How to Use This Article
This article intentionally brings together all major glomerular diseases that cause nephrotic and nephritic syndromes into a single article, allowing direct comparison between conditions. This mirrors how these topics are commonly tested in examinations.
The content is divided into two sections:
- Glomerular disease overview – covering general principles and core concepts relevant to glomerular disease
- Causes of nephrotic and nephritic syndromes – detailing information specific to individual glomerular diseases (features, diagnosis, management)
Glomerular Disease Overview
Definitions
Glomerular disease refers to any pathology affect the glomeruli, a broad umbrella term that includes both nephrotic (non-inflammatory) and nephritic (inflammatory) patterns:
- Nephrotic syndrome: a clinical syndrome caused by non-inflammatory glomerular injury (primary problem: ↑ glomerular permeability to proteins)
- Nephritic syndrome: a clinical syndrome caused by inflammatory glomerular injury (primary problem: glomerular inflammation and capillary injury)
Nephrotic Syndrome
Nephrotic syndrome is defined by triad of:
- Nephrotic range proteinuria (see below for definition)
- Hypoalbuminemia (serum albumin <30 g/L)
- Oedema
Specifically, to diagnose nephrotic syndrome, the patient must have nephrotic range proteinuria PLUS hypoalbuminaemia OR oedema
Nephrotic-range proteinuria is defined based on the patient’s age:
| Adults | Gold standard:
Alternative:
|
| Children (1-18 y/o) | ANY of the following can be used to identify nephrotic-range proteinuria:
|
Nephritic Syndrome
Nephritic syndrome is defined as the presence of: [Ref]
- Haematuria, and
- RBC casts
RBC casts consist of intact red blood cells embedded within a cylindrical proteinaceous matrix (Tamm-Horsfall protein) formed in the renal tubules.
(on urine microscopy), and - Proteinuria
- In nephritic syndrome, proteinuria is typically sub-nephrotic range: 500mg – 3g per day
- However, nephrotic-range proteinuria (≥3.5 g per day) is also possible
Aetiology
Glomerular diseases can be broadly categorised into their predominant clinical presentation (nephrotic vs nephritic syndrome). This is a non-exhaustive list, only the key exam-important ones are included:
| Nephrotic syndrome | Nephritic syndrome | Mixed / both |
Primary forms:
Secondary forms:
|
|
|
Some key patterns / associated to be aware of:
| Epidemiology facts |
|
| Rapidly progressive glomerulonephritis | Rapidly progressive glomerulonephritis is a clinical syndrome, defined as rapid loss of renal function (over days to weeks). It is most commonly caused by necrotising crescentic glomerulonephritis, which is a histopathological pattern.
The classic causes:
|
| Lung-renal syndrome | Lung-renal syndrome is a clinical presentation defined by the combination of lung involvement (typically pulmonary haemorrhage) and renal involvement (typically rapidly progressive glomerulonephritis).
The classic 3:
|
Clinical Manifestation
The following section outlines the non-specific clinical manifestations of nephrotic and nephritic syndromes themselves, irrespective of the underlying cause.
Clinical features specific to individual conditions are outlined in the second section (below) of the article.
Nephrotic Syndrome
Key manifestations / complications of nephrotic syndrome: [Ref]
| Component | Mechanism | Clinical manifestation |
|---|---|---|
| Proteinuria | ↑ Glomerular permeability to proteins (esp. albumin) | Proteinuria itself can cause frothy / foamy urine |
| Oedema | Oedema occurs due to hypoalbuminaemia → ↓ intravascular oncotic pressure |
|
| ↑ Risk of thrombotic events | ↑ Urinary loss of anticoagulants: anti-thrombin III, protein C, protein S and more
↑ Hepatic production of clotting factors and fibrinogen (stimulated by hypoalbuminaemia) |
Venous thrombosis (more common):
Arterial thrombosis (uncommon):
|
| ↑ Risk of infection | ↑ Urinary loss of immunoglobulins and immune-mediators |
|
| Hyperlipidaemia | Hypoalbuminaemia → compensatory hepatic upregulation (synthesis of proteins and lipoproteins) |
|
Other:
- Anaemia (from urinary loss of transferrin)
- Vitamin D deficiency (from urinary loss of vitamin D-binding protein)
Nephritic Syndrome
Key manifestations / complications of nephritic syndrome: [Ref]
- Haematuria – prominent
- Hypertension – common
- Oedema (usually mild / moderate, less severe than in nephrotic syndrome)
- Oliguria or AKIAcute kidney injury in more severe cases (depending on the cause)
Investigation and Diagnosis
Initial Tests
The following initial investigations are primarily used to differentiate between nephrotic and nephritic syndromes and to identify impaired renal function, as these findings largely stratify the likely diagnosis (as outlined in the aetiology section):
| Test | Key interpretation |
|---|---|
| Urinalysis |
|
| Urine microscopic examination |
|
| Proteinuria quantification (ideally a 24-hour urine collection, see the definition section above for alternatives) |
|
| Serum albumin level |
|
| Renal function assessment – serum creatinine and eGFR |
|
Work Up
The aim of a glomerular disease work-up is to identify the underlying cause of nephrotic or nephritic syndrome. A typical work-up includes:
| Test(s) | Purpose |
|---|---|
| Lipid profile and glucose testing | To assess for hyperlipidaemia and screen for diabetes |
Antibody screen:
|
|
| Anti-streptolysin O titre and anti-DNAse B | +ve → post-streptococcal glomerulonephritis |
| Complement level (C3, C4) | Low complement is seen in:
|
| Cryoglobulins | To test for cryoglobulinaemic vasculitis Cryoglobulinaemic vasculitis is an immune-complex–mediated small-vessel vasculitis caused by circulating cryoglobulins (immunoglobulins that precipitate at low temperatures). |
| Serum protein electrophoresis and serum free light chain assay | To test for multiple myeloma Multiple myeloma can cause both nephrotic syndrome (most commonly) and nephritic syndrome. |
| Viral serology (Hep B, Hep C, HIV) | To screen for infectious triggers |
One would NOT be expected to memorise the full investigative work-up for glomerular diseases, as it varies according to local practice and clinical context. This section is included for completeness and to illustrate how different investigations relate to specific diagnostic aims.
In exams, students are typically expected to either 1) identify the most appropriate investigation to confirm the most likely diagnosis, or 2) interpret given investigation results and determine the most likely diagnosis.
Kidney Biopsy
A kidney biopsy is the gold standard for the diagnostic evaluation of glomerular diseases. Kidney biopsy should be analysed with:
- Light microscopy
- Immunohistochemistry (check for IgG, IgA, IgM, C3, C4, C1q, fibrin, Gamma + Kappa light chain)
- Electron microscopy
Exceptions where a kidney biopsy is NOT necessary:
- Children with steroid-sensitive nephrotic syndrome
- Minimal change disease is the most likely cause of nephrotic syndrome in children; therefore a kidney biopsy is usually unnecessary, as it is unlikely to alter management and would expose the child to an invasive procedure
- Kidney biopsy is reserved for those who are NOT steroid-sensitive (i.e., not responding well to steroid therapy)
- Children with post-streptococcal glomerulonephritis
Diseases where a kidney biopsy is mandatory for diagnosis:
- Minimal change disease / post-streptococcal glomerulonephritis in adults
- IgA nephropathy (as there is no validated diagnostic marker)
- Membranous nephropathy (however, if anti-PLA2 antibody is +ve, a kidney biopsy is NOT required)
Management Principles of Glomerular Disease
Non-specific supportive care management for glomerular diseases:
| Management aspect | Nephrotic-syndrome-related | Nephritic syndrome-related |
|---|---|---|
| Lifestyle advice |
|
|
| Proteinuria and hypertension | 1st line: ACE inhibitor / ARBAngiotensin receptor blocker
|
|
| Oedema |
|
|
| Hypercoagulability |
Warfarin or heparin is the anticoagulant of choice Why is warfarin / heparin preferred? |
Risk is less significant in nephritic syndrome |
| Increased risk of infection | Offer the following vaccinations:
|
|
For those receiving high-dose steroids or other heavy immunosuppression, prophylactic trimethoprim–sulfamethoxazole (co-trimoxazole) is often prescribed to prevent Pneumocystis pneumonia
Nephritic Syndrome
Clinical conditions where treatment can be considered without a kidney biopsy:
- Ones with +ve serology
- ANCA vasculitis
- Anti-GBM disease
- SLE
- Membranous nephropathy with PLA2Rab+ve
- Genetic ones
- Alport disease
- Fabry disease
- Familial FSGS with well-characterised mutations
Nephrotic Syndrome Causes
Minimal Change Disease (MCD)
Epidemiology
MCD is the most common cause of nephrotic syndrome in children (>90%), and a significant cause in adults (10-25%)
Aetiology
Most cases of MCD are idiopathic.
Secondary causes of MCD do exist, but are considered rare:
- Hodgkin’s lymphoma
- Lithium
- NSAIDs
Clinical Features
MCD is typically characterised by a sudden and abrupt onset of nephrotic syndrome (see clinical manifestation section above)
Otherwise, there are not many MCD-specific clinical features
- In children, AKI is uncommon and renal function is typically maintained (esp. with proper treatment)
- In adults, AKI is relatively common during the active disease phase
If a child presents with nephrotic syndrome, the most likely diagnosis is MCD.
This is true for both exams and clinical practice.
Investigation and Diagnosis
| Test / category | Findings |
|---|---|
| Urinalysis and bloods | Nephrotic syndrome |
| Kidney biopsy | Light microscopy: normal glomeruli appearance (no visible glomerular lesions – this “minimal” change is what gives the disease its name) |
Electron microscopy – diagnostic gold standard:
|
|
| Immunofluorescence -ve staining (there are no immune deposits) |
MCD in adults can only be diagnosed with a kidney biopsy.
In children (<12 y/o) with nephrotic syndrome, they are typically treated presumptively as MCD, without a kidney biopsy. Kidney biopsies are generally not necessary if the nephrotic syndrome is steroid-sensitive.
See the Idiopathic Nephrotic Syndrome in Children article for more information.
Management
See the Idiopathic Nephrotic Syndrome in Children for paediatric diagnosis and management. Remember, idiopathic nephrotic syndrome in children is treated presumptively as MCD without kidney biopsy, and the diagnosis is therefore not histologically proven.
Definitive management:
- 1st line: high-dose oral prednisolone
- 2nd line (for steroid resistance / steroid-dependent / frequent relapses): steroid-sparing agents
- Levamisole
- Cyclophosphamide
- Calcineurin inhibitor (ciclosporin, tacrolimus)
- Mycophenolate mofetil
- Rituximab – last resort
Also see the ‘Management Principles of Glomerular Disease’ section above for long-term management.
Prophylactic trimethoprim–sulfamethoxazole should be considered in patients receiving high-dose prednisone (or other immunosuppressive agents) for PCPPneumocystis Pneumonia prophylaxis.
ACE inhibitor / ARB should NOT be started in acute nephrotic syndrome, due to the risk of developing AKIAcute kidney injury
They are primarily used as part of longer-term management to reduce persistent proteinuria and/or treat hypertension once the patient is clinically stable.
In minimal change disease, ACE inhibitors or ARBs are often unnecessary, as proteinuria typically resolves with immunosuppressive therapy alone.
Prognosis
| Children | Adults |
|---|---|
|
|
Core monitoring for all forms of glomerular disease:
- Proteinuria quantification – while 24-hour urine collections are the gold standard, PCRProtein:creatinine ratio are used for more frequent monitoring
- Kidney Function – measured via serum creatinine and eGFR
- Blood Pressure
Membranous Nephropathy (MN)
Epidemiology
Predominantly affects adults (>18 y/o)
2nd most common cause of nephrotic syndrome in adults (after focal segmental glomerulosclerosis)
Aetiology
There are 2 types of MN:
| Primary MN | An autoimmune condition where antibodies target podocyte antigens
Most common (~80% cases): M-type anti-phospholipase A2 receptor (anti-PLA2R) |
| Secondary MN | Triggered by underlying conditions:
|
Clinical Features
MN presents with nephrotic syndrome (see clinical manifestation section above)
MN carries a uniquely high risk of venous and arterial thrombosis, compared to other glomerular diseases
- Renal vein thrombosis is classic, DVT and PE are also common
- Arterial thrombosis is less common but has been reported in nearly all vascular beds (specifically the aorta, mesenteric, axillary, pulmonary, iliac, renal, femoral, popliteal, ophthalmic, and cerebral circulations)
Investigation and Diagnosis
| Test / category | Findings |
|---|---|
| Urinalysis and bloods | Nephrotic syndrome |
| 1st line test: serology | Anti-PLA2RAnti-phospholipase A2 receptor +ve is 99% specific for MN
|
| Gold standard: kidney biopsy | Light microscopy:
|
Electron microscopy – diagnostic gold standard:
|
|
Immunofluorescence:
|
Apart from the above diagnostic tests, ALL patients must be screened for secondary causes (regardless of antibody status):
- National breast and colon cancer screening
- PSA testing in males >50-6o y/o
- Chest X-ray / CT to detect occult cancers
- HBV/HCV serology
- ANA for SLESystemic lupus erythematosus
Management
Main management principles:
- All patients: optimal supportive care for at least 6 months (see “Management Principles of Glomerular Disease” section above for more details)
- Immunosuppressive therapy in selected patients
- Indicated in moderate / high / very high risk patients
- Key drugs: rituximab (1st line in most patients), calcineurin inhibitor (tacrolimus, ciclosporin), corticosteroids
Longitudinal monitoring of anti-PLA2RAnti-phospholipase A2 receptortitres helps predict relapses and response to therapy
Full Management Algorithm
Although this level of detail goes beyond the undergraduate level, it is included for completeness and to provide insight into MN management in practice.
As mentioned above, MN is management based on the risk of progressive loss of kidney function:
|
Risk Category
|
Definition (Criteria)
|
Management Strategy
|
|
Low Risk
|
|
|
|
Moderate Risk
|
|
Rituximab has a lower relapse rate than calcineurin inhibitor monotherapy |
|
High Risk
|
|
Concurrent supportive care is key.
Immunosuppressive therapy is indicated in this group:
|
|
Very High Risk
|
|
|
Prognosis
MN follows the rule of thirds:
- 1/3 undergo spontaneous remission
- 1/3 remain stable with proteinuria
- 1/3 progress to kidney failure
Relapse is common (risk is ~30% even after transplant)
Poor prognostic factors:
- High anti-PLA2R titres (conversely, an undetectable titre is a powerful predictor of remission)
- Low serum albumin (<25 g/L) (also the strongest predictor for thromboembolic events)
- Impaired renal function (eGFR <60)
- Severe proteinuria (>8 g/day, proteinuria that does not decrease by 50% after supportive care)
Focal Segmental Glomerulosclerosis (FSGS)
Epidemiology
FSGS is the most common cause of nephrotic syndrome in adults (10-25% cases)
Aetiology
FSGS is most commonly secondary to:
- Viral infections – HIV (most recognised), CMV, EBV, SARS-CoV-2, Hep C, parvovirus B19
- Drugs – calcineurin inhibitors, mTOR inhibitors, interferon, lithium, NSAIDs, anabolic steroids, heroin
- Causes of adaptive changes (glomerular hyperfiltration → “wear and tear” response)
- Renal agenesis, nephrectomy, and reflux nephropathy
- Obesity
- Sickle cell disease
- Hypertension and diabetes
- Genetic mutations (e.g. mutations in podocyte genes and APOL1 risk alleles)
Primary focal segmental glomerulosclerosis is less well characterised and is thought to arise from circulating permeability factors and genetic susceptibility, causing podocyte injury.
Clinical Features
FSGS most commonly presents with proteinuria, but without nephrotic syndrome at onset (only in ~50-60% of adults at diagnosis).
- Primary FSGS typically presents as an abrupt onset of nephrotic syndrome
- Secondary FSGS is more likely to present with proteinuria without nephrotic syndrome (i.e. without hypoalbuminaemia and oedema)
For exams, FSGS is best regarded as a cause of nephrotic syndrome; differentiation between primary and secondary forms is usually unnecessary.
Investigation and Diagnosis
| Test / category | Findings |
|---|---|
| Urinalysis and bloods | Nephrotic syndrome (as mentioned above, ~40-50% cases can present as proteinuria without nephrotic syndrome – i.e. normal albumin, or sub-nephrotic range proteinuria) |
| Kidney biopsy | Light microscopy: focal and segmental sclerosis In the context of glomerular disease, "focal" means that only some glomeruli within the kidney biopsy specimen are affected by sclerosis, while others appear normal. "Segmental" means that within an individual affected glomerulus, only a portion (segment) of the glomerular tuft is sclerosed, rather than the entire glomerulus being involved. +/- hyalinosis (not diffuse) |
Electron microscopy:
|
|
| Immunofluorescence: most commonly -ve staining |
Evaluation for secondary causes of FSGS is necessary (esp. if nephrotic syndrome is absent):
- Viral screening: HIV, CMV, parvovirus B19, EBV, SARS-CoV-2, Hep C
- Evaluation for adaptive changes
- BMI assessment
- Imaging (ultrasound / CT) to look for reduced nephron number caused by reflux nephropathy, renal dysplasia, or age-related loss of kidney mass
- Clinical history to assess for sickle cell disease, long-standing hypertension, and diabetes
- Genetic testing is recommended in certain patient populations
- A strong family history of kidney disease
- Presence of syndromic features (abnormalities in other organ systems)
- Steroid resistance (failure to respond to initial high-dose glucocorticoids)
- Ancestry-specific risks: Testing for APOL1 risk variants in patients of recent African ancestry, especially if they are potential kidney donors
Primary FSGS is the clinical-pathological syndrome characterised by abrupt-onset nephrotic syndrome + diffuse foot process effacement
Both MCD and FSGS demonstrate diffuse podocyte foot process effacement on electron microscopy.
The key distinguishing feature is light microscopy, which is normal in MCD but shows focal and segmental sclerosis in FSGS.
Management
Management principles:
- All patients: optimal supportive care
- Primary FSGS (defined by abrupt-onset nephrotic syndrome + diffuse foot process effacement): treat with immunosuppressive therapy
- 1st line: high-dose steroids
- 2nd line: calcineurin inhibitors (ciclosporin, tacrolimus)
- Secondary FSGS: do NOT offer immunosuppressive therapy, treat the underlying cause instead
Prognosis
FSGS is the leading cause of irreversible kidney damage, but prognosis is highly variable:
- Most critical prognostic factor: proteinuria
- Nephrotic-range proteinuria is associated with poor prognosis (10-year kidney survival rate ~57%)
- Non-nephrotic-range proteinuria have excellent prognosis (10-year kidney survival rate >90%)
- Relapse is common
- Relapse occurs in 40-70% of patients after withdrawal of calcineurin inhibitors
- Each subsequent relapse increases the risk of progressive CKD
- Steroid resistance is associated with poor prognosis
- Secondary FSGS have more favourable outcomes (as they lack the full nephrotic syndrome and diffuse foot process effacement)
Nephritic Syndrome Causes
Anti-GBM Disease (Goodpasture Disease)
Epidemiology
Very rare
Bimodal age distribution: peak incidences in 3rd and 6th-7th decades of life
Aetiology
Idiopathic development of anti-GBM antibodies that target type IV collagen of the basement membrane found in the kidney and lungs
Environmental triggers:
- Smoking – strongly associated with pulmonary haemorrhage (relapses of the disease are mostly seen in smokers)
- Lung irritants exposure
- Hydrocarbon exposure
Clinical Features
Anti-GBM disease classically present as a lung-renal syndrome:
| Lung manifestation |
|
| Renal manifestation |
|
Isolated kidney disease is common, but lung-renal involvement (termed Goodpasture syndrome) occurs in 40%–60% of cases
Investigation and Diagnosis
| Test / category | Findings |
|---|---|
| Urinalysis and bloods | Nephritic syndrome |
| 1st line test: serology | Anti-GBM antibodies +ve is ~90% sensitive for anti-GBM disease
|
| Gold standard: kidney biopsy | Light microscopy: necrotising crescentic glomerulonephritis
|
Electron microscopy
|
|
Immunofluorescence: diagnostic gold standard
|
|
| Lung imaging | Not required for diagnosis for anti-GBM disease, but is used to test for alveolar haemorrhage
Gold standard (but rarely needed): bronchoscopy with bronchoalveolar lavage Diagnosis is confirmed when sequential lavage samples become increasingly hemorrhagic and cytological analysis reveals hemosiderin-laden macrophages, which are indicative of prior or ongoing alveolar bleeding. |
Testing for alveolar haemorrhage:
- 1st line: chest X-ray
- Often bilateral, perihilar diffuse alveolar opacities
- A normal heart size helps distinguish from cardiogenic pulmonary oedema
- Confirmatory imaging: HRCTHigh-resolution CT
- Hallmark: diffuse / patchy ground-glass opacities
- Gold standard (but rarely needed): bronchoscopy with bronchoalveolar lavage
Apart from testing for anti-GBM antibodies which helps diagnose anti-GBM disease, concurrent testing for ANCA antibodies are standard
- Testing for both is required to differentiate the underlying cause (as both anti-GBM disease and ANCA-associated vasculitis can present as rapidly progressive glomerulonephritis).
- There is a significant overlap between these 2 conditions, 1/3 of patients with +ve anti-GBM antibodies also test +ve for ANCA, termed double positivity.
- These double-positive patients require different long-term management because they have a higher risk of relapse compared to those with isolated anti-GBM disease, see management section below for more details.
In fact, any suspected rapidly progressive glomerulonephritis should undergo dual testing for both anti-GBM antibodies and ANCA.
Management
Anti-GBM disease is a medical emergency, treatment must be started urgently as soon as the diagnosis is suspected:
- Treatment should be initiated without delay if anti-GBM disease is suspected, even before the diagnosis is formally confirmed by serology or biopsy
- If serology (anti-GBM antibodies) is +ve → proceed with full induction therapy, WITHOUT awaiting for kidney biopsy confirmation
Acute Management
Induction triple therapy:
- Immediate plasmapheresis
Plasmapheresis (plasma exchange) is a procedure that removes a patient’s plasma and replaces it with a substitute (e.g. albumin or fresh frozen plasma) to eliminate circulating antibodies.
, and - Cyclophosphamide for 2-3 months, and
- High-dose glucocorticoid therapy for 6 months (initial pulse IV methylprednisolone, followed by oral prednisolone)
Generally speaking, induction therapy is indicated for almost ALL patients with anti-GBM disease and for both kidney-limited disease and lung-renal syndrome.
Induction therapy should only be withheld if ALL of the following 3 criterias are met:
- Patient is already dialysis-dependent
- Kidney biopsy shows irreversible kidney damage (100% crescents / >50% global glomerulosclerosis)
- No lung involvement (i.e. pulmonary haemorrhage)
Rationale: low-chance of recovery
Chronic Management
This is where ANCA serology results affects management:
- No maintenance therapy is necessary in those with isolated anti-GBM +ve (i.e. ANCA -ve)
- Double-positive patients (i.e. anti-GBM plus ANCA +ve) at at high risk of relapse and should receive long-term maintenance therapy (as if they have ANCA-associated vasculitis)
- 1st line: rituximab
- Alternative: azathioprine +/- low-dose glucocorticoids
Prognosis
| Patient survival |
Most deaths occur in the acute phase, primarily due to respiratory failure from massive lung haemorrhage |
| Kidney survival |
|
| Lung survival |
|
| Risk of relapse |
Recurrence risk of very low (<3%) post-transplantation, assuming antibodies have remained undetectable for at least 6 months before the transplant. |
ANCA-Associated Vasculitis
Definition
ANCA (anti-neutrophil cytoplasmic antibody)-associated vasculitis is a type of small vessel vasculitis, that encompasses 3 disorders:
- Granulomatosis with polyangiitis (GPA) (former name: Wegener’s granulomatosis)
- Microscopic polyangiitis (MPA)
- Eosinophilic granulomatosis with polyangiitis (EGPA) (former name: Churg-Strauss syndrome)
Epidemiology
Typical age of onset: 38-75 y/o (depending on the subtype)
There is a distinct “East-West” divide in ANCA-associated vasculitis subtypes:
- GPAGranulomatosis with polyangiitis is most common in European ancestry populations, and rare in East Asia
- MPAMicroscopic polyangiitis is the predominant form in East Asia (China and Japan)
Aetiology
ANCA-associated vasculitis arise from the loss of immunological tolerance to specific neutrophil proteins:
- Loss of tolerance to proteinase 3 (PR3) and myeloperoxidase (MPO)
- The immune system produces ANCA (anti-neutrophil cytoplasmic antibody) that binds to and active neutrophils
- Activated neutrophils adhere to walls of small vessels (capillaries, arterioles, venules) → microvascular endothelial inflammation
Such loss of tolerance is driven by a combination of genetic predisposition and environmental triggers:
- Family history is a risk factor
- Silica exposure – most consistently documented trigger
- Infections (specifically, chronic nasal carriage of Staphylococcus aureus)
Clinical Features and Diagnostics
Overview of key information: [Ref]
| Condition | Clinical features | Serology | Other tests | Biopsy |
|---|---|---|---|---|
| Granulomatosis with polyangiitis (GPA) | Classic triad of:
Other features:
|
Predominantly cANCA (PR3) +ve |
|
|
| Microscopic polyangiitis (MPA) | Classic presentation:
URTUpper respiratory tract<br /> (ENTEar, nose, and throat) involvement is classically absent Other features:
|
Predominantly pANCA (MPO) +ve |
|
|
| Eosinophilic granulomatosis with polyangiitis (EGPA) | Characteristic severe allergic asthma +/- sinusitis and rhinitis (often before vasculitis emerges)
Other features:
|
Predominantly pANCA (MPO) +ve (however it is frequently ANCA -ve) |
|
|
Characteristics kidney biopsy finding in ANCA-associated vasculitis:
- Light microscopy: necrotising crescentic glomerulonephritis
- Necrotising = fibrinoid necrosis of glomerular capillary loops
- Crescentic = crescents (crescent-shaped cellular proliferation within Bowman's space) in >50% of glomeruli
- Immunofluorescence: pauci-immune
Pauci-immune means "few immune deposits", specifically when immunofluroescence shows little or no staining for IgA, IgG, IgM, C3
(distinguishes ANCA-associated vasculitis from immune-complex–mediated glomerular diseases, including anti-GBM disease, lupus nephritis, IgA nephropathy, and post-streptococcal glomerulonephritis)
The hallmark feature of various ANCA-associated vasculitis:
- GPA = URTUpper respiratory tract (ENTEar, nose and throat) involvement
- MPA = renal involvement
- EGPA = allergic asthma (renal involvement is less common)
Clinical features and serological findings (without awaiting biopsy) are sufficient to make a diagnosis and to initiate acute treatment.
Management
ANCA-associated vasculitis is considered a medical emergency, esp. when it presents as rapidly progressive glomerulonephritis or lung-renal syndrome
- If serology (ANCA) is +ve → start treatment without awaiting kidney biopsy
- If serology (ANCA) is -ve → perform urgent biopsy to confirm diagnosis
Acute Management
Initial management involves induction therapy with immunosuppressive therapy:
- Standard regimen: steroids + rituximab OR cyclophosphamide
- Latest guidelines lists 3 options to induce remission
- Rituximab + steroid or avacopan
- Cyclophosphamide + steroid or avacopan
- Rituximab + cyclophosphamide + steroid
Avacopan is a new drug that is now formally recommended as an alternative to steroids (MoA: C5a receptor antagonist)
Plasmapheresis should NOT be routinely performed (unlike in anti-GBM disease), it should only be considered in patients with:
- Severe kidney failure (serum creatinine >300 µmol/L or rapidly increasing serum creatinine), or
- Diffuse alveolar haemorrhage (esp. when causing hypoxaemia), or
- Double positive of ANCA and anti-GBM antibodies, or
- Refractory to immunosuppressive therapy
Chronic Management
Most patients require long-term maintenance therapy (to prevent the high risk of relapse)
- 1st line: rituximab
- Alternative: azathioprine +/- low-dose glucocorticoids
Prognosis
- Diffuse alveolar haemorrhage is associated with poor prognosis
- Relapse is common (cANCA / PR3 +ve patients at higher risk of relapse, than pANCA / MPO)
- Low recurrence risk post-transplantation (assuming antibodies have remained undetectable for at least 6 months before the transplant)
IgA Nephropathy (Berger Disease)
Epidemiology
IgA nephropathy is the most common cause of primary glomerular disease worldwide, and a leading cause of CKD and kidney failure
- Predominantly affect young adults
- Most common people of East Asian ancestry, followed by Caucasians (relatively rare in individuals of African descent)
Aetiology
IgA nephropathy is caused by predominant or co-dominant IgA deposition in the kidney, with 2 main forms:
- Primary (idiopathic) IgA nephropathy – most common
- Secondary IgA nephropathy – conditions that can cause IgA deposition
- IgA vasculitis (Henoch-Schönlein purpura)
- Liver cirrhosis
- Inflammatory bowel disease
- HIV and Hepatitis (B and C) infection
- Bacterial (Staphylococcus aureus, E. coli, Klebsiella)
- Schistosomiasis
For UKMLA purposes, IgA nephropathy should be regarded as a primary glomerular disease.
Although secondary associations exist, detailed knowledge of secondary causes is generally low yield at the undergraduate level. The most important secondary cause to be aware of is IgA vasculitis (Henoch–Schönlein purpura).
Clinical Features
There are 2 main categories of IgA nephropathy presentation:
| Asymptomatic – most common | These cases are typically diagnosed via incidental finding:
|
| Symptomatic | Characteristic symptomatic presentation: visible (gross) haematuria (cardinal sign) that follows an URTI (during or within days of the URTI)
Other possible presentations:
|
Investigation and Diagnosis
IgA nephropathy can ONLY be diagnosed with a kidney biopsy (unlikely other glomerular disease, there are NO validated diagnostic serum / urine biomarkers for IgA nephropathy):
| Light microscopy |
|
| Electron microscopy |
|
| Immunofluorescence | Definitive diagnostic tool:
|
Urine studies and bloods: nephritic syndrome
Management
1st line (ALL patients): supportive care for at least 3 months (see “Management Principles of Glomerular Disease” section above for more details)
Monitor the following parameters:
- Proteinuria quantification (24 hour urine collection for adults and first morning PCR for children)
- Blood pressure
- Renal function (eGFR)
- Haematuria persistence (urine sediment microscopy to assess erythrocyte morphology)
Glucocorticoids (and other immunosuppressive therapy) should NOT be offered routinely:
- Steroids should only be considered in high-risk patients
- Definition of high-risk: proteinuria remains >0.75-1 g/day depste 3 months of maximal supportive care
- However KDIGO warns that the clinical benefit is not fully established and carries a significant risk of toxicity, particularly in patients with an eGFR <50
Haematuria Monitoring: The magnitude and persistence of haematuria (blood in the urine) should be monitored, as it has significant prognostic value
Prognosis
| Key prognostic information |
|
| Main poor prognostic predictors |
|
| Less significant ones |
|
Post-Streptococcal Glomerulonephritis (PSGN)
Epidemiology
PSGN most commonly affects children and elderly patients
Aetiology
PSGN is a type of type III hypersensitivity (immune-complex-mediated reaction):
- Primary trigger: Streptococcal infection (esp. from pharyngitis, or impetigo)
- PSGN is NOT caused by a direct infection of the kidney itself, but rather by the body’s immune system response to bacterial antigens → immune complex deposition in the glomeruli → inflammation and damage
Traditionally, the term post-streptococcal glomerulonephritis (PSGN) has often been used to describe the entire spectrum of post-infectious glomerulonephritis. However, this is inaccurate: PSGN represents a specific subset of infection-related glomerulonephritis.
In the modern era, streptococcal infections account for a declining proportion of infection-related glomerulonephritis cases (approximately 28–47%), with an increasing contribution from alternative pathogens, including Staphylococcus aureus (around 12–24%) and Gram-negative bacteria (up to ~22%).
For undergraduate-level examinations, it is sufficient to be familiar with PSGN as the stereotypical example of post-infectious glomerulonephritis.
Clinical Features
A characteristic PSGN presentation involves:
| Evidence of preceding bacterial infection |
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| Acute nephritic syndrome | Sudden onset of:
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Investigation and Diagnosis
Diagnostic approach differs according to age:
- Children (<12 y/o): characteristic symptoms and tests are sufficient to diagnose PSGN and start treatment (kidney biopsy is NOT necessary)
- However, if serum C3 levels remain low for >3 months → a biopsy is necessary (to rule out C3 glomerulopathy)
- Adults: kidney biopsy is mandatory for diagnosis
| Test / category | Findings |
|---|---|
| Urine studies | Nephritic syndrome |
| Streptococcal infection marker | Increased titres in:
Anti-DNAse B and anti-hyaluronidase are generally preferred for impetigo-triggered PSGN |
| Serology |
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| Gold standard: kidney biopsy | Light microscopy: exudative glomerulonephritis (diffuse endocapillary hypercellularity with prominent neutrophil and mononuclear cell infiltration)
Electron microscopy:
Immunofluorescence:
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Management
There are 2 main management principles of PSGN:
- 1st line (ALL patients): supportive care (see “Management Principles of Glomerular Disease” section above for more details)
- Antibiotic therapy
- Indicated if there is active infection, supported by +ve culture from any site (most commonly from a throat swab)
- The choice of antibiotic is typically oral penicillin V or amoxicillin
- Goal: to treat the underlying infection and to prevent the spread of Streptococcus within the community (important: antibiotics do NOT alter the course of PSGN once the kidney inflammation has started)
Immunosuppressive therapy is generally not indicated due to the lack of robust data supporting its use.
Monitor the following parameters:
- Important: serum C3 and C4 levels
- Monitoring C3 levels is critical for diagnostic confirmation (especially in children who haven’t undergone a kidney biopsy)
- If serum C3 levels remain low for >3 months, a kidney biopsy is indicated to rule out C3 glomerulopathy
- Urine studies
- Proteinuria quantification (24 hour urine collection for adults and first morning PCR for children)
- Haematuria persistence (urine sediment microscopy to assess erythrocyte morphology)
- Blood pressure
- Renal function (eGFR)
Prognosis
Children:
- Prognosis is excellent
- Most patients achieve complete recovery of kidney function without long-term complications
Adults and elderly:
- In regions where the disease is endemic, some adults may develop persistent albuminuria or a low eGFR following the acute episode
- Poor prognosis in the elderly who develop persistent albuminuria (mortality rate can be as high as 20%)
Mixed Nephrotic / Nephritic Syndrome
Lupus Nephritis
Epidemiology
The lifetime incidence of lupus nephritis is 20-60% in those with SLE
- Lupus nephritis is almost exclusively seen in the context of SLESystemic lupus erythematosus
- Higher risk in patients of Asian, African/Caribbean, and Hispanic descent
- Lupus nephritis is more common in childhood-onset SLE (and tends to be more severe)
Aetiology
Primary driver of lupus nephritis is the deposition of immune complexes within the glomeruli (type III hypersensitivity).
Clinical Features
Lupus nephritis can present as ANY of the following (depends on the histological classification, see investigation and diagnosis section below)
- Asymptomatic (most commonly associated with class I and II)
- Nephritic syndrome (most commonly associated with proliferative forms – class III and IV)
- Nephrotic syndrome (most commonly associated with class V membranous lupus nephropathy)
Investigation and Diagnosis
Initial tests:
- Urine studies may demonstrate nephrotic or nephritic syndrome
- Serology
- ANA (less specific)
- Anti-dsDNA (rising titres correspond with disease activity)
- Low serum C3 and C4 levels are supportive of active disease
Gold standard (necessary for all patients): kidney biopsy to determine the specific histological ISN/RPS classification (to guide management):
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Class
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Name
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Clinical & Histologic Characteristics
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Class I
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Minimal mesangial disease
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Class II
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Mesangial proliferative disease
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Class III
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Focal proliferative disease
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Class IV
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Diffuse proliferative disease
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Class V
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Membranous disease
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Class VI
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Advanced sclerosing disease
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Key takeaway: class III and IV (proliferative forms) are considered the most aggressive, associated with a very poor long-term prognosis (despite early glucocorticoid treatment).
Class IV is the most common, also the most severe form, with the highest risk of kidney failure if untreated.
Management
The key takeaway for management of lupus nephritis is:
- All patients should be treated with hydroxychloroquine
- Class III and IV (proliferative disease) need aggressive immunosuppressive induction and maintenance therapy (specific regimens unlikely to be tested at undergraduate level)
Hydroxychloroquine should be offered to ALL patients, irrespective of histological classification.
Additional management depends on the histological classification:
| Class I and II (minimal mesangial and mesangial proliferative disease) | Generally, no additional treatment is necessary |
| Class III and IV (focal and diffuse proliferative disease) | Aggressive immunosuppressive therapy is necessary:
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| Class V (membranous disease) | Treatment depends on the severity of proteinuria:
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| Class VI (advanced sclerosing disease) | Supportive care for CKD (as there is already permanent scarring) |
Cryoglobulinaemic Vasculitis
Aetiology
Cryoglobulins are abnormal antibodies (IgA, IgM, IgG) with the specific property of precipitating in the cold (typically < 37 °C), which leads to cryoglobulinaemic vasculitis
Causes of cryoglobulinaemia can be categorised according to cryoglobulin type as follows:
| Type II and III (i.e. mixed cryoglobulinaemia) – 90% cases |
|
| Type I (monoclonal immunoglobulins – typically IgM or IgG) | Often associated with monoclonal gammopathies (e.g. multiple myeloma, CLL, non-Hodgkin’s lymphoma, Waldenström macroglobulinemia)
Often classified as monoclonal gammopathy of renal significance when a clone is detected |
Clinical Features
| Renal manifestation | Often a mix of nephrotic and nephritic syndrome (as cryoglobulins cause both structural leaking and active inflammation of the glomeruli)
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| Extra-renal manifestations | Cryoglobulinaemic vasculitis is a type of small-vessel vasculitis
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Investigation and Diagnosis
Key serology findings:
- Cryoglobulin quantification (% of serum that precipitates when cooled – >5% is clinically significant)
- Low C4 (+/- C3)
- Rheumatoid factor is often +ve in type II mixed cryoglobulinaemia
Kidney biopsy findings:
- Light microscopy: membranoproliferative glomerulonephritis pattern of injury (characterised by increased intraglomerular cells and thickened capillary walls)
- Immunofluorescence: granular deposition of IgM, IgG and C3
A comprehensive screen is often done to identify the underlying cause:
- Hep C and Hep B serology
- Testing for bacterial endocarditis (e.g. blood cultures)
- Serology testing for systemic autoimmune disease
- Monoclonal protein screening (e.g. serum and urine electrophoresis, serum free light chain levels)
Management
- All patients: supportive care (see “Management Principles of Glomerular Disease” section above for more details)
- Treat any underlying causes (e.g. direct-acting antivirals for Hep C)
- If there is severe/life-threatening vasculitis: rituximab + glucocorticoids +/- plasmapheresis
References
KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases
KDIGO 2024 Clinical Practice Guideline for the management of LUPUS NEPHRITIS