Nephritic syndrome

Notes

Overview

Nephritic syndrome is classically described as the presence of haematuria, variable proteinuria, renal impairment, and hypertension.

Nephritic syndrome is also known as gomerulonephritis or simply ‘nephritis’. It describes the presence of an inflammatory process within the glomeruli. The nephritic syndrome describes a very classic presentation of glomerular disease that is characterised by

  • Haematuria
  • Variable proteinuria (may be nephrotic range)
  • Renal impairment
  • Hypertension

Glomerulonephritis is a more encompassing term than nephritic syndrome because it reflects the variable clinical presentation of glomerular inflammation. Some patients may have minimal haematuria and proteinuria whereas others develop rapidly progressive renal impairment.

Aetiology

The cause of nephritic syndrome is commonly differentiated based on the underlying mechanism.

Glomerular inflammation is the hallmark of nephritic syndrome. This may be due to inflammation of the small vessels within the capillary tuft (i.e. vasculitis), immune complex deposition or formation of anti-glomerular basement membrane (GBM) autoantibodies.

Immune complex deposition

This refers to the deposition of components of the immune system (e.g. immunoglobulins, cryoglobulins, complement) that may initiate a local inflammatory response. This type of injury is typical of a systemic disease process.

  • Systemic lupus erythematosus (i.e. lupus nephritis)
  • Post-streptococcal glomerulonephritis (PSGN)
  • IgA Nephropathy
  • Cyroglobulinaemia

Small vessel vasculitis

This is characterised by very limited or no immune deposition in the glomeruli. Instead, patients usually have circulating autoantibodies known an anti-neutrophil cytoplasmic antibody (ANCA). These autoantibodies target self-antigens leading to a vasculitis (inflammation of arterioles, capillaries & venules) that may be limited to the kidneys or multisystem.

ANCA-associated vasculitis is an umbrella term for three conditions:

  • Microscopic polyangiitis (MPA)
  • Granulomatosis with polyangiitis (GPA): previously known as Wegener’s granulomatosis
  • Eosinophilic granulomatosis with polyangiitis (EGPA): previously known as Churg-Strauss syndrome

Anti-GBM autoantibodies

Anti-GBM disease is a rare small-vessel vasculitis that results from the formation of GBM antibodies that target type IV collagen within the basement membrane. This results in linear deposition of IgG in the glomerular capillaries. Due to different pathogenesis, this condition is discussed differently to the ANCA-associated vasculitides.

Clinical presentation

The clinical presentation of glomerulonephritis can be highly variable.

Nephritic syndrome is a distinct clinical syndrome characterised by haematuria, variable proteinuria, renal impairment, and hypertension. However, this represents a single presentation that forms part of a spectrum of severity in patients with glomerulonephritis.

Presentation pattern

Presentation of glomerulonephritis is highly variable and may include:

  • Minimal haematuria and proteinuria
  • Acute self-limiting disease
  • Acute severe disease: severe renal impairment usually develops without treatment
  • Rapidly progressive glomerulonephritis: deterioration in renal function over days to weeks to a few months
  • Chronic kidney disease: slowly progressive deterioration in renal function due to inflammation

Patients with an acute, severe presentation of glomerulonephritis will usually show features of nephritic syndrome.

Symptoms

  • Lethargy
  • Recent infection: fever, sore throat, coryzal symptoms. Typical of poststreptococcal glomerulonephritis and IgA nephropathy
  • Haematuria
  • Oliguria: reduce urine output
  • Oedema: peripheral or periorbital
  • Shortness of breath: due to fluid overload
  • Haemoptysis: due to pulmonary haemorrhage (e.g. Anti-GBM, ANCA-vasculitis)

Signs

  • Haematuria
  • Hypertension
  • Oedema: peripheral, periorbital
  • Fluid overload: raised JVP, bibasal crackles on auscultation, peripheral oedema, ascites
  • Reduce urine output

Extra-renal manifestations

This refers to clinical features reflecting involvement of other organs systems. It is typically seen in patients with systemic causes (e.g. vasculitis, systemic lupus erythematosus, anti-GBM disease).

  • Skin: vasculitic rash (palpable purpura)
  • ENT: rhinosinusitis, nasal discharge, polychondritis (inflammation of cartilage)
  • Eyes: red, painful eyes (e.g. conjunctivitis, scleritis, uveitis)
  • Lungs: haemoptysis, pleuritic pain, wheeze
  • Heart: chest pain due to pericardial or myocardial involvement
  • Nervous system: mononeuropathies

Diagnosis & investigations

The diagnosis of nephritic syndrome is based on identification of worsening renal function, haematuria and proteinuria.

Several conditions may cause haematuria and worsening renal function (e.g. urinary tract infection, renal stones). Therefore, it is important to interpret these findings with the clinical history and to look at the extent of proteinuria.

Look for features supportive of haematuria of glomerular origin:

  • Dysmorphic red blood cells: red cell structure appears abnormal under the microscope
  • Red blood cell casts: identification of red bloods cells within urinary casts seen under the microscope. A cast is a microscopic cluster of particles wrapped in uromodulin (Tamm-Horsfall protein). Uromodulin is secreted by epithelial cells lining the loop of Henle, distal tubule & collecting duct.

Any patient with haematuria, proteinuria and declining renal function or evidence of an underlying disorder (e.g. new mononeuropathy or vasculitic rash) requires urgent assessment for suspected glomerulonephritis. In these patients a full renal screen should be requested and the majority of patients will need to undergo renal biopsy to confirm the underlying diagnosis.

For more information on the work-up of glomerulonephritis see our notes on Glomerular disease.

Management

The management of nephritic syndrome depends on the underlying cause.

An accurate diagnosis of the underlying cause of nephritic syndrome is essential to offer specific treatments. Some causes of nephritic syndrome require aggressive immunosuppressive therapy, particularly the causes of rapidly progressive glomerulonephritis.

General supportive measures for acute kidney injury are required in all patients who can have significant renal impairment. Temporary renal replacement therapy (RRT) may be required while treatment is initiated and others may develop end-stage renal disease despite treatment.

For more information on broad management strategies see our notes on Glomerular disease.

For more information on the management of renal impairment see our notes on Acute kidney injury.

Complications

Nephritic syndrome can cause severe acute kidney injury and associated complications.

The main complication associated with nephritic syndrome is renal impairment that may be severe and require RRT. In some cases, it is not possible to achieve renal recovery and patients require long-term RRT or transplantation. Many causes of nephritic syndrome are multisystem and can lead to widespread organ dysfunction. More specific complications depend on the underlying cause.

Poststreptococcal glomerulonephritis

Poststreptococcal glomerulonephritis occurs due to a prior infection with a group A beta-haemolytic Streptococcus.

Poststreptococcal glomerulonephritis (PSGN) is the most common cause of glomerulonephritis in children worldwide. It refers to the development of glomerulonephritis following infection by Group A Streptococcus (GAS). The widespread use of antibiotics in developed countries has led to a reduced incidence.

In adults, PSGN is less common and the term postinfectious glomerulonephritis is more appropriate as others microorganisms (e.g. staphylococcus) are more common.

Aetiology & pathophysiology

PSGN is usually associated with a recent skin or throat infection by Group A beta-haemolytic Streptococcus. After 1-3 weeks (longer for skin infection) patients develop features of glomerular disease, however the presentation is highly variable. Patients may be asymptomatic, have non-visible haematuria or develop acute severe nephritic syndrome.

The condition is thought to occur due to the development of immune complexes that contain streptococcal antigens. These get deposited within the renal glomeruli as the antibodies within the complexes cross-react with important glomerular structures due to ‘cross-reactivity’. This is known as molecular mimicry (similarity in antigen lead to autoreactivity) and causes an inflammatory response with development of glomerulonephritis.

Diagnosis

In children, the diagnosis is usually suspected by the development of features of glomerulonephritis (e.g. haematuria, proteinuria, renal impairment) with evidence of a recent streptococcal infection. The evidence for recent infection may be made by measuring antibody titres against specific components of streptococcus such as an anti-streptolysin titre (ASOT).

In adults, the diagnosis is made by renal biopsy that is almost always warranted in the presence of glomerulonephritis.

Management

There is no specific treatment for PSGN and management is targeted at the complications (e.g. hypertension, oedema). In severe cases, renal replacement therapy is rarely needed. In children, resolution is usually rapid and long-term outcome excellent although the outcome in adults is more variable.

Evidence of active infection should be treated with antibiotics.

Lupus nephritis

Lupus nephritis refers to renal involvement in patients with systemic lupus erythematosus.

Lupus nephritis is a complex topic, which is classified based on the histological findings on renal biopsy. At its core, there is deposition of immune complexes within the glomeruli leading to a glomerular injury and a range of histological changes. Clinically, the presentation is highly variable and may present in a myriad of ways including both nephrotic syndrome and nephritic syndrome.

Aetiology & pathophysiology

The pathophysiology of lupus nephritis is complex and involves a variety of mechanisms. Immune complexes form due to anti-double-stranded DNA and deposit within the renal glomeruli. Other immune components may be involved. The area of deposition varies and can include the mesangium, endothelium or epithelium. The clinical presentation is usually related to the location of deposition and immune reaction.

Diagnosis

The diagnosis of lupus nephritis is typically made on renal biopsy completed in patients with known systemic lupus erythematosus (SLE) who develop haematuria, proteinuria and/or worsening renal function. Lupus nephritis may be the presenting feature of the SLE.

Lupus nephritis may be classified based on histological findings on renal biopsy.

  • Class I (minimal mesangial): rarely diagnosed as patients usually asymptomatic
  • Class II (mesangial proliferative): typically causes non-visible haematuria and proteinuria
  • Class III (focal): variable presentation. May have haematuria, proteinuria, renal impairment and/or nephrotic syndrome
  • Class IV (diffuse): most common and most severe form. May present with nephrotic or nephritic syndrome.
  • Class V (membranous): presents with nephrotic syndrome similar to membranous nephropathy
  • Class VI (advance sclerosis): global sclerosis and slowly worsening renal function

Management

The management depends on the underlying histological class. In patients with severe lupus nephritis (e.g. class IV) high dose systemic immunosuppression is typically require and patients may require renal replacement therapy.

IgA nephropathy

IgA nephropathy is the most common primary chronic glomerular disease worldwide.

IgA nephropathy leads to deposition of IgA immunoglobulins within the glomeruli. This develops because galactose deficient IgA1 has an exposed N-acetylgalactosamine in the hinge region that is recognised by IgG and IgA1 leading to immune complex formation. IgA nephropathy commonly presents with visible haematuria or non-visible haematuria and proteinuria. Rarely it can cause nephritic syndrome or even nephrotic syndrome. Treatment of IgA nephropathy is largely supportive with good blood pressure control..

For more information see our notes on IgA nephropathy.

ANCA-associated vasculitis

ANCA-associated vasculitis is an umbrella term for three small-vessel vasculitides characterised by ANCA autoantibodies.

ANCA-associated vasculitis is an umbrella term for three conditions:

  • Microscopic polyangiitis (MPA)
  • Granulomatosis with polyangiitis (GPA): previously known as Wegener’s granulomatosis
  • Eosinophilic granulomatosis with polyangiitis (EGPA): previously known as Churg-Strauss syndrome

These conditions are all small vessel vasculitides that can affect arterioles, capillaries and venules. They are characterised by positive ANCAs, which are involved in the pathogenesis of these conditions. These autoantibodies specifically target myeloperoxidase and proteinase 3 and can affect multiple organs systems. Patients may develop rapidly progressive glomerulonephritis and treatment involves high dose immunosuppression.

For more information see our notes on the ANCA-associated vasculitides:

Anti-GBM disease

Anti-glomerular basement membrane (Anti-GBM) disease is a rare small-vessel vasculitis.

Anti-glomerular basement membrane (Anti-GBM) disease is a small vessel vasculitis with an annual incidence of one case per million population. It is characterised by the formation of anti-GBM antibodies that are directed against type IV collagen in the kidneys and lungs. This can lead to life-threatening glomerulonephritis and/or pulmonary haemorrhage.

Treatment requires potent immunosuppression and plasmapheresis that involves removing a patients plasma from the body and replacing it with another solution such as human albumin to remove the circulating autoantibodies.

For more information see our notes on Anti-GBM disease.


Last updated: October 2021

References
Kelepouris, E. et al. Overview of heavy proteinuria and the nephrotic syndrome. Uptodate. 2021.
KDIGO. Clinical Practice Guideline for Glomerulonephritis. 2021. Available online.
Appel, GB. et al. Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis. 2021.
Musa, R. et al. Lupus nephritis. 2021. Available online.

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