How is chronic nephritis diagnosed?

Diagnosis of Chronic Nephritis

Chronic nephritis is diagnosed by demonstrating persistent kidney damage (proteinuria ≥0.5 g/24 hours, active urinary sediment with RBC/WBC casts, or hematuria) or decreased GFR (<60 mL/min/1.73 m²) for ≥3 months, with kidney biopsy serving as the definitive diagnostic test to determine the specific glomerular injury pattern and guide treatment. 1, 2

Initial Clinical Assessment

Laboratory Screening

The diagnostic workup begins with specific laboratory markers that identify kidney damage:

• Urinalysis with microscopy is mandatory to detect proteinuria, hematuria, and cellular casts 2, 3
• Proteinuria quantification using either 24-hour urine collection or spot urine protein-to-creatinine ratio (PCR), with a threshold of ≥0.5 g/24 hours indicating significant glomerular disease 1, 2, 3
• Active urinary sediment defined as >5 RBC/hpf, >5 WBC/hpf (without infection), or presence of RBC/WBC casts suggests active glomerular inflammation 1, 2
• Dysmorphic red blood cells on microscopy indicate glomerular origin of hematuria 4, 3

Renal Function Assessment

• Serum creatinine and estimated GFR (eGFR) using the CKD-EPI equation to quantify kidney function, with GFR <60 mL/min/1.73 m² representing loss of ≥50% of normal kidney function 1, 3
• Persistent abnormalities for ≥3 months are required to distinguish chronic from acute kidney disease 1

Serologic Testing

Targeted serologic evaluation helps identify the underlying etiology but does not replace biopsy:

• ANCA panel (MPO and PR3) for ANCA-associated vasculitis 4, 3
• ANA and anti-dsDNA antibodies for lupus nephritis 1, 4, 3
• Anti-GBM antibodies to exclude Goodpasture syndrome 4, 3
• Complement levels (C3, C4) typically reduced in immune complex-mediated disease 4, 3
• Serum and urine immunofixation with free light chains when monoclonal immunoglobulin disease is suspected 4, 3
• Hepatitis B, C, and HIV serologies for infection-associated glomerulonephritis 3

Critical pitfall: Serological markers provide supportive but not definitive information—they cannot replace kidney biopsy for diagnosis 2

Kidney Biopsy: The Gold Standard

Indications for Biopsy

Kidney biopsy is the definitive diagnostic test and should be performed in the following situations:

• Proteinuria ≥1.0 g/24 hours alone, or proteinuria ≥0.5 g/24 hours with hematuria or cellular casts 2
• Previously untreated patients with clinical evidence of active nephritis to classify disease by ISN/RPS criteria 1, 4
• Unexplained decline in GFR with no attributable cause other than suspected glomerular disease 1, 4
• Need to differentiate primary from secondary causes of glomerular injury 4
• Assessment of disease activity versus chronicity to guide treatment decisions 1, 4

The American Society of Nephrology recommends performing biopsy within the first month after disease onset, preferably before starting immunosuppressive treatment 2

Essential Biopsy Components

A complete diagnostic biopsy requires three modalities:

1. Light microscopy with minimum 10 glomeruli, using H&E, PAS, Masson's trichrome, and silver stains to identify glomerular injury patterns (membranoproliferative, crescentic, sclerosing) 4, 2

2. Immunofluorescence for IgG, IgA, IgM, C3, C1q, and kappa/lambda light chains to detect immune complex deposition patterns and complement-dominant patterns like C3 glomerulopathy 4, 2

3. Electron microscopy to localize immune deposits (subepithelial, subendothelial, mesangial, intramembranous) 4, 2

Quantification of Chronic Damage

The biopsy must document chronicity features that inform prognosis:

• Percentage of globally sclerotic glomeruli 4
• Tubular atrophy and interstitial fibrosis (IFTA) quantified as: mild <25%, moderate 25-50%, severe >50% 4
• Vascular changes graded as mild, moderate, or severe 4
• Chronicity index score to guide therapeutic decisions 4

Critical distinction: Patients with advanced chronic damage (≥90% glomerular sclerosis, severe IFTA) generally require preparation for renal replacement therapy rather than immunosuppression 1

Histologic Classification and Treatment Implications

The specific histologic diagnosis determines treatment strategy:

• Class I/II lupus nephritis (minimal/mesangial disease) generally does not require immunosuppressive treatment 1
• Class III/IV lupus nephritis (proliferative disease) requires aggressive therapy with glucocorticoids and immunosuppressive agents 1
• Class V lupus nephritis (membranous) when combined with III/IV is treated as proliferative disease; pure membranous may be approached differently 1
• Class VI (≥90% sclerosis) requires renal replacement preparation, not immunosuppression 1

Imaging Studies

• Renal ultrasound showing increased cortical echogenicity suggests chronic glomerular disease, while normal or enlarged kidneys are typical of acute or early chronic disease 4
• Imaging is NOT part of the standard nephritis diagnostic workup—ultrasound, CT, and MRI are not beneficial for diagnosing glomerulonephritis 2

Common Diagnostic Pitfalls

• Relying on dipstick alone without microscopic examination misses dysmorphic RBCs and cellular casts 3
• Inadequate biopsy tissue with insufficient glomeruli prevents accurate diagnosis 4
• Missing monoclonal immunoglobulin disease by failing to perform serum/urine immunofixation when membranoproliferative pattern is identified 4
• Delayed biopsy in rapidly progressive disease—when ANCA-associated vasculitis, anti-GBM disease, or lupus nephritis is strongly suspected, initiate immunosuppression promptly and obtain biopsy as soon as feasible 4
• Overlooking chronic analgesic or NSAID use, which causes permanent renal insufficiency in 56% of NSAID-induced acute interstitial nephritis cases that transition to chronic disease 5

Special Considerations

Lupus Nephritis

For lupus nephritis specifically, diagnosis is valid when meeting ACR criteria (persistent proteinuria >0.5 g/day or >3+ by dipstick, and/or cellular casts) or based on opinion of a rheumatologist or nephrologist 1. However, biopsy remains optimal to demonstrate immune complex-mediated glomerulonephritis compatible with lupus nephritis 1

Hepatitis C-Associated Nephritis

Renal biopsy is mandatory in HCV patients with urinary abnormalities or unexplained renal impairment, as diffuse membranoproliferative glomerulonephritis occurs in ~80% of HCV-related cases 4