Pharmacological Treatment of Glomerulonephritis

1. Corticosteroids

• High-dose oral prednisone (e.g., 1 mg/kg/day up to 80 mg/day) is standard induction in minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN).
• IV methylprednisolone pulses (500–1000 mg/day × 3 days) are used in rapidly progressive GN (RPGN) and crescentic GN before oral steroids.
• Toxicities: hyperglycemia, hypertension, osteoporosis, adrenal suppression, infection, weight gain, cataracts. Cumulative dose and duration must be minimized.

2. Calcineurin Inhibitors (CNIs)

• Cyclosporine and tacrolimus inhibit T-cell activation via calcineurin blockade.
• Used in: steroid-dependent/resistant MCD, FSGS, MN (especially as steroid-sparing agents), and lupus nephritis (LN).
• Tacrolimus is preferred over cyclosporine due to a better side-effect profile (less hirsutism, gingival hyperplasia).
• Key toxicities: nephrotoxicity (dose-dependent), hypertension, hyperkalemia, neurotoxicity (tacrolimus).
• Therapeutic drug monitoring (trough levels) is essential.

3. Alkylating Agents

• Cyclophosphamide (CYC) — oral or IV pulse (NIH protocol).
  • First-line induction for ANCA-associated vasculitis/crescentic GN (with high-dose steroids).
  • Used in severe lupus nephritis (class III/IV).
  • Also used in MN and fibrillary GN.
  • Toxicities: hemorrhagic cystitis (prevent with hydration ± mesna), myelosuppression, gonadal toxicity (cumulative dose-dependent), bladder cancer, opportunistic infections.
• Chlorambucil — alternative alkylating agent, largely replaced by cyclophosphamide.

4. Mycophenolic Acid (MPA) / Mycophenolate Mofetil (MMF)

• Inhibits inosine monophosphate dehydrogenase → blocks de novo purine synthesis in lymphocytes.
• Standard of care for lupus nephritis (both induction and maintenance); non-inferior to IV cyclophosphamide in many trials.
• Used in IgA nephropathy, MN (as part of combination regimens), and FSGS.
• Teratogenic — mandatory pregnancy counseling and contraception.
• Toxicities: GI (diarrhea, nausea), leukopenia, infection risk.

5. Azathioprine

• Purine analog; inhibits DNA synthesis in proliferating lymphocytes.
• Primarily a maintenance agent in ANCA vasculitis (after remission with cyclophosphamide).
• Also used in lupus nephritis maintenance.
• Toxicities: myelosuppression, hepatotoxicity, pancreatitis. TPMT/NUDT15 genotyping before use is advisable.

6. Rituximab (Anti-CD20 Monoclonal Antibody)

• Depletes B cells → reduces autoantibody production.
• ANCA-associated vasculitis: rituximab is non-inferior to cyclophosphamide for induction (RAVE and RITUXVAS trials) and is preferred in relapsing disease and for patients wishing to preserve fertility.
• Membranous nephropathy: rituximab is now a first-line option (based on MENTOR trial); produces durable remissions with favorable toxicity vs. cyclosporine.
• Lupus nephritis: used in refractory disease.
• Steroid-dependent/resistant MCD and FSGS.
• Toxicities: infusion reactions, infection (PJP prophylaxis often co-prescribed), reactivation of hepatitis B, progressive multifocal leukoencephalopathy (rare).

7. Eculizumab (Anti-C5 Complement Inhibitor)

• Blocks terminal complement activation.
• Used in C3 glomerulopathy (C3GN, dense deposit disease) and atypical HUS-associated GN.
• Prior meningococcal vaccination (ideally ≥2 weeks before) and prophylactic antibiotics (penicillin V) are mandatory due to risk of encapsulated bacterial infections, especially Neisseria meningitidis.

8. Adrenocorticotrophic Hormone (ACTH / Tetracosactide)

• Repository corticotropin injection (Acthar Gel) stimulates adrenal steroid production but also has direct melanocortin receptor effects on podocytes.
• Used in membranous nephropathy and MCD, particularly in patients intolerant of other agents.
• Still an emerging option; evidence base is smaller than for other agents.

Disease-Specific Summary

Adjunctive Pharmacotherapy (All Forms)

• ACE inhibitors / ARBs: reduce proteinuria and slow progression in virtually all forms of GN — first-line background therapy.
• Statins: manage dyslipidemia (especially in nephrotic GN).
• Anticoagulation: consider in membranous nephropathy with serum albumin <2.5 g/dL (high thrombosis risk).
• PJP prophylaxis (trimethoprim-sulfamethoxazole): whenever high-dose steroids + another immunosuppressant are combined.
• Calcium/vitamin D + bisphosphonates: for steroid-induced osteoporosis.

Surgical/Interventional Treatments for Glomerulonephritis

1. Plasma Exchange (Plasmapheresis)

2. Renal Biopsy

• Percutaneous ultrasound-guided needle biopsy of the native kidney.
• Classifies GN type (e.g., crescentic, membranous, IgA, minimal change) and grades activity vs. chronicity.
• Performed under local anesthesia; major complications (significant bleeding requiring intervention) occur in ~1–2% of cases.
• Without biopsy, appropriate pharmacological or interventional therapy cannot be selected.

3. Renal Replacement Therapy (RRT)

a. Haemodialysis (HD)

• Acute HD: Used as a bridge in severe RPGN/crescentic GN while awaiting immunosuppression to take effect.
• Chronic HD: Long-term option if GN leads to ESKD. Involves creation of an arteriovenous (AV) fistula or AV graft (surgical procedure) for vascular access, or tunnelled central venous catheter.

b. Peritoneal Dialysis (PD)

• An alternative to HD; a surgical tunnelled PD catheter is inserted into the peritoneal cavity.
• Less haemodynamically stressful; suitable for selected patients with GN-related ESKD.

4. Kidney Transplantation

• Living donor (laparoscopic donor nephrectomy) or deceased donor transplant.
• Offers superior outcomes vs. long-term dialysis.

5. Central Venous Access / Vascular Access Procedures

• Required for plasmapheresis (temporary HD catheter) and acute haemodialysis.
• AV fistula creation (surgical anastomosis of artery and vein, usually radiocephalic or brachiocephalic) is the gold standard for permanent HD access — preferred over grafts or catheters.

Key Principle

Glomerulonephritis has no direct surgical cure — all surgical interventions are either supportive (dialysis access, transplantation) or adjunctive (plasma exchange, biopsy). Immunosuppression remains the cornerstone of treatment, with procedural interventions reserved for acute crises, renal failure, or when pharmacological therapy has been exhausted.

Patient Education & Counselling for Glomerulonephritis

1. Understanding the Disease

• The kidneys contain tiny filtering units called glomeruli. In GN, the immune system damages these filters, causing protein and blood to leak into the urine.
• GN is not a single disease — it includes many subtypes (IgA nephropathy, membranous, FSGS, ANCA vasculitis, lupus nephritis, post-streptococcal, etc.), each with a different cause, treatment, and outlook.
• Some forms are acute (e.g., post-streptococcal GN — most children recover fully), while others are chronic and can slowly progress to kidney failure if uncontrolled.
• The disease is diagnosed by a kidney biopsy, which directly guides treatment decisions.

2. Monitoring: When to Seek Immediate Medical Attention

3. Blood Pressure Control

• Target BP: Generally <130/80 mmHg; stricter if proteinuria is significant.
• Patients should be taught to self-monitor blood pressure at home with a validated device.
• ACE inhibitors (e.g., ramipril) or ARBs (e.g., losartan) are the preferred agents — they both lower BP and reduce protein leak from the kidneys.
• Missing antihypertensive doses can cause dangerous BP spikes and accelerate kidney damage.
• Dietary sodium restriction (less salt) directly lowers BP and potentiates the effect of ACE inhibitors/ARBs.

4. Dietary Counselling

5. Medications — Adherence and Safety

• Take medications exactly as prescribed. Missing doses, especially corticosteroids, can precipitate disease flares.
• Do not stop steroids abruptly — this can cause adrenal crisis. Taper must always be supervised by a doctor.
• Mycophenolate mofetil (MMF): Strictly contraindicated in pregnancy — must use reliable contraception. Report any diarrhoea or infections.
• Cyclophosphamide: Drink 2–3 litres of fluid daily to reduce bladder toxicity (haemorrhagic cystitis). Report blood in urine immediately.
• Tacrolimus/cyclosporine: Avoid grapefruit juice (inhibits metabolism, raises drug levels). Take at consistent times daily.
• Rituximab: Ensure vaccinations are up to date before starting. Report any signs of infection promptly.
• Eculizumab: Must receive meningococcal vaccine ≥2 weeks before starting. May also require prophylactic antibiotics long-term. — Brenner and Rector's The Kidney

6. Infection Prevention

• Avoid contact with people who have active infections (chickenpox, TB, influenza).
• Vaccinations: Administer all recommended vaccines (influenza, pneumococcal, hepatitis B) — ideally before starting immunosuppression, as live vaccines (MMR, varicella, yellow fever) are contraindicated during active immunosuppression.
• Good hand hygiene; avoid raw/undercooked foods.
• Report any fever >38°C promptly — even mild infections can be life-threatening in immunosuppressed patients.
• Prophylactic trimethoprim-sulfamethoxazole (co-trimoxazole) is routinely prescribed when high-dose steroids are combined with another immunosuppressant — explain its purpose to the patient.

7. Pregnancy and Fertility Counselling

• Women of childbearing age must receive explicit counselling:
  • MMF (mycophenolate) and cyclophosphamide are teratogenic — effective contraception is mandatory during and for several months after treatment.
  • Safer options in pregnancy: Corticosteroids and azathioprine have a more acceptable safety profile. — National Kidney Foundation Primer on Kidney Diseases, 8e
  • Pregnancy outcomes in GN depend on BP control, degree of proteinuria, and GFR — women with minimal proteinuria (<1 g/day) and normal GFR generally do well.
  • Women with ANCA vasculitis in remission may still relapse during pregnancy — close monitoring is essential.
  • Anti-GBM disease: must achieve full serological remission (antibody negativity) before considering pregnancy.
  • All pregnancies in women with GN are high-risk and require joint obstetric-nephrology care.
  • Post-partum: anticoagulation should continue ≥6 weeks after delivery in women with nephrotic syndrome (hypercoagulable state). — Creasy & Resnik's Maternal-Fetal Medicine
• Men on cyclophosphamide: Discuss risk of gonadal toxicity (oligospermia, azoospermia); offer sperm banking before treatment initiation, especially in young men. — Brenner and Rector's The Kidney

8. Lifestyle Modifications

• Smoking cessation: Smoking accelerates CKD progression and dramatically increases cardiovascular risk (already elevated in GN).
• Exercise: Moderate, regular aerobic exercise (walking, swimming) is beneficial. Avoid strenuous exercise during active disease or with significant oedema.
• Weight management: Obesity worsens proteinuria and hypertension.
• Alcohol: Limit intake; alcohol raises BP and can interact with immunosuppressants (especially methotrexate and tacrolimus).
• NSAIDs (ibuprofen, naproxen, diclofenac): Strictly avoid — they reduce GFR, worsen proteinuria, and can precipitate acute kidney injury in GN patients.

9. Regular Follow-Up and Monitoring

10. Prognosis — Setting Realistic Expectations

• Post-streptococcal GN (PSGN): ~95% of children recover fully; up to 20% of adults develop chronic renal insufficiency. — Swanson's Family Medicine Review
• IgA Nephropathy: Usually slow progression; ~30–40% reach ESKD over 20–30 years.
• Minimal Change Disease: Excellent response to steroids in children; relapses are common but long-term prognosis is good.
• FSGS: More guarded prognosis; up to 50% progress to ESKD without sustained remission.
• ANCA Vasculitis / Anti-GBM: Can be life-threatening; early aggressive treatment critical for renal recovery.
• The most common cause of death in CKD from GN is cardiovascular disease (MI, stroke) — not kidney failure itself. Cardiovascular risk reduction is therefore a core counselling priority. — Swanson's Family Medicine Review

11. Psychological Support

• Chronic GN, particularly on long-term immunosuppression, carries significant psychological burden (anxiety, depression, body image concerns from steroid side effects — weight gain, cushingoid features, acne).
• Acknowledge these concerns; refer to psychology, support groups, or social work as appropriate.
• Family counselling may be appropriate in hereditary forms (e.g., Alport syndrome).

Conclusion & Future Directions in Glomerulonephritis

Conclusion

• Biopsy-guided, disease-specific treatment has replaced empirical broad immunosuppression.
• Randomised controlled trials (CYCLOPS, RAVE, RITUXVAS, MENTOR, AURORA, BLISS-LN) have established evidence-based protocols for major GN subtypes.
• Individualisation of therapy — balancing the risk of disease progression against the cumulative toxicity of immunosuppressants — is now the guiding principle of management. As stated in Brenner and Rector's The Kidney: "Decisions regarding therapy should be tailored to the individual patient, with thoughtful balance of the risk of disease progression and the risk of treatment toxicity."
• Novel targeted biologics (rituximab, eculizumab, voclosporin, belimumab) have expanded the therapeutic armamentarium beyond the traditional corticosteroid–cyclophosphamide backbone.
• Despite these advances, 10–30% of patients with lupus nephritis develop kidney failure, and many forms of GN (FSGS, fibrillary GN, MPGN) carry a poor long-term renal prognosis — underscoring that there is significant unmet need. — Goldman-Cecil Medicine

Future Directions

1. Precision Medicine & Biomarker-Driven Therapy

• Serological biomarkers are already transforming diagnosis and monitoring:
  • Anti-PLA2R antibodies for membranous nephropathy
  • ANCA titres (PR3-ANCA, MPO-ANCA) for vasculitic GN
  • DNAJB9 — a novel, highly specific biomarker for fibrillary GN identified in both tissue and serum — enabling non-invasive diagnosis. — Brenner and Rector's The Kidney; Comprehensive Clinical Nephrology, 7th Edition
• Future goal: non-invasive "liquid biopsies" using urine/serum proteomics, cell-free DNA, and microRNA panels to monitor disease activity and predict flares without repeated renal biopsies.
• Genetic and pharmacogenomic profiling: TPMT/NUDT15 genotyping before azathioprine; future expansion to predict response to rituximab, MMF, or CNIs at an individual level.

2. Newly Approved Targeted Therapies (Recent FDA Approvals)

• Voclosporin + MMF + low-dose steroids (triple therapy) demonstrated significantly higher complete renal response in lupus nephritis without the need for high-dose steroids, representing a paradigm shift away from steroid toxicity. — Harrison's Principles of Internal Medicine 22E
• Belimumab (inhibits B-cell activating factor/BAFF) added to standard therapy further increases remission rates in lupus nephritis. — Goldman-Cecil Medicine
• Avacopan (C5a receptor blocker) in ANCA vasculitis-associated GN demonstrated non-inferiority to high-dose prednisone while causing significantly less steroid toxicity — pointing toward a steroid-sparing future.

3. Complement-Targeted Therapies

• Eculizumab (anti-C5): Established in atypical HUS and C3 glomerulopathy; under investigation for MPGN and post-transplant recurrence of C3GN.
• Next-generation complement inhibitors targeting C3 (pegcetacoplan), Factor D (danicopan), Factor B (iptacopan), and C5a receptor (avacopan) are in clinical trials for C3 glomerulopathy, IgA nephropathy, and lupus nephritis.
• The emerging classification of MPGN into complement-mediated vs. immunoglobulin-mediated subtypes is already directing complement-specific treatment — a trend that will intensify. — Goldman-Cecil Medicine; Comprehensive Clinical Nephrology

4. B-Cell and Plasma Cell Targeting

• Rituximab (anti-CD20): Now first-line in membranous nephropathy and ANCA vasculitis relapse; expanding use in FSGS, MCD, and lupus nephritis.
• Ocrelizumab (second-generation anti-CD20): Under evaluation in GN.
• Obinutuzumab: More potent B-cell depletion than rituximab; trials ongoing in lupus nephritis.
• Daratumumab (anti-CD38): Targets plasma cells responsible for persistent autoantibody production; early-phase trials in anti-GBM disease and refractory lupus nephritis.
• CAR-T cell therapy: Emerging data in refractory autoimmune disease suggests potential applicability to severe, refractory GN in the future.

5. Steroid-Sparing Strategies

• Avacopan in ANCA-GN
• Voclosporin + low-dose steroids in lupus nephritis
• Targeted-release budesonide (Nefecon) in IgA nephropathy — acts on gut Peyer's patches to reduce IgA1 overproduction with minimal systemic steroid exposure
• Development of ACTH analogues with direct podocyte protection independent of adrenal stimulation

6. SGLT2 Inhibitors as Nephroprotective Agents

• Originally developed for diabetes, SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) have demonstrated significant proteinuria reduction and GFR preservation in CKD of various causes, including non-diabetic GN.
• Multiple landmark trials (DAPA-CKD, EMPA-KIDNEY) included patients with IgA nephropathy and other GN subtypes — SGLT2 inhibitors are now being integrated as background nephroprotective therapy across GN subtypes regardless of diabetes status.

7. Improved Global Access and Epidemiological Understanding

• The true burden of GN is grossly underestimated globally, particularly in low- and middle-income countries where renal biopsy registries are lacking. — Brenner and Rector's The Kidney
• Establishment of international GN registries and collaborative databases (e.g., NEPTUNE, ERA-EDTA registry) will enable precision phenotyping, discovery of novel genetic risk loci, and better natural history data.
• Post-infectious GN — particularly streptococcal — remains a major cause of GN in children in developing nations; improved sanitation and antimicrobial access remain public health priorities.

Summary Table: Current Limitations → Future Solutions

The overarching future of GN management lies in moving from broad immunosuppression to precision, mechanism-based therapy — identifying the right drug for the right patient at the right time, with the least toxicity.

Symptoms and Signs of Glomerulonephritis

The Two Core Clinical Syndromes

Nephritic Syndrome

Nephrotic Syndrome

Symptoms (What the Patient Complains Of)

"Hematuria is the most common symptom of glomerulonephritis but may be subclinical (microscopic). Symptoms related to hypertension may be the chief complaint of a child with undiagnosed glomerulonephritis. Patients may complain of bloody or foamy urine, oliguria, nausea, fatigue, or lethargy." — Tintinalli's Emergency Medicine

Signs (What the Clinician Finds)

Vital Signs

• Hypertension — often the most prominent sign; can be severe
• Tachycardia — if anaemia or volume overload present
• Reduced urine output on fluid balance charts

General Examination

• Pallor (anaemia from haematuria or reduced erythropoietin in CKD)
• Uraemic complexion (sallow, yellowish tinge in chronic disease)
• Uraemic frost (rare — late end-stage only)

Eyes

• Periorbital oedema — characteristic morning finding

Cardiovascular

• Elevated JVP (fluid overload)
• S3 gallop or displaced apex (hypertensive cardiomegaly)
• Pulmonary crepitations (pulmonary oedema)

Abdomen

• Shifting dullness / fluid thrill (ascites in nephrotic presentations)
• Renal angle tenderness (occasionally in acute GN)

Limbs

• Pitting oedema — ankles, legs, sacrum
• Signs of deep vein thrombosis (risk in nephrotic syndrome due to loss of antithrombotic proteins)

Urinalysis — The Key Diagnostic Sign

Rapidly Progressive GN (RPGN) — A Medical Emergency

• Rapid loss of kidney function over days to weeks (50% decline in GFR within 3 months)
• Nephritic syndrome features + progressive oliguria/anuria
• May present with pulmonary haemorrhage (haemoptysis, hypoxia) — the pulmonary-renal syndrome in:
  • ANCA vasculitis (GPA, MPA)
  • Anti-GBM disease (Goodpasture syndrome)
• Without urgent treatment, progresses to dialysis-dependent ESKD within weeks

Disease-Specific Symptom Highlights

Summary: The Classic Triad of Nephritic GN

Haematuria + Hypertension + Oedema with reduced GFR and sub-nephrotic proteinuria

Classification of Glomerulonephritis

I. By Aetiology: Primary vs. Secondary

A. Primary (Idiopathic) GN

B. Secondary GN

II. By Clinical Syndrome / Course

1. Acute GN

• Abrupt onset nephritic syndrome
• Most common example: Post-streptococcal GN — occurs 1–4 weeks after Group A β-haemolytic streptococcal pharyngitis or skin infection (impetigo)
• Usually self-limiting in children (~95% full recovery); less benign in adults

2. Rapidly Progressive GN (RPGN) / Crescentic GN

• Rapid loss of kidney function over days to weeks
• Defined by the presence of crescents (extracapillary proliferation) in >50% of glomeruli on biopsy
• A nephrological emergency
• Three immunological subtypes (see Section III below)

3. Chronic GN

• Slowly progressive over years to decades
• May present late with CKD signs (hypertension, anaemia, small shrunken kidneys)
• End result of many primary and secondary GN forms (IgA nephropathy, FSGS, MPGN)

4. Recurrent Macroscopic Haematuria

• Episodic gross haematuria triggered by mucosal infections
• Hallmark of IgA Nephropathy ("synpharyngitic" — haematuria appears simultaneously with URTI, not weeks later)

5. Asymptomatic Urinary Abnormalities

• Microscopic haematuria ± proteinuria discovered incidentally
• May represent subtle or early GN (IgA nephropathy, thin basement membrane nephropathy)

III. By Immunopathology (Immunofluorescence Pattern)

Type I — Anti-GBM Antibody-Mediated GN

• Linear IgG deposits along the glomerular basement membrane (GBM) on immunofluorescence
• Caused by autoantibodies against the α3 chain of type IV collagen
• With pulmonary haemorrhage = Goodpasture syndrome
• Without lung involvement = renal-limited anti-GBM disease
• Treatment: plasma exchange + cyclophosphamide + steroids (urgent)

Type II — Immune Complex–Mediated GN

• Granular ("lumpy-bumpy") deposits of IgG, IgA, IgM and/or C3 on immunofluorescence
• Deposits located in: mesangium, subendothelial, subepithelial, or mixed locations
• Includes:
  • Post-infectious GN
  • Lupus nephritis
  • IgA nephropathy
  • MPGN type I
  • Henoch-Schönlein purpura / IgA vasculitis
  • Cryoglobulinaemic GN
  • Fibrillary GN
  • C3 glomerulonephritis

Type III — Pauci-Immune GN

• Little or no immunoglobulin/complement on immunofluorescence ("pauci" = few/sparse)
• Most commonly associated with ANCA antibodies (antineutrophil cytoplasmic antibodies)
• Subtypes:
  • C-ANCA / PR3-ANCA → Granulomatosis with Polyangiitis (GPA, formerly Wegener's)
  • P-ANCA / MPO-ANCA → Microscopic Polyangiitis (MPA) or Eosinophilic GPA (EGPA/Churg-Strauss)
  • Renal-limited ANCA vasculitis
  • Idiopathic (ANCA-negative)
• Most common cause of RPGN in adults, especially older adults — Brenner and Rector's The Kidney

Complement-Mediated (C3 Dominant) GN — Emerging 4th Category

• C3-only or C3-dominant deposits with absent or trace immunoglobulin
• Caused by dysregulation of the alternative complement pathway
• Subtypes:
  • Dense Deposit Disease (DDD / MPGN type II): extremely electron-dense ribbon-like deposits within GBM
  • C3 Glomerulonephritis (C3GN): mesangial/subendothelial C3 deposits
• Associated with: C3 nephritic factor (C3NeF), mutations in Factor H/I/CFHR5
• Treatment: eculizumab (anti-C5 complement inhibitor)

"A practical classification divides crescentic GN into several groups based on immunologic findings." — Robbins, Cotran & Kumar Pathologic Basis of Disease

IV. By Histopathology (Light Microscopy Pattern)

V. RPGN Crescentic GN Classification Summary Table

VI. Lupus Nephritis — ISN/RPS Classification (Special Case)

Quick-Reference Classification Overview

Glomerulonephritis
├── By Aetiology
│   ├── Primary (renal-limited)
│   └── Secondary (systemic disease)
│
├── By Clinical Course
│   ├── Acute GN
│   ├── Rapidly Progressive (Crescentic) GN
│   ├── Chronic GN
│   ├── Recurrent Haematuria
│   └── Asymptomatic Urinary Abnormalities
│
├── By Immunopathology (IF pattern)
│   ├── Type I — Anti-GBM (linear)
│   ├── Type II — Immune Complex (granular)
│   ├── Type III — Pauci-Immune (absent Ig)
│   └── C3 Dominant (complement-mediated)
│
└── By Histopathology (LM pattern)
    ├── Minimal change
    ├── Focal segmental sclerosis
    ├── Diffuse/focal proliferative
    ├── Membranous
    ├── Membranoproliferative
    └── Crescentic (RPGN)

Primary and Secondary Prevention of Glomerulonephritis

PRIMARY PREVENTION

1. Prevention of Post-Streptococcal GN (PSGN) — The Most Preventable Form

a. Prompt Treatment of Streptococcal Infections

• Antibiotic therapy for Group A β-haemolytic streptococcal pharyngitis (throat infection) prevents rheumatic fever but does NOT reliably prevent PSGN once the nephritogenic process has been triggered.
• However, treating an active streptococcal infection at the time of GN diagnosis with benzathine penicillin G (1.2 million units IM) is indicated to eradicate the organism and prevent spread of nephritogenic strains to contacts. — Goldman-Cecil Medicine
• For glomerulonephritis specifically, no specific antibiotic prophylaxis is indicated — unlike rheumatic fever prevention. — Medical Microbiology, 9e
• Oral options: penicillin V, amoxicillin (first-line); oral cephalosporin or macrolide for penicillin-allergic patients.

b. Public Health and Sanitation Measures

• Skin infections (impetigo) are a major trigger of PSGN, particularly in children, and are strongly associated with overcrowding and poor hygiene. — Robbins, Cotran & Kumar
• Preventive strategies in endemic areas:
  • Improved sanitation, clean water access, and adequate housing
  • Skin hygiene education — wound care and prevention of skin infections
  • Early recognition and treatment of impetigo and pyoderma in school-aged children
  • School-based screening programmes for haematuria in high-prevalence regions

c. Prevention of Other Infection-Triggered GN

• Hepatitis B vaccination: prevents HBV-associated MPGN and membranous nephropathy
• Hepatitis C treatment (direct-acting antivirals — sofosbuvir, etc.): eradicating HCV prevents cryoglobulinaemic GN and HCV-associated MPGN
• HIV treatment (antiretroviral therapy): prevents HIV-associated nephropathy (collapsing FSGS)
• Infective endocarditis prevention: antibiotic prophylaxis before dental/surgical procedures in at-risk patients prevents endocarditis-associated GN
• Malaria prevention (insecticide-treated nets, antimalarial chemoprophylaxis): reduces malaria-associated GN in endemic regions

2. Prevention of Secondary GN (by Controlling Systemic Disease)

3. Avoidance of Nephrotoxic and Immunogenic Triggers

• NSAIDs: reduce renal blood flow and can precipitate acute GN exacerbations; avoid in patients with existing renal vulnerability
• Hydrocarbon solvents (paints, dyes): implicated in triggering anti-GBM antibody formation — occupational exposure reduction
• Certain drugs causing drug-induced GN: gold salts, penicillamine, mercury compounds — use safer alternatives where possible
• Illicit drugs: heroin nephropathy (collapsing FSGS); cocaine — counsel against use

4. Smoking Cessation as Primary Prevention

• Glomerular hyperfiltration and proteinuria in healthy individuals
• Progression from subclinical to clinical GN
• Albuminuria and CKD development

"Smoking was associated with an increased risk of developing glomerular hyperfiltration (OR 1.32 vs. non-smokers), as well as proteinuria (OR 1.51 vs. non-smokers)." — Brenner and Rector's The Kidney

SECONDARY PREVENTION

1. Slow progression to CKD/ESKD
2. Prevent flares and relapses
3. Reduce cardiovascular risk
4. Prevent treatment-related complications

1. Renin-Angiotensin-Aldosterone System (RAAS) Blockade

• ACE inhibitors (ramipril, enalapril) or ARBs (losartan, irbesartan) reduce:
  • Intraglomerular hypertension
  • Proteinuria (direct antiproteinuric effect independent of systemic BP)
  • TGF-β-mediated renal fibrosis
  • Rate of GFR decline
• Indicated in all patients with GN and proteinuria >0.5–1 g/day, regardless of systemic blood pressure

• "Both ACE inhibitors and ARBs prevent hypertension, limit proteinuria [and slow disease progression]." — Brenner and Rector's The Kidney

• For IgA nephropathy with proteinuria ≥1 g/day: ACE inhibitor/ARB is the first-line intervention before immunosuppression is considered

2. Blood Pressure Control

• Target: <130/80 mmHg (tighter in those with significant proteinuria)
• Uncontrolled hypertension is the most powerful accelerant of glomerulosclerosis and progression to ESKD
• Regular home BP monitoring; combination antihypertensives if needed
• Salt restriction (<2 g/day sodium) potentiates RAAS blockade and reduces oedema

3. Proteinuria Reduction — A Key Surrogate Target

• Reducing 24-hour proteinuria to <0.5–1 g/day is strongly associated with preserved GFR and halted progression
• Strategies: RAAS blockade, immunosuppression (disease-specific), SGLT2 inhibitors (see below), dietary protein moderation
• Monitoring: urine protein:creatinine ratio at every follow-up visit

4. SGLT2 Inhibitors (Emerging Secondary Prevention)

• Dapagliflozin, empagliflozin, canagliflozin demonstrate robust nephroprotection in CKD — including non-diabetic GN
• Reduce proteinuria, slow GFR decline, decrease cardiovascular events
• Now integrated as background secondary prevention therapy in IgA nephropathy and other GN-related CKD regardless of diabetes status (DAPA-CKD, EMPA-KIDNEY trials)

5. Lipid Management

• GN — especially nephrotic syndrome — causes significant hyperlipidaemia with elevated LDL and cardiovascular risk
• Statin therapy (atorvastatin, rosuvastatin) is standard:
  • Reduces cardiovascular events (the leading cause of death in CKD patients)
  • May have a modest renoprotective effect via anti-inflammatory and anti-fibrotic actions

6. Smoking Cessation (Secondary Prevention)

• IgA nephropathy
• Lupus nephritis
• Primary GN
• Diabetic nephropathy

"Smoking has been identified as a significant risk factor for disease progression in a variety of forms of CKD, including IgA nephropathy, lupus nephritis, and primary glomerulonephritis. Smoking cessation may contribute to slowing the rate of progression of CKD." — Brenner and Rector's The Kidney

7. Immunosuppression Maintenance — Preventing Relapses and Flares

• Lupus nephritis: long-term hydroxychloroquine (reduces flare frequency by ~50%); maintenance MMF or azathioprine; avoid sun exposure and infections as flare triggers
• ANCA vasculitis: maintenance rituximab or azathioprine after remission; monitor ANCA titres for early relapse detection
• Membranous nephropathy: monitor anti-PLA2R antibody levels; rising titres predict clinical relapse before overt proteinuria worsens
• MCD / FSGS: minimise steroid dose with CNI or MMF as steroid-sparing agents; educate patients to recognise oedema as a relapse sign

8. Prevention of Thrombotic Complications

• Nephrotic syndrome (especially membranous nephropathy) confers a high risk of renal vein thrombosis, DVT, and pulmonary embolism due to urinary loss of antithrombotic proteins (antithrombin III, protein C/S)
• Anticoagulation with warfarin or LMWH is indicated when serum albumin <2.5 g/dL
• Mobilisation; avoid prolonged immobility

9. Prevention of Infectious Complications (in Immunosuppressed Patients)

• Pneumocystis jirovecii prophylaxis: cotrimoxazole (TMP-SMX) whenever high-dose steroids are combined with a second immunosuppressant
• Vaccination before initiating immunosuppression (influenza, pneumococcal, hepatitis B, meningococcal — the latter mandatory before eculizumab)
• Live vaccines (MMR, varicella) contraindicated during active immunosuppression
• Monitoring for TB reactivation before rituximab or cyclophosphamide use

10. Prevention of Transplant Recurrence

Summary Table

Guidelines & Key Articles Behind the Glomerulonephritis Data

I. Primary Clinical Practice Guidelines

1. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases

Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1–S276.

• The single most important and comprehensive guideline for GN management globally
• Covers: minimal change disease, FSGS, membranous nephropathy, IgA nephropathy, lupus nephritis, ANCA vasculitis, anti-GBM disease, C3 glomerulopathy, infection-related GN
• Updated in 2021 from the original 2012 version — now incorporates rituximab, voclosporin, belimumab, sparsentan, SGLT2 inhibitors, avacopan
• Referenced throughout Brenner and Rector's, Comprehensive Clinical Nephrology, and Harrison's

2. KDIGO 2012 Clinical Practice Guideline for Glomerulonephritis

KDIGO Glomerulonephritis Work Group. Kidney Int Suppl. 2012;2(2):139–274.

• The foundational guideline predecessor to KDIGO 2021
• Still referenced in many major textbooks
• Chapters cover infection-related GN, IgA nephropathy, lupus nephritis, ANCA vasculitis, anti-GBM disease, membranous nephropathy, MPGN
• Referenced in: Campbell Walsh Wein Urology; Brenner and Rector's The Kidney; National Kidney Foundation Primer

3. KDIGO 2012 Clinical Practice Guideline for CKD

KDIGO CKD Work Group. Kidney Int Suppl. 2013;3:1–150.

• Underpins all secondary prevention recommendations (BP targets, proteinuria management, RAAS blockade, CKD staging)

4. ISN/RPS Classification of Lupus Nephritis

Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15:241–250. Bajema IM, Wilhelmus S, et al. Revision of the ISN/RPS classification for lupus nephritis. Kidney Int. 2018;93:789–796.

• Provides the Class I–VI histological classification system for lupus nephritis used in all guidelines and clinical practice

II. Landmark Randomised Controlled Trials (RCTs)

ANCA Vasculitis / Crescentic GN

Membranous Nephropathy

Lupus Nephritis

IgA Nephropathy

FSGS / Nephrotic Syndrome

III. Key Textbooks Used as Primary Sources

IV. Key Supporting Guidelines (Non-GN-Specific but Referenced)

V. Key Individual Articles Referenced Across the Conversation

All clinical statements, drug recommendations, dosing regimens, trial outcomes, and prevention strategies presented in this conversation are grounded in KDIGO 2021 as the primary guideline, supported by KDIGO 2012, and validated through the landmark RCTs and major nephrology/internal medicine textbooks listed above.

Overview of Glomerulonephritis

Definition

"Glomerulonephritis is an inflammatory process affecting the glomerulus. It usually results from deposition of immune complexes within the glomeruli. These activate complement, recruit leukocytes, and release cytokines and growth factors, leading to inflammation, injury, sclerosis, and fibrosis." — Tintinalli's Emergency Medicine

Epidemiology

• The annual incidence of primary GN in U.S. adults is estimated at 0.2 to 2.5 per 100,000 per year, with lower rates in children. — Goldman-Cecil Medicine
• GN is the third most common cause of ESKD globally, after diabetes mellitus and hypertension.
• The true burden is likely grossly underestimated due to lack of biopsy registries in low-income countries. — Brenner and Rector's The Kidney
• Incidence varies significantly by age, sex, geography, and GN subtype:

Fig. Epidemiology of biopsy-proven primary GN by age — Comprehensive Clinical Nephrology, 7th Edition

• IgA nephropathy: most common primary GN worldwide; peak in 15–65-year age group; predominant in Asia and Europe; rare in African ancestry
• Membranous nephropathy (MN): most common cause of nephrotic syndrome in adults >60 years
• Minimal Change Disease (MCD): predominant in children <15 years; commonest cause of childhood nephrotic syndrome
• FSGS: increasing incidence in adults; particularly in people of African descent
• RPGN: incidence rises sharply in patients >65 years (pauci-immune/ANCA-associated predominates)
• PSGN: commonest in children 6–10 years in developing nations; decreasing in high-income countries due to antibiotic access

Anatomy & Structure Relevant to GN

• Endothelial cells (with fenestrae)
• Glomerular basement membrane (GBM) — type IV collagen, laminin, proteoglycans
• Podocytes (visceral epithelial cells with foot processes) — the final filtration barrier
• Mesangial cells — structural support and immune surveillance

Aetiology

• Primary (idiopathic) — confined to the kidney (IgA nephropathy, FSGS, membranous nephropathy, MCD, MPGN)
• Secondary — manifestation of systemic disease (lupus nephritis, ANCA vasculitis, diabetic nephropathy, post-infectious GN, Goodpasture syndrome)

Pathogenesis

1. Immune Complex Deposition (Type II — Granular IF pattern)

• Circulating immune complexes (antigen-antibody) are deposited in the glomerulus, OR
• In situ complex formation — antibodies bind directly to glomerular antigens (e.g., anti-PLA2R in membranous nephropathy, streptococcal antigen in PSGN)
• Activates complement (classical and alternative pathways) → C3a/C5a → neutrophil and monocyte recruitment → release of oxidants, proteases, cytokines (TNF-α, IL-1), and TGF-β
• TGF-β drives eventual glomerulosclerosis and fibrosis
• Examples: PSGN, lupus nephritis, IgA nephropathy, MPGN, cryoglobulinaemic GN

2. Anti-GBM Antibody-Mediated (Type I — Linear IF pattern)

• Autoantibodies against α3 chain of type IV collagen in GBM → linear IgG deposits
• Complement activation + neutrophil infiltration → severe crescentic GN
• With lung involvement: Goodpasture syndrome (pulmonary-renal syndrome)

3. Pauci-Immune / ANCA-Mediated (Type III — Absent IF deposits)

• ANCA (anti-neutrophil cytoplasmic antibodies — PR3-ANCA or MPO-ANCA) prime and activate neutrophils
• Activated neutrophils directly attack glomerular capillary walls → necrotising lesions and crescents
• Most common cause of RPGN in adults
• Associated with GPA, MPA, EGPA

4. Complement-Mediated (C3 Dominant)

• Dysregulation of the alternative complement pathway (mutations in Factor H, Factor I, CFHR5; C3 nephritic factor)
• C3-only deposits without immunoglobulin
• C3 glomerulonephritis (C3GN) and Dense Deposit Disease (DDD)

"Invading neutrophils and monocytes, as well as resident glomerular cells, can damage the glomerulus through oxidants, chemoattractants, proteases, cytokines, and growth factors. Transforming growth factor-β has been related to eventual glomerulosclerosis and chronic glomerular damage." — Goldman-Cecil Medicine

Fig. Granular capillary wall deposits of IgG on immunofluorescence in membranous glomerulopathy — Goldman-Cecil Medicine

Clinical Presentation

Diagnosis

Management Summary

Prognosis

Key Takeaway

Glomerulonephritis is not a single disease but a family of immune-mediated disorders of the glomerulus with diverse causes, presentations, histological patterns, and outcomes. Accurate diagnosis — requiring renal biopsy in most cases — is essential to guide appropriate, targeted therapy and prevent progression to end-stage kidney disease.