Glomerular disease: Evaluation in children

INTRODUCTION — There are numerous causes of glomerular diseases in children. Many of these conditions vary in their presentation from mild or no symptoms to serious kidney disease with life-threatening complications. As a result, the diagnosis of a specific glomerular disease is challenging in children but important so that therapy, if helpful and needed, can be initiated.

The diagnostic evaluation of children with glomerular disease will be reviewed here. Pathogenesis and causes of glomerulonephritis in children, as well as the evaluation of children with nonglomerular causes of isolated hematuria or proteinuria, are discussed separately. (See "Overview of the pathogenesis and causes of glomerulonephritis in children" and "Evaluation of microscopic hematuria in children" and "Evaluation of gross hematuria in children" and "Evaluation of proteinuria in children".)

GLOMERULAR DISEASE PRESENTATIONS — Numerous primary (kidney disease alone) [1] and secondary (due to systemic autoimmune disorders, vasculitis, or infection) disorders produce glomerular disease (table 1).

Findings suggestive of a glomerular disease include proteinuria, hematuria (which may be microscopic or macroscopic), nephrotic syndrome, arterial hypertension, and kidney insufficiency. The presence of these manifestations and their severity can be used to describe several different clinical patterns that often correspond to different underlying etiologies [2].

●Acute nephritic syndrome – An acute nephritic syndrome pattern is associated with active urine sediment with red cells, white cells, cellular casts, a variable degree of proteinuria, and, often, elevated blood pressure and a rising serum creatinine. Histologic examination demonstrates inflammation. This pattern is most often seen in children with poststreptococcal glomerulonephritis but may also be secondary to a membranoproliferative glomerulonephritis (table 1). (See "Poststreptococcal glomerulonephritis" and "Overview of the pathogenesis and causes of glomerulonephritis in children".)

●Isolated nephrotic syndrome – Isolated nephrotic syndrome presents with nephrotic-range proteinuria and, usually, an inactive urine sediment with few cells or casts. Most often, it is secondary to an idiopathic nephrotic syndrome with a rapid onset and peripheral edema. (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children".)

●Macroscopic hematuria – Recurrent macroscopic hematuria episodes are commonly seen in patients with an immunoglobulin A (IgA) nephropathy but may also be seen in patients with Alport syndrome. Microscopic hematuria may be observed in patients with IgA nephropathy, Alport syndrome, thin basement membrane syndrome, or poststreptococcal glomerulonephritis. (See "Clinical manifestations, diagnosis, and treatment of Alport syndrome (hereditary nephritis)" and "IgA nephropathy: Clinical features and diagnosis".)

●Rapidly progressive glomerulonephritis – Rapidly progressive glomerulonephritis typically presents with heavy proteinuria, active urine sediment, and kidney failure that does not resolve spontaneously. The kidney biopsy shows extensive cellular crescents in most glomeruli. (See "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis" and "Overview of the pathogenesis and causes of glomerulonephritis in children", section on 'Rapidly progressive glomerulonephritis'.)

●Chronic glomerulonephritis – Chronic glomerulonephritis is associated with proteinuria, microscopic hematuria, hypertension, and, often, kidney function impairment.

Both nephritic and nephrotic patterns can present with an acute or insidious time course, and elements of both may be also seen in some patients simultaneously or sequentially. Thus, it is important to recognize that patients with glomerulonephritis may also present with nephrotic syndrome. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

INITIAL EVALUATION — The clinical manifestations, urinalysis, and rate of protein excretion are important findings that help guide evaluation and determine the underlying cause of glomerular disease.

Clinical features — The clinical features may help to identify a specific glomerular pattern (see 'Glomerular disease presentations' above):

●An acute nephritic syndrome pattern is characterized by a constellation of findings that includes edema, hypertension, reddish-brown to brown-colored urine, and a rising serum creatinine.

●Patients with nephrotic syndrome may have anasarca with ascites. Patients with glomerulonephritis and nephrotic syndrome may have overlapping clinical findings.

●Patients with secondary causes of glomerular disease often have nonrenal symptoms and signs (eg, fever, arthralgias, rash, and pulmonary hemorrhage) that are suggestive of a specific underlying systemic disease.

Urinalysis and urinary protein — Testing of the urine is the most important noninvasive test in determining whether or not a child has glomerular disease and distinguishes among the patterns of glomerular disease. Children who have evidence of glomerular bleeding may have acute or chronic glomerulonephritis, and those with heavy proteinuria are likely to have nephrotic syndrome.

●Glomerulonephritis – The following urinalysis findings, if present, are indicative of glomerular bleeding and glomerulonephritis. However, the absence of these findings does not exclude glomerulonephritis.

•Red cell casts (pathognomonic for glomerular bleeding) (picture 1)

•Red blood cells that are dysmorphic in appearance (picture 2 and picture 3)

•Proteinuria

●Nephrotic syndrome – The urinalysis of children with idiopathic nephrotic syndrome is associated with heavy proteinuria and lipiduria but few cells or cast. Although the urinary dipstick measurement is a qualitative test, a 4+ recording, which corresponds to a concentration of urinary albumin of 1000 mg/dL, is suggestive of nephrotic range proteinuria, defined as a urinary protein excretion greater than 50 mg/kg per day or 40 mg/m² per hour.

Nephrotic-range proteinuria is confirmed by a quantitative measurement of a timed 24-hour urine collection or by measuring the total protein:creatinine ratio on a spot urine sample (calculator 1). The urine sample should be a first morning void to exclude the possibility of orthostatic proteinuria. The ratio that is indicative of nephrotic-range proteinuria is greater than 3 mg protein/mg creatinine (300 mg protein/mmol creatinine). (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children", section on 'Confirming the diagnosis'.)

●Isolated proteinuria – Isolated proteinuria may be benign due to normal physiologic variations or be indicative of glomerular disease.

•Transient proteinuria, which may occur during exercise or fever. Repeat testing is necessary to see if proteinuria is persistent as transient proteinuria excludes any underlying kidney disease.

•Orthostatic proteinuria is a frequent finding, especially in adolescents. It is characterized by an increased protein excretion in the upright position but the absence of protein excretion in the supine position. This is a benign condition that needs no further evaluation.

•Persistent isolated nonnephrotic proteinuria requires further evaluation as these patients are at risk for glomerular disease.

The evaluation to differentiate between benign and glomerular causes of proteinuria is discussed separately. (See "Evaluation of proteinuria in children", section on 'Approach to the child with proteinuria'.)

●Isolated hematuria – Macroscopic and microscopic hematuria may be benign or be caused by either nonglomerular or glomerular conditions. The evaluation to differentiate glomerular disease in children who present with isolated hematuria from other conditions is discussed separately. (See "Evaluation of microscopic hematuria in children" and "Evaluation of gross hematuria in children".)

Kidney function — Once glomerular disease is identified, the presence and degree of kidney dysfunction is assessed by an estimation of the glomerular filtration rate (GFR). A reduction in GFR implies either progression of the underlying disease or the development of a superimposed and often reversible problem, such as decreased renal perfusion due to volume depletion.

The most common method utilized to estimate the GFR is measuring the serum creatinine concentration and estimating the creatinine clearance based on the serum creatinine.

The GFR can be estimated by using the Schwartz formula, which is based on serum creatinine, age, height, and sex (in adolescents)(calculator 2).

Height represents the body height measured in centimeters, and serum creatinine is measured in mg/dL. The constant k is directly proportional to the muscle component of the body and varies with age based on the laboratory assay used to measure serum creatinine [3].

●Enzymatic methodology using isotope dilution mass spectrometry – When the serum creatinine is determined using enzymatic methodology, the value for k is 0.413 mg/dL (36.5 micromol/L) for all children with chronic kidney disease between ages 1 and 16 years [4].

●Jaffe method – When serum creatinine is measured by the Jaffe method, the values for k are:

•Premature infants through the first year of life: 0.33 mg/dL (29.2 micromol/L)

•Term infants through the first year of life: 0.45 mg/dL (39.8 micromol/L)

•Children and adolescent girls: 0.55 mg/dL (48.6 micromol/L)

•Adolescent boys: 0.7 mg/dL (61.9 micromol/L)

Most laboratories use the enzymatic methods for creatinine determination rather than the older Jaffe method, which has interference from chromogens. (See "Chronic kidney disease in children: Definition, epidemiology, etiology, and course", section on 'Definitions and diagnosis' and "Chronic kidney disease in children: Clinical manifestations and evaluation", section on 'Serum creatinine and glomerular filtration rate'.)

FURTHER EVALUATION

Overview — Based on the initial evaluation, an underlying disease process may be identified based on the clinical pattern of findings.

●Nephrotic syndrome – Children with nephrotic-range proteinuria and inactive urine sediment are likely to have idiopathic nephrotic syndrome. In this setting, an empirical course of glucocorticoids therapy is a reasonable option as more than 80 percent of patients will respond to this intervention. For children who do not respond to glucocorticoid therapy, genetic testing and a kidney biopsy are performed. (See "Treatment of idiopathic nephrotic syndrome in children".)

●Glomerulonephritis – Children presenting with a different clinical pattern, such as active nephritis, require further evaluation to determine the underlying glomerular disease, as discussed below [5].

●Components of both nephritis and nephrosis – Children with components of both glomerulonephritis and nephrotic syndromes are evaluated in a similar manner to those with nephritis. Several of the glomerulonephritides may also present with nephrotic syndrome, whereas idiopathic nephrotic syndrome does not typically have an inflammatory component.

●Hematuria – Children who are suspected of having glomerular disease but don't fit either category are also included in the glomerulonephritis category. For example, children who present with recurrent gross hematuria after an upper respiratory infection without an active sediment or proteinuria may have a mild course of IgA nephropathy. Children who present with isolated microscopic hematuria may have Alport syndrome.

Glomerulonephritis — Glomerulonephritis represents a variety of disorders that are caused by immunologic injury that result in inflammation of the glomeruli. These disorders may be primary (only kidney involvement) or secondary (due to systemic disease or infection) (table 1). (See "Overview of the pathogenesis and causes of glomerulonephritis in children".)

Blood tests — The evaluation of glomerulonephritis in children focuses on identifying the underlying diagnosis and includes the following diagnostic blood tests (algorithm 1):

●Serologic testing to screen for a recent antecedent streptococcal infection (ie, antistreptolysin, antihyaluronidase, antistreptokinase, antinicotinamide-adenine dinucleotidase, and anti-DNase B antibodies). Positive serology indicates a recent streptococcal infection and fulfills a criterion for the diagnosis of poststreptococcal glomerulonephritis. (See "Poststreptococcal glomerulonephritis", section on 'Serology' and "Poststreptococcal glomerulonephritis", section on 'Diagnosis'.)

●Antinuclear antibodies (ANA) and anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies – An elevated ANA titer or anti-dsDNA antibody titer fulfills one of the classification criteria for systemic lupus erythematosus (table 2). (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Diagnosis'.)

●Complement studies including complement components 3 and 4 (C3 and C4) and total hemolytic complement (CH50).

•Low C3 levels due to activation of the alternative pathway of complement are associated with poststreptococcal and C3 glomerulopathies including C3-dense deposit disease and C3 glomerulonephritis. The C3 levels typically return to normal within four to six weeks of presentation in patients with poststreptococcal glomerulopathy, whereas they remain persistently low in patients with C3 glomerulopathies [6,7]. (See "Poststreptococcal glomerulonephritis", section on 'Complement' and "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Clinical features'.)

•Low C3 and C4 levels are due to activation of the classical pathway due to immune complex formation. This combination of hypocomplementemia is seen in lupus nephritis and immune complex-mediated membranoproliferative glomerulonephritis shunt nephritis, as well as nephritis associated with subacute bacterial endocarditis. (See "Acquired disorders of the complement system", section on 'Systemic lupus erythematosus' and "Kidney disease in the setting of infective endocarditis or an infected ventriculoatrial shunt", section on 'Clinical features and kidney biopsy findings'.)

●Antineutrophil cytoplasmic antibodies (ANCA) – A positive test for ANCA is seen in most patients with granulomatosis with polyangiitis or microscopic polyangiitis [8,9]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)

●Other blood tests that can be performed based on clinical presentation, results of previous testing, and clinical judgment of the clinician include:

•IgA levels may be elevated in patients with IgA nephropathy or IgA vasculitis (Henoch-Schönlein purpura). A promising assay that screens for antibodies to galactose-deficient IgA1 may, in the future, be helpful in diagnosing IgA nephropathy [10]. (See "IgA nephropathy: Clinical features and diagnosis", section on 'Diagnosis'.)

•Serologic testing for Epstein-Barr virus or hepatitis B and C [11].

•Antiglomerular basement membrane (GBM) antibody screening, especially in a child with concurrent pulmonary symptoms, may be helpful in diagnosing anti-GBM disease [12]. (See "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Evaluation and diagnosis'.)

Kidney biopsy — A kidney biopsy is performed to confirm a diagnosis, determine the extent of kidney injury and degree of histologic activity and chronicity, and/or predict renal outcome [13]. The timing of a kidney biopsy depends on the clinical setting. In patients with rapidly progressive glomerulonephritis, which is rare in children, early diagnosis with kidney biopsy and serologic testing and early initiation of appropriate therapy are essential to minimize the degree of irreversible kidney injury. (See "Overview of the pathogenesis and causes of glomerulonephritis in children", section on 'Rapidly progressive glomerulonephritis' and "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis".)

Isolated proteinuria — Isolated proteinuria in an asymptomatic child can present as (see "Evaluation of proteinuria in children", section on 'Approach to the child with proteinuria'):

●Transient proteinuria, which may occur during exercise or fever. Repeat testing is necessary to see if proteinuria is persistent as transient proteinuria excludes any underlying kidney disease.

●Orthostatic proteinuria is a frequent finding, especially in adolescents. It is characterized by an increased protein excretion in the upright position but the absence of protein excretion in the supine position. This is a benign condition that needs no further evaluation.

●Persistent isolated nonnephrotic proteinuria requires further evaluation as these patients are at-risk for glomerular disease.

Nephrotic syndrome — Nephrotic syndrome in children is classified into three categories. The evaluation depends on the classification of nephrotic syndrome and is discussed separately. In the majority of cases, steroid therapy is initiated in children with isolated nephrotic syndrome as the vast majority of these patients will have minimal change disease, which usually responds to therapy within four weeks. Further evaluation is reserved for those who fail to respond to steroid therapy or who have components of both nephrosis and glomerulonephritis (active urinary sediment), for whom evaluation is the same as that of a child with glomerulonephritis alone. (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children", section on 'Classification and etiology' and "Steroid-resistant nephrotic syndrome in children: Management", section on 'Diagnostic evaluation' and "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children", section on 'Additional evaluation'.)

●Primary nephrotic syndrome, which refers to nephrotic syndrome in the absence of an identifiable systemic disease. Within this category are two subgroups:

•Isolated nephrotic syndrome – Disorders without glomerular inflammation on kidney biopsy. These include causes of idiopathic nephrotic syndrome (eg, minimal change nephrotic syndrome, focal segmental glomerulosclerosis, and mesangial proliferation) and some cases of membranous nephropathy. Included in this group are idiopathic nephrotic syndrome and some cases of membranous nephropathy, which are discussed elsewhere. (See "Membranous nephropathy: Pathogenesis and etiology" and "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children", section on 'Primary nephrotic syndrome'.)

•Nephrotic syndrome and nephritis – These disorders are characterized by nephrotic-range proteinuria with features of nephritis (identified by active urine sediment, ie, red cells and cellular casts) with presence of glomerular inflammation on kidney biopsy. Causes include membranoproliferative glomerulonephritis and IgA nephropathy, which are discussed separately. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis" and "IgA nephropathy: Clinical features and diagnosis" and 'Glomerulonephritis' above.)

●Secondary nephrotic syndrome, which refers to nephrotic syndrome that is caused by a systemic disease.

●Congenital and infantile nephrotic syndrome. (See "Congenital nephrotic syndrome".)

SUMMARY AND RECOMMENDATIONS

●Glomerular disease presentations – Findings suggestive of a glomerular disease include proteinuria, hematuria (which may be microscopic or macroscopic), nephrotic syndrome, arterial hypertension, and kidney insufficiency. The presence of these manifestations and their severity can be used to describe different clinical patterns that often correspond to different underlying etiologies. These include:

•Nephritic pattern – Acute nephritis, rapidly progressive glomerulonephritis, or chronic glomerulonephritis

•Isolated nephrotic syndrome

•Macroscopic hematuria

(See 'Glomerular disease presentations' above and "Overview of the pathogenesis and causes of glomerulonephritis in children".)

●Initial evaluation – The initial evaluation that includes review of the presenting clinical manifestations, urinalysis, rate of protein excretion, and kidney function can be used to guide the evaluation process to identify underlying glomerular disease. (See 'Initial evaluation' above.)

•Children with acute nephritis typically have a constellation of findings that includes edema, hypertension, reddish-brown to brown-colored urine, a rising serum creatinine, an active urinary sediment (eg, red cell casts and dysmorphic red blood cells), and variable degrees of proteinuria (picture 1 and picture 2 and picture 3). (See "Overview of the pathogenesis and causes of glomerulonephritis in children".)

•Children with isolated nephrotic syndrome may have anasarca with ascites, nephrotic-range proteinuria, and an inactive urinary sediment (eg, few cells and casts).

•Some children may have components of both nephritic and nephrotic syndrome.

•Patients with secondary causes of glomerular disease often have nonrenal symptoms and signs (eg, fever, arthralgias, rash, and pulmonary hemorrhage) that are suggestive of a specific underlying systemic disease.

•Persistent isolated proteinuria or hematuria is often caused by etiologies other than glomerular disease, many of which are benign. However, glomerular disease occasionally presents with these isolated findings. (See "Evaluation of proteinuria in children", section on 'Approach to the child with proteinuria' and "Evaluation of microscopic hematuria in children" and "Evaluation of gross hematuria in children".)

●Further evaluation – Further evaluation is based on the specific glomerular disease classification.

•Nephritic syndrome pattern – Assessment includes serologic testing for a recent streptococcal infection, antinuclear antibodies (ANA) and anti-double-stranded DNA antibodies (dsDNA), complement studies, and antineutrophil cytoplasmic antibodies (ANCA). A kidney biopsy is performed to confirm a diagnosis, determine the extent of kidney injury, and/or predict renal outcome. The timing of a kidney biopsy depends on the clinical setting. (See 'Glomerulonephritis' above.)

•Isolated nephrotic syndrome – In the majority of cases, steroid therapy is initiated in children with isolated nephrotic syndrome as the vast majority of these patients will have minimal change disease, which usually responds to therapy within four weeks. Further evaluation is reserved for those who fail to respond to steroid therapy and is presented separately. (See "Steroid-resistant nephrotic syndrome in children: Management", section on 'Diagnostic evaluation'.)

•Nephritic and nephrotic patterns – Children with both nephritic and nephrotic syndrome patterns are evaluated in a similar manner to those with nephritic syndrome. (See 'Further evaluation' above.)