Glomerular Disease

Classification · Pathogenesis · Diagnosis · Management

Evidence-based lecture deck
Sources: KDIGO 2021 Clinical Practice Guideline · peer-reviewed reviews · StatPearls
Every slide carries its own citation — replace with your prescribed textbook chapter as needed

Learning Objectives

What you should be able to do

Describe the structure of the glomerular filtration barrier and how its disruption produces disease.
Distinguish nephrotic from nephritic syndrome clinically, and explain the pathophysiological basis of each.
Explain why terms such as FSGS, MPGN and crescentic GN describe patterns of injury, not specific diseases.
Compare the histopathological classification with the emerging immunopathogenesis-based classification.
Outline the diagnostic pathway — urinalysis, serology, and the role of kidney biopsy.
State the general principles of management from the KDIGO 2021 guideline.

Framework adapted from: KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases; Qasim et al., Cureus 2025.

Part 1

Foundations: the glomerulus and its barrier

Anatomy & Physiology

The glomerular filtration barrier (GFB)

Tri-layered structure

A highly selective interface formed by fenestrated endothelial cells, the glomerular basement membrane (GBM), and visceral epithelial cells (podocytes).

Function

Enables ultrafiltration of plasma — restricting large macromolecules and negatively charged proteins while allowing water and small solutes into the urinary space.

Why it matters

Maintains plasma oncotic pressure and fluid–electrolyte balance. Its integrity is critical to renal function.

Central concept: Disruption of the barrier — by immune complex deposition, podocyte injury, basement membrane abnormality, or endothelial dysfunction — is the final common pathway of glomerular injury.

Source: Qasim et al., "Patterns of Glomerular Injury: Histopathological Classification and Clinical Correlation," Cureus 17(9): e91728, 2025.

Burden of Disease

Why glomerular disease matters

Glomerular diseases are a major contributor to chronic kidney disease (CKD) and end-stage renal disease (ESRD) worldwide, imposing a significant burden on healthcare systems and quality of life.
Podocyte injury — structural damage, detachment, or effacement of foot processes — has emerged as a central mechanism in many proteinuric disorders.
Clinically, glomerular diseases present along a spectrum: nephrotic syndrome, nephritic syndrome, or asymptomatic urinary abnormalities.

Source: Qasim et al., Cureus 2025; Merck Manual Professional Edition, "Overview of Glomerular Disorders," 2025.

Part 2

Clinical syndromes: nephrotic vs. nephritic

Clinical Definitions

The two ends of a spectrum

Feature	Nephrotic syndrome	Nephritic syndrome
Core definition	Heavy proteinuria >3.5 g/day, hypoalbuminemia, edema, often hyperlipidemia	Nephritic urine sediment, with or without hypertension, elevated creatinine, and oliguria
Urine sediment	Typically bland — fatty casts, oval fat bodies, few cells/cellular casts	Dysmorphic RBCs and RBC or mixed cellular casts; may be gross, cola-colored
Mechanism	Podocyte or GBM injury without significant inflammation; protein leaks into urine	Immune complex deposition with complement activation; glomerular capillary wall damage
Typical causes	MCD, primary FSGS, membranous nephropathy, advanced diabetic nephropathy	Post-infectious GN, IgA nephropathy (flares), proliferative lupus nephritis

Overlap is common. Several disorders — fibrillary and immunotactoid glomerulopathies, MPGN, and lupus nephritis — typically manifest with features of both syndromes.

Sources: Qasim et al., Cureus 2025; Merck Manual Professional, 2025; StatPearls, "Glomerulonephritis," 2023.

Pathophysiology

Why edema forms, and why complications follow

Edema

Decreased oncotic pressure from hypoalbuminemia. Often facial/periorbital in the morning, becoming dependent later.

Hyperlipidemia

The liver compensates for hypoalbuminemia by increasing lipoprotein production → hypercholesterolemia and lipiduria (fatty casts, oval fat bodies).

Thromboembolism

Urinary loss of anticoagulants such as antithrombin III. Membranous nephropathy with NS is a particularly high-risk situation.

Infection

Urinary loss of immunoglobulins → secondary immunodeficiency. Pneumococcal vaccination is advised in NS.

Sources: Qasim et al., Cureus 2025; Nature Reviews Immunology, "Glomerulonephritis: immunopathogenesis and immunotherapy," 2023; KDIGO 2021 Executive Summary, Kidney International.

Rapidly Progressive GN

Crescentic GN — a medical emergency

Severe cases may evolve into rapidly progressive glomerulonephritis (RPGN), featuring crescents on biopsy and rapid renal decline. RPGN is a medical emergency.

Traditionally divided into three categories:

Pauci-immune (ANCA-associated) — systemic small-vessel vasculitides with circulating ANCA; no or few immune deposits on immunofluorescence. Subdivided into granulomatosis with polyangiitis (GPA, anti-PR3) and microscopic polyangiitis (MPA, anti-MPO).
Anti-GBM disease — linear IgG along the GBM.
Immune complex disorders — lupus nephritis, IgA nephropathy, mixed cryoglobulinemia, post-infectious GN.

Terminology caution: crescents may be seen in any of these disorders. Crescentic GN is therefore a pattern of injury — the mechanism should be added to the name (e.g. PR3-ANCA crescentic GN).

Sources: "Update on the etiology, classification, and management of glomerular diseases"; Qasim et al., Cureus 2025.

Part 3

Classification: from pattern to pathogenesis

Key Principle

Pattern of injury ≠ disease entity

A consensus report by the Mayo Clinic and the Renal Pathology Society (2016) emphasised that a glomerular disease diagnosis should include three elements: the pattern of injury, the etiology/pathogenesis, and the specific disease entity.
Example: rather than "membranous nephropathy," the diagnosis becomes anti-PLA2R membranous nephropathy.
The same disease or mechanism can cause multiple patterns of injury, and the same pattern can result from multiple diseases.
Consequently, terms such as FSGS, MPGN and crescentic GN remain useful descriptively but are no longer adequate as disease labels.

Sources: "Update on the etiology, classification, and management of glomerular diseases"; "The five types of glomerulonephritis classified by pathogenesis, activity and chronicity (GN-AC)".

Classification I

Histopathological / clinical classification

Traditional classification is based on clinical presentation and biopsy appearance:

Group	Entities
Nephrotic	Minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN)
Nephritic	IgA nephropathy / IgA vasculitis, post-infectious GN, lupus nephritis
Mixed	Membranoproliferative GN (MPGN), lupus nephritis, RPGN

Histological patterns (descending order of prevalence in GN): diffuse, focal, and mesangial proliferative GN. Light microscopy, immunofluorescence and electron microscopy are interpreted together to distinguish morphologic and immunopathologic patterns.

Sources: StatPearls, "Glomerulonephritis," 2023; Qasim et al., Cureus 2025.

Classification II — the modern paradigm

Five categories by immunopathogenesis

Category	Representative entities	Therapeutic logic
Infection-related GN	Post-infectious GN, infection-related immune complex GN	Pathogen identification and control
Autoimmune GN	IgA nephropathy, lupus nephritis, anti-GBM GN, autoimmune MN	Suppression of adaptive immunity
Alloimmune GN	GN in transplant recipients	Suppression of adaptive immunity
Autoinflammatory GN	C3 glomerulopathy, dense deposit disease, inborn errors of innate immunity	Inhibition of single cytokines or complement factors
Monoclonal gammopathy-related GN	Proliferative GN with monoclonal Ig deposits, monoclonal Ig deposition disease, fibrillary GN with monoclonal deposits, immunotactoid glomerulopathy	B-cell or plasma-cell clone-directed therapy

Why this matters: current histopathological patterns do not align well with underlying pathological mechanisms, and therefore do not inform optimal therapy. An immunopathogenesis-based grouping directs treatment to the actual driver of disease.

Sources: Nature Reviews Immunology, 2023; StatPearls, 2023; GN-AC classification, 2023.

Worked Example

MPGN — why the old classification collapsed

Old system (by deposit location)

Type I — subendothelial immune complex deposits
Type II — dense deposit disease (intramembranous)
Type III — subendothelial + subepithelial/intramembranous

New system (by immunohistochemistry)

C3 glomerulopathy — C3-only or C3-dominant deposits; subdivided into C3 glomerulonephritis and dense deposit disease. Driven by persistent activation of the alternative complement pathway (C3 low, C4 normal).
Ig- and C3-positive MPGN — due to infections (bacterial endocarditis, hepatitis B/C, malaria), autoimmune disease (lupus nephritis, rheumatoid arthritis) or monoclonal gammopathy.

Teaching point: MPGN is a pattern of injury with a broad differential of completely different disorders requiring completely different therapies — which disqualifies the term as a disease entity.

Sources: Etiology/classification update review; GN-AC classification, 2023.

Epidemiology

Age and presentation narrow the differential

Age (yrs)	Nephritic	Nephrotic	Mixed
<15	Alport syndrome, IgA vasculitis, IgA nephropathy, lupus nephritis, mild PIGN, thin basement membrane disease	Congenital nephrotic syndromes, FSGS, lupus nephritis (membranous subtype), MCD	Lupus nephritis, MPGN
15–40	Alport syndrome, IgA nephropathy, lupus nephritis, PIGN, RPGN, thin basement membrane disease	Diabetic nephropathy, FSGS, IgA nephropathy, late PIGN, lupus nephritis, MN, MCD, preeclampsia	Fibrillary and immunotactoid GN, lupus nephritis, MPGN, RPGN
>40	IgA nephropathy, PIGN, RPGN, vasculitides	Amyloidosis (primary), diabetic nephropathy, FSGS, IgA nephropathy, late PIGN, light chain deposition disease, MN, MCD	Fibrillary and immunotactoid GN, IgA nephropathy, RPGN

Clinical correlate: Primary GN presenting as nephrotic syndrome is likely MCD in the young and membranous nephropathy in adults. Nephritic syndrome in children is likely post-infectious; in adults, suspect IgA nephropathy. Lupus nephritis is seen more commonly in young women (20–30 years).

Sources: Merck Manual Professional, "Glomerular Disorders by Age and Presentation," 2025; StatPearls, 2023.

Part 4

Diagnosis and management

Diagnostic Approach

From urinalysis to kidney biopsy

A glomerular disorder is usually suspected when testing reveals an elevated serum creatinine and abnormal urinalysis (hematuria with or without casts, proteinuria, or both).
First step: distinguish predominantly nephritic from predominantly nephrotic features, then narrow by age, accompanying illness, time course, systemic manifestations and family history.
Kidney biopsy is the gold standard for diagnostic evaluation of glomerular diseases, providing insight into etiology, activity, chronicity and reversibility. Repeat biopsy should be performed if it will alter diagnosis, therapy or prognosis.
Quantification: 24-hour urine collection for total protein excretion in adults; first-morning protein–creatinine ratio in children. eGFR by CKD-EPI (adults) or modified Schwartz (children).
Urine sediment must be examined for erythrocyte morphology, red cell casts and/or acanthocytes in all forms of GN.
Biopsy may be avoidable in selected cases — e.g. ANCA-associated vasculitis can be diagnosed with serum ANCA plus hematuria, proteinuria and impaired kidney function; a similar concept applies to anti-GBM disease.

Sources: KDIGO 2021 Executive Summary; Merck Manual Professional, 2025; GN-AC classification, 2023.

Therapy — General Principles

Supportive care applies to every patient

Blood pressure & proteinuria

ACEi or ARB at maximally tolerated dose is first-line. Target systolic BP <120 mmHg (standardised office measurement). Proteinuria targets vary by GN type.

Edema & sodium

Loop diuretics are preferred; dietary sodium <2.0 g/day. Add mechanistically different diuretics if response is insufficient — watch for hyponatremia, hypokalemia, GFR reduction, volume depletion.

Anticoagulation

Full anticoagulation for thromboembolic events in NS. Prophylactic anticoagulation when thromboembolism risk exceeds bleeding risk — notably membranous nephropathy with NS.

Infection prevention

Pneumococcal vaccine in NS and/or CKD; influenza vaccine for patients and household contacts. Consider prophylactic trimethoprim–sulfamethoxazole on high-dose steroids, rituximab or cyclophosphamide.

Lipids & lifestyle

Consider a statin for persistent dyslipidemia, especially with other cardiovascular risk factors. Normalise BMI, limit central obesity, regular physical activity.

Immunosuppression safety

Screen for TB, HBV, HCV, HIV and syphilis where clinically appropriate. Meningococcal vaccine/prophylaxis if complement-deficient or on complement inhibitors.

Source: KDIGO 2021 Executive Summary of the Guideline for the Management of Glomerular Diseases, Kidney International.

Disease-Specific Therapy

Selected KDIGO 2021 recommendations

Disease	Key guidance
Minimal change disease (adults)	Requires biopsy confirmation (unlike children). High-dose oral glucocorticoids are initial treatment (Grade 1C) unless contraindicated. Alternatives: cyclophosphamide, calcineurin inhibitors, MMF, possibly rituximab. High-dose steroids should not exceed 16 weeks; taper begins 2 weeks after remission.
Membranous nephropathy	Use and interpret the anti-PLA2R antibody assay; evaluate for associated conditions; risk-stratify for progressive loss of kidney function and treat according to risk. Immunologic monitoring after starting therapy.
IgA nephropathy	Initial assessment and management guided by the International IgAN Prediction Tool; glucocorticoids considered only where there is uniform use of RAS inhibition. Specific situations exist where glucocorticoids should be avoided or used with great caution.
ANCA-associated vasculitis	Rituximab plays an increasing role in both induction and maintenance therapy of ANCA-positive RPGN; reduced-dose glucocorticoid regimens are addressed.
Lupus nephritis	Classified by the Renal Pathology Society / International Society of Nephrology system (six classes). Note: Chapter 10 of KDIGO 2021 has been superseded by the 2024 Lupus Nephritis guideline.

Sources: KDIGO 2021 Executive Summary; KDIGO Glomerular Diseases guideline portal (updated chapter-by-chapter); etiology/classification update review.

Future Directions

Where the field is heading

Immunophenotyping at the centre of diagnosis — expanded autoantibody panels, serum complement studies, bone marrow aspirate and flow cytometry, alongside biopsy.
Genetic testing (e.g. whole-exome sequencing) where infections, autoantibodies, transplant and monoclonal gammopathy are absent — the only route to identifying autoinflammatory GN.
Biomarker-based diagnosis and monitoring of immunological activity and chronicity, potentially reducing reliance on kidney biopsy.
Emerging autoantibodies — e.g. anti-nephrin antibodies to identify autoimmune podocytopathies in MCD/FSGS.
Digital pathology and artificial intelligence are beginning to transform precision nephrology.
Refined classification — the proposed GN-AC matrix adds immunological Activity and Chronicity to disease type, to tailor an expanding armamentarium of immunomodulatory drugs.

Sources: GN-AC classification, 2023; Qasim et al., Cureus 2025; KDIGO 2021 Executive Summary.

Summary

Key take-home messages

Glomerular disease spans nephrotic, nephritic and mixed presentations — driven by disruption of the tri-layered glomerular filtration barrier.
FSGS, MPGN and crescentic GN are patterns of injury, not diagnoses. A complete diagnosis names the pattern, the etiology/pathogenesis, and the disease entity.
Classification is shifting from histopathological description to immunopathogenesis: infection-related, autoimmune, alloimmune, autoinflammatory, and monoclonal gammopathy-related.
Kidney biopsy remains the gold standard, but serology, genetics and biomarkers increasingly allow diagnosis without it.
Supportive care is universal: RAS blockade, BP <120 mmHg, sodium restriction, loop diuretics, risk-based anticoagulation, vaccination, lipid and lifestyle management.
Immunosuppression is disease-specific and must be matched to the underlying mechanism — with prophylaxis against its complications.

Synthesised from all sources cited in this deck, principally KDIGO 2021, Cureus 2025, Nature Reviews Immunology 2023 and StatPearls.

References

Sources cited in this deck

Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021. kdigo.org/guidelines/gd/
Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, et al. Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases. Kidney International. 2021. doi:10.1016/j.kint.2021.05.015
Qasim H, Abu Shugaer M, Dibian S, Ktaifan M, Khattab K, Leoni MLG, et al. Patterns of Glomerular Injury: Histopathological Classification and Clinical Correlation. Cureus. 2025;17(9):e91728. doi:10.7759/cureus.91728
Glomerulonephritis: immunopathogenesis and immunotherapy. Nature Reviews Immunology. 2023. nature.com/articles/s41577-022-00816-y
The five types of glomerulonephritis classified by pathogenesis, activity and chronicity (GN-AC). PMC10635795
Update on the etiology, classification, and management of glomerular diseases. PMC7252613
Glomerulonephritis. StatPearls [Internet]. 2023. NCBI Bookshelf NBK560644
Overview of Glomerular Disorders. Merck Manual Professional Edition. 2025. merckmanuals.com

Note on sourcing: all content above is drawn from the peer-reviewed articles and guidelines listed. No textbook chapter was available for extraction — insert your prescribed reference here before presenting (e.g. Robbins & Cotran; Harrison's Principles of Internal Medicine; Brenner & Rector's The Kidney). Verify every figure against your local edition.