Nephrotic and Nephritic Syndromes

KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases

KDIGO 2024 Clinical Practice Guideline for the Management of Antineutrophil Cytoplasmic Antibody (ANCA)–Associated Vasculitis

KDIGO 2024 Clinical Practice Guideline for the management of LUPUS NEPHRITIS

Article Last Updated:07/03/2026

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:

24-hour urine collection
Nephrotic threshold: $\geq$ 3.5 g per 24 hours

Alternative:

First morning void urine for PCR
Nephrotic threshold: $\geq$ 300 mg/mmol

Children (1-18 y/o)

ANY of the following can be used to identify nephrotic-range proteinuria:

24-hour urine collection: ≥40 mg/m²/h (often inaccurate in children)
Urine PCR ≥200 mg/mmol from a first morning void or 24-hour sample
Urine dipstick: protein 3+ or greater
Urine protein concentration $\geq$ 300 mg/dl

Nephritic Syndrome

Nephritic syndrome is defined as the presence of: ^[Ref]

Haematuria, and
RBC casts (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:

Minimal change disease (MCD)
Membranous nephropathy
Primary focal segmental glomerulosclerosis (FSGS)

Secondary forms:

Diabetic nephropathy
Amyloid nephropathy

Anti-GBM disease
ANCA-associated vasculitis
IgA nephropathy (Berger disease)
IgA vasculitis / Henoch-Schonlein purpura (HSP)
Post-streptococcal glomerulonephritis (PSGN) and other post-infectious glomerulonephritis (e.g. endocarditis)

Lupus nephritis
- Class III and IV are typically nephritic
- Class V is typically nephrotic
Cryoglobulinemia
- Most commonly causes a mixed nephritic–nephrotic picture
- Primary category is typically nephritic
Multiple myeloma
- Can cause glomerular disease that can manifest as both nephrotic (more common) AND nephritic syndrome

Some key patterns / associated to be aware of:

Epidemiology facts

Most common primary glomerular disease worldwide: IgA nephropathy
Most common cause of nephrotic syndrome in children: minimal change disease
Most common cause of nephrotic syndrome in adults: focal segmental glomerulosclerosis (> membranous nephropathy)

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:

Anti-GBM disease
Pauci-immune cause: ANCA-associated vasculitis
Immune-complex mediated causes:
- IgA-related disease (IgA nephropathy and IgA vasculitis)
- Post-streptococcal glomerulonephritis
- Lupus nephritis

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:

Anti-GBM disease
ANCA-associated vasculitis
SLE

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	Periorbital oedema (esp. in the morning) Peripheral oedema (ankles, lower limb, sacrum) Weight gain Scrotal / vulval oedema Ascites (transudative) Pleural effusion (transudative) Generalised oedema (anasarca) can be seen in severe cases
↑ 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): Renal vein thrombosis – classic (and particularly associated with membranous nephropathy) DVT, PE Rare: IVC thrombosis, cerebral venous sinus thrombosis Arterial thrombosis (uncommon): Cerebral artery thrombosis → ischaemic stroke / TIA Coronary artery thrombosis → myocardial infarction Acute limb ischaemia Mesenteric ischaemia (rare)
↑ Risk of infection	↑ Urinary loss of immunoglobulins and immune-mediators	Streptococcus pneumoniae → pneumonia Neisseria meningitidis → meningitis Varicella zoster virus → shingles (varicella) Spontaneous bacterial peritonitis Cellulitis
Hyperlipidaemia	Hypoalbuminaemia → compensatory hepatic upregulation (synthesis of proteins and lipoproteins)	↑ Total cholesterol ↑ LDL (most prominent) ↑ Triglycerides Lipiduria (fat droplets / oval fat bodies)

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 AKI 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	Nephritic pattern → red blood cell AND protein +ve Nephrotic pattern → protein +ve only
Urine microscopic examination	Nephritic pattern → RBC cast (most specific) or dysmorphic RBCs Both findings support a glomerular (renal) source of haematuria rather than a lower urinary tract cause (e.g. stones, infection, or urological malignancy) Nephrotic pattern → lipiduria (fat droplets / oval fat bodies)
Proteinuria quantification (ideally a 24-hour urine collection, see the definition section above for alternatives)	Nephrotic range-proteinuria (≥3.5g / day) → nephrotic syndrome likely Sub-nephrotic range-proteinuria → nephritic syndrome likely
Serum albumin level	<30 g/L → nephrotic syndrome likely Serum albumin level is also used to assess risk of thrombotic events (the lower, the higher the thrombotic risk)
Renal function assessment – serum creatinine and eGFR	Impaired renal function (↑ creatinine, ↓ eGFR) is suggestive of nephritic syndrome

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-GBM antibodies Anti-PLA2R ANCA (MPO and PR3) ANA and anti-dsDNA	Anti-GBM antibody +ve → anti-GBM disease Anti-PLA2R +ve → primary membranous nephropathy ANCA +ve → ANCA-associated vasculitis ANA and anti-dsDNA +ve → SLE
Anti-streptolysin O titre and anti-DNAse B	+ve → post-streptococcal glomerulonephritis
Complement level (C3, C4)	Low complement is seen in: Post-streptococcal glomerulonephritis → ↓C3 Cryoglobulinaemia/cryoglobulinaemic vasculitis → ↓C4 SLE → ↓ C3 and C4 (+ ↑ ESR and normal CRP)
Cryoglobulins	To test for cryoglobulinaemic vasculitis
Serum protein electrophoresis and serum free light chain assay	To test for multiple myeloma
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	Restrict dietary sodium intake (<2.0g / day) to control blood pressure and oedema Do NOT routinely restrict dietary protein intake Suggested intake: 0.8-1.0 g/kg/day Supplementing losses might be necessary in those with massive proteinuria: add 1 g of protein for every 1 g of protein lost in the urine (up to a maximum addition of 5 g/day) Healthy diet (esp. in nephrotic syndrome – low-fat diet is necessary due to hyperlipidaemia) Regular physical activity Smoking cessation and weight normalisation
Proteinuria and hypertension	1st line: ACE inhibitor / ARB Indicated in proteinuria and/or hypertension Note that ACE inhibitor / ARB should NOT be started in acute nephrotic syndrome, due to the risk of developing AKI
Oedema	1st line: loop diuretics If ineffective: add thiazide-like or potassium-sparing diuretic (amiloride) IV albumin may be used in diuretic-resistant oedema if serum albumin is <20 g/L
Hypercoagulability	Do NOT routinely offer prophylactic anticoagulation Only consider if serum albumin <20-25 g/L with other risk factors Warfarin or heparin is the anticoagulant of choice for both prophylaxis and the treatment of thromboembolic events	Risk is less significant in nephritic syndrome
Increased risk of infection	Offer the following vaccinations: Pneumococcal vaccination Influenza vaccination (annual) Shingles vaccine	Risk is less significant in nephritic syndrome

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: Diffuse effacement of podocyte foot processes Absence of electron-dense (immune-complex) deposits
	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 PCP prophylaxis.

ACE inhibitor / ARB should NOT be started in acute nephrotic syndrome, due to the risk of developing AKI

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
Excellent prognosis overall Very rare risk of progression to CKD / ESRD (esp. in steroid-sensitive cases) Hypertension is uncommon or mild Typically a relapsing-remitting course that often resolves spontaneously after puberty Relapse is very common (occurs in the 1st year in up to 80-90% of patients) – can be triggered by URTI, allergies, vaccinations 15-25% cases persist into adulthood	Excellent prognosis for steroid-sensitive cases Worse prognosis in steroid-resistant cases Relapses are common – repeat biopsies often reveal FSGS lesions (which carry a poorer prognosis)

Children

Adults

Excellent prognosis overall
Very rare risk of progression to CKD / ESRD (esp. in steroid-sensitive cases)
Hypertension is uncommon or mild
Typically a relapsing-remitting course that often resolves spontaneously after puberty
- Relapse is very common (occurs in the 1st year in up to 80-90% of patients) – can be triggered by URTI, allergies, vaccinations
- 15-25% cases persist into adulthood

Excellent prognosis for steroid-sensitive cases
Worse prognosis in steroid-resistant cases
Relapses are common – repeat biopsies often reveal FSGS lesions (which carry a poorer prognosis)

Core monitoring for all forms of glomerular disease:

Proteinuria quantification – while 24-hour urine collections are the gold standard, PCR 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: Malignancy Infections (Hep B, Hep C, syphilis) Drugs (NSAIDs, gold, penicillamine) Class V lupus nephritis

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-PLA2R +ve is 99% specific for MN If +ve and eGFR is stable → kidney biopsy is NOT required to confirm the diagnosis If -ve (or +ve antibody with declining eGFR) → perform a kidney biopsy
Gold standard: kidney biopsy	Light microscopy: Diffuse thickening of glomerular capillary walls without significant hypercellularity Silver staining may reveal the classic spike and dome appearance along the basement membrane (reflecting projections of the basement membrane between immune deposits)
	Electron microscopy – diagnostic gold standard: Subepithelial electron-dense immune deposits along the glomerular basement membrane
	Immunofluorescence: Granular IgG (mainly) and C3 deposition along the glomerular capillary loops Modern IF is also used to detect specific target antigens like PLA2R directly in the tissue

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 SLE

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-PLA2R titres 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	Normal eGFR with proteinuria <3.5 g/d and serum albumin >30 g/l	Supportive care only Immunosuppressive therapy is NOT required for this group
Moderate Risk	Normal eGFR with proteinuria >3.5 g/d + no decrease >50% after 6 months of conservative therapy	Continue supportive care only, or Start rituximab or a calcineurin inhibitor (tacrolimus, ciclosporin) Rituximab has a lower relapse rate than calcineurin inhibitor monotherapy
High Risk	eGFR <60 ml/min/1.73 m², OR Proteinuria>8 g/day for >6 months, OR Normal eGFR with proteinuria >3.5 g/d (no 50% decrease) plus anti-PLA2R >50 RU/ml or serum albumin <25 g/l	Concurrent supportive care is key. Immunosuppressive therapy is indicated in this group: Rituximab (preferred due to a more favourable safety profile), OR Cyclophosphamide plus glucocorticoids, OR Rituximab plus a calcineurin inhibitor (tacrolimus, ciclosporin)
Very High Risk	Life-threatening nephrotic syndrome (e.g., severe infections, thromboembolism), OR Rapidly deteriorating kidney function not explained by other causes	Immediate initiation of cyclophosphamide plus glucocorticoids Rituximab may be offered if cyclophosphamide is not tolerated

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 +/- hyalinosis (not diffuse)
	Electron microscopy: Diffuse effacement of podocyte foot processes – esp. in primary FSGS Segmental effacement is typically seen in secondary FSGS
	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

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	Diffuse alveolar haemorrhage → Haemoptysis Dyspnoea Hypoxaemia and respiratory failure
Renal manifestation	Rapidly progressive glomerulonephritis → oliguric / anuric at presentation Haematuria (part of nephritic syndrome)

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 If +ve → start treatment immediately (do not delay treatment to await for biopsy) If -ve → urgent kidney biopsy (as anti-GBM is -ve in up to 10% of patients)
Gold standard: kidney biopsy	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
	Electron microscopy Absence of electron-dense deposits (clumps of immune complex) – as antibodies are spread evenly along the membrane in anti-GBM disease
	Immunofluorescence: diagnostic gold standard Linear IgG deposition along the entire length of the glomerular basement membrane
Lung imaging	Not required for diagnosis for anti-GBM disease, but is used to test 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: HRCT Hallmark: diffuse / patchy ground-glass opacities Gold standard (but rarely needed): bronchoscopy with bronchoalveolar lavage

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: HRCT
- 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 , 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	>90% 5-year survival with induction therapy Mortality rate is 96% without aggressive induction therapy Most deaths occur in the acute phase, primarily due to respiratory failure from massive lung haemorrhage
Kidney survival	Kidney prognosis is almost entirely determined by the severity of damage at the time of presentation ~50% of treated patients maintain or recover independent kidney function at 5 years
Lung survival	In contrast to the kidneys, aggressive treatment almost always results in the complete recovery of the lungs from alveolar haemorrhage
Risk of relapse	Relapses are uncommon (0-6%), and exceptionally rare beyond 6 months However, double positive (anti-GBM and ANCA +ve) patients have a much higher risk of relapse (similar to those with ANCA-associated vasculitis) 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:

GPA is most common in European ancestry populations, and rare in East Asia
MPA 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: URT (ENT) involvement (sinusitis / rhinitis, saddle nose deformity, otitis media, hearing impairment) LRT involvement (haemoptysis, dyspnoea) Kidney involvement (RPGN – nephritic syndrome) Other features: Eye involvement – conjunctival injection, uveitis, proptosis Skin – purpura, focal necrosis, ulcers	Predominantly cANCA (PR3) +ve	CXR / CT findings: pulmonary nodules, cavitating lesions (from granulomas) Sinus CT may show bone destruction	Characterised by necrotising small-vessel vasculitis, WITH granulomatous inflammation Lung / nasal biopsy often show pathognomic multinucleated giant cells
Microscopic polyangiitis (MPA)	Classic presentation: LRT involvement (haemoptysis, dyspnoea) Kidney involvement (RPGN – nephritic syndrome) URT (ENT) involvement is classically absent Other features: Fever, malaise Necrotising vasculitis	Predominantly pANCA (MPO) +ve	CXR / CT findings: diffuse ground-glass opacities (from interstitial pulmonary fibrosis)	Characterised by necrotising small-vessel vasculitis, WITHOUT granulomatous inflammation
Eosinophilic granulomatosis with polyangiitis (EGPA)	Characteristic severe allergic asthma +/- sinusitis and rhinitis (often before vasculitis emerges) Other features: Peripheral neuropathy (mononeuritis multiplex) Significant risk of eosinophilic myocarditis	Predominantly pANCA (MPO) +ve (however it is frequently ANCA -ve)	Blood: >10% eosinophilia Cardiac imaging (echo / MRI) is used to assess for myocardial involvement	Characterised by eosinophil-rich, necrotising small-vessel vasculitis, WITH granulomatous inflammation

Condition

Clinical features

Serology

Other tests

Biopsy

Granulomatosis with polyangiitis (GPA)

Classic triad of:

URT (ENT) involvement (sinusitis / rhinitis, saddle nose deformity, otitis media, hearing impairment)
LRT involvement (haemoptysis, dyspnoea)
Kidney involvement (RPGN – nephritic syndrome)

Other features:

Eye involvement – conjunctival injection, uveitis, proptosis
Skin – purpura, focal necrosis, ulcers

Predominantly cANCA (PR3) +ve

CXR / CT findings: pulmonary nodules, cavitating lesions (from granulomas)
Sinus CT may show bone destruction

Characterised by necrotising small-vessel vasculitis, WITH granulomatous inflammation
Lung / nasal biopsy often show pathognomic multinucleated giant cells

Microscopic polyangiitis (MPA)

Classic presentation:

LRT involvement (haemoptysis, dyspnoea)
Kidney involvement (RPGN – nephritic syndrome)

URT (ENT) involvement is classically absent

Other features:

Fever, malaise
Necrotising vasculitis

Predominantly pANCA (MPO) +ve

CXR / CT findings: diffuse ground-glass opacities (from interstitial pulmonary fibrosis)

Characterised by necrotising small-vessel vasculitis, WITHOUT granulomatous inflammation

Eosinophilic granulomatosis with polyangiitis (EGPA)

Characteristic severe allergic asthma +/- sinusitis and rhinitis (often before vasculitis emerges)

Other features:

Peripheral neuropathy (mononeuritis multiplex)
Significant risk of eosinophilic myocarditis

Predominantly pANCA (MPO) +ve (however it is frequently ANCA -ve)

Blood: >10% eosinophilia
Cardiac imaging (echo / MRI) is used to assess for myocardial involvement

Characterised by eosinophil-rich, necrotising small-vessel vasculitis, WITH granulomatous inflammation

Characteristics kidney biopsy finding in ANCA-associated vasculitis:

Light microscopy: necrotising crescentic glomerulonephritis
Immunofluorescence: pauci-immune (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 = URT (ENT) 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

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:

Microscopic haematuria / low-level proteinuria detected on routine screening
Most patients typically still have a normal eGFR and normotensive at diagnosis

Symptomatic

Characteristic symptomatic presentation: visible (gross) haematuria (cardinal sign) that follows an URTI (during or within days of the URTI)

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	Mesangial hypercellularity
Electron microscopy	Electron-dense immune complex deposits in the mesangium
Immunofluorescence	Definitive diagnostic tool: Dominant or co-dominant IgA deposition in the mesangium Frequently accompanied by C3

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	IgA nephropathy follows a slow, progressive course ~25%–30% of patients will develop kidney failure within 20–25 years of presentation Relapse is a significant concern in children
Main poor prognostic predictors	Sustained proteinuria (>1 g/day or 0.75-1 g/day despite treatment) – most powerful predictor Persistence of haematuria (also the magnitude of haematuria) Uncontrolled hypertension Reduced renal function at diagnosis Kidney biopsy findings: Tubular atrophy / interstitial fibrosis (strongest histological predictor) Segmental sclerosis Crescents (reflects active severe disease, likely necrotising crescentic glomerulonephritis) Endocapillary hypercellularity (associated with worse outcomes but may respond to immunosuppression) East asian ancestry (followed by Caucasians)
Less significant ones	Male (faster rate of kidney function decline) Older age Older age is associated with more chronic damage at diagnosis, lower renal reserve and higher likelihood of hypertension Furthermore, children are often diagnosed earlier than adults because visible haematuria occurs more frequently in the paediatric population

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	Pharyngitis: 1-2 weeks prior the onset of nephritic syndrome Impetigo: 4-6 weeks prior the onset of nephritic syndrome
Acute nephritic syndrome	Sudden onset of: Haematuria – cardinal manifestation Oedema Hypertension

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-streptolysin O – classic marker for pharyngitis (but can be unreliable for impetigo) Anti-DNAse B Anti-hyaluronidase Anti-DNAse B and anti-hyaluronidase are generally preferred for impetigo-triggered PSGN
Serology	Low C3 Normal C4
Gold standard: kidney biopsy	Light microscopy: exudative glomerulonephritis (diffuse endocapillary hypercellularity with prominent neutrophil and mononuclear cell infiltration) Electron microscopy: Large subepithelial humps (of electron-dense immune deposits) Typically located on the outer aspect of the glomerular basement membrane Immunofluorescence: Granular (“starry sky”) staining for C3 and IgG The intensity of C3 deposition commonly exceeds that of IgG

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 SLE
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):

Class	Name	Clinical & Histologic Characteristics
Class I	Minimal mesangial disease	Patients typically have normal kidney function and low-level proteinuria Histology: no changes on light microscopy, mesangial immune deposits on immunofluorescence
Class II	Mesangial proliferative disease	Patients typically have low-level proteinuria or microscopic haematuria Histology: mesangial hypercellularity or matrix expansion on light microscopy
Class III	Focal proliferative disease	Patients typically present with nephritic syndrome and impaired kidney function (rapidly progressive glomerulonephritis) Histology: proliferative and/or necrotising lesions involving <50% of all glomeruli
Class IV	Diffuse proliferative disease	Patients typically present with more severe nephritic syndrome and impaired kidney function (rapidly progressive glomerulonephritis) Histology: proliferative and/or necrotising lesions involving >50% of all glomeruli
Class V	Membranous disease	Patients typically present with full nephrotic syndrome Histology: subepithelial immune deposits +/- class III or IV changes
Class VI	Advanced sclerosing disease	Represents late-stage disease Histology: >90% of glomeruli are globally sclerosed without evidence of residual active inflammation

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: Induction therapy: Mycophenolic acid analogue + steroids, or Cyclophosphamide + steroids, or Belimumab + mycophenolic acid analogue or cyclophosphamide Mycophenolic acid analogue + voclosporin or tacrolimus Maintenance therapy with mycophenolic acid analogue (alternative: azathioprine)
Class V (membranous disease)	Treatment depends on the severity of proteinuria: Sub-nephrotic range proteinuria: only requires ACE inhibitor or ARB and optimise blood pressure control Nephrotic range proteinuria: glucocorticoid + another immunosuppressant (e.g. mycophenolic acid analogue, cyclophosphamide, calcineurin inhibitor, rituximab)
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	Hepatitis C – most common Hepatitis B Bacterial endocarditis (caused by Staphylococcus aureus) Systemic autoimmune diseases (e.g. SLE, Sjogren’s syndrome, RA)
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) Impaired kidney function Hypertension Proteinuria (often nephrotic range) and haematuria Oedema
Extra-renal manifestations	Cryoglobulinaemic vasculitis is a type of small-vessel vasculitis Skin manifestation: palpable purpura, necrosis, ulceration Arthralgia, myalgia Chronic liver disease (due to its association with hepatitis B and C) Polyneuropathy Pulmonary haemorrhage (in severe cases – mimicking anti-GBM disease)

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

Share Your Feedback Below Cancel reply

You must be logged in to post a comment.