Glomerular Diseases

Glomerular diseases encompass a spectrum of renal disorders and are the second-most common cause of end-stage kidney disease (ESKD) in children, following congenital anomalies of the kidneys and urinary tract (CAKUT). A comprehensive review of glomerular diseases in children is beyond the scope of this guide (see the reference section for further reviews and resources). In this section, we cover nephrotic syndrome and glomerulonephritis.

Diseases affecting the glomerulus can be described as primary if the disease process originates in the kidney or secondary if the glomerular disease has a known trigger or is part of a more systemic process.

• Primary causes of glomerular disease include:

  • minimal change disease

  • IgA nephropathy

  • focal segmental glomerulosclerosis (FSGS)

  • membranoproliferative glomerulonephritis (MPGN)

  • membranous nephropathy (MN)

• The most common causes of secondary glomerular diseases are:

  • postinfectious

  • rheumatologic disorders

  • malignancy

Recent research suggests that a subset of nephrotic syndrome patients may have autoantibodies that target nephrin, a structural podocyte protein, supporting the possibility of an autoimmune etiology.

Nephrotic Syndrome

Clinical findings of nephrotic syndrome in children include the following:

• edema

• hypoalbuminemia (serum albumin <3 g/dL)

• nephrotic-range proteinuria

  • urine protein-to-creatinine ratio >2 mg/mg on a first morning urine specimen OR urine protein >40 mg/m²/hr

• hyperlipidemia (typical, but not required for diagnosis)

Classification

Primary or idiopathic nephrotic syndrome is more common than secondary nephrotic syndrome related to other disease processes. The three main histologic changes seen on renal biopsy in childhood nephrotic syndrome are:

• Minimal change disease: The most common cause of nephrotic syndrome in children (typically ages 1 to 6 years). Glomeruli appear normal on light microscopy but show podocyte foot-process effacement on electron microscopy (see image below). Minimal change disease is associated with the best prognosis, and patients are most likely to respond to glucocorticoids. As many as 80% of children with minimal change disease have at least one relapse. Some cases may progress to focal segmental glomerulosclerosis (FSGS).

Loss of the glomerular slit diaphragms (top image) and a continuous layer of podocyte cytoplasm (bottom image). This process is termed foot process effacement and is reversible, as when therapy induces a remission. (Source: The National Institute of Diabetes and Digestive and Kidney Diseases 2023.)

• Focal segmental glomerulosclerosis (FSGS): FSGS is the second-most common cause of nephrotic syndrome in children and more likely to present in older children (school-age to adolescent). Segmental scarring is visible in some, but not all, glomeruli. Patients with FSGS are less likely to respond to glucocorticoids and more likely to progress to ESKD. Mutations have been identified in various genes expressed in podocytes (e.g., NPHS1, NPHS2, WT1, ACTN4, INF2, and TRPC6) that disrupt normal podocyte function and invariably progress to FSGS.

• Membranous nephropathy (MN): While primary membranous nephropathy is the most common cause of nephrotic syndrome in adults, it is much less common in children and usually secondary to another disease process (e.g., systemic lupus erythematosus [SLE]). Diffuse glomerular capillary-wall thickening without increased cellularity is visible on light microscopy, with subepithelial immune deposits on electron microscopy in cases of primary MN.

Management

• Glucocorticoids: In children with no other signs or symptoms suggestive of a secondary cause, empiric glucocorticoids are generally used to achieve remission. Most children with idiopathic nephrotic syndrome have minimal change disease and can be expected to have a good response to glucocorticoids. Children who are “steroid-responsive” usually demonstrate improvement within 4 weeks of treatment.

• Loop diuretics may be used to reduce edema by promoting forced diuresis. Some centers may also add intravenous (IV) albumin replacement, particularly when there is concern for intravascular volume depletion (e.g., tachycardia, hypotension, acute kidney injury [AKI]).

• Pneumococcal vaccine: Patients with nephrotic syndrome lose immunoglobulins and anti-clotting factors in addition to albumin and are at risk for infection and venous thrombosis.

  • Risk of infection is especially high for encapsulated organisms, and patients older than 2 years should the appropriate pneumococcal polysaccharide vaccine(s) per Centers for Disease control guidelines. The exact vaccines indicated can be complex and may include a combination of PCV15 followed by PPSV23 or PCV20 alone. For patients who have previously completed the vaccine series, either a booster with PPSV23 or an additional dose of PCV20 may be indicated.

• Fluid restriction and low-sodium diet should be instituted to prevent further worsening of edema. Vitamin D deficiency is also common and should be monitored.

• Renal biopsy should be considered in the following situations:

  • children >12 years (less likely to be inimal change disease)

  • failure to achieve remission after a 4- to 6-week trial of glucocorticoids

  • concurrent features of glomerulonephritis (see below)

• Glucocorticoid-sparing (or steroid-sparing) agents (e.g., mycophenolate mofetil, cyclophosphamide, calcineurin inhibitors, or rituximab) may be considered in glucocorticoid-dependent or -resistant cases.

Glomerulonephritis

The following clinical findings of glomerulonephritis are caused by one of several disease processes that cause glomerular inflammation:

• hematuria

• proteinuria

• hypertension

• azotemia

• oliguria

Evaluation

The basic evaluation for acute glomerulonephritis includes the following:

• complete blood count

• serum electrolytes, blood urea nitrogen (BUN), and creatinine

• urinalysis with urine microscopy

  • common findings of glomerulonephritis on urinary sediment include dysmorphic RBCs and RBC casts (see images below)

• quantified urine protein excretion (urine protein-to-creatinine ratio)

• C3 and C4 complement

  • low C3, normal C4: postinfectious glomerulonephritis, C3 glomerulopathy (MPGN type II)

  • low C3 and C4: lupus nephritis, MPGN (types I and III)

  • normal C3, C4: IgA nephropathy, antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, anti-glomerular basement membrane (GBM) disease, viral-related glomerulonephritis (e.g., hepatitis B virus, hepatitis C virus, HIV)

• additional serologies (antistreptolysin antibody, antinuclear antibody, ANCA, anti-GBM antibody) based on clinical history and physical exam findings

• renal biopsy if indicated (e.g., presentation with nephrotic syndrome, increasing creatinine, hypertension, staging for lupus nephritis)

Note that the red blood cells are not uniform in size, the salient feature of dysmorphic red blood cells (bright-field view). Photographed by the late Michael Linshaw, MD. Courtesy of Mrs. Diane Linshaw.

Note that red blood cells are clearly identifiable in this cast, which is shown in the upper view in a Nomarski microscope and in the lower, bright-field view. Photographed by the late Michael Linshaw, MD. Courtesy of Mrs. Diane Linshaw.

Types of Glomerulonephritis

• IgA nephropathy:

  • most common cause of acute glomerulonephritis worldwide

  • classically presents with episodes of gross hematuria concurrent with upper respiratory infection (URI) or pharyngitis symptoms

  • typically suspected clinically and can be confirmed with biopsy with stains to identify IgA deposits

• post-streptococcal or post-infectious glomerulonephritis:

  • occurs 2-3 weeks after an acute infection, classically streptococcal pharyngitis or cellulitis; can occur simultaneously with some acute infections (e.g., staphylococcal infections)

  • laboratory studies notable for a low C3, which normalizes 6-8 weeks after the acute phase of illness

  • generally associated with a good prognosis, although it may take up to 1-2 years for residual microscopic hematuria to resolve

• lupus nephritis:

  • kidney disease that occurs in the setting of systemic lupus erythematosus (SLE), with a range of clinical presentations from microscopic hematuria and proteinuria to rapidly progressive glomerulonephritis

  • laboratory studies notable for low C3 and C4, and typically positive antinuclear antibody (ANA) and anti-dsDNA

  • biopsy crucial for staging and classification to determine medical treatment, which in more advanced stages consists of an induction phase of intense immunosuppression followed by a maintenance phase

  • biopsy notable for “full house” immunofluorescence, including IgG, IgA, IgM, C1q, and C3 deposition in a granular fashion in both the GBM and mesangium

• ANCA-associated vasculitis

  • granulomatosis with polyangiitis (GPA) typically cytoplasmic ANCA (c-ANCA) autoantibody positive

  • microscopic polyangiitis (MPA) typically perinuclear ANCA (p-ANCA) autoantibody positive

  • may have lung and kidney involvement, GPA typically with more sinus involvement

  • laboratory studies demonstrate normal complement

  • may be associated with rapidly progressive glomerulonephritis; renal biopsy is notable for a pauci-immune immunofluorescence staining and can demonstrate a necrotizing crescentic pattern of the glomeruli

• anti-GBM disease (Goodpasture syndrome)

  • due to autoantibody to glomerular basement membrane

  • can present with both lung and kidney involvement

  • laboratory tests demonstrate normal complement levels, and a linear staining of IgG in the glomerular basement membrane (epitope is collagen 4-alpha3)

  • treatment involves immunosuppression and plasmapheresis

• membranous glomerulonephritis (see above)

  • main clinical findings are isolated nephrotic syndrome rather than symptoms of an acute glomerulonephritis

  • often primary (75% of cases) but can be due to secondary causes (e.g., SLE) or medications (e.g., penicillamine, nonsteroidal anti-inflammatory drugs [NSAIDs])

  • primary membranous nephropathy can be due to genetic causes (antibodies raised against podocyte antigens PLA2R or THSD7A)