Division of Pediatric Nephrology St. Joseph’s Hospital and Medical Center, 2346 North Central Avenue, Phoenix, AZ 85004, USA Although there is little information in the literature regarding adolescents with persistent proteinuria or the nephrotic syndrome (NS) patients in this agegroup appear to demonstrate a variety of histopathologic lesions that are nottypical for young children or mature adults. This article comments in detail on theevaluation of adolescents with normal and abnormal levels of proteinuria,including those with nephrotic ranges of proteinuria. Specific attention is givento determining which adolescents with proteinuria need to be sent to a specialistfor consultation.
Protein handling by the kidneys in normal adolescents and those with kidneydisease Under normal circumstances, the glomeruli restrict the passage of large serum proteins, such as albumin. Relatively low-molecular-weight (LMW) proteins maybe filtered by the glomeruli but are reabsorbed in the proximal tubules. Thenormal rate of protein excretion is considered to be less than 4 mg/m2/h or lessthan 100 mg/m2/d throughout adolescence. This rate equates to a urine protein-to-creatinine ratio of approximately 0.2 mg/mg, or urine albumin-to-creatinine ratioof 30 mg/g creatinine.
Excess urinary protein losses may be caused by increased passage of large serum proteins across the glomeruli or decreased reabsorption of LMW proteinsby the renal tubules. The finding of increased urinary protein excretion on routine 1547-3368/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.admecli.2004.09.009 screening of adolescents is fairly common. A recent report describing a highprevalence was based on the findings of the Third National Health andNutritional Examination Study The study included 4088 children aged 8 to18 years, who were evaluated as part of a nationally representative cross-sectionalsample of apparently healthy individuals in the United States between 1988 and1994. The method used to define abnormal proteinuria was an albumin-to-creatinine ratio (N30 mg/g) on a random urine specimen. The authors reportedthat 12% of the population sampled had albumin excretion of greater than30 mg/g creatinine. Notably, the highest rates were found in adolescents in thelater stages of puberty, with the highest level occurring in Tanner Stage 4individuals, particularly girls, and in those who had a low or normal body massindex. However, it is likely that many of the subjects had transient or orthostaticproteinuria, as described in the next two sections. This caveat significantlydecreases the potential health consequences of the high rates of proteinuria inadolescents that were described by Mueller et al When abnormal levels of proteinuria are found, the first step is to determine whether it is transient, orthostatic, or persistent in type. Transient proteinuria,which may be defined as proteinuria that is noted on one or two occasions but isnot present on subsequent testing, is not considered to be indicative of underlyingrenal disease. Large-scale studies reporting the prevalence of proteinuria ingroups of children describe much lower rates when the positive cases are definedas children with three or more consecutive urines showing proteinuria. Therefore,the finding of abnormal proteinuria in an adolescent should be confirmed on atleast one additional urine, preferably a first morning urine, before additionalstudies are ordered.
Orthostatic proteinuria, which may be defined as protein excretion that is elevated when the subject is upright but resolves during recumbency, occurs mostcommonly in adolescents and young adults. This proteinuria may result in 3+ to4+ protein on a random dipstick but rarely exceeds 1 g/m2/d in a 24-hour urinespecimen. Long-term follow-up studies have shown that this condition is benignin most affected individuals.
Persistent proteinuria, defined as proteinuria of 1+ or greater by dipstick or a urine protein-to-creatinine ratio of more than 0.2 on multiple first morning urinesamples, is of more concern, especially if the urinalysis shows other abnor-malities, such as hematuria (not associated with menses in adolescent females),glycosuria, or casts in the urinary sediment.
The most frequently used screening method for proteinuria is the urinary dipstick. It is important to note that false-positive results may occur when thedipstick is used to assess proteinuria in very alkaline urine (pH 8), inconcentrated urine specimens (specific gravity (SG) N1.025), or after theadministration of radiographic dyes. Although protein excretion in adolescents has been measured traditionally using 24-hour urine collections, accurately timedurine collections of any duration are often difficult to obtain (particularly in thisage group). As a result, the protein-to-creatinine (UP/C) ratio of an untimed(‘‘spot’’) urine specimen (preferably a first morning specimen) is recommendedto estimate protein excretion in adolescents. The normal UP/C in adolescents isless than 0.2. This approach has been endorsed by a panel of pediatricnephrologists assembled by the National Kidney Foundation, as describedin detail in a recent publication in Pediatrics An alternative approach isto measure the urine albumin-to-creatinine ratio, although this will not detectLMW globulins.
Fig. 1. Evaluation of proteinuria in adolescents. ANA, antinuclear antibody; Hep, hepatitis; P/C,protein/creatinine; U/A, urine albumin; U/S, ultrasonography.
The first step in the evaluation of an adolescent with persistent dipstick proteinuria (1+) is to obtain a complete urinalysis and a first morning ‘‘spot’’urine for UP/C ratio (The physician should stress the importance of thepatient’s voiding just before going to bed and remaining recumbent until justbefore obtaining this specimen. If the urinalysis is normal and the UP/C ratio onthe first morning urine sample is less than 0.2, a diagnosis of orthostatic pro-teinuria may be made, and no additional studies are necessary. However, if theurinalysis shows other abnormalities or the first morning UP/C ratio is greaterthan 0.2, blood should be sent for total serum protein, albumin, creatinine,cholesterol, and electrolytes. In addition, measurement of serum C3 complement,antinuclear antibody, and serologies for hepatitis B and C and HIV should beconsidered. These last studies are particularly appropriate if patients havehematuria, hypertension, a decrease in renal function, or symptoms or signs ofextrarenal disease.
Association between proteinuria and cardiovascular disease Severe persistent proteinuria is almost certainly a long-term risk factor for cardiovascular disease in adolescents with persistent NS. As proteinuria becomesmore severe, it induces a variety of disturbances that contribute to cardiovasculardisease, such as hypercholesterolemia, hypertriglyceridemia, and hypercoagula-bility In some patients, other factors such as hypertension, renal insufficiency,and steroid therapy may also contribute to the risk for cardiovascular disease.
Proteinuria in adolescents with insulin-deficient or insulin-resistantconditions Although good glycemic control is the first line of defense against renal injury in patients with Insulin Dependent Diabetes Mellitus (IDDM), it has beenrecognized in recent years that adolescents with long-standing IDDM who havepersistent microalbuminuria are at high risk for progressive kidney disease andprobably at increased risk for cardiovascular disease In this patientpopulation, it is appropriate to monitor the urinary albumin excretion rather thantotal protein excretion Normal albumin excretion is usually defined as lessthan 20 mg/min/1.73m2, microalbuminuria as 20 to 200 mg/min/1.73 m2, andovert proteinuria as greater than 200 mg/min/1.73m2. Alternatively, micro-albuminuria may be defined as 30 to 300 mg albumin per gram creatinine on afirst morning urine specimen.
Recent years have also seen the recognition that patients with other insulin- resistant states, often associated with obesity, may develop significant levels ofproteinuria. The long-term consequences in this population, including cardio- vascular disease, have not yet been elucidated, but there is concern that thesepatients are at high risk. Obesity per se has been associated with proteinuria andglomerulosclerosis with increasing frequency in recent years. Although most ofthe patients with this condition are adults and most do not develop NS, they are atrisk for progressive disease, and some patients have been diagnosed as young as8 years of age Treatment options for persistent proteinuria in the nonnephrotic range Although dietary protein restriction has not been shown by controlled studies to be beneficial in adolescents with chronic proteinuric renal disease, it seemsreasonable to avoid an excess of dietary protein in such patients, because highdietary protein intake may actually worsen proteinuria and does not result in ahigher serum albumin.
Better preservation of renal function is often seen in patients with renal dis- ease when lower systolic blood pressures are achieved. Certain classes of anti-hypertensive agents (eg, the angiotensin-converting enzyme inhibitors [ACEi]and the angiotensin II receptor blockers) may, in addition to reducing systemicblood pressure, offer other beneficial effects. Because of these possible benefits,which include reducing urinary protein excretion and decreasing the risk for renalfibrosis, these agents may be preferred in adolescents with chronic kidney diseaseassociated with persistent proteinuria However, the long-term benefit ofACEi in such patients remains to be defined.
Spectrum of adolescent-onset nephrotic syndrome So far there have been only five published studies containing specific information about adolescent patients with NS. All of these were retrospectivestudies, and most included only those patients who underwent kidney biopsy.
In the report of the Southwest Pediatric Nephrology Study Group, 31% of 65 patientshad minimal change disease (MCD), 18.5% each had Focal SegmentalGlomerulosclerosis (FSGS) and membranous glomerulonephritis (MGN), and12% had membranoproliferative glomerulonephritis (MPGN) The inves-tigators observed a significantly higher frequency of MPGN among adolescentsthan in younger children.
In a recent study by Gulati et al 63 Indian adolescents with NS were described. FSGS was the most common cause (46.3%) in these adolescent pa-tients. The authors also observed a significantly higher frequency of MPGN (27.5%) among adolescents compared with younger children. In this raciallyhomogeneous Indian population, only 16.3% of the adolescents had MCD. Gulatiet al concluded that adolescent-onset NS differs from the childhood variety inhaving a significantly higher frequency of histopathology other than MCD,especially MPGN.
In another recent report, McKinney et al reported that 7 of 34 patients (20%) in Yorkshire, United Kingdom who presented with NS between 10 and15 years of age had steroid-resistant disease; by contrast, only 17 of 160 patients(10%) with NS aged less than 9 years who presented over the same period ofstudy were steroid-resistant. The older children in this study represented 29% ofall steroid-resistant cases, but only 16% of the steroid-responsive patients. Theoverall incidence of NS was lower in the older children (1.1 case per 100,000persons per year in the 10–15-year age group versus 4.6 cases and 1.9 cases per100,000 persons per year in the patients aged 1–4 and 5–9 years, respectively).
It is evident from these published reports that more serious forms of glo- merular disease (ie, MGN and FSGS) are present more frequently in adolescentswith NS than in younger patients with this condition. For example, the frequencyof MGN and FSGS in young children with NS is only 2% and 8%, respectively Treatment options for children and adolescents with nephrotic syndrome When to obtain a biopsy and what to expect The decision to perform a biopsy in all adolescents with NS is not entirely clarified by the reported series. It is necessary to evaluate all aspects of a patient’sclinical presentation—in addition to age—before deciding whether a biopsyshould be performed before a trial of therapy. Some pediatric nephrologistsbelieve that many adolescents with NS may be treated without a kidney biopsy,because some will have steroid-responsive minimal-lesion NS and will thus bespared the trauma of a biopsy. However, consideration should be given toperforming a pretreatment biopsy in adolescents with NS if they have signscompatible with a diagnosis other than minimal-lesion disease. Both sides of thisissue have previously been discussed in detail and are beyond the scopeof this discussion. This review does not discuss the various therapeutic optionsthat may be selected after the specific diagnosis has been established by the renalbiopsy, because most of these are still being evaluated by clinical trials; hence,definitive advice is not available.
In general, a renal biopsy should be strongly considered in the evaluation of adolescents with NS under the following circumstances: ! Persistent gross hematuria (in the absence of infection) ! Low serum complement levels (C3 or CH50) ! Renal failure not explicable by hypovolemia and prerenal causes ! Frequent relapses before ‘‘third-line’’ medications such as cyclosporine A, The final recommendation regarding the need for a diagnostic renal biopsy should be made by a pediatric nephrologist after reviewing the advantages anddisadvantages of ‘‘biopsy first’’ or ‘‘trial of therapy first’’ with the patient and hisor her parents.
This section briefly considers the therapy that is usually prescribed for adolescents who are found to have minimal-change NS or in whom the ‘‘trial oftherapy first’’ approach is adopted.
Glucocorticoids, usually in the form of prednisone, have been and continue to be the mainstay of treatment in adolescents with idiopathic NS. Several proto-cols are in current use. A typical treatment course is prednisone, 2 mg/kg/d or60 mg/m2/d (maximum 80 mg/d) in one to three divided doses, for initial treat-ment. This treatment is continued until the patient becomes free of proteinuria—or, more commonly, for periods of up to 4 to 6 weeks. The patient is thenconverted to alternate-day treatment (ie, 2 mg/kg or 40 mg/m2 [maximum 60 mg]given as a single dose every other morning) The optimum duration of thecourse of alternate-day treatment is somewhat controversial and may range from4 to 12 weeks, depending on the pediatric nephrologist who is involved in thecase. Most patients are given 4 to 6 weeks of alternate-day therapy.
Glucocorticoids have many side effects, and it is crucial to discuss these at length with the patient and his or her parents. These medications are oftenassociated with short-term side effects that may result in significant physical andpsychological problems for adolescent patients. These include increase inappetite, acne, cushingoid facies, behavioral and psychological changes(eg, mood lability and depression), gastric irritation, and hypertension. Steroidpsychosis is rare but can be an extremely serious side effect. Long-term treatmentwith glucocorticoids can lead to bone demineralization, growth failure, anddiabetes mellitus.
Cytotoxic drugs and other immunosuppressive regimens When serious steroid side effects develop or when there is failure to respond to steroid therapy, other strategies should be considered in patients with minimal- change NS. Cyclophosphamide (Cytoxan) and chlorambucil (Leukeran), eachgiven over a period of 8 to 12 weeks, may be associated with a long-termremission in adolescents with frequently relapsing or steroid-dependent NS However, these drugs may be associated with a variety of side effects (eg, bonemarrow suppression, possibility of future malignancy, oligospermia or azoo-spermia, ovarian fibrosis); the risk is highest in patients who are close to or inpuberty. The cumulative dose of cyclophosphamide should be restricted to lessthan 170 mg/kg body weight. In addition to these general side effects, hemor-rhagic cystitis may occur with cyclophosphamide. Seizures occur only—andrarely—with chlorambucil.
A treatment option to be considered in adolescents with steroid-resistant (SR) or steroid-dependent (SD) NS is cyclosporine A (CsA) Unfortunately,many of the patients who respond to CsA tend to relapse once the medication iswithdrawn. This relapse is a concern because long-term use of CsA is potentiallynephrotoxic. In addition, CsA may cause increases in blood pressure or aggravatepre-existing hypertension. Hypertrichosis and gingival hyperplasia are othercommon side effects that are particularly troubling for teenagers and often lead tononadherence with the prescribed therapy. More recently, mycophenolate mofetilhas also been reported to be useful in patients with SDNS or SRNS. However,the results of studies using this medication are preliminary.
Adjunctive therapy with angiotensin-converting enzyme inhibitors ACEi have been used in a variety of renal diseases to reduce proteinuria and thereby lessen the secondary consequences of NS. Available evidence suggeststhat ACEi may decrease the rate of protein loss by as much as 50%. Hence, it iscommon for pediatric nephrologists to prescribe an ACEi if an adolescent hasnephrotic-range proteinuria that is resistant to specific therapy Nonspecific management of nephrotic syndrome in adolescents Numerous other practical aspects of managing adolescents with NS are important to address with the patients and parents. It is helpful to educate schoolpersonnel about nephrotic syndrome and its therapy. Each patient should have anindividual assessment for any changes that might be needed in schooling,activities, and diet. Recommendations about sports participation while on high-dose steroids should be approached on an individual basis.
Nutritional counseling about a nutritious, ‘‘relatively’’ junk-food-free diet is important (although it has variable levels of response!). The adoption of anutritious, relatively low-calorie diet will help patients avoid large weight gains.
Salt intake should be limited to control edema and decrease risk of hypertension.
In addition, setting a fluid-intake limit of about twice insensible water loss may behelpful in an already edematous patient. Diuretics should be discouraged in mostadolescent patients with NS. However, judicious use of diuretics, such as furo-semide 1 to 2 mg/kg/d, may be considered if severe edema is present (eg, edemaassociated with severe scrotal/vulvar swelling, gastrointestinal symptoms, and soon). No indication exists for using diuretics in adolescents with mild edema.
Persistent proteinuria of various degrees of severity in adolescents should be regarded seriously, because recent evidence points to this abnormality’s beingassociated with chronic kidney disease However, it is also important forprimary care physicians to be aware that most adolescents who are found to haveproteinuria on a screening urinalysis do not have renal disease, and the pro-teinuria will usually resolve on repeat testing Appropriate measures todetermine whether the proteinuria is fixed and not orthostatic can and should beconducted expeditiously, because they will allay stress for most patients. For theminority of patients in whom more serious forms of proteinuria exist, timelyconsultation with a pediatric nephrologist is recommended.
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[7] Hogg RJ, Portman RJ, Milliner D, et al. Evaluation and management of proteinuria and nephrotic syndrome in children: recommendations from a pediatric nephrology panel established at theNational Kidney Foundation Conference on Proteinuria, Albuminuria, Risk, Assessment,Detection, and Elimination (PARADE). Pediatrics 2000;105:1242 – 9.
[8] Schlege HW. Thromboembolic risks and complications in nephrotic children. Semin Thromb [9] Mogensen CE, Keane WF, Bennett PH, et al. Prevention of diabetic renal disease with special reference to microalbuminuria. Lancet 1995;346:1080 – 4.
[10] Hogg RJ, Furth S, Lemley KV, et al. National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children andadolescents: evaluation, classification, and stratification. Pediatrics 2003;111:1416 – 21.
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[13] Moxey-Mims M, Stapleton FB, Feld LG. Applying decision analysis to management of adolescent idiopathic nephrotic syndrome. Pediatr Nephrol 1994;8:660 – 4.
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[15] Hogg RJ, Portman RJ, Milliner D, et al. Recognizing and treating the nephrotic syndrome: avoid unnecessary delays. Contemp Pediatr 2000;17(11):84 – 93.
[16] Kaplan RE, Springate JE, Feld LG. Screening dipstick urinalysis: a time to change. Pediatrics [17] 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 Nephrol1996;7:56 – 63.
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