Glomerular diseases — Medicine Library

Summary

Renal glomeruli excrete urinary substances and excess water as an ultrafiltrate into the urine by selectively filtering the blood. Any damage to the glomeruli disrupts the filtration process and results in the appearance of blood components (proteins and red blood cells) in the urine. Glomerular damage is commonly caused by immune-mediated processes, which often lead to glomerulonephritis. Non-inflammatory causes, such as metabolic disease (e.g., diabetes, amyloidosis), can also result in significant damage to the glomeruli. The pathophysiology of glomerular diseases is complex; most patients present with either nephritic syndrome (low-level proteinuria, microhematuria, oliguria, and hypertension) or nephrotic syndrome (high-level proteinuria and generalized edema). All glomerular diseases can progress to acute or chronic renal failure. Thus, quick diagnosis and immediate initiation of therapy are required to prevent irreversible kidney damage.

Definitions

Terminology of glomerular diseases

Primary: a kidney disease specifically affecting the glomeruli (e.g., minimal change glomerulonephritis)
Secondary: a disease affecting the glomeruli in the context of a systemic disease (e.g., lupus nephritis in SLE) or a disease affecting another organ (e.g., diabetic nephropathy)
Diffuse: > 50% of glomeruli affected (e.g., diffuse proliferative glomerulonephritis)
Focal: < 50% of glomeruli affected (e.g., focal segmental glomerulosclerosis)
Global: entire glomerulus is affected
Segmental: only part of the glomerulus is affected
Proliferative: an increased number of cells in the glomerulus
Membranous: thickening of the glomerular basement membrane (e.g., membranous nephropathy)
Sclerosing: scarring of the glomerulus
Necrotizing: cell death within the glomerulus
Crescentic: accumulation of cells such as macrophages, fibroblasts, and epithelial cells in Bowman space

Pathophysiology

The
glomerular filtration barrier consists of
3 parts
Initial segment: Fenestrated glomerular capillary endothelium prevents large proteins from passing through.

Second segment: The glomerular basement membrane (GBM) contains a negative charge produced by heparan sulfate.

Final segment: Visceral epithelial cells produce/maintain the GBM and contain intercellular junctions created by podocytes that prevent further protein loss.
Damage to the
glomeruli → disruption of the
glomerular filtration barrier → can lead to nephritic or nephrotic syndrome

See “Pathophysiology” in “Nephritic syndrome.“

See “Pathophysiology” in “Nephrotic syndrome.“

Glomerular filtration barrier

Nephritic-nephrotic syndrome

Some diseases that manifest with nephritic syndrome can simultaneously cause nephrotic-range proteinuria (; > 3.5 g/24 h), the main feature of nephrotic syndrome.
When the criteria for both syndromes are fulfilled, the findings are referred to as mixed nephritic-nephrotic syndrome.
Most common causes of
nephritic-nephrotic syndrome:
- Membranoproliferative glomerulonephritis
- Diffuse proliferative glomerulonephritis
Classifying the patient's presentation as nephritic, nephrotic, or mixed nephritic-nephrotic can help narrow down the list of likely differential diagnoses.

Nephrotic vs. nephritic syndrome [1][2]

Nephritic syndrome and nephrotic syndrome are both common clinical manifestations of glomerular diseases.
Both syndromes are composed of characteristic clinical (e.g., edema, hypertension) and laboratory findings (e.g., glomerular hematuria, massive proteinuria), which result from damage to the glomeruli.
Glomerular diseases are usually categorized by the syndrome they cause, which is either nephritic or nephrotic.

	Nephritic syndrome	Nephrotic syndrome
Presentation	Proteinuria (< 3.5 g/24 h) (can be in nephrotic range in severe cases ) Hematuria with acanthocytes RBC casts in urine Mild to moderate edema Oliguria Azotemia Hypertension Sterile pyuria Rapidly progressive glomerulonephritis (RPGN)	Heavy proteinuria (> 3.5 g/24 h) Hypoalbuminemia Generalized edema Hyperlipidemia and fatty casts in urine → frothy urine Hypertension ↑ Risk of thromboembolism: (via loss of antithrombin III) ↑ Risk of infection (via loss of IgG and tissue edema which compromises the local blood supply and immune response)
Pathophysiology	Inflammatory response within glomeruli → GBM disruption → loss of renally excreted RBCs (acanthocytes) and ↓ GFR → hematuria, oliguria, azotemia, and ↑ renin → edema and hypertension	Damage to podocytes → structural damage of glomerular filtration barrier → massive renal loss of protein
Causes	Poststreptococcal glomerulonephritis IgA nephropathy (Berger disease) Granulomatosis with polyangiitis Microscopic polyangiitis Eosinophilic granulomatosis with polyangiitis Goodpasture disease (anti-GBM disease) Alport syndrome (hereditary nephritis) Thin basement membrane disease Lupus nephritis	Due to primary or secondary podocyte damage Minimal change disease Focal segmental glomerulosclerosis Membranous nephropathy Due to secondary podocyte damage Diabetic nephropathy Amyloid light-chain (AL) amyloidosis, light chain deposition disease Lupus nephritis

All glomerular diseases can lead to acute and chronic kidney failure.

Nephritic and nephrotic syndromes

Membranoproliferative glomerulonephritis (MPGN)

Overview of membranoproliferative glomerulonephritis [3][4][5][6]
		Immunoglobulin-mediated MPGN	Complement-mediated MPGN
Epidemiology		Rare form of chronic glomerulonephritis Most common in children and young adults
Definition		Histopathological pattern of glomerular injury characterized by increased number of intraglomerular cells and diffuse thickening of the glomerular capillary walls on light microscopy [6]
Pathophysiology		Immune complex deposits → activation of the classical complement pathway → cell injury, mesangial proliferation, and matrix expansion	Intramembranous deposition of complement C3 (C3 nephritic factor, an IgG autoantibody that stabilizes C3 convertase and continuously activates C3, leading to its depletion) → activation of the alternative complement pathway
Etiology		Primary disease (occurs mainly in children) [3] Secondary disease Infections: HBV, HCV Autoimmune diseases (e.g., SLE, cryoglobulinemia) Malignancy: lymphoma, monoclonal gammopathy of undetermined significance (MGUS) Hereditary diseases (e.g., sickle cell disease, α1-antitrypsin deficiency) Drugs (e.g., heroin, IFN α) Vascular and clotting disorders (e.g., thrombotic microangiopathy, antiphospholipid syndrome)	Anomalous regulation of the alternative complement pathway (e.g., dense deposit disease, C3 glomerulonephritis) caused by mutations in (or antibodies to) complement or complement regulatory proteins Often associated with a trigger (e.g., infection, MGUS)
Clinical features		May manifest with nephritic-nephrotic syndrome, nephritic syndrome, or nephrotic syndrome Proteinuria (frequently with nephrotic syndrome) Hematuria Hypertension Abnormal kidney function
Laboratory studies		↓ Serum C3 complement levels Urianalyisis: nephritic or nephrotic sediment
Biopsy findings	LM	H&E or PAS stain shows mesangial ingrowth, which leads to thickening and splitting of the glomerular basement membrane GBM (tram-track appearance).
Biopsy findings	EM [3]	MPGN type 1: subendothelial and mesangial IgG immune complex deposits with granular appearance MPGN type 2: intramembranous C3 deposits (dense deposit disease) on basement membrane MPGN type 3: subendothelial and subepithelial immune complex deposits
Management[6]		Treat the underlying cause Glucocorticoids ± other immunosuppressants (e.g., cyclophosphamide, mycophenolate mofetil) Supportive care (e.g., RAAS inhibitors or other antihypertensives) Complement-targeting therapy (eculizumab) for patients with complement abnormalities whose illness does not respond to other therapies
LM = light microscopy, EM = electron microscopy

MPGN is characterized by deposition of antibodies and/or complement factors in the mesangium and along capillary walls.

Tram-track appearance in membranoproliferative glomerulonephritis

Diffuse proliferative glomerulonephritis

Definition
- A histopathological pattern of glomerular injury characterized by increased cellularity in > 50% of the glomeruli
- Most common and severe manifestation of lupus nephritis in systemic lupus erythematosus (SLE)
- Also seen in IgA nephropathy and in other inflammatory, autoimmune, and infectious diseases
Clinical features
- Nephritic syndrome
- Nephritic-nephrotic syndrome (i.e., nephritic with nephrotic-range proteinuria)
- Can lead to immune complex-mediated RPGN
Diagnostics
- Laboratory studies
  - ↓ Serum C3 complement levels
  - In lupus nephritis: positive ANA, anti-dsDNA antibodies
- Microscopy
  - LM
    
    Thickening of glomerular capillaries (resembling wire loops)
    
    Characterized by increased cellularity in more than half of the glomeruli
  - IM: granular appearance
  - EM
    
    More commonly: subendothelial immune deposits (IgG immune complexes, C3, and C1q)
    
    Less commonly: subepithelial or intramembranous deposits
Management: depends on underlying cause

Lupus nephritis

Inherited glomerular disorders

Overview of inherited glomerular disorders
		Alport syndrome[7]	Thin basement membrane disease (benign familial hematuria) [8]
Epidemiology		♂ > ♀ (∼ 85% X-linked dominant, ∼ 15% autosomal recessive) [9] Severe disease typically manifests during adolescence. Most common type of hereditary nephritis (but rare)	Affects 5–9% of the general population [10]
Pathophysiology		Mutation in gene encoding type IV collagen	Hereditary disorder Abnormalities of type IV collagen causing thinning of GBM
Distinguishing features		Persistent microhematuria with intermittent gross hematuria Associated with sensorineural hearing loss and abnormalities of the eye (anterior lenticonus, retinopathy) Often leads to ESRD	Persistent microhematuria and episodic gross hematuria (e.g., following an upper respiratory tract infection or exercise) Good prognosis
Laboratory studies		Genetic testing to confirm diagnosis Skin biopsy: alternative test showing absence of collagen type IV alpha 5 chains See “Diagnostics” in “Alport syndrome.”	Urinalysis: persistent microhematuria Renal biopsy provides definitive diagnosis. See “Diagnostics” in “Thin basement membrane nephropathy.”
Renal biopsy	LM	Mesangial cell proliferation and sclerosis	No abnormalities
	IM	Collagen IV immunostaining shows absence of collagen IV.	Negative Ig and complement Occasional trace positivity for IgM and C3 in segmental mesangium Rare trace positivity for IgG and IgA in segmental mesangium
	EM	Splitting and alternating thickening and thinning of the GBM (lamellated, basket-weave appearance)	Diffuse thinning of GBM
Management		Supportive measures to help slow progression of the disease, e.g., ACE inhibitors in patients with proteinuria Renal replacement therapy in ESRD See “Treatment” in “Alport syndrome.”	No treatment for isolated hematuria ACE inhibitors for patients with proteinuria See “Treatment” in “Thin basement membrane nephropathy.”

**Anterior lenticonus in Alport syndrome**
Slit-lamp photograph of the right eye (mydriatic pupil)
The light of the slit-lamp produces an optical cross section of the cornea (left optical cross section) and the lens (right optical cross section). Compared to the cornea, the anterior surface of the lens appears conical (normal physiological shape is indicated by the dashed line).
This protrusion of the anterior cortex of the lens is referred to as “anterior lenticonus” and it is associated with Alport syndrome.

Source: “Figure 1. in: Clear lens phacoemulsification in the anterior lenticonus due to Alport Syndrome: two case reports” by Ghassem Amir Aslanzadeh, Davoud Gharabaghi & Niloofar Naderi, Journal of Medical Case Reports, BioMed Central, licensed under CC BY 2.0. The supplementary image with overlays of relevant areas was adapted from the image mentioned above (© AMBOSS).

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