# Comprehensive Medical Student Review: Evaluation and Treatment of Nephrotic and Nephritic Syndromes

## 1. Definitions

### Nephrotic Syndrome

Nephrotic syndrome combines heavy proteinuria with hypoalbuminemia; edema and hyperlipidemia are common consequences. In adults, nephrotic-range protein excretion is usually above 3.5 g/day. Pediatric definitions use body-size-adjusted thresholds. Nephrotic-range proteinuria alone is not the complete syndrome.

Injury to the glomerular filtration barrier, including podocytes, permits excess protein loss. The underlying disease determines treatment. Assess kidney function, urine protein, serum albumin, edema, thrombosis risk, and possible secondary causes. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256)

### Nephritic Syndrome

Nephritic syndrome reflects glomerular inflammation: hematuria, often with dysmorphic red cells or red-cell casts, variable proteinuria, reduced GFR, hypertension, and edema. Nephrotic and nephritic features can overlap. Heavy proteinuria does not exclude inflammatory glomerulonephritis. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256)

## 2. Urine Microscopy

### Nephrotic Syndrome

- **Oval fat bodies and fatty casts:** support lipiduria in a proteinuric syndrome; lipid can show a Maltese-cross appearance under polarized light.
- **Hematuria:** can occur, depending on the underlying disease. Its presence does not exclude nephrotic syndrome.
- **Waxy or granular casts:** reflect additional kidney pathology rather than a unique diagnosis.

### Nephritic Syndrome

- **Dysmorphic red cells, especially acanthocytes:** support a glomerular source of hematuria.
- **Red-cell casts:** strongly support glomerular bleeding in the appropriate setting, but their absence does not exclude glomerulonephritis.
- **White-cell casts and sterile pyuria:** may accompany inflammation but are not specific.
- **Muddy brown granular casts:** suggest concurrent tubular injury; interpret the full sediment and clinical course.

## 3. Serological Evaluation of Nephritic Syndrome

### Complement Evaluation

Measure C3 and C4 together as part of the clinical evaluation. Their pattern can suggest complement consumption, but it does not identify the cause on its own.

#### Low Complement Nephritic Syndromes

**Low C3 and C4:** can accompany immune-complex diseases such as lupus nephritis, cryoglobulinemia, and infection-related glomerulonephritis. The pattern suggests pathway consumption but does not establish the diagnosis.

**Low C3 with relatively preserved C4:** raises consideration of alternative-pathway activation, including infection-related GN and C3 glomerulopathy. Serum levels, biopsy findings, infection evaluation, and specialized complement testing must be interpreted together. [\[2\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-30405598)

#### Normal Complement Nephritic Syndromes

Serum complement is often normal in IgA nephropathy, ANCA-associated GN, and anti-GBM disease. Normal levels cannot rule out active GN or prove a particular cause. Alport syndrome and thin basement membrane disorders cause glomerular hematuria through different mechanisms. Polyarteritis nodosa causes medium-vessel ischemic kidney injury and usually spares glomeruli. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256)

### Table: Glomerular Diseases by Complement Pattern and Systemic/Renal Classification

These are typical patterns, with exceptions; they are clues rather than diagnostic criteria.

| Pattern | Examples to consider | Interpretation |
|----|----|----|
| Low C3 and C4 | Lupus nephritis; cryoglobulinemic or infection-related GN | Evaluate immune complexes, systemic disease, and infection. |
| Low C3, relatively preserved C4 | C3 glomerulopathy; infection-related GN | Consider alternative-pathway activation; biopsy and clinical context distinguish causes. |
| Often normal C3 and C4 | IgA nephropathy; ANCA-associated GN; anti-GBM disease | Normal values do not exclude severe glomerular inflammation. |

Thrombotic microangiopathy and medium-vessel vasculitis are separate kidney-injury patterns; neither should be classified as glomerulonephritis solely from complement results.

### Detailed Discussion of Normal Complement Glomerulonephritides

#### A. Anti-GBM Disease and Goodpasture Syndrome

Anti-GBM antibodies usually target the α3 chain of type IV collagen. Kidney disease may occur alone or with pulmonary hemorrhage. The presentation can be rapidly progressive; serum complement is often normal.

Obtain anti-GBM serology promptly. Kidney biopsy typically shows linear IgG along the glomerular basement membrane and may show necrosis and crescents. Pulmonary hemorrhage or rapidly deteriorating kidney function requires urgent specialist treatment while diagnostic work proceeds. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256)

#### B. ANCA-Associated Vasculitides (AAV)

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) can cause pauci-immune necrotizing and crescentic GN. GPA commonly includes upper-airway disease and granulomatous respiratory lesions; MPA can cause pulmonary capillaritis. Renal-limited disease can occur without obvious systemic symptoms. Eosinophilic GPA has a different clinical context, often including asthma and eosinophilia.

**Antibody interpretation:** PR3 and MPO are antigen targets; c-ANCA and p-ANCA are immunofluorescence patterns. They are related but not interchangeable. High-quality antigen-specific testing is interpreted with the phenotype and, when feasible, biopsy. ANCA-negative disease occurs, and positive ANCA can occur outside primary vasculitis. There is no universal predictive value applicable to every patient.

For severe GPA/MPA, induction generally uses rituximab or cyclophosphamide with a glucocorticoid regimen selected for disease severity and toxicity. Complement levels are often normal but may be low. [\[3\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-38388102)

**Avacopan:** the ADVOCATE publication was retracted in 2026. The FDA proposed withdrawal of the Tavneos approval on April 27, 2026; a proposal is not a completed withdrawal. The retracted trial must not be used as reliable evidence of efficacy. [\[4\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-42377355) [FDA notice](https://www.fda.gov/drugs/drug-alerts-and-statements/cder-proposes-withdraw-approval-tavneos).

## 4. Immunosuppression in Nephrotic Syndrome

### Traditional Therapies

Supportive treatment accompanies disease-specific therapy: control blood pressure and edema, reduce proteinuria when appropriate, assess infection and thrombosis risk, and monitor kidney function. Immunosuppression requires a defined indication. A treatment effective in primary MCD or FSGS may be inappropriate in genetic, adaptive, or infection-associated disease. Pediatric and adult protocols differ. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256)

### A. Minimal Change Disease (MCD)

#### Initial Treatment

For adult minimal change disease, glucocorticoids are usual initial therapy. KDIGO 2021 describes high-dose treatment for no longer than 16 weeks, with tapering beginning after remission; the dose, schedule, and taper require individualization. A prolonged high-dose course should not continue automatically despite toxicity or absent response. When glucocorticoids are unsuitable, discuss alternative agents with nephrology. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256) [\[5\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-27940460)

#### Frequently Relapsing and Steroid-Dependent MCD

Relapse is common. Frequent relapse and steroid dependence require attention to cumulative steroid exposure, the accuracy of the diagnosis, adherence, and secondary causes.

- **Rituximab, cyclophosphamide, calcineurin inhibitors, or mycophenolic acid analogues** are possible steroid-sparing options in adults.
- **Selection** depends on previous response, fertility concerns, infection risk, kidney function, adverse effects, and patient preference.
- **Monitoring** differs by agent; calcineurin inhibitors require attention to drug exposure and nephrotoxicity, while B-cell depletion and cytotoxic drugs require infection-risk assessment.

No single remission percentage can be promised across these regimens or populations. Pediatric dosing should not be transferred directly to adult practice. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256) [\[6\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-36751385)

### B. Focal Segmental Glomerulosclerosis (FSGS)

#### Initial Treatment

FSGS is a biopsy lesion with multiple causes. Establish whether the clinical syndrome is primary FSGS, secondary/adaptive disease, a genetic disorder, or FSGS of undetermined cause before selecting immunosuppression.

High-dose oral glucocorticoids are an initial option for **primary FSGS with nephrotic syndrome**. Steroid resistance is assessed after an adequate tolerated course, up to 16 weeks in KDIGO guidance. Race alone does not determine treatment response or justify withholding therapy; consider the individual phenotype, biopsy, genetic findings, and clinical course. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256) [\[7\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-28242845)

#### Non-Steroid Immunosuppression for FSGS

For steroid-resistant primary FSGS, cyclosporine or tacrolimus is recommended for an adequate trial, generally at least six months, with kidney-function and drug-exposure monitoring. A calcineurin inhibitor may also be considered when high-dose glucocorticoids are contraindicated.

Persistent resistance or intolerance warrants specialist reassessment of the diagnosis, possible genetic testing or repeat biopsy, and clinical-trial consideration. Cyclophosphamide, sirolimus, and mycophenolate are not interchangeable standard rescue treatments. Secondary and most genetic forms are managed by addressing the cause and providing supportive care rather than routine empiric immunosuppression. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256) [\[8\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-32721952)

### C. Membranous Nephropathy

#### Diagnosis

In an adult with nephrotic syndrome and a convincingly positive anti-PLA2R test, membranous nephropathy may sometimes be diagnosed without biopsy. Biopsy remains useful when the course is atypical, kidney function is impaired, another process is suspected, or the result would change management.

Evaluate associated infections, autoimmune disease, medications, and malignancy according to the clinical context. A positive anti-PLA2R result does not eliminate every secondary association. Hepatitis-associated disease requires coordinated kidney and antiviral management. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256) [\[9\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-37934599) [\[10\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-37657881)

#### Risk Stratification and When to Start Immunosuppression

Risk assessment in membranous nephropathy integrates the level and persistence of proteinuria, eGFR and its trajectory, serum albumin, anti-PLA2R levels and trends, and complications of nephrotic syndrome. Protein excretion is expressed in g/day or an appropriate protein-to-creatinine ratio, not mg/dL alone.

Patients at low risk may receive supportive care and observation. Persistent high-risk disease, progressive kidney dysfunction, or serious nephrotic complications may warrant immunosuppression. Spontaneous remission is possible, but its likelihood varies. Immunologic improvement may precede reduction in proteinuria; follow both rather than using an isolated antibody threshold as an automatic treatment rule. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256) [\[11\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-38915435)

#### Treatment Options for Membranous Nephropathy

- **Rituximab:** an option for patients requiring immunosuppression. In MENTOR, complete or partial remission at 24 months occurred in 60% with rituximab versus 20% with cyclosporine. This result applies to that trial population and comparator; retreatment is individualized. [\[12\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-31269364)
- **Cyclophosphamide plus glucocorticoids:** an established approach, particularly in high-risk disease, balanced against infection, fertility, and malignancy risks.
- **Calcineurin inhibitors:** can reduce proteinuria but require toxicity monitoring and a plan for relapse risk after withdrawal.
- **Hepatitis-associated disease:** prioritize appropriate antiviral evaluation and coordinate any immunosuppression because viral reactivation and drug toxicity matter. Historical interferon or adefovir regimens should not be treated as a universal current prescription. [\[10\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-37657881)

Use risk-stratified, disease-specific guidance rather than ranking all regimens from unrelated trials. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256) [\[9\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-37934599)

### Biologics

B-cell-directed therapy has established roles in selected glomerular diseases, including rituximab in membranous nephropathy, relapsing MCD, and AAV. Evidence for other antibodies or combination B-cell/plasma-cell strategies is disease- and population-specific. A proposed mechanism or registered trial does not establish effectiveness or justify routine off-label combinations. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256)

## 5. New and Emerging Treatments

### A. GI-Focused Steroids: Tarpeyo (Budesonide)

Targeted-release budesonide delivers a glucocorticoid to the gut mucosal immune system implicated in IgA nephropathy. It is disease-specific treatment, not a general treatment for every nephrotic syndrome.

The NefIgArd phase 3 trial studied adults with persistent proteinuria despite optimized renin–angiotensin system blockade. Its two-year findings support preservation of kidney function in the studied population. Glucocorticoid-related adverse effects still require monitoring; a targeted formulation does not eliminate systemic risk. [\[13\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-37591292)

### B. Endothelin Receptor Antagonists

#### Sparsentan (Dual ERA/ARB)

Sparsentan blocks endothelin A and angiotensin II type 1 receptors. In PROTECT, it reduced proteinuria and better preserved kidney function than irbesartan in the studied IgA nephropathy population. [\[14\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-37931634)

DUPLEX has reported its results: in FSGS, sparsentan improved the proteinuria response but did **not** significantly improve the primary eGFR-slope outcome at 108 weeks compared with irbesartan. The distinction between a surrogate response and the primary kidney-function outcome matters. [\[15\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-37921461)

Endothelin-directed agents differ in receptor selectivity, indications, safety requirements, and supporting evidence. Check the current product-specific label and do not extrapolate one disease's trial to another. [\[16\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-38059359)

#### Atrasentan

The prespecified ALIGN interim analysis found lower proteinuria with atrasentan than placebo in adults with IgA nephropathy. That publication assessed a proteinuria endpoint; it should not be represented as proof of a final kidney-failure benefit. Fluid retention remains an important class concern. [\[17\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-39460694)

#### Combination Therapy

Endothelin antagonists combined with SGLT2 inhibitors are being evaluated to balance albuminuria reduction and fluid-retention risk. Results depend on the agent, dose, and population. Short-term albuminuria changes should not be equated with proven long-term kidney-failure prevention, and trial combinations should not be transferred automatically into clinical practice. [\[18\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-38660120)

### C. Other Drugs in the Pipeline

#### Gene Therapy

A 2023 study restored podocin expression in human cell models and improved disease in mouse models of genetic nephrotic syndrome. This is preclinical evidence. It did not demonstrate a cure in people or an available single-dose treatment for steroid-resistant nephrotic syndrome. [\[19\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-37556557)

#### HDAC Inhibitors

Histone deacetylase inhibition is an experimental research approach. Mechanistic and preclinical findings cannot establish an effective or safe regimen for nephrotic syndrome. It is not a routine treatment option in the clinical framework described here.

#### Network Pharmacology Approaches

Computational drug-target networks can generate hypotheses for laboratory testing. They do not by themselves establish drug efficacy, dosing, or safety. Valproate or retinoic acid should not be prescribed for nephrotic syndrome on the basis of such hypotheses.

### D. Other Disease-Specific Options

**Iptacopan** inhibits complement factor B. In APPLAUSE-IgAN, the final 24-month analysis showed slower eGFR decline than placebo in the studied adults with IgA nephropathy. Serious infections were more frequent with iptacopan, underscoring the need for product-specific infection prevention and monitoring. [\[20\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-41910396)

**Sparsentan** is discussed above. Regulatory indications, vaccination requirements, contraindications, and monitoring must be checked for each product; these agents are not interchangeable therapies for all glomerular diseases.

## 6. Rapidly Progressive Glomerulonephritis (RPGN): Diagnosis and Treatment

### Definition and Clinical Features

RPGN is a clinical syndrome of rapidly worsening kidney function over days to weeks or months, usually with an inflammatory urine sediment. Crescent formation is a common biopsy finding. Urgent evaluation should not wait for an arbitrary percentage fall in eGFR or a fixed percentage of crescents.

Look for hematuria, proteinuria, hypertension, edema, systemic inflammation, and pulmonary hemorrhage. Assess competing causes of AKI at the same time. The disease mechanism and degree of reversible injury guide treatment. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256) [\[3\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-38388102)

### Classification

- **Anti-GBM disease:** linear glomerular IgG staining; kidney-limited or pulmonary–renal presentation.
- **Immune-complex GN:** granular deposits; examples include lupus nephritis, infection-related GN, cryoglobulinemic GN, and IgA nephropathy.
- **Pauci-immune GN:** few immune deposits; commonly associated with MPO-ANCA or PR3-ANCA, but seronegative cases occur.
- **Double-positive disease:** both ANCA and anti-GBM antibodies; treatment and relapse follow-up require attention to both mechanisms.

The relative frequency of these categories varies by setting. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256)

### Diagnostic Approach

#### Laboratory Evaluation

Obtain serial creatinine, electrolytes, quantified urine protein, and urine microscopy. Send anti-GBM antibodies, antigen-specific MPO/PR3 testing, complement levels, and lupus serology promptly when indicated. Evaluate hepatitis, cryoglobulins, streptococcal infection, or endocarditis according to the clinical setting. Include blood count and assessment for treatment-related infection risk.

ANCA results change diagnostic probability but neither prove nor exclude disease alone. Test performance depends on the assay and the pretest probability. Do not apply a fixed 95% or 98% predictive value across clinical settings. [\[3\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-38388102)

#### Renal Biopsy

Urgent kidney biopsy often establishes the mechanism, active lesions, and chronic damage. Light microscopy, immunofluorescence, and electron microscopy provide complementary information. Cellular crescents and necrosis differ from established fibrosis, but interpretation depends on the entire biopsy.

In a compelling life-threatening presentation, treatment should not be delayed solely while awaiting biopsy. Obtain tissue when feasible and safe, and revisit the diagnosis as results arrive. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256) [\[3\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-38388102)

### Treatment Approach

Treatment must be initiated urgently, often before biopsy results are available. The approach depends on the underlying etiology:

#### Type I: Anti-GBM Disease

Standard treatment for active anti-GBM disease usually combines plasma exchange, cyclophosphamide, and glucocorticoids. Begin urgently when suspicion is high; plasma exchange is generally continued until anti-GBM antibodies are undetectable.

Benefit depends on pulmonary involvement and the likelihood of kidney recovery. Dialysis dependence with extensive irreversible biopsy injury can change the treatment balance, especially without pulmonary hemorrhage. Such decisions require specialist assessment; a single creatinine cutoff should not determine treatment. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256)

#### Type II: Immune Complex Disease

Treat the underlying cause. Infection-related GN calls for infection control and supportive kidney care; immunosuppression is not automatic and can worsen an active infection. Proliferative lupus nephritis uses a disease-specific immunosuppressive regimen guided by biopsy, severity, and current guidance. [\[21\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-38182286)

In IgA nephropathy, crescents alone do not create a rule to give steroids below 25% or cyclophosphamide above 25%. A rapidly progressive clinical course, competing causes of AKI, and the full biopsy determine whether an RPGN-directed regimen is appropriate. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256)

#### Type III: Pauci-Immune (ANCA-Associated)

**Induction:** use rituximab or cyclophosphamide with an individualized glucocorticoid regimen for severe GPA/MPA. Reduced-dose glucocorticoid strategies can limit infection risk. Select drugs, dose adjustments, and prophylaxis according to kidney function, age, fertility concerns, infection risk, and disease severity. [\[3\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-38388102)

**Plasma exchange:** PEXIVAS did not show an overall reduction in death or kidney failure. Consider it selectively for severe kidney disease, rapidly increasing creatinine, hypoxemic diffuse alveolar hemorrhage, or anti-GBM overlap under specialist guidance; it is not required for every patient with a particular creatinine value. [\[22\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-32053298)

**Maintenance:** rituximab or azathioprine-based treatment is commonly used after remission. Duration and alternatives are individualized to relapse risk and toxicity. An isolated change in ANCA titer should not automatically trigger escalation.

**Avacopan:** the 2026 ADVOCATE retraction and FDA withdrawal proposal materially affect interpretation of the older guideline and trial. Do not present the retracted result as reliable efficacy evidence. [\[4\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-42377355)

### Monitoring and Prognosis

Monitor kidney function, electrolytes, urine findings, fluid status, blood pressure, and systemic disease activity at a frequency appropriate to acuity. Monitor blood counts, infection, and drug-specific toxicity during treatment.

Recovery depends on the underlying disease, kidney function at presentation, the amount of active versus chronic biopsy injury, and response to treatment. Dialysis at presentation does not always imply permanent kidney failure. Relapse risk varies; a single mortality, dialysis, or relapse percentage cannot describe all RPGN populations. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256) [\[3\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-38388102)

### Special Considerations

Renal-limited vasculitis can be severe despite absent respiratory or skin findings. Geographic differences in disease frequency do not replace individual testing. The historical Japanese RPGN guideline emphasizes rapid recognition and treatment, but current disease-specific guidance and subsequent safety information should guide present care. [\[23\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-27099135)

## 7. Secondary Causes of Glomerular Diseases

### Secondary Causes of Minimal Change Disease

Review medication exposure, infection, systemic disease, and malignancy when evaluating MCD. Recognized associations include NSAIDs and Hodgkin lymphoma. Other reported links have varying levels of evidence; temporal association, including after an infection or vaccination, does not alone establish causation.

Use a focused history and examination, medication review, age-appropriate cancer screening, and targeted testing. A universal exhaustive panel is unnecessary without clinical clues. Lupus podocytopathy is distinct from the usual proliferative immune-complex lesions and requires integrated biopsy and clinical interpretation.

When an associated cause is identified, address it alongside kidney-directed care: withdraw a suspected offending drug when appropriate, treat infection, or coordinate cancer care. Remission is not guaranteed solely by treating the associated condition. [\[24\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-12953043) [\[5\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-27940460)

### Secondary Causes of Focal Segmental Glomerulosclerosis

Distinguish adaptive FSGS, viral or drug-associated injury, and genetic disease from primary FSGS. Adaptive settings include reduced nephron mass, obesity-related glomerular stress, and reflux-associated injury. Viral disease such as HIV and drug exposures can produce different injury patterns. Genetic testing can be useful in selected patients, including early-onset or familial disease.

Nephrotic syndrome, the degree of foot-process effacement, biopsy pattern, and clinical context inform classification. No single histologic variant proves the cause. APOL1-associated risk is a genetic finding, not an assumption based on racial identity.

Treat the cause where possible, such as antiretroviral therapy for HIV or withdrawal of an implicated drug. Optimize blood pressure, antiproteinuric treatment, and general CKD care. Routine immunosuppression is not recommended for secondary FSGS or FSGS of undetermined cause without the primary nephrotic phenotype. Prognosis varies substantially with cause and chronic injury. [\[1\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-34556256) [\[7\]](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html#ref-28242845)

## 8. Key Clinical Pearls

1.  **Syndrome is not etiology:** nephrotic and nephritic features guide evaluation but can overlap.
2.  **Complement and ANCA are contextual tests:** normal or abnormal values cannot replace clinical assessment and biopsy when indicated.
3.  **Persistent low complement after infection-related GN:** reassess the diagnosis and course rather than applying a rigid timeline alone.
4.  **RPGN is urgent:** identify reversible active disease while evaluating infection and treatment risk.
5.  **Treatment follows cause:** primary, genetic, adaptive, autoimmune, and infection-associated disease require different approaches.
6.  **Read the endpoint:** lower proteinuria, slower eGFR decline, and fewer kidney-failure events are distinct findings.

## References

1.  Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276. [PubMed](https://pubmed.ncbi.nlm.nih.gov/34556256/)
2.  Ekdahl KN, Persson B, Mohlin C, et al. Interpretation of Serological Complement Biomarkers in Disease. Front Immunol. 2018;9:2237. [PubMed](https://pubmed.ncbi.nlm.nih.gov/30405598/)
3.  Kidney Disease: Improving Global Outcomes (KDIGO) ANCA Vasculitis Work Group. KDIGO 2024 Clinical Practice Guideline for the Management of Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis. Kidney Int. 2024;105(3S):S71-S116. [PubMed](https://pubmed.ncbi.nlm.nih.gov/38388102/)
4.  Rubin EJ. Retraction: Jayne DRW et al. Avacopan for the Treatment of ANCA-Associated Vasculitis, N Engl J Med 2021;384:599-609. N Engl J Med. 2026;. [PubMed](https://pubmed.ncbi.nlm.nih.gov/42377355/)
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6.  Koirala A, Jefferson JA. Steroid Minimization in Adults with Minimal Change Disease. Glomerular Dis. 2021;1(4):237-249. [PubMed](https://pubmed.ncbi.nlm.nih.gov/36751385/)
7.  Rosenberg AZ, Kopp JB. Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol. 2017;12(3):502. [PubMed](https://pubmed.ncbi.nlm.nih.gov/28242845/)
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9.  Radhakrishnan Y, Zand L, Sethi S, et al. Membranous nephropathy treatment standard. Nephrol Dial Transplant. 2024;39(3):403-413. [PubMed](https://pubmed.ncbi.nlm.nih.gov/37934599/)
10. Sharma P, Sawtell R, Wang Q, et al. Management of Hepatitis C Virus and Hepatitis B Virus Infection in the Setting of Kidney Disease. Adv Kidney Dis Health. 2023;30(4):343-355. [PubMed](https://pubmed.ncbi.nlm.nih.gov/37657881/)
11. Trujillo H, Caravaca-Fontán F, Praga M. Ten tips on immunosuppression in primary membranous nephropathy. Clin Kidney J. 2024;17(6):sfae129. [PubMed](https://pubmed.ncbi.nlm.nih.gov/38915435/)
12. Fervenza FC, Appel GB, Barbour SJ, et al. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. N Engl J Med. 2019;381(1):36. [PubMed](https://pubmed.ncbi.nlm.nih.gov/31269364/)
13. Lafayette R, Kristensen J, Stone A, et al. Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial. Lancet. 2023;402(10405):859. [PubMed](https://pubmed.ncbi.nlm.nih.gov/37591292/)
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15. Rheault MN, Alpers CE, Barratt J, et al. Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis. N Engl J Med. 2023;389(26):2436-2445. [PubMed](https://pubmed.ncbi.nlm.nih.gov/37921461/)
16. Schiffrin EL, Pollock DM. Endothelin System in Hypertension and Chronic Kidney Disease. Hypertension. 2024;81(4):691-701. [PubMed](https://pubmed.ncbi.nlm.nih.gov/38059359/)
17. Heerspink HJL, Jardine M, Kohan DE, et al. Atrasentan in Patients with IgA Nephropathy. N Engl J Med. 2025;392(6):544-554. [PubMed](https://pubmed.ncbi.nlm.nih.gov/39460694/)
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## Educational Resources

- Student Guide: Dipstick Proteinuria — PA/medical student educational guide


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[Website version](https://urinenephrology.org/mastery/glomerular/nephrotic-nephritic-comprehensive.html) · Markdown synchronized October 3, 2026.