Low Complement Nephritic Syndromes

Low C3 and C4 (Classical Pathway Activation): Low levels of C3 associated with low levels of C4 demonstrate classical pathway activation and strongly suggest immune complex disease. - Systemic lupus erythematosus (SLE) - SLE, antiphospholipid syndrome and urticarial vasculitis are autoimmune immune complex diseases - Cryoglobulinemia - Subacute bacterial endocarditis - Shunt nephritis

Low C3, Normal C4 (Alternative Pathway Activation): Low levels of C3 associated with normal levels of C4 demonstrate alternative pathway activation suggestive of infectious disease or nephritic factor activity. - Post-streptococcal glomerulonephritis: Low C3 levels are found in almost all patients with acute poststreptococcal nephritis; C4 levels may be slightly low - C3 glomerulopathy (Dense deposit disease, C3 glomerulonephritis) - All patients with C3 glomerulopathy should undergo screening for autoantibodies. C3 nephritic factors and C5 nephritic factors are the autoantibodies most frequently identified

Normal Complement Nephritic Syndromes

Normal serum complement levels suggest a visceral abscess, polyarteritis nodosa, Goodpasture syndrome, or Henoch-Schönlein purpura. Also includes: - IgA nephropathy - ANCA-associated vasculitis - Thin basement membrane disease - Alport syndrome

A. Anti-GBM Disease and Goodpasture Syndrome

Definition and Pathophysiology: Anti-GBM disease is characterized by autoantibodies directed against the NC1 domain of the α3 chain of type IV collagen in the glomerular and alveolar basement membranes. When kidney disease occurs alone, it’s termed anti-GBM nephritis. When both kidney and lung involvement occur, it’s called Goodpasture syndrome.

Clinical Features: - Rapidly progressive glomerulonephritis (RPGN) - Pulmonary hemorrhage in Goodpasture syndrome - Peak incidence in 20s (predominantly males) and 60s (equal sex distribution) - Complement levels remain normal throughout disease course

Diagnosis: - Anti-GBM antibodies (serum) - Linear IgG staining on immunofluorescence of kidney biopsy - Crescentic glomerulonephritis on histology

B. ANCA-Associated Vasculitides (AAV)

ANCA-associated vasculitides are a heterogeneous group of rare autoimmune conditions that cause inflammation of blood vessels. This group includes 3 main diseases—granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA).

1. Antibody Patterns: - P-ANCA/MPO-ANCA: The indirect IF staining pattern in microscopic polyangiitis is often perinuclear (P-ANCA). MPO is the antigen at which these autoantibodies are most often directed - C-ANCA/PR3-ANCA: PR3-ANCA is known as C-ANCA because of its granular and cytoplasmic staining pattern

2. Microscopic Polyangiitis (MPA) MPA is more likely to have renal involvement than GPA. MPA is part of a group of disorders known as pulmonary-renal syndrome. The kidneys are affected in up to 80% of cases with signs of blood and protein in the urine. Typically P-ANCA/MPO positive (70-80%). Can present as renal-limited vasculitis or with systemic involvement. Diffuse capillaritis is a typical pulmonary finding in patients with MPA, distinguishing it from GPA, which is characterized by the presence of granulomatous lesions.

3. Granulomatosis with Polyangiitis (GPA, formerly Wegener’s) GPA is characterized by a pulmonary-renal syndrome associated with otorhinolaryngological manifestations. GPA typically involves the upper and lower respiratory tracts and kidneys. Upper respiratory tract symptoms include bloody nasal discharge, nasal ulceration, sinusitis, and chronic otitis media. Typically C-ANCA/PR3 positive (90% of generalized disease). Necrotizing granulomatous inflammation distinguishes it from MPA. Can present with limited disease (upper respiratory only) or generalized disease.

4. Renal-Limited Vasculitis Pauci-immune crescentic glomerulonephritis without systemic features. Can be either MPO-ANCA or PR3-ANCA positive. Other ANCA-associated diseases include drug-induced vasculitis and renal-limited vasculitis.

5. Polyarteritis Nodosa (PAN) Medium-vessel vasculitis that is typically ANCA negative (important distinction from MPA and GPA). Spares glomeruli and pulmonary circulation. May have normal complement levels. Note: PAN is not technically an ANCA-associated vasculitis despite being a systemic vasculitis.

Key Diagnostic Points: A positive C-ANCA test finding has a posttest probability of GPA of 98% in patients with sinusitis, pulmonary infiltrates or nodules, and active urinary sediment with RBC casts. Renal biopsy findings in MPA typically range from mild focal or segmental to diffuse necrotizing and sclerosing glomerulonephritis, often presenting as crescentic glomerulonephritis. These biopsies usually show minimal to no immune complex deposits, a characteristic described as “pauci-immune”. All ANCA-associated vasculitides maintain normal complement levels.

Treatment Considerations: Treatment typically begins with induction of remission using cyclophosphamide in addition to high-dose steroids. Recently, intravenous rituximab has been used for remission induction. In 2021, the medication avacopan (Tavneos®) was approved by the FDA as an adjunctive treatment in adults for severe active ANCA-associated vasculitis (specifically MPA and GPA).

Initial Treatment

First-line therapy consists of oral prednisone at a daily single dose of 1 mg/kg (up to 80 mg/day) or an alternate-day single dose of 2 mg/kg (up to 120 mg every other day). Initial high dose of corticosteroids should be maintained for a minimum of 4 weeks if complete remission is achieved or for a maximum period of 16 weeks if complete remission is not achieved. Following remission, corticosteroids should be tapered off slowly over up to 6 months.

Frequently Relapsing and Steroid-Dependent MCD

Relapses occur in 65%–80% of adults with minimal change disease. Patients who relapse two or more times within 6 months or four or more times within 12 months are “frequent relapsers,” and those patients having two relapses with steroid taper or within 1 month of ending therapy are “steroid dependent”.

Treatment Options:

1. Cyclophosphamide: KDIGO guidelines suggest to use cyclophosphamide as a first-line therapy for frequently relapsing NS or steroid-dependent NS. Oral cyclophosphamide is initiated at 1–2 mg/kg per day for 8–12 weeks. Using this approach, a remission rate of up to 80% with a relapse rate at 1 year of <10% has been observed. Only 35% of patients experienced no relapse after cyclophosphamide therapy.

2. Calcineurin Inhibitors: Cyclosporin has also been effective in the treatment of frequently relapsing/steroid-dependent adults, with complete remission rates of up to 80%. Relapse of nephrotic syndrome is frequent during cyclosporin tapering, often leading to the need for long-term treatment.

3. Mycophenolate Mofetil: MMF is promising therapy in frequently relapsing MCD, even in those with disease that continued to relapse after cyclophosphamide therapy. The posology is 1,200 mg/m²/day, divided into two doses.

4. Rituximab: Rituximab, an anti-B cell antibody, has proved to be an effective steroid-sparing agent in the pediatric population. At 1 year, all patients were in remission, 60% of patients were off of all immunosuppressive agents, and 50% never relapsed.

Initial Treatment

Prednisone 1 mg/kg/day (maximum 80 mg) or 2 mg/kg on alternate days for at least 8-16 weeks. Blacks and patients with collapsing FSGS are generally unresponsive to treatment and progress to kidney failure.

Non-Steroid Immunosuppression for FSGS

Guidelines from Kidney Disease/Improving Global Outcomes (KDIGO) suggest considering calcineurin inhibitors (cyclosporine or tacrolimus) as first-line therapy for patients who fail to respond to corticosteroids or experience significant adverse effects, as well as for patients with relative contraindications to high-dose corticosteroids.

1. Calcineurin Inhibitors:

   • Cyclosporine: 5-10 mg/kg/d may be beneficial in patients unresponsive to prednisone and cyclophosphamide
   • Tacrolimus: 0.1–0.2 mg/kg/day, divided into two doses, was effective and well tolerated in patients with SRNS and resulted in complete remission in 81% of cases
   • An initial CNI plus low-dose corticosteroid approach in primary FSGS reduces corticosteroid exposure with a response-to-therapy rate similar to that of the currently recommended high-dose corticosteroid regimen

2. Mycophenolate Mofetil: MMF can be an alternative agent for patients who have adverse effects from calcineurin inhibitors. MMF can reduce the combined rate of complete and partial remission by 67% in patients with SRNS

3. Sirolimus: In patients with steroid-resistant FSGS, sirolimus reduced proteinuria and glomerular pore size and increased Kf in patients with steroid-resistant FSGS

4. Cyclophosphamide: In patients whose FSGS is refractory to 2-3 months of prednisone therapy, the recommendation is to reduce the steroid dose and to add cyclophosphamide (2.5 mg/kg [150-200 mg/d])

Diagnosis

Anti-PLA2R Antibodies: Phospholipase A2 receptor (PLA2R) antibody testing without kidney biopsy may be a valid strategy to make a non-invasive diagnosis of MN in patients with a negative work-up for secondary causes. Circulating PLA2R-antibody (PLA2R-Ab) is detected in 70% to 80% of patients with PMN. The anti-PLA2R antibody test has a sensitivity of 0.78, with a specificity of 0.99. A kidney biopsy is not required to confirm the diagnosis of membranous nephropathy (MN) in patients with nephrotic syndrome and a positive anti-PLA2R antibody test.

Secondary Causes - Hepatitis Association: The association between chronic hepatitis B virus (HBV) infection and renal disease was first reported in 1971. HBV-related membranous nephropathy is the best-recognized disorder. The hepatitis B e antigen (HBeAg) has been shown to have an important pathogenetic role. PLA2R staining on biopsy was positive in 10/19 patients: 4 with HBV-MN, 3 with HCV-MN. The most common form of glomerulonephritis in hepatitis B patient was MN and in hepatitis C patient was MPGN.

Risk Stratification and When to Start Immunosuppression

Kidney Diseases Improving Global Outcomes (KDIGO) advocate the use of clinical and laboratory criteria to determine risk. Patients are stratified into low, moderate, high, and very high risk of progressive loss of kidney function.

Risk Categories (KDIGO 2021): - Low risk: Normal eGFR and proteinuria <3.5 mg/dL, and serum albumin greater than 30 g/L - advised to receive supportive care - Moderate risk: Can receive symptomatic therapy, rituximab or calcineurin inhibitors - High/Very high risk: Require immunosuppressive treatment

Factors for Progressive Disease: - Older age at presentation - Proteinuria >4 g/day - Decreased eGFR or decline in kidney function - High titer of anti-PLA2R antibodies (PLA2R >150 RU/mL) - Kidney biopsies findings such as segmental glomerulosclerosis and degree of interstitial fibrosis

Treatment Decisions: MN has a reported spontaneous remission (complete and partial) of about 30% on supportive therapy. Anti-PLA2R antibody–positive MN has been shown to have a lower rate of spontaneous remission compared with PLA2R-negative MN. The ultimate goal of the immunosuppressive treatment in PLA2R-Ab–positive patients with PMN should be complete disappearance of antibody.

Treatment Options for Membranous Nephropathy

1. Rituximab: The main modifications in KDIGO 2021 guidelines are the inclusion of rituximab as a first line treatment. RTX was superior in maintaining complete or partial remission at 24 months (60% vs 20%), with lower adverse events in the RTX group (17% vs 31%). Re-treatment warranted for those failing to attain immunological remission after 3 months.

2. Cyclophosphamide and Steroids: Modified Ponticelli regimen remains effective. Although immunological response was faster in the CYC group at 6 months (92% vs 70%), it was comparable at 24 months (88% vs 83%).

3. Calcineurin Inhibitors: Cyclosporine 3–5 mg/kg/day targeting trough 125–175 ng/mL. Higher relapse rates compared to other treatments.

4. Special Considerations for Hepatitis-Associated MN: Treatment with naturally occurring cytokines (such as interferon-α2b) and other candidate therapies accelerates clearance of the virus and proteinuria. The use of lamivudine in 1996 and entecavir and adefovir in 2000 resulted in improved outcomes.

Sparsentan (Dual ERA/ARB)

Sparsentan, a dual angiotensin II type 1 and endothelin type A (ETA) receptor antagonist, was already tested in the DUET trial that included patients with primary focal segmental glomerulosclerosis (FSGS).

FDA Status: The approved indications to date of ET blockade are, for many years, primary pulmonary hypertension and, recently, IgAN following the PROTECT trial.

Clinical Trials: - PROTECT study (IgA nephropathy): sparsentan, a single-molecule, dual endothelin angiotensin receptor antagonist, not only reduces proteinuria by 40% compared with irbesartan, but also maintained this reduction in proteinuria - DUPLEX study (FSGS): Ongoing phase 3 trial

Atrasentan

Atrasentan in patients with IgA nephropathy. N Engl J Med. 2025;392(4):544–554. - ALIGN study: Phase 3 trial in IgA nephropathy - AFFINITY study: sparsentan (PROTECT and DUPLEX trial) and atrasentan (AFFINITY) are reportedly well-tolerated in patients with FSGS and IgA nephropathy.

Combination Therapy

Moreover, combined administration of a low dose of the ETA-selective ERA, zibotentan, with the sodium–glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, enhanced albuminuria reduction and mitigated fluid retention in patients with CKD.

Gene Therapy

In a new study published in Science Translational Medicine, researchers at the University of Bristol have shown that just one dose of gene therapy targeting cells in the kidney called podocytes has the potential to cure steroid-resistant nephrotic syndrome.

HDAC Inhibitors

HDAC inhibitors have been greatly explored in the recent past for their anti-fibrotic, anti-inflammatory and immunosuppressive effects in several tissues and organs. Increasing evidence suggests that treatment with HDAC inhibitors can attenuate renal sclerosis, fibrosis and proteinuria associated with chronic kidney diseases.

Network Pharmacology Approaches

Recently, epigenetic mechanisms were identified that promote progression of many renal diseases. Therefore, in the present study, we investigated two epigenetic drugs valproic acid (VPA) and all-trans retinoic acid (ATRA).

Laboratory Evaluation

Essential Tests: 1. Serum creatinine and eGFR: Document rapid decline 2. Urinalysis with microscopy: RBC casts (pathognomonic for glomerulonephritis), dysmorphic RBCs, proteinuria (variable, may be nephrotic range) 3. Serologic workup: Anti-GBM antibodies, ANCA (both immunofluorescence and antigen-specific assays), ANA, anti-dsDNA, complement levels (C3, C4), cryoglobulins, hepatitis B and C serologies, ASO titers 4. CBC: Anemia common 5. Inflammatory markers: ESR, CRP often elevated

ANCA Testing Interpretation: The positive predictive value (PPV) of a positive ANCA result in a patient with classic features of RPGN is 95%. Combined immunofluorescence and ELISA testing maximizes sensitivity and specificity. Negative predictive value is greater than 95%.

Renal Biopsy

Essential for diagnosis unless contraindicated. Determines disease activity and chronicity. Guides treatment decisions. Findings include cellular crescents (indicate active disease), fibrous crescents (indicate chronic damage), immunofluorescence pattern distinguishes types, and degree of interstitial fibrosis predicts prognosis.

Type I: Anti-GBM Disease

Induction Therapy: 1. Plasmapheresis: Daily exchanges for 14 days or until anti-GBM antibodies undetectable. Essential for antibody removal. Most effective if started before serum creatinine >5.7 mg/dL.

2. Immunosuppression: IV methylprednisolone 1g daily × 3 days, then oral prednisone 1 mg/kg/day. Cyclophosphamide 2 mg/kg/day (oral) or IV monthly pulses.

Prognosis: Patient survival is greatly improved with treatment and is as high as 90%. Renal recovery depends on initial severity. Dialysis dependence at presentation predicts poor renal recovery.

Type II: Immune Complex Disease

Treatment varies by underlying cause. Post-streptococcal GN is usually self-limiting with supportive care in most cases. Corticosteroids for severe crescentic disease. Lupus nephritis requires corticosteroids plus cyclophosphamide or mycophenolate mofetil. IgA nephropathy with crescents: corticosteroids if <25% crescents, add cyclophosphamide if >25% crescents.

Type III: Pauci-Immune (ANCA-Associated)

Induction Therapy: 1. Corticosteroids: IV methylprednisolone 0.5 to 1 g/d for 3 days followed by oral prednisone 1 mg/kg for 1 month and then tapered over 3 to 4 months

2. Cyclophosphamide: IV 15 mg/kg initially every 2 weeks or daily orally 1.5 to 2 mg/kg. Duration: 3-6 months. IV route may have fewer adverse effects but higher relapse rates.

3. Rituximab: Alternative to cyclophosphamide for induction. 375 mg/m² weekly × 4 or 1g × 2 doses. Equal efficacy to cyclophosphamide in trials.

4. Plasmapheresis: Recommended at diagnosis if there is a rapid decline in kidney function or severe involvement of renal. Indications include serum creatinine >4 mg/dL, dialysis dependence, pulmonary hemorrhage, or concomitant anti-GBM antibodies.

5. Avacopan: In 2021, the medication avacopan (Tavneos®) was approved by the FDA as an adjunctive treatment in adults for severe active ANCA-associated vasculitis. Complement C5a receptor antagonist used with standard immunosuppression.

Maintenance Therapy: Azathioprine 2 mg/kg/day, mycophenolate mofetil 1g twice daily, rituximab 500mg every 6 months, and low-dose prednisone (controversial). Duration: minimum 18-24 months.