Pediatric IgA Nephropathy Workup

Updated: Jun 03, 2022
  • Author: Mohammad Ilyas, MD, FAAP; Chief Editor: Craig B Langman, MD  more...
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Workup

Approach Considerations

Given the range of clinical presentations among patients with IgA nephropathy, the diagnosis should be suspected in any patient who presents with one or more of the following clinical features:

  1. One or more episodes of gross hematuria, especially if accompanied by an upper respiratory tract infection
  2. Persistent microscopic hematuria with or without proteinuria
  3. Slowly progressive kidney function impairment
  4. Patients with IgA nephropathy may present less commonly with nephrotic syndrome or rapidly progressive glomerulonephritis

Establishing the diagnosis

The diagnosis of IgA nephropathy is confirmed by kidney biopsy, with immunofluorescence or immunoperoxidase staining demonstrating the presence of dominant or co-dominant deposition of IgA. There are no specific laboratory findings that can be used to confirm the diagnosis of IgA nephropathy.

Not every patient needs a kidney biopsy to diagnose IgA nephropathy; however, patients with proteinuria or impaired renal function may require a kidney biopsy to determine the underlying  extent of disease. The indication to perform a renal biopsy varies among physicians, particularly if the patient has no proteinuria or decline in renal function and thus may not need a kidney biopsy. Once the diagnosis of IgA nephropathy has been established, underlying  secondary causes of  IgA nephropathy should be considered according to the patient's clinical status and history. 

A few new tests have been recognized for further evaluation and diagnosis of IgA nephropathy, including measurement of poorly galactosylated IgA1 O-glycoforms and/or poorly galactosylated IgA1-specific IgG antibodies in the serum and measurement of certain microRNAs (miRNAs) that affect O-galactosylation of IgA1. [25]  However, none of these tests has proven utility as a diagnostic marker for IgA nephropathy.

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Laboratory Studies

The diagnosis of IgA nephropathy is based on clinical history and laboratory data, but it can only be confirmed by kidney biopsy. The IgA deposits within mesangium visualized by immunofluorescence or immunoperoxidase studies confirm the IgA nephropathy.

Although circulating autoantibodies, including antiendothelin antibodies, have been reported in IgA nephropathy, none appears to be disease specific.

The following studies are used to identify immunoglobulin A (IgA) nephropathy and to rule out other causes of nephropathy:

  • Urinalysis (UA) usually reveals hematuria, proteinuria, and leukocytes. Microscopic examination shows dysmorphic RBCs and RBC casts suggestive of glomerular origin of RBC but not specific for IgA nephropathy

  • CBC count with differential to identify anemia, leukocytosis, and thrombocytopenia help exclude other underlying causes for nephritis

  • A 24-hour urine collection estimates creatinine clearance (CrCl) and protein excretion; proteinuria is associated with histologic lesions and a risk for progression; proteinuria also helps determine therapeutic course as discussed in the treatment section

  • The ratio of urine calcium (Ca) to creatinine (Cr) measures hypercalciuria (normal is < 0.2), a common cause for microhematuria

  • Serum electrolyte levels; Na, K+, Cl, and HCO3 could help detect early abnormalities

  • BUN and Cr levels estimate renal function and help in further management decisions

  • Serum C3 and C4 levels are usually normal; C3 is routinely measured to eliminate the diagnosis of postinfectious glomerulonephritis (PSAGN) or membranoproliferative glomerulonephritis (MPGN); low C3 and C4 suggest lupus nephritis

  • Antistreptolysin-O (ASO) titer or streptozyme tests help exclude PSAGN

  • Plasma polymeric IgA1 levels are elevated in 30-50% of cases, but this suggestive finding is not sufficiently specific to establish the diagnosis; measurement of the proportion of poorly galactosylated IgA1 O-glycoforms in the serum with or without measurement of poorly galactosylated IgA1-specific IgG has been proposed as a clinically useful diagnostic test [26]

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Imaging Studies

Renal ultrasonography is an excellent diagnostic tool to detect structural abnormalities leading to hematuria, such as renal stone, neoplasm, cystic lesion, hydronephrosis, dilated urinary tract, and bladder abnormalities. However, it cannot be used to confirm, support, or reject the diagnosis of IgA nephropathy.

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Procedures

Percutaneous renal biopsy is essential for the confirmation of IgA nephropathy. The diagnosis of IgA nephropathy is based on the presence of IgA in the glomerular mesangium. The indications for kidney biopsy include the following:

  • Macroscopic (gross) hematuria

  • Microscopic hematuria with significant proteinuria (>2 mg/kg/d)

  • Acute nephritic syndrome (hematuria with hypertension or renal insufficiency)

  • Nephrotic syndrome

A skin biopsy, looking for IgA deposition in the dermal capillaries, has not proven to be sufficiently predictive in IgA nephropathy. [27]

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Histologic Findings

The diagnostic histopathologic hallmark of IgA nephropathy by light, immunofluorescence, and electron microscopy is the presence of IgA in the glomerular mesangium. See the images below.

Glomerulus with mesangial hypercellularity and int Glomerulus with mesangial hypercellularity and intact capillary loops. Trichrome Stain, original magnification 400x. Image courtesy of Patrick D Walker, MD.
Mesangial deposits of immunoglobulin A (IgA). Fluo Mesangial deposits of immunoglobulin A (IgA). Fluoresceinated Anti-IgA Antibody, Immunofluorescence microscopy, original magnification 400x. Image courtesy of Patrick D Walker, MD.
Electron photomicrograph showing mesangial electro Electron photomicrograph showing mesangial electron dense deposits (arrow). Uranyl acetate and lead citrate stain, original magnification 12,000x. Image courtesy of Patrick D Walker, MD.

With light microscopy, the most characteristic abnormality is mesangial enlargement produced by hypercellularity and mesangial matrix increase. The severity of renal involvement can be graded based on mesangial cell proliferation.

Immunofluorescence microscopy demonstration of predominately mesangial deposition of IgA is pathognomonic of IgA nephropathy. Mesangial immunoglobulin G (IgG), immunoglobulin M (IgM), C3, and properdin may also be observed. Electron microscopy reveals mesangial or perimesangial deposits occurring in the same distribution as observed with immunofluorescence microscopy.

A retrospective cohort study on 47 pediatric patients with IgAN by Fabiano et al considered whether glomerular C4d immunostaining can be a prognostic marker in pediatric IgAN. The study found that C4d-positive patients presented higher baseline proteinuria, a progressive decline in baseline estimated glomerular filtration rate, and end-stage renal disease when compared with C4d-negative patients. [28]

Minimal lesion

The glomeruli appear normal. The number of mesangial cells per peripheral mesangial area does not exceed 3. Small foci of tubular atrophy and interstitial lymphocyte infiltration may be present.

Focal mesangial proliferation

The glomeruli show moderate to severe mesangial cell proliferation (ie, >3 mesangial cells per peripheral mesangial area). The proliferation may be associated with increased matrix, small crescent, capsular adhesions and prolapsed.

Diffuse mesangial proliferative and crescentic glomerulonephritis can occur. A small number of patients may have global sclerosis, tubular atrophy, interstitial fibrosis, and interstitial lymphocyte infiltrate.

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Staging

The Oxford classification of IgA nephropathy, or MEST score, published in 2009, comprises four histological features that are independent predictors of clinical outcome. The IgA Nephropathy Classification Working Group added crescents to the Oxford classification, to form the MEST-C score. The features that determine the MEST-C score are as follows: 

  • M – Mesangial cellularity, defined as more than four mesangial cells in any mesangial area of a glomerulus: M0 is mesangial cellularity in < 50% of glomeruli; M1 ≥50%
  • E – Endocapillary proliferation, defined as hypercellularity due to an increased number of cells within glomerular capillary lumina: E0 is absence of hypercellularity; E1 is hypercellularity in any glomeruli
  • S – Segmental glomerulosclerosis, defined as adhesion or sclerosis (obliteration of capillary lumina by matrix) in part of but not the whole glomerular tuft: S0 is absence of segmental glomerulosclerosis, S1 is presence of segmental glomerulosclerosis in any glomerulus
  • T – Tubular atrophy/interstitial fibrosis, defined as the estimated percentage of cortical area showing tubular atrophy or interstitial fibrosis, whichever is greater: T0 is 0-25%; T1 is 25-50%; T2 is >50%
  • C – Crescents: C0 (no crescents), C1 (crescents in less than one-fourth of glomeruli), and C2 (crescents in over one-fourth of glomeruli).
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