What is the appropriate diagnostic and treatment approach for a patient suspected of having glomerulonephritis, including the use of a glomerulonephritis panel?

Glomerulonephritis Panel: Diagnostic and Treatment Approach

When evaluating a patient for suspected glomerulonephritis, obtain a kidney biopsy as the definitive diagnostic test, combined with a comprehensive serologic workup including ANCA, anti-GBM antibodies, complement levels, cryoglobulins, and hepatitis serologies, while simultaneously initiating supportive care with ACE inhibitors or ARBs for blood pressure control and proteinuria reduction. 1

Essential Diagnostic Workup

Kidney Biopsy - The Gold Standard

• Kidney biopsy is mandatory for definitive diagnosis and must include light microscopy, immunofluorescence microscopy, and electron microscopy to determine the etiology, severity, and chronicity of glomerulonephritis 1, 2
• Perform biopsy in patients with unexplained kidney disease, proteinuria, hematuria, or declining renal function 1
• The biopsy determines whether the glomerulonephritis is immune complex-mediated, ANCA-associated, anti-GBM, monoclonal immunoglobulin-mediated, or C3 glomerulopathy 3
• Do not delay immunosuppressive therapy while awaiting biopsy if clinical presentation is compatible with ANCA-associated vasculitis and ANCA serology is positive 1

Serologic Testing Panel

• Measure ANCA serially in suspected ANCA-associated vasculitis (microscopic polyangiitis or granulomatosis with polyangiitis) 1
• Determine cryoglobulins and hepatitis C serology for cryoglobulinemic glomerulonephritis 1
• Test for hepatitis B and C in all patients with proteinuric glomerular disease given the >5% global prevalence of chronic HBV infection 2
• Measure complement levels (C3, C4) to identify complement-mediated disease 4
• Obtain anti-GBM antibodies when rapidly progressive glomerulonephritis is suspected 5

Renal Function Assessment

• Calculate eGFR using the CKD-EPI creatinine equation in adults or modified Schwartz equation in children - baseline GFR is the most potent predictor of renal outcome 1
• Use cystatin C-based eGFR when creatinine-based estimates are unreliable due to altered creatinine generation or tubular secretion 1
• Monitor serum creatinine with consideration for dietary intake and muscle mass 1

Proteinuria Quantification

• Obtain 24-hour urine collection for total protein excretion as the preferred method in adults 1
• Use first morning protein-creatinine ratio (PCR) in children 1
• Perform urine protein electrophoresis to differentiate glomerular versus tubular proteinuria and as a surrogate parameter for serial evaluation 1

Inflammatory Markers

• Measure CRP and/or ESR regularly as serologic markers of disease activity, though interpret results in clinical context 1
• Note that serial ANCA measurements have inconclusive predictive value for routine monitoring but remain useful in clinical trials 1

Advanced Testing When Indicated

• Use flow cytometry or immunotyping of bone marrow when monoclonal gammopathy of renal significance (MGRS) is suspected 1
• Apply mass spectrometry for renal amyloid typing when immunofluorescence is negative or equivocal 1
• Consider genetic testing (whole exome sequencing) in selected cases, particularly for complement gene mutations in C3 glomerulopathy 1, 4
• Use pronase immunofluorescence when standard immunofluorescence is negative but monoclonal immunoglobulin-related disease is suspected 1

Universal Supportive Care (Initiate Immediately)

Blood Pressure and Proteinuria Management

• Start ACE inhibitors or ARBs at maximally tolerated doses as first-line therapy for all patients with hypertension and proteinuria 6, 7
• Target systolic blood pressure <120 mmHg in adults using standardized office BP measurement 6, 7
• In children, target 24-hour mean arterial pressure at ≤50th percentile for age, sex, and height by ambulatory monitoring 6, 7
• Hold RAS inhibitors during intercurrent illnesses with volume depletion risk 6

Edema Management

• Use diuretics as first-line agents for edema 6, 7
• Add mechanistically different diuretics if response is insufficient 6
• Monitor for hyponatremia, hypokalemia, GFR reduction, and volume depletion 6

Dietary Modifications

• For nephrotic-range proteinuria: prescribe 0.8-1 g/kg/day protein with additional protein to compensate for losses (up to 5 g/day) 6, 7
• For eGFR <60 ml/min/1.73 m² with nephrotic-range proteinuria: limit to 0.8 g/kg/day 6
• Avoid protein restriction <0.6 g/kg/day due to malnutrition risk 6
• Restrict sodium to <2.0 g/day to control hypertension and fluid retention 7

Disease-Specific Treatment Approaches

Post-Infectious Glomerulonephritis

• Administer penicillin (or erythromycin if penicillin-allergic) even in absence of persistent infection to decrease antigenic load 6, 7
• First-generation cephalosporins (cephalexin) are appropriate alternatives for non-anaphylactic penicillin allergies 7
• Manage nephritic syndrome with diuretics, antihypertensives, supportive care, and dialysis if necessary 6
• For severe crescentic post-streptococcal GN, consider corticosteroids based on anecdotal evidence 6
• For infective endocarditis-related GN: continue antibiotics for 4-6 weeks, recognizing that hematuria, proteinuria, and azotemia may persist for months 6
• Critical pitfall: IgA-dominant postinfectious GN must be distinguished from idiopathic IgA nephropathy to avoid inappropriate corticosteroid treatment 6

Membranous Nephropathy

• Consider observation for 6 months before initiating immunosuppression unless severe symptoms or declining kidney function are present 6, 7
• For patients requiring immunosuppression: use 6-month course of alternating monthly cycles of oral and IV corticosteroids with oral cyclophosphamide (preferred over chlorambucil) 6, 7
• Consider cyclosporine or tacrolimus for at least 6 months in patients with contraindications to cyclical corticosteroid/alkylating-agent regimens 6

Focal Segmental Glomerulosclerosis (FSGS)

• For nephrotic syndrome due to FSGS, initiate high-dose corticosteroids for minimum 4 weeks, up to maximum 16 weeks as tolerated or until complete remission 6, 7
• Taper corticosteroids slowly over 6 months after achieving complete remission 6, 7
• For steroid-resistant or steroid-intolerant cases, use calcineurin inhibitors (cyclosporine or tacrolimus) 6
• Patients with resistance to or intolerance of CNIs should be referred to specialized centers for consideration of rebiopsy, alternative treatment, or enrollment in clinical trial 2

Membranoproliferative Glomerulonephritis (MPGN)

• For nephrotic syndrome with progressive decline in kidney function, active nephritic syndrome, or rapidly progressive disease: use oral cyclophosphamide or MMF plus low-dose alternate-day or daily corticosteroids for <6 months 6, 7
• For children with MPGN and nephrotic syndrome and/or impaired renal function, consider alternate-day steroids (40 mg/m²) for 6-12 months 6
• Patients with normal eGFR and non-nephrotic-range proteinuria may be treated conservatively 6
• Avoid immunosuppression in patients with advanced CKD, severe tubulointerstitial fibrosis, small kidney size, or chronic inactive disease 6
• Note that MPGN classification is evolving toward mechanistic classification based on complement (Ig+C3 and Ig-C3) 6

Minimal Change Disease (MCD)

• Use high-dose corticosteroids for initial treatment, tapered over 4 weeks if complete remission achieved, maximum 16 weeks if not 6, 7
• For contraindications or intolerance to high-dose corticosteroids: use oral cyclophosphamide or calcineurin inhibitors 6, 7

IgA Nephropathy (High-Risk Patients)

• Consider glucocorticoids after individualized risk-benefit discussion for patients with proteinuria >1 g/day despite ≥3 months of optimized supportive care 7
• Do NOT use mycophenolate mofetil in non-Chinese patients; it may be used as glucocorticoid-sparing agent in Chinese patients only 7

HCV-Related Glomerulonephritis

• For HCV-infected patients with CKD Stages 1 or 2 and GN: use combined antiviral treatment with pegylated interferon and ribavirin 6
• For HCV-infected patients with CKD Stages 3,4, or 5 and GN not yet on dialysis: use monotherapy with pegylated interferon, with doses adjusted to kidney function 6
• For cryoglobulinemic nephritis with diffuse or focal MPGN: use strong immunomodulating treatment including glucocorticoids and/or immunosuppressive agents and plasma exchange in escalation protocols as first-line approach 2
• For mesangial glomerulonephritis: use antiviral therapy as first-line approach 2

HBV-Related Glomerulonephritis

• Treat with interferon-α or nucleoside analogues as recommended for the general population 6

Immunosuppression Safety Protocol

Pre-Treatment Requirements

• Screen for latent infections (TB, HIV, HBV, HCV) prior to initiating immunosuppression 6, 7
• Review and update vaccination status before starting immunosuppression 6, 7
• Provide pneumococcal vaccine, influenza vaccine, and herpes zoster vaccination (Shingrix) 6
• Consider fertility preservation where indicated 6

Prophylactic Measures

• Consider prophylactic trimethoprim-sulfamethoxazole for patients receiving high-dose prednisone or other immunosuppressive agents 6

Ongoing Monitoring

• Monitor therapeutic drug levels where clinically indicated 6
• Monitor for development of cancers or infections during immunosuppressive therapy 6

Monitoring Treatment Response

• Assess proteinuria regularly - reduction in proteinuria is the primary marker of treatment response 6, 7
• Monitor for ≥40% decline in eGFR from baseline over 2-3 years as surrogate outcome for kidney failure 6, 7
• Perform repeat kidney biopsy only if patient has rapidly deteriorating kidney function or if it will potentially alter diagnosis or therapeutic plan 1, 6

Critical Pitfalls to Avoid

• Avoid prolonged immunosuppression or multiple rounds of immunosuppression due to cumulative toxic drug exposure 6, 7
• Do not extrapolate pediatric treatment data directly to adults - adults respond more slowly and variably to steroids with higher risk of side effects 7
• Recognize that glomerulonephritis is relatively infrequent, limiting individual center experience, and many treatment recommendations are based on small underpowered trials 2
• The heterogeneous nature of glomerulonephritis requires disease-specific approaches rather than pattern-based treatment 5, 3