What is the appropriate workup and treatment for a patient with suspected glomerulonephritis (inflammation of the glomeruli in the kidneys)?

Glomerulonephritis Workup and Treatment

Initial Diagnostic Workup

The workup for suspected glomerulonephritis requires urgent urinalysis with microscopy, autoimmune serologies (ANCA, ANA, anti-GBM antibodies, complement levels), and kidney biopsy when feasible, while treatment should not be delayed if clinical presentation and serology strongly suggest rapidly progressive disease. 1

Clinical Presentation Assessment

• Evaluate for the classic triad of acute glomerulonephritis: hematuria, edema, and hypertension (the latter two resulting from sodium and water retention) 2
• Assess for rapidly progressive glomerulonephritis (RPGN) warning signs: rapid decline in kidney function over days to weeks, oliguria, severe hypertension, and pulmonary hemorrhage 1, 3
• Document extrarenal manifestations: hemoptysis, arthalgias, muscle pain, palpable purpura, constitutional symptoms (fever, weight loss) 3
• Compare current serum creatinine/eGFR with historical results to identify acute deterioration 4

Laboratory Evaluation

Urinalysis and Urine Studies:

• Perform urine dipstick for protein and blood, followed by microscopic examination for glomerular hematuria (dysmorphic RBCs, acanthocytes) and red blood cell casts 1
• Quantify proteinuria using 24-hour urine collection in adults; first morning protein-creatinine ratio is more appropriate in children 1
• Proteinuria >3 g/day is diagnostic for glomerular damage 3

Serologic Testing:

• Obtain ANCA (MPO and PR3), ANA, anti-double stranded DNA, anti-GBM antibodies, and complement levels (C3, C4) 1, 3
• Screen for infections: HIV, hepatitis B, hepatitis C, and bacterial infections as clinically indicated 3
• For membranous nephropathy, test for anti-phospholipase A2 receptor antibodies 3

Basic Laboratory Panel:

• Complete blood count, erythrocyte sedimentation rate, CRP, serum creatinine, urea, glucose 3
• Calculate eGFR using CKD-EPI creatinine equation in adults or modified Schwartz equation in children 1

Kidney Biopsy

• Kidney biopsy remains the gold standard for diagnosis and should be performed when feasible to confirm diagnosis and provide prognostic information 1
• However, if clinical presentation is compatible with ANCA vasculitis and MPO- or PR3-ANCA is positive, do not delay starting immunosuppressive therapy while waiting for biopsy 1
• The same principle applies for suspected anti-GBM disease or lupus nephritis presenting as RPGN 1
• Always exclude infection with as much certainty as possible before initiating significant immunosuppression 1

Imaging

• Perform renal ultrasound to assess kidney size and rule out obstruction 3
• Small kidneys suggest chronic disease with advanced tubulointerstitial fibrosis 4

Treatment Approach

Supportive Care (All Patients)

Blood Pressure Management:

• Use ACE inhibitors or ARBs at maximally tolerated doses as first-line therapy for patients with hypertension and proteinuria 5, 3
• Target systolic blood pressure <120 mmHg in adults using standardized office measurement 5
• In children, target 24-hour mean arterial pressure ≤50th percentile for age, sex, and height 5
• Hold RAS inhibitors during intercurrent illnesses with volume depletion risk 5

Edema Management:

• Use diuretics as first-line agents; add mechanistically different diuretics if response is insufficient 5, 6
• Restrict dietary sodium to <2.0 g/day 5, 6
• Monitor for hyponatremia, hypokalemia, GFR reduction, and volume depletion 5

Dietary Protein Management:

• For nephrotic-range proteinuria: 0.8-1 g/kg/day with additional protein to compensate for losses (up to 5 g/day) 5
• For eGFR <60 ml/min/1.73 m² with nephrotic-range proteinuria: limit to 0.8 g/kg/day 5
• Avoid protein restriction <0.6 g/kg/day due to malnutrition risk 5

Disease-Specific Immunosuppressive Treatment

ANCA-Associated Vasculitis (Most Common Cause of RPGN):

Induction Therapy:

• For initial treatment, use cyclophosphamide plus corticosteroids (Grade 1A) or rituximab plus corticosteroids as an alternative (Grade 1B) 1
• Cyclophosphamide is preferred for severe GN (serum creatinine >4 mg/dl [354 μmol/L]); combination of two IV pulses of cyclophosphamide with rituximab can be considered 1
• Rituximab is preferred for patients with contraindications to cyclophosphamide, relapsing disease, or PR3-ANCA positivity 1

Adjunctive Plasmapheresis:

• Add plasmapheresis for patients requiring dialysis or with rapidly increasing serum creatinine (Grade 1C) 1
• Add plasmapheresis for diffuse pulmonary hemorrhage (Grade 2C) - perform daily until bleeding stops, then every other day for total of 7-10 treatments 1
• Use 60 ml/kg volume replacement per treatment 1
• Do not use plasmapheresis routinely in AAV without these indications 1

Maintenance Therapy:

• Initiate maintenance therapy in patients who achieve remission (Grade 1B) 1
• Use azathioprine 1-2 mg/kg/day orally as first-line maintenance (Grade 1B), or rituximab (preferred by KDIGO 2021) 1
• MMF up to 1 g twice daily can be used for patients allergic to or intolerant of azathioprine (Grade 2C) 1
• Continue maintenance therapy for at least 18 months in patients who remain in complete remission (Grade 2D) 1

Lupus Nephritis:

• Use corticosteroids (Grade 1A) combined with either cyclophosphamide (Grade 1B) or mycophenolate mofetil (Grade 1B) for initial therapy 1
• If worsening occurs during first 3 months (rising creatinine, worsening proteinuria), change to alternative therapy or perform repeat biopsy 1

Membranous Nephropathy:

• Consider observation for 6 months before initiating immunosuppression unless severe symptoms or declining kidney function are present 1, 5, 6
• For patients requiring treatment, use 6-month course of alternating monthly cycles of oral and IV corticosteroids with oral cyclophosphamide (preferred over chlorambucil) 1, 5
• Consider cyclosporine or tacrolimus for at least 6 months in patients with contraindications to cyclophosphamide regimens 1, 5

Focal Segmental Glomerulosclerosis (FSGS):

• Use prednisone or prednisolone at 1 mg/kg/day (maximum 80 mg) or alternate-day 2 mg/kg (maximum 120 mg) for minimum 4 weeks, up to maximum 16 weeks as tolerated (Grade 2C) 1
• Taper corticosteroids slowly over 6 months after achieving complete remission (Grade 2D) 1, 5
• Consider calcineurin inhibitors as first-line for patients with contraindications to high-dose corticosteroids (uncontrolled diabetes, psychiatric conditions, severe osteoporosis) 1

Post-Infectious Glomerulonephritis:

• Treat post-streptococcal GN with penicillin (or erythromycin if penicillin-allergic) even without persistent infection 5
• Manage with supportive care: diuretics, antihypertensives, dialysis if necessary 5
• Consider corticosteroids only for severe crescentic disease based on anecdotal evidence 5

Membranoproliferative Glomerulonephritis (MPGN):

• For nephrotic syndrome with progressive decline in kidney function, use oral cyclophosphamide or MMF plus low-dose alternate-day or daily corticosteroids for <6 months 5
• Avoid immunosuppression in patients with advanced CKD, severe tubulointerstitial fibrosis, or small kidneys 5

Immunosuppression Safety Measures

Pre-Treatment Screening:

• Screen for latent infections: tuberculosis, hepatitis B, hepatitis C, HIV, syphilis 5, 6
• Review and update vaccination status before starting immunosuppression 1, 5
• Consider fertility preservation where indicated 1, 5

Prophylaxis:

• Administer pneumococcal vaccine, influenza vaccine, and herpes zoster vaccination (Shingrix) 5, 6
• Consider prophylactic trimethoprim-sulfamethoxazole for patients receiving high-dose prednisone or other immunosuppressive agents 5, 6

Monitoring:

• Monitor therapeutic drug levels where clinically indicated 1, 5
• Monitor for development of cancers or infections during therapy 1, 5

Monitoring Treatment Response

• Assess proteinuria regularly - reduction in proteinuria is a key marker of treatment response 5, 7
• Monitor for ≥40% decline in eGFR from baseline over 2-3 years as a surrogate outcome for kidney failure 5, 7
• Perform repeat kidney biopsy only if rapidly deteriorating kidney function occurs or if results will alter diagnosis or therapeutic plan 1, 5

Critical Pitfalls to Avoid

• Do not delay treatment in RPGN while waiting for biopsy if clinical presentation and serology are strongly suggestive - mortality risk is high without prompt intervention 1
• Do not start immunosuppression without excluding infection as thoroughly as possible 1
• Do not discontinue cyclophosphamide before 3 months in dialysis-dependent patients with extrarenal manifestations 1
• Distinguish IgA-dominant post-infectious GN from IgA nephropathy to avoid inappropriate corticosteroid treatment 5
• Recognize that prolonged or multiple rounds of immunosuppression increase cumulative toxic drug exposure 1, 5