and adolescents and the evaluation of such patients. A more detailed description of the subject and a comprehensive bibliography is available on request (telephone: 1-800-345-4426; e-mail: info{at}spnsg.org)

	CLINICAL TESTING FOR PROTEINURIA

The most frequently used screening method for proteinuria is the urinary dipstick, which primarily detects albumin, leaving low molecular weight (LMW) proteins undetected (Table 1). A color reaction between urinary albumin and tetrabromphenol blue produces various green hues based on the concentration of albumin in the sample, eg, trace (15 mg/dL); 1+ (30 mg/dL); 2+ (100 mg/dL); 3+ (300 mg/dL); and 4+ (2000 mg/dL). Because it is the concentration of urine protein that is measured, false-negative results may occur with very dilute urine. Conversely, false-positive results may occur with very alkaline or concentrated urine specimens in the presence of contaminating antiseptics, such as chlorhexidine and benzalkonium chloride, or after the administration of radiographic contrast, eg, after an intravenous (IV) pyelogram. An alternative office procedure to measure urinary protein in patients with questionable proteinuria by dipstick uses protein precipitation with sulfosalicylic acid. This technique provides a more quantitative estimate of all the urinary proteins including LMW proteins.

Urinary protein excretion in adults is usually measured in 24-hour urine collections. However, in young children, accurately timed urine collections are difficult to obtain. Accordingly, the protein/creatinine (Pr/Cr) ratio of an untimed (spot) urine specimen (preferably a first morning specimen, because urine protein concentrations can vary significantly during the day) is often used to estimate protein excretion in children. The urine Pr/Cr ratio has been shown to reflect 24-hour urine protein excretion quite accurately, particularly since first morning specimens eliminate the possibility of postural proteinuria.^10,11

	PROTEIN HANDLING BY THE KIDNEYS IN NORMAL CHILDREN

The normal rate of protein excretion in the urine is <4 mg/m²/hour or <100 mg/m²/day throughout childhood in both boys and girls (Table 1). Approximately 50% of this small amount of protein consists of Tamm-Horsfall protein, a glycoprotein secreted by the ascending limb of the loop of Henle. The rest is comprised of small quantities of plasma proteins filtered by the glomeruli, eg, albumin, immunoglobulins, transferrin, and ₂-microglobulin, with albumin comprising <30% of the total urinary protein in normal individuals. The low excretion rate of protein occurs because: 1) the glomeruli restrict filtration of large serum proteins such as albumin and immunoglobulins, and 2) the proximal tubules reabsorb most of the LMW proteins, such as insulin or ₂-microglobulin, which are filtered across the glomeruli. The resultant modest proteinuria that is present in normal individuals is usually not detected on routine dipstick testing.

	PROTEIN HANDLING BY THE KIDNEYS IN CHILDREN WITH RENAL DISORDERS

Excess urinary protein losses may be caused by either: 1) increased permeability of the glomeruli to the passage of serum proteins (glomerular proteinuria), or 2) decreased reabsorption of LMW proteins by the renal tubules (tubular proteinuria). The finding of proteinuria in a single urine specimen in children and adolescents is relatively common. The prevalence varies in different studies but is generally between 5% and 15%. However, the finding of persistent proteinuria on repeated testing is much less common. In 1 study, which involved nearly 9000 school-aged children, proteinuria by dipstick was found in 1 of 4 samples in 10.7% of the children; however, only .1% had proteinuria in all 4 urine specimens tested.¹²

When proteinuria is detected, it is important to determine whether it is transient, orthostatic, or persistent in type. Transient proteinuria, which is most often associated with fever, stress, dehydration, or exercise, is not considered to be indicative of underlying renal disease. Orthostatic proteinuria, defined as 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/m²/day. Long-term follow-up studies have documented the benign nature of orthostatic proteinuria in such individuals, although rare cases of glomerulosclerosis have been identified later in life in patients who were initially found to have proteinuria with an orthostatic component.^13,14 Persistent proteinuria, defined as proteinuria of 1+ by dipstick on multiple occasions, is abnormal and should be further investigated.

	ASSOCIATION BETWEEN PROTEINURIA AND PROGRESSIVE RENAL DAMAGE

Recent studies have shown that increasing levels of proteinuria provide the best predictor of progressive renal damage in both adults and children with proteinuric renal disease.^15,16 Over the past decade, there has been mounting evidence that persistent proteinuria should be viewed not only as a marker of renal disease, but also as a cause of progressive renal injury.^3-5 Some of the mechanisms whereby proteinuria seems to induce renal injury are listed in Table 2.

	ASSOCIATION BETWEEN PROTEINURIA AND CARDIOVASCULAR DISEASE

Proteinuria of any magnitude has been identified as a risk factor for cardiovascular disease in adults.^6-8 Severe persistent proteinuria may also be a long-term risk factor for atherosclerosis in children.¹⁷ As the severity of proteinuria increases, it is associated with a variety of metabolic disturbances that contribute to cardiovascular disease, eg, hypercholesterolemia, hypertriglyceridemia, and hypercoagulability. In some patients, factors such as hypertension, renal insufficiency, and steroid therapy may also contribute to the risk for cardiovascular disease.

	EVALUATING CHILDREN WITH PROTEINURIA

The first step in the evaluation of a child with persistent dipstick proteinuria (1+) should be to obtain a complete urinalysis and a first morning spot urine specimen to determine the Pr/Cr ratio (Fig 1). It is important to have the child void before going to bed and remain recumbent until just before obtaining this specimen. If the urinalysis is normal and the urine Pr/Cr ratio on the first morning urine sample is <.2, a diagnosis of orthostatic proteinuria may be made and no additional studies are necessary. However, if the urinalysis shows other abnormalities and/or the first morning urine Pr/Cr ratio is >.2, the complete history and physical examination, including blood pressure, should be reviewed, and the blood level of albumin, creatinine, cholesterol, and electrolytes should be determined. Renal ultrasonography and measurement of serum C3/C4 complement, antinuclear antibody, and serologies for hepatitis B and C and human immunodeficiency virus should also be considered. If any of the studies are abnormal, the child should be referred to a pediatric nephrologist for further evaluation.

View larger version (39K): [in this window] [in a new window]   Fig. 1.   Algorithm describing the evaluation of asymptomatic proteinuria in children.

	NONSPECIFIC TREATMENT OPTIONS FOR PERSISTENT PROTEINURIA

Dietary Recommendations

Although some benefit from dietary protein restriction has been described in a small series of children with chronic renal insufficiency,¹⁸ a recent controlled study has not demonstrated a significant impact of protein restriction on the rate of progression of renal disease.¹⁶ However, it seems reasonable to avoid an excess of dietary protein in children with proteinuric renal diseases, because high dietary protein intake may actually worsen proteinuria, at least in some patients with nephrotic syndrome (NS), and does not result in a higher serum albumin. Thus, it is recommended that children with proteinuria receive the recommended daily allowance of protein for age.^16,19

Blood Pressure Control/Inhibition of Angiotensin Effects

Renal function is better preserved in children with chronic renal disease when lower systolic blood pressures are achieved. The choice of antihypertensive agent for such patients should be individualized and determined in consultation with a pediatric nephrologist. Certain classes of antihypertensive agents, eg, the angiotensin converting enzyme inhibitors (ACEi) and the angiotensin II receptor blockers may, in addition to reducing systemic blood pressure, exert other beneficial effects, such as reducing urinary protein excretion and decreasing the risk of renal fibrosis.²⁰ However, the long-term benefit of ACEi in children and adolescents with proteinuria remains to be established definitively, and there are some concerns with the use of these agents in infants.^21-23 It is known that infants born to mothers receiving ACEi during the second and third trimesters of pregnancy may develop oligohydramnios, pulmonary hypoplasia, hypocalvaria, postnatal hypertension, and anemia. In several such neonates who died, postmortem examination revealed severe glomerular and tubular malformations in the kidneys.²³ It is clear, therefore, that ACEi are contraindicated during pregnancy. Risks of ACEi and angiotensin II receptor blockers in young infants are unknown.

	APPROACH TO PROTEINURIA IN ADOLESCENTS WITH INSULIN-DEPENDENT DIABETES MELLITUS (IDDM)

Good glycemic control remains the first goal in preventing renal injury in IDDM, the first sign of which is usually microalbuminuria.²⁴ However, a consensus is developing to treat young patients with IDDM who have persistent microalbuminuria or proteinuria with low doses of an ACEi.^25-27 Microalbuminuria may be defined as 20 to 200 µg/minute/1.73 m², or 30 to 300 mg albumin/g creatinine, on a first morning urine specimen. Overt proteinuria is associated with albuminuria >200 µg/minute/1.73 m². Although there are currently no controlled studies in children indicating exactly when ACEi therapy should be started, a reasonable approach in children with IDDM is to begin such treatment when urinary albumin excretion exceeds the normal range.

	EVALUATION AND TREATMENT OF PATIENTS WITH NS

NS may be defined as heavy proteinuria, that is severe enough to cause hypoalbuminemia, hypercholesterolemia, and usually edema. The prevalence of NS in childhood is lowapproximately 2 to 3 cases per 100 000 children. Hence, it is common for pediatricians and family physicians to encounter very few children with NS in their practices. In view of the relative rarity and serious nature of the condition, once a child has been found to have NS, early referral to a pediatric nephrologist is recommended. Long-term and day-to-day management of a child with NS should be a collaborative effort between the primary care physician and pediatric nephrologist.

In clinical practice, most children with NS are treated initially without undergoing a kidney biopsy, because the majority will have steroid-responsive minimal change NS.²⁸ However, a pretreatment biopsy should be considered for patients who develop NS in the first year of life or during adolescence²⁹ or for those who have presenting features that make the possibility of minimal change NS less likelysuch as persistent hematuria, hypertension, depressed serum complement levels, or reduced renal function.

Clinical Problems Associated With Childhood NS

Edema Edema is usually the first clinical feature that brings a child with NS to the attention of a physician. Initially, the edema is often mild and variable in distributionbeing periorbital in the early morning hours and more generalized after the patient has been ambulatory. This gravity-dependent movement of fluid frequently results in a patient with NS being misdiagnosed as having an allergic disorder until the edema becomes more severe (and persistent) or until a urinalysis is obtained. More severe degrees of edema may result in clinically significant problems with ascites, pleural effusions, scrotal or vulvar edema, and skin breakdown. Mild degrees of edema do not require specific measures, whereas more severe edema may require diuretic therapy (as discussed in "Approaches to Treatment in Children and Adolescents With NS").

Electrolyte Disturbances in NS Although NS is usually associated with avid sodium retention, serum sodium concentrations are low in some patients. In many instances, this hyponatremia results from even more avid water retention, secondary to high antidiuretic hormone levels. It should be appreciated, however, that total body sodium is almost always increased in children with NS, especially those who are edematous, despite low serum sodium concentrations and, in some patients, reduced intravascular volume. In other patients with NS, apparent hyponatremia may result from very high lipid levels. This condition, known as pseudo-hyponatremia, is dependent on the methodology by which sodium is measured. In some laboratories, the technology used to assay serum sodium levels excludes the lipid phase, in which case pseudo-hyponatremia does not occur.

Infections A varicella antibody titer should be obtained in all children with NS who have not been vaccinated or have not had chickenpox in the past, because this infection may be very serious in a nephrotic child taking steroids or other immunosuppressive agents. If a susceptible child on steroids is exposed to a patient with chickenpox, varicella-zoster immunoglobulin should be given within 72 hours of exposure to prevent or lessen the severity of the disease. In such a patient, the dose of glucocorticoid should be tapered to no more than 1 mg/kg/day until the incubation period has passed. Acyclovir or valacylovir should be given if varicella does develop. In severe cases, consultation with an infectious disease specialist is recommended.

Immunizations Immunization practices and recommendations from pediatric nephrologists have been published in detail previously.^32,33 This section will provide only a brief update. Although the risk of precipitating a relapse is often stated as a reason for not giving immunizations to children with NS, there are no data to support this stance. In general, the benefits conferred by a standard vaccination program seem to outweigh the potential risks, but the advantages and disadvantages of each vaccine should be considered on an individual basis with the parents of each child. Live viral vaccines should not be given to a child receiving high doses of steroids or other immunosuppressive drugs.

Hyperlipidemia Transient hypercholesterolemia in patients with steroid-responsive NS can be quite severe (eg, serum cholesterol levels 300-500 mg/dL or more) but usually resolves when the NS has been treated successfully. In contrast, persistent hypercholesterolemia and hypertriglyceridemia are common in patients who have treatment-resistant NS. The potential implications of this hyperlipidemia are of concern because preliminary data indicate that atherosclerosis may develop at a relatively young age in children with persistent nephrotic range proteinuria.¹⁷ However, the treatment of hyperlipidemia is not well-studied in children, and dietary modification is usually of limited benefit. Cholestyramine is currently the only drug approved for children but small uncontrolled studies suggest that hepatic hydroxymethylglutaryl coenzyme A reductase inhibitors may be safe and effective in children with hypercholesterolemia associated with refractory NS.^35,36

Thromboembolism Patients with NS usually demonstrate laboratory features of a hypercoagulable state. Venous or, much less commonly, arterial thrombosis represents a particular problem and may be associated with pulmonary embolism. Reduced intravascular volume predisposes to thrombotic events. Hence, it is important to recognize and treat such patients. The use of diuretics must be judicious and must be avoided in patients known to have sustained a thromboembolic event. Antiplatelet drugs and/or anticoagulants are recommended for patients with thrombo-embolic events. Whether prophylactic use of these agents is beneficial for the prevention of thrombotic episodes in children with NS has not been studied carefully. We recommend that such measures only be considered after pediatric nephrology consultation.

	APPROACHES TO TREATMENT IN CHILDREN AND ADOLESCENTS WITH NS

Specific Treatment Options

We recommend that, whenever possible, the specific treatments listed in this section, particularly those described in the subsections entitled "IV Pulse Steroids" to "Levamisole," only be given after referral to a pediatric nephrologist (Fig 2). Note that a number of the terms used in this section to define responses to treatment in childhood NS are provided in Table 3.

View larger version (49K): [in this window] [in a new window]   Fig. 2.   Algorithm describing the management of NS in children/adolescents.

Prednisone/Prednisolone Prednisone and prednisolone represent the mainstay of treatment in children with idiopathic NS. Liquid preparations of prednisolone (eg, Prelone [Muro Pharmaceutical, Inc, Tewksbury, MA] and Pediapred [prednisolone sodium phosphate; Fisons Corporation, Rochester, NY]) allow for accurate dosing and increased palatability in young children. A typical protocol is to start with high-dose prednisone or prednisolone (2 mg/kg/day or 60 mg/m²/day; maximum: 80 mg/day) in 1 to 3 divided doses. This treatment is continued until the patient becomes free of proteinuria or for a period of 4 to 6 weeks. The patient is then converted to a maintenance dose of alternate-day treatment, ie, 2 mg/kg or 40 mg/m² every other day in the morning, and this dose is gradually tapered and stopped after an additional 4 to 6 weeks. Some recent studies suggest that 6 weeks of daily therapy followed by 6 weeks of alternate day therapy (6 + 6 weeks) induce a higher rate of long remissions than the standard 4 + 4 weeks of treatment. However, the frequency of adverse events is higher with the longer courses, and the degree of benefit has been variable. Hence, there is currently no consensus on the optimal duration of the initial course of therapy.

IV Pulse Steroids Infusions of high-dose methylprednisolone (eg, 30 mg/kg of body weight, up to 1 g/infusion) have been used recently with success in some patients with steroid-resistant NS.³⁷ The first 6 infusions are usually given every other day, followed by a tapering regimen for periods up to 18 months. The decision to use such treatment regimens in children should only be made by a pediatric nephrologist. Side effects of IV steroids are essentially the same as the problems noted above with oral prednisone. Additionally, the patient may become hypertensive during the infusions, and cardiac arrhythmias have been described rarely in adults receiving such therapy.

Cytotoxic Drugs When steroid side effects become troublesome after multiple courses of steroids, or when there is failure to respond to steroid therapy, other strategies should be considered. Many pediatric reports indicate that cyclophosphamide or chlorambucil, each given over a period of 8 to 12 weeks, can achieve long periods of remission and reduce the need for steroids.³⁸

Cyclosporine A An alternative treatment for patients with steroid-dependent or -resistant NS is cyclosporine A.^39,40 However, patients who respond to cyclosporine A tend to relapse once the medication is withdrawn. Cyclosporine A may increase blood pressure or aggravate preexisting hypertension. Some patients demonstrate nephrotoxicity, as evidenced by an increase in serum creatinine. Increase in serum potassium and occasionally a decrease in serum magnesium may also be seen. Hypertrichosis and gingival hyperplasia are common. A pediatric nephrologist should manage all children with renal disease who are on cyclosporine A.

Levamisole Levamisole, which has been used for treating frequently relapsing NS in children outside the United States, has been reported to be effective and well-tolerated in such patients. Early side effects that may occur with Levamisole, such as neutropenia, rash, gastrointestinal disturbances, and, rarely, seizures, were not seen in the patients reported.^41,42 Levamisole therapy must be continued for relatively long periods in most patients to maintain them in remission. Such patients must be monitored for long-term side effects.^41,42

Other Practical Aspects of the Management of Children With NS

Each child should have an individual assessment for any changes that might be needed in day care, schooling, activities, and diet. Most children can and do limit their own activities when nephrotic. Recommendations about sports participation while on high-dose steroids should be considered on an individual basis. Age-appropriate explanations about the appetite-stimulating effects of steroids, and recommendations for a nutritious, relatively low-fat diet with age-adjusted recommended daily allowance of protein, carbohydrates, and other components will help children avoid large weight gains.⁴³ Salt intake should be limited to control edema and reduce the risk of hypertension especially when daily glucocorticoids are given. Setting a fluid intake limit of about twice the rate of insensible water loss may be helpful in an edematous child. This restriction should be discontinued when the urine output increases in response to specific treatment.

In practice, most patients with NS are monitored closely at home by their parents (or themselves when old enough). Frequent monitoring of body weight and urine dipstick protein levels are undertaken, and the records of these findings are very important in the clinic evaluations of the patients. Such records also often provide the first indication of a relapseleading the parents to call the health care provider to ask for therapy modification before edema is apparent. Specific approaches of individual pediatric nephrologists to the management of such events vary, but the important role of parents in identifying relapses and treatment complications should be stressed. Waiting for edema to herald a relapse of NS often results in much higher patient morbidity.

Adjunctive therapy with ACEi in patients with steroid-resistant NS is now being prescribed more frequently. This therapy may decrease the rate of urinary protein excretion by as much as 50%. However, the long-term benefit of ACEi in childhood NS is unproven with regards to progression of disease; and these agents should only be given under the direction of a pediatric nephrologist. ACEi should not be given to children with NS during the time they are receiving their initial course of prednisone because they could become hypotensive and have an increased risk of thrombosis, particularly if they have a rapid diuresis.

Diuretics should not be used to treat mild degrees of edema in children with NS. Judicious use of diuretics, such as furosemide (1-2 mg/kg/day) may be used under the direction of a pediatric nephrologist if the child has severe edema. The combined use of IV albumin and furosemide to raise serum albumin and induce a diuresis should be undertaken with caution, because it carries significant inherent risks for hypertension and even pulmonary edema. Hypertension may also be a serious problem when patients with NS receive over-the-counter decongestants, especially while they are on daily steroids.

	CONCLUSION

Top Abstract Conclusion References

It is evident that in recent years proteinuria has become increasingly recognized as a marker and mediator of progressive renal insufficiency and a risk factor for cardiovascular disease. It is important, therefore, that the management of children with persistent proteinuria or NS should be conducted or supervised by physicians who are experienced in treating patients with these problems. Hence, a pediatric nephrologist should be consulted regularly even if the patient resides in an area where there is no pediatric nephrologist in close proximity. In all cases, optimal therapy of children with persistent proteinuria or NS will be achieved by the combined efforts of a primary care physician and a pediatric nephrologist.

	ACKNOWLEDGMENT

This work was sponsored by the National Kidney Foundation.

	FOOTNOTES

Received for publication Apr 14, 1999; accepted Sep 20, 1999.

Reprint requests to (R.J.H.) North Texas Hospital for Children at Medical City, 7777 Forest Ln, C-740, Dallas, TX 75230-2518. E-mail: info{at}spnsg.org

	ABBREVIATIONS

LMW, low molecular weight; IV, intravenous; Pr/Cr, protein/creatinine; NS, nephrotic syndrome; ACEi, angiotensin converting enzyme inhibitors; IDDM, insulin-dependent diabetes mellitus.

	REFERENCES

Top Abstract Conclusion References

1. Cameron JS Proteinuria and progression in human glomerular diseases. Am J Nephrol 1990; 10:81-87
2. Peterson JC, Adler S, Burkart JM, Blood pressure control, proteinuria, and the progression of renal disease. Ann Intern Med 1995; 123:754-762 [Abstract/Free Full Text]
3. Eddy AA, McCulloch L, Kiu E, Adams J A relationship between proteinuria and acute tubulointerstial disease in rats with experimental nephrotic syndrome. Am J Pathol 1991; 138:1111-1123 [Abstract]
4. Magil AB Tubulointerstitial lesions in human membranous glomerulonephritis: relationship to proteinuria. Am J Kidney Dis 1995; 25:375-379 [Medline]
5. Remuzzi G, Ruggenenti P, Benigni A Understanding the nature of renal disease progression. Kidney Int 1997; 51:2-15 [Medline]
6. Grimm RH, Svendsen KH, Kasiske B, Keane WF, Wahi MM Proteinuria is a risk factor for mortality over 10 years of follow-up: MRFIT Research Group, Multiple Risk Factor Intervention Trial. Kidney Int Suppl 1997; 63:S10-S14 [CrossRef][Medline]
7. Haffner SM, Stern MP, Gruber MK, Microalbuminuria: potential marker for increased cardiovascular risk factors in nondiabetic subjects. Arteriosclerosis 1990; 10:727-731 [Abstract/Free Full Text]
8. Kannel WB, Stampfer MJ, Castelli WP, Verter J The prognostic significance of proteinuria: the Framingham Study. Am Heart J 1984; 108:1347-1352 [CrossRef][Medline]
9. Keane WF, Eknoyan G Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): a position paper of the National Kidney Foundation. Am J Kidney Dis 1999; 33:1004-1010 [Medline]
10. Houser MT Assessment of proteinuria using random urine samples. J Pediatr 1984; 104:845-848 [Medline]
11. Houser MT, Jahn MF, Kobayashi A, Assessment of urinary protein excretion in the adolescent: effect of body position and exercise. J Pediatr 1986; 109:556 [CrossRef][Medline]
12. Vehaskari V, Rapola J Isolated proteinuria: analysis of a school-age population. J Pediatr 1982; 101:661-668 [CrossRef][Medline]
13. Ryland DA, Spreiter S Prognosis in postural (orthostatic) proteinuria: forty- to fifty-year follow-up of six patients after diagnosis by Thomas Addis. N Engl J Med 1981; 305:618-621 [Medline]
14. Berns JS, McDonald B, Gaudio KM, Progression of orthostatic proteinuria to focal and segmental glomerulosclerosis. Clin Pediatr 1986; 25:165
15. Ruggenenti P, Perna A, Mosconi L, Pisoni R, Remuzzi G Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. Kidney Int 1998; 53:1209-1216 [CrossRef][Medline]
16. Wingen AM, Fabian-Bach C, Schaefer F, Mehls O Randomised, multicentre study of a low-protein diet on the progression of renal failure in children. Lancet 1997; 349:1117-1123 [CrossRef][Medline]
17. Portman RJ, Hawkins E, Verani R Premature atherosclerosis in pediatric renal patients: report of the Southwest Pediatric Nephrology Study Group. Pediatr Res 1991; 29:349A
18. Jureidini KF, Hogg RJ, van Renen MJ, Evaluation of long-term aggressive dietary management of chronic renal failure in children. Pediatr Nephrol 1990; 4:1-10 [CrossRef][Medline]
19. Uauy RD, Hogg RJ, Brewer ED, Dietary protein and growth in infants with chronic renal insufficiency: a report from the Southwest Pediatric Nephrology Study Group and the University of California, San Francisco. Pediatr Nephrol 1994; 8:45-50 [CrossRef][Medline]
20. Peters H, Border WA, Noble NA Targeting TGF- overexpression in renal disease: maximizing the antifibrotic action of angiotensin II blockade. Kidney Int 1998; 54:1570-1580 [CrossRef][Medline]
21. Pryde PG, Sedman AB, Nugent CE, Barr M Angiotensin-converting enzyme inhibitor fetopathy. J Am Soc Nephrol 1993; 3:1575-1582 [Abstract]
22. Friberg P, Sundelin B, Bohman, S-O, et al Renin-antiotensin system in neonatal rats: induction of a renal abnormality in response to ACE inhibition or angiotensin II antagonism. Kidney Int 1994; 45:485-492 [Medline]
23. Sedman AB, Kershaw DB, Bunchman TE Recognition and management of converting enzyme inhibitor fetopathy. Pediatr Nephrol 1995; 9:382-385 [CrossRef][Medline]
24. Gorman D, Sochett E, Daneman D The natural history of microalbuminuria in adolescents with type 1 diabetes. J Pediatr 1999; 134:333-337 [CrossRef][Medline]
25. Cook J, Daneman D, Spino M, Angiotensin converting enzyme inhibitor therapy to decrease microalbuminuria in normotensive children with insulin-dependent diabetes mellitus. J Pediatr 1990; 117:39-45 [CrossRef][Medline]
26. Mogensen CE, Keane WF, Bennett PH, Prevention of diabetic renal disease with special reference to microalbuminuria. Lancet 1995; 346:1080-1084 [CrossRef][Medline]
27. Bennett PH, Haffner S, Kasiske B, Screening and management of microalbuminuria in patients with diabetes mellitus: recommendations to the Scientific Advisory Board of the National Kidney Foundation from an Ad Hoc Committee of the Council on Diabetes Mellitus of the National Kidney Foundation. Am J Kidney Dis 1995; 25:107-112 [Medline]
28. International Study of Kidney Disease in Children Nephrotic syndrome in children: prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. Kidney Int 1978; 13:159-165 [Medline]
29. Hogg R, Silva F, Berry P, Wenzl J Glomerular lesions in adolescents with gross hematuria or the nephrotic syndrome. Pediatr Nephrol 1993; 7:27-31 [CrossRef][Medline]
30. Leonard M, Wilson B, Zemel B, Stallings V, Feldman H Discrepancies in pediatric bone mineral density (BMD) reference data in the evaluation of children with nephrotic syndrome (NS). J Am Soc Nephrol 1998; 9:547A
31. Feinstein EI, Chesney RW, Zelikovic I Peritonitis in childhood renal disease. Am J Nephrol 1988; 8:147-165 [Medline]
32. Schnaper HW Immunization practices in childhood nephrotic syndrome: a survey of North American pediatric nephrologists. Pediatr Nephrol. 1994; 8:4-6 [CrossRef][Medline]
33. Steele RW Current status of vaccines and immune globulins for children with renal disease. Pediatr Nephrol 1994; 8:7-10 [CrossRef][Medline]
34. Fivush B, Arbus G, Tarver J, Hogg R, Furth S Immunogenicity and persistence of antibody levels following Varivax in children and adolescents with nephrotic syndrome: a report of the Southwest Pediatric Nephrology Study Group. J Am Soc Nephrol 1999; 10:72A
35. Coleman J, Watson A Hyperlipidaemia, diet and simvastatin therapy in steroid-resistant nephrotic syndrome of childhood. Pediatr Nephrol 1996; 10:171-174 [Medline]
36. Sanjad S, Al-Abbad A, Al-Shorafa S Management of hyperlipidemia in children with refractory nephrotic syndrome: the effect of statin therapy. J Pediatr 1997; 130:470-474 [CrossRef][Medline]
37. Tune BM, Lieberman E, Mendoza SA Steroid-resistant nephrotic focal segmental glomerulosclerosis: a treatable disease. Pediatr Nephrol 1996; 10:772-778 [CrossRef][Medline]
38. Takeda A, Ohgushi H, Niimura F, Matsutani H Long-term effects of immunosupressants in steroid-dependent nephrotic syndrome. Pediatr Nephrol 1998; 12:746-750 [CrossRef][Medline]
39. Gregory MJ, Smoyer WE, Sedman A, Long-term cyclosporine therapy for pediatric nephrotic syndrome: a clinical and histologic analysis. J Am Soc Nephrol 1996; 7:543-549 [Abstract]
40. Lieberman KV, Tejani A A randomized double-blind placebo controlled trial of cyclosporine in steroid-resistant idiopathic focal segmental glomerulosclerosis in children. J Am Soc Nephrol 1996; 7:56-63 [Abstract]
41. Bagga A, Sharma A, Srivastava RN Levamisole therapy in corticosteroid-dependent nephrotic syndrome. Pediatr Nephrol 1997; 11:415-417 [CrossRef][Medline]
42. Tenbrock K Muller-Berghaus J, Fuchshuber A, Michalk D, Querfeld U. Levamisole treatment in steroid-sensitive and steroid-resistant nephrotic syndrome. Pediatr Nephrol 1998; 12:459-462 [CrossRef][Medline]
43. Zukerman E, Ingelfinger JR. Coping With Prednisone. New York, NY: St Martin's Press; 1997