Learning objectives
By the end of this chapter, the learner should be able to distinguish glomerular hematuria and proteinuria from nonglomerular urinary abnormalities; classify nephritic, nephrotic, rapidly progressive, and mixed syndromes; use urine microscopy, serology, complement patterns, and kidney biopsy strategically; recognize crescentic GN as a time-critical clinicopathologic syndrome; interpret biopsy findings using light microscopy, immunofluorescence, and electron microscopy; initiate safe supportive care while awaiting a diagnosis; and select disease-specific treatment pathways for IgA nephropathy, membranous nephropathy, podocytopathies, lupus nephritis, ANCA-associated vasculitis, anti-GBM disease, infection-related GN, and complement-mediated disease.
Scope and currency. The general framework in this chapter follows the KDIGO 2021 Glomerular Diseases guideline, with focused updates for lupus nephritis in 2024, ANCA-associated vasculitis in 2024, and IgA nephropathy/IgA vasculitis in 2025. KDIGO continues to update the glomerular-disease guideline chapter by chapter; local protocols, pathology expertise, drug labeling, and multidisciplinary consultation remain essential.[1–4]
16.1 Why glomerular disease requires a syndrome-first approach
Glomerular disease is not a single diagnosis. It is a group of disorders affecting the filtration barrier, mesangium, glomerular endothelium, podocytes, or the associated immune and complement systems. The same biopsy pattern may arise from different causes, while the same systemic disease may produce different renal lesions. Therefore, the initial task is not to label a disease from a single laboratory result, but to integrate the clinical syndrome, time course, urine sediment, kidney function, serologic pattern, and pathology.
The highest-risk presentations are a rapidly rising creatinine with active sediment, pulmonary–renal syndrome, nephrotic syndrome with severe hypoalbuminemia or thrombosis, malignant hypertension, severe infection-related GN, and GN in a solitary or transplanted kidney. These presentations require parallel action: stabilize the patient, exclude infection and obstruction, obtain urgent serology and cultures when indicated, involve nephrology and pathology early, and determine whether biopsy or empiric treatment is time-critical.
Nephritic syndrome
Nephritic syndrome is defined by glomerular hematuria—often dysmorphic erythrocytes or red-cell casts—accompanied by variable proteinuria, hypertension, edema, and a fall in GFR. Protein excretion may be subnephrotic or nephrotic; the presence of nephrotic-range proteinuria does not exclude inflammatory GN. Common causes include IgA nephropathy, infection-related GN, lupus nephritis, ANCA-associated GN, anti-GBM disease, and C3 glomerulopathy.
Nephrotic syndrome
Nephrotic syndrome comprises heavy proteinuria, hypoalbuminemia, and clinically important edema, often with hyperlipidemia and lipiduria. A commonly used adult threshold is protein excretion above 3–3.5 g/day, but the syndrome is clinical rather than a single numerical cutoff. The differential includes membranous nephropathy, minimal change disease, FSGS, diabetic kidney disease, amyloidosis, lupus podocytopathy, and advanced immune-complex disease.
Nephrotic syndrome creates risks beyond edema. Urinary loss of anticoagulant proteins, platelet hyperreactivity, inflammation, immobility, infection, and disease-specific factors may increase venous and arterial thrombosis. The decision to provide prophylactic anticoagulation in selected patients—particularly in membranous nephropathy—requires individualized assessment of serum albumin, proteinuria, histology, prior thrombosis, bleeding risk, kidney function, age, medications, and patient preferences; no single albumin threshold applies universally.
Rapidly progressive glomerulonephritis
RPGN is a clinical syndrome of rapid loss of kidney function over days to weeks with an active urine sediment, usually accompanied by crescents or severe necrotizing lesions on biopsy. Crescents are a response pattern, not a diagnosis: they may occur in ANCA-associated GN, anti-GBM disease, immune-complex GN, infection-related GN, and other conditions. Treatment should be guided by the immunopathologic category and clinical urgency.
Asymptomatic urinary abnormalities and mixed syndromes
Persistent microscopic hematuria, albuminuria, or both may be the earliest manifestation of IgA nephropathy, thin basement membrane disease, Alport-spectrum disease, early lupus nephritis, or a monoclonal gammopathy-associated lesion. Mixed nephritic–nephrotic presentations are common in proliferative lupus nephritis, infection-related GN, MPGN-pattern disease, and some forms of IgA nephropathy. The absence of edema does not exclude clinically important proteinuria.
Immune-complex disease
Immune complexes may form in situ or circulate and deposit in the glomerulus. Their location, composition, and associated complement activation influence the pattern of injury. Lupus nephritis, IgA nephropathy, infection-related GN, and many MPGN-pattern lesions are immune-complex-mediated or contain prominent immunoglobulin deposits.
Anti-GBM antibody disease
Anti-GBM disease is caused by pathogenic autoantibodies directed against the glomerular basement membrane, classically the noncollagenous domain of the alpha-3 chain of type IV collagen. Immunofluorescence typically shows strong linear IgG staining. It is not an immune-complex disease. Pulmonary hemorrhage, rapidly progressive renal failure, and a positive anti-GBM assay constitute a medical emergency; treatment should not wait for biopsy when the clinical and serologic picture is compelling.
Pauci-immune injury and ANCA-associated vasculitis
ANCA-associated GN is characterized by necrotizing and crescentic lesions with absent or scant immunoglobulin deposition. PR3-ANCA and MPO-ANCA associations provide useful diagnostic and prognostic information but do not replace clinical assessment or biopsy when biopsy is feasible. ANCA negativity does not exclude pauci-immune vasculitis.
Complement-mediated injury
Complement activation may be triggered through the classical, lectin, or alternative pathway. C3 glomerulopathy is defined by dominant C3 staining with absent or limited immunoglobulin, after excluding infection-related and monoclonal gammopathy-associated causes. Complement levels and genetic testing can support evaluation but are not by themselves diagnostic.
Podocyte and filtration-barrier injury
Podocyte foot-process effacement is a response to injury and may be seen in minimal change disease, FSGS, membranous nephropathy, diabetic kidney disease, and other proteinuric states. MCD is usually normal or near-normal by light microscopy, with diffuse foot-process effacement on electron microscopy. FSGS is a pattern of segmental sclerosis; it must be classified as primary, secondary, or genetic because immunosuppression is not appropriate for all forms.
16.4 Urine microscopy and protein quantification
Urine microscopy remains one of the most information-dense tests in nephrology. Dysmorphic erythrocytes, acanthocytes, and red-cell casts support glomerular bleeding. White-cell casts may occur in interstitial nephritis, pyelonephritis, and some GN. Oval fat bodies and lipiduria support heavy proteinuria but are not disease-specific. A bland sediment does not rule out membranous nephropathy, MCD, or early diabetic kidney disease.
Quantify proteinuria with a spot urine albumin-to-creatinine ratio and, when clinically useful, a protein-to-creatinine ratio. A 24-hour collection is not routinely required when a reliable spot ratio is available, but it can be useful when creatinine excretion is unusual, results are discordant, or treatment decisions depend on a precise measurement. Interpret ratios in context of muscle mass, acute kidney injury, exercise, menstruation, infection, and urine concentration.
16.5 Diagnostic pathway for suspected glomerular disease
Step 1: Confirm the pattern and assess urgency
Repeat or confirm urinalysis when contamination is possible. Review sediment personally or with an experienced laboratory. Determine whether the patient has AKI, rapidly progressive loss of GFR, nephrotic syndrome, severe hypertension, pulmonary hemorrhage, systemic vasculitis, infection, or a transplant/solitary kidney. Check medication exposure, recent infections, autoimmune symptoms, malignancy risk, family history, and pregnancy status when relevant.
Step 2: Obtain targeted laboratory studies
Initial tests commonly include creatinine/eGFR, electrolytes, bicarbonate, albumin, CBC, urinalysis with microscopy, urine ACR/PCR, and blood pressure measurement. Depending on the syndrome, obtain C3/C4, ANA, anti-dsDNA, ANCA with antigen-specific PR3/MPO testing, anti-GBM antibody, hepatitis B and C, HIV, ASO or anti-DNase B when relevant, blood cultures if infection-related GN is possible, and cryoglobulins. In adults with unexplained proteinuria, hematuria, anemia, hypercalcemia, neuropathy, or disproportionate kidney dysfunction, evaluate for monoclonal gammopathy with serum and urine immunofixation and serum free light chains, interpreted with kidney-function-adjusted ranges.
Step 3: Decide whether biopsy is indicated and safe
Kidney biopsy is the diagnostic reference standard for many glomerular diseases, but it is not automatically required in every patient. Biopsy is particularly valuable when the result will change treatment, when the diagnosis is uncertain, when there is unexplained AKI or significant proteinuria, or when systemic disease may have multiple renal patterns. Consider bleeding risk, uncontrolled hypertension, thrombocytopenia, anticoagulant exposure, small echogenic kidneys, pregnancy, and the availability of transjugular or other alternative approaches. A biopsy should be processed for light microscopy, immunofluorescence, and electron microscopy; add special stains, immunohistochemistry, or mass spectrometry when indicated.
Step 4: Treat emergencies in parallel with diagnostic work-up
For pulmonary–renal syndrome, rapidly progressive AKI with active sediment, or severe suspected anti-GBM/AAV, obtain urgent serology and biopsy when feasible, but do not delay specialist-directed empiric therapy for a life-threatening process while awaiting results. Before immunosuppression, obtain cultures and infection screening as clinically appropriate. In suspected infection-related GN, source control and antimicrobial therapy are central; immunosuppression may worsen infection.
| Clinical pattern | Priority tests | Interpretive purpose |
|---|---|---|
| Active sediment with AKI | C3/C4, ANCA PR3/MPO, anti-GBM, ANA/dsDNA, CBC, cultures when indicated | Separate pauci-immune, anti-GBM, immune-complex, and infection-related processes |
| Nephrotic syndrome | ACR/PCR, albumin, lipids, PLA2R, hepatitis/HIV testing, monoclonal studies when indicated | Quantify severity, evaluate primary MN and secondary causes, assess complications |
| Low complement | Repeat complements, infection evaluation, cryoglobulins, hepatitis, monoclonal studies | Evaluate immune-complex, infection-related, cryoglobulinemic, and complement-mediated GN |
| Unexplained proteinuria or eGFR decline | Urine microscopy, ACR/PCR, kidney imaging, biopsy-risk assessment | Determine whether biopsy will change diagnosis and treatment |
16.6 Pathology: integrating LM, IF, and EM
Light microscopy assesses cellularity, proliferation, capillary-wall changes, necrosis, crescents, sclerosis, thrombi, and chronicity. Immunofluorescence determines whether deposits are immunoglobulin-dominant, complement-dominant, mixed, linear, or pauci-immune. Electron microscopy identifies subepithelial, subendothelial, intramembranous, or mesangial deposits and characterizes podocyte foot-process effacement.
A pathology report should be interpreted with the clinical syndrome. In lupus nephritis, the ISN/RPS class, activity index, and chronicity index inform treatment and prognosis. In IgA nephropathy, the Oxford MEST-C score adds prognostic information but should not be used as a stand-alone treatment algorithm. In AAV, the Berden classification provides prognostic context but does not replace clinical assessment. Tubulointerstitial fibrosis and tubular atrophy are important markers of chronic damage across many diseases, but they are not the only determinants of outcome.
Supportive care for proteinuric glomerular disease
Control blood pressure and reduce albuminuria with renin–angiotensin system blockade when indicated and tolerated, monitoring creatinine and potassium after initiation or dose changes. Avoid dual ACE inhibitor/ARB therapy. Use dietary sodium reduction, individualized diuretic therapy for edema, vaccination and infection-prevention strategies, cardiovascular risk management, and avoidance of nephrotoxins. SGLT2 inhibitors may provide kidney protection in selected stable CKD/proteinuric patients, but they are not a substitute for urgent treatment of active GN and require attention to eGFR, volume status, ketoacidosis risk, and acute illness.
IgA nephropathy and IgA vasculitis
The KDIGO 2025 update emphasizes biopsy-based diagnosis when clinically appropriate, dynamic risk reassessment, optimized supportive care, and lower proteinuria targets. Depending on risk, kidney function, availability, and regulatory approval, treatment options may include SGLT2 inhibition, sparsentan, targeted-release budesonide, or a reduced-dose systemic glucocorticoid regimen with prophylaxis. The International IgAN Prediction Tool supports risk communication but should not be treated as a validated stand-alone treatment-selection instrument. Rapidly progressive IgAN requires a separate urgent pathway.
Membranous nephropathy
Assess for secondary causes, including infections, autoimmune disease, medications, malignancy according to age and risk, and monoclonal gammopathy. Anti-PLA2R antibody status informs diagnosis, risk stratification, and response monitoring, but seronegativity does not exclude membranous nephropathy. Treatment is risk-based and may include supportive care, rituximab, calcineurin inhibitor-based therapy, or cyclophosphamide–glucocorticoid regimens in selected high-risk patients. Thrombotic-risk assessment is integral.
Minimal change disease and FSGS
MCD is generally steroid-responsive, but relapse, steroid toxicity, secondary causes, and infection risk require structured follow-up. FSGS must be categorized as primary, secondary, or genetic. Immunosuppression is directed toward primary FSGS with nephrotic syndrome and compatible pathology; secondary or adaptive FSGS is treated with cause-specific and supportive measures rather than routine immunosuppression.
Lupus nephritis
The KDIGO 2024 focused update incorporates modern multidrug regimens and add-on belimumab or voclosporin in appropriate patients. Treatment depends on biopsy class, activity/chronicity, proteinuria, kidney function, reproductive plans, infection risk, and comorbidity. Hydroxychloroquine is generally recommended unless contraindicated, with ophthalmologic monitoring. The 2025 EULAR update should be considered alongside KDIGO in multidisciplinary SLE care. Maintenance therapy, adherence, pregnancy planning, and monitoring of proteinuria and eGFR are as important as induction therapy.
ANCA-associated vasculitis
The KDIGO 2024 update supports rituximab or cyclophosphamide-based induction with glucocorticoid minimization strategies, and recognizes avacopan as an alternative glucocorticoid-sparing option in appropriate settings. Plasma exchange is reserved for selected severe presentations and is particularly important in anti-GBM overlap; it is not routine for every AAV patient. Maintenance therapy commonly uses rituximab or azathioprine-based strategies, with relapse risk, infection prevention, immunoglobulin levels, vaccination, and Pneumocystis prophylaxis considered explicitly.
Anti-GBM disease
Treatment is urgent plasma exchange plus glucocorticoids and cyclophosphamide in patients likely to benefit, with individualized decisions in advanced irreversible kidney failure without pulmonary hemorrhage. Double-positive anti-GBM/ANCA patients require treatment and long-term relapse surveillance appropriate to both diseases.
Infection-related, complement-mediated, and monoclonal gammopathy-associated GN
Infection-related GN requires identification and treatment of the infection, source control, volume and blood-pressure management, and careful avoidance of empiric immunosuppression unless a specialist has established a compelling indication. C3 glomerulopathy requires evaluation for infection, monoclonal gammopathy, complement abnormalities, and genetic predisposition; therapy is individualized and may involve supportive care, immunomodulation, or complement-targeted treatment in selected settings. Monoclonal gammopathy of renal significance requires coordinated hematology–nephrology management because clone-directed therapy may preserve kidney function.
16.8 Monitoring and complication prevention
Follow proteinuria/albuminuria, eGFR, blood pressure, serum albumin, electrolytes, disease-specific biomarkers, medication toxicity, infection, and treatment adherence. Before and during immunosuppression, address vaccination, hepatitis and tuberculosis screening when relevant, Pneumocystis prophylaxis, bone protection, fertility and pregnancy counseling, malignancy screening, and glucocorticoid toxicity. Reassess the diagnosis when the response is atypical; persistent proteinuria may reflect chronic scarring, untreated disease, treatment-resistant disease, a second process, or nonadherence.
Case 1: Pulmonary–renal syndrome
A 62-year-old patient has hemoptysis, creatinine rising from 1.0 to 4.2 mg/dL over 10 days, dysmorphic RBCs, RBC casts, low hemoglobin, and positive MPO-ANCA. The immediate priorities are admission, nephrology and respiratory consultation, urgent anti-GBM testing, cultures, chest imaging, kidney biopsy if feasible, and specialist-directed induction therapy. A positive ANCA does not eliminate the need to consider anti-GBM overlap or infection.
Case 2: Nephrotic syndrome with thrombosis risk
A 48-year-old patient has proteinuria 8 g/day, albumin 1.9 g/dL, preserved eGFR, and positive anti-PLA2R antibodies. The clinician should evaluate membranous nephropathy and secondary causes, assess thrombosis and bleeding risk, optimize supportive care, and select disease-specific therapy according to risk. Anticoagulation is not determined by albumin alone.
Case 3: IgA nephropathy with residual risk
A 35-year-old patient has biopsy-proven IgAN, eGFR 68, and persistent proteinuria of 0.8 g/day despite maximized tolerated RAS blockade and blood-pressure control. The next step is dynamic risk assessment and consideration of approved supportive or targeted therapies based on local availability and eligibility. The older concept that proteinuria below 1 g/day is automatically low risk is no longer adequate.
Case 4: Low complement and infection
A patient with endocarditis develops AKI, hematuria, low C3, and an MPGN pattern on biopsy. The priority is antimicrobial therapy and infection source control. Immunosuppression should not be reflexively added while infection is active; persistent renal disease after infection control requires reassessment.
16.10 Clinical pearls
- A urine sediment with acanthocytes or RBC casts is a clinical emergency signal when accompanied by a rising creatinine.
- Crescents describe a lesion pattern; they do not identify the cause.
- Anti-GBM disease produces linear immunofluorescence and requires urgent treatment; it is not immune-complex GN.
- FSGS is a pattern, not automatically a primary steroid-responsive disease.
- A positive PLA2R antibody supports primary membranous nephropathy but does not eliminate the need for clinical assessment of secondary causes.
- The 2025 KDIGO IgAN framework moves toward dynamic risk assessment and lower proteinuria targets; the International Prediction Tool is not a treatment prescription.
- In infection-related GN, source control and antimicrobial therapy come before reflex immunosuppression.
- Nephrotic thrombosis prophylaxis must balance thrombosis and bleeding risk rather than rely on a universal albumin cutoff.
- Biopsy processing is part of diagnosis: LM, IF, and EM are complementary, not interchangeable.
- Chronicity on biopsy can limit reversibility, but activity and the clinical trajectory determine urgency and treatment potential.
16.11 Summary
Glomerular diseases should be approached by syndrome, tempo, urine sediment, kidney function, serologic pattern, and pathology rather than by isolated laboratory thresholds. Nephritic, nephrotic, mixed, and rapidly progressive presentations overlap and require careful classification. The diagnostic work-up combines microscopy, quantitative protein assessment, complement and disease-specific serology, monoclonal-protein testing when indicated, and strategically performed kidney biopsy. Management begins with stabilization and supportive CKD care, then becomes diagnosis-specific. Current practice must incorporate the KDIGO 2024 updates for lupus nephritis and ANCA-associated vasculitis, the KDIGO 2025 IgAN/IgAV guideline, and the 2025 EULAR SLE-with-kidney-involvement recommendations. The most important safety principle is to treat time-critical pulmonary–renal and anti-GBM syndromes urgently while avoiding indiscriminate immunosuppression in infection-related disease.
Question 1
A patient has creatinine increasing from 1.1 to 4.0 mg/dL over 2 weeks, dysmorphic RBCs, RBC casts, pulmonary hemorrhage, and positive PR3-ANCA. Which additional test is most urgent because it changes immediate treatment and prognosis?
A. Anti-PLA2R antibody B. Anti-GBM antibody C. Serum IgE D. Genetic complement panel
Answer: B. Anti-GBM antibody. ANCA positivity does not exclude anti-GBM overlap. Double-positive disease carries important treatment and relapse implications, and anti-GBM disease is a time-critical indication for plasma exchange-based treatment in appropriate patients.
Question 2
Which statement best describes FSGS?
A. It is always primary and steroid-responsive. B. It is defined by diffuse podocyte foot-process effacement only. C. It is a histologic pattern that requires classification as primary, secondary, or genetic. D. It is diagnosed by positive anti-PLA2R antibodies.
Answer: C. FSGS is a pattern of segmental sclerosis. Etiologic classification determines whether immunosuppression is appropriate.
Question 3
A patient with biopsy-proven IgAN has persistent proteinuria of 0.7 g/day despite optimized supportive care. Which principle best reflects current guidance?
A. Proteinuria below 1 g/day is automatically low risk. B. The International IgAN Prediction Tool alone determines therapy. C. Risk should be reassessed dynamically, with consideration of approved supportive or targeted therapies according to eligibility. D. Kidney biopsy is never needed when hematuria is present.
Answer: C. Current IgAN care emphasizes dynamic risk assessment, sustained proteinuria reduction, eGFR trajectory, and individualized therapy.
Question 4
A patient with active bacterial endocarditis develops low-complement AKI and an immune-complex GN pattern. What is the most appropriate immediate management?
A. High-dose cyclophosphamide before treating infection B. Rituximab monotherapy C. Antimicrobial therapy and infection source control with supportive kidney care D. Plasma exchange for all patients
Answer: C. Infection-related GN is managed primarily by treating the infection and controlling volume and blood pressure. Immunosuppression may worsen active infection.
Question 5
Which pathology combination is most consistent with anti-GBM disease?
A. Full-house granular immune deposits B. Pauci-immune staining with necrotizing crescents C. Strong linear IgG staining along the GBM D. Dominant C3 staining with no immunoglobulin
Answer: C. Linear IgG staining supports antibody binding along the GBM. Clinical anti-GBM disease requires urgent specialist management.
Question 6
A patient with nephrotic syndrome has albumin 2.1 g/dL and no bleeding history. What is the correct approach to thrombosis prophylaxis?
A. Anticoagulate every patient below 2.5 g/dL. B. Never anticoagulate unless thrombosis has already occurred. C. Individualize the decision using disease-specific thrombosis risk, albumin, proteinuria, bleeding risk, kidney function, and patient preferences. D. Use aspirin as an equivalent substitute in all cases.
Answer: C. Prophylaxis is individualized; membranous nephropathy and severe hypoalbuminemia may increase risk, but bleeding risk and comorbidity are equally important.
Question 7
Which statement about kidney biopsy is most accurate?
A. It is mandatory for every patient with hematuria. B. It is never useful when serology is positive. C. It should be performed when the expected diagnostic value outweighs procedural risk and will change management. D. Electron microscopy is unnecessary if light microscopy is abnormal.
Answer: C. Biopsy is strategic, not reflexive, and LM, IF, and EM provide complementary information.
Question 8
A patient with lupus nephritis is considering pregnancy. Which issue should be incorporated before treatment selection?
A. Only the current creatinine value B. Reproductive plans, teratogenicity, disease activity, and the safety of induction and maintenance agents C. Avoid all immunosuppression regardless of disease activity D. Stop hydroxychloroquine routinely
Answer: B. Pregnancy planning is integral to lupus nephritis care and should be coordinated with nephrology, rheumatology, and obstetrics.