Glomerulonephritis (GN) is an umbrella term. It simply refers to inflammation in and/or around the glomerulus and nephron. It is distinct from interstitial nephritis which refers to inflammation of the space between the tubules.
Glomerulonephritis includes damage to the glomerulus, basement membrane, glomerular capillaries and the glomerular tugs. The term nephritis is a generic, non-specific term that implies there is inflammation of the kidneys. We cannot use it as a diagnosis.
We can divide glomerulonephritis it into 2 groups of syndromes:
- Nephrotic syndrome
- Nephritic syndrome
1. Nephrotic syndrome
These are a group of symptoms that include a triad of:
- Proteinuria >3.5g/day - equivalent to an ACR of 250mg/mmol or PCR of 300mg/mmol.
- Hypoalbuminaemia <30g/L - our normal albumin range is 34-34g/L.
- Oedema
We can also include hypercholestrolaemia and hypercoagulability as a feature of nephrotic syndrome.
The patient must meet these criteria to be considered as having nephrotic syndrome.
The GFR is often normal to mildly reduced.
2. Nephritic syndrome
Nephritic syndrome simply means a patient has a group of symptoms, but once again it does not specify the diagnosis. There are also no set criteria (unlike nephrotic syndrome), but has a set of symptoms that are associated with it, such as:
- Peripheral oedema
- Proteinuria <3.5g/day
- Oliguria
- Haematuria
Hypertension is also a more common feature in nephritic syndrome than in nephrotic syndrome. The GFR is moderately-severely reduced in nephritic syndrome.
- Nephrotic syndrome - proteinuria >3.5g/day (nephrotic = proteinuria)
- Nephritic syndrome - proteinuria <3.5g/day (nephritic = inflammatory)
Think of “nephrot is a lot” and “nephrit is a little”.
The conditions that are associated with glomerulonephritis can subsequently be divided into nephritic and nephrotic syndromes:
Nephrotic syndrome
- Focal segmental glomerulosclerosis
- Minimal change disease
- Membranous nephropathy
- Diabetic glomerulonephropathy
- Amyloidosis
- Membranoproliferative glomerulonephritis
- Lupus nephritis
Nephritic syndrome
- Lupus nephritis
- Vasculitis
- Anti-glomerular basement membrane antibody (anti-GBM)
- Rapidly progressing glomerulonephritis
- Post-infectious glomerulonephritis (post-streptococcal glomerulonephritis)
- Alport syndrome
- IgA nephropathy
- Membranoproliferative glomerulonephritis
We will discuss these in more detail below…
Pathophysiology
Glomerulonephritis may be due to systemic inflammatory conditions such as SLE (leading to lupus nephritis), infection (post-streptococcal glomerulonephritis), nephrotoxic drugs (NSAIDs, cocaine, heroine, captopril, penicillamine etc.), metabolic disorders (diabetic nephropathy), malignancies, hereditary disorders (Alport syndrome) and deposition diseases (amyloidosis).
Most glomerulonephritis’ are triggered by immune-mediated injury from both cellular (innate) and humoral (adaptive) arms of the immune system.
- Cellular infiltration of lymphocytes and macrophages without antibody deposition.
- Humoral antibody and immune complex deposition leads to complement activation in the glomerulus.
Other mechanisms that may lead to glomerular injury include drugs, toxins, metabolic street and haemodynamic stress.
🔍 Investigations
We will discuss the investigations for the relevant conditions, but some common themes can be found throughout:
🏆 Renal biopsy is the gold-standard investigation that confirms all diagnosis of glomerulonephritis. It should be done urgently in any suspected case of glomerulonephritis. Core-needle biopsy is the most sensitive and specific diagnostic test.
- FBC
- U&Es - creatinine, hypoalbuminaemia and GFR (GFR is better than creatinine alone).
- LFTs - if related to hepatitis B or C.
- CRP
- Immunoglobulins, electrophoresis, complement
- Autoantibodies - ANA, ANCA, anti-dsDNA, anti-GBM
Ultimately clinical suspicion of the disease will guide diagnosis.
- Urinalysis - looking for evidence of haematuria, proteinuria, leukocytes.
- MC&S
- ACR/PCR
- Renal ultrasound
These are a group of symptoms that include a triad of:
- Proteinuria >3.5g/day - equivalent to an ACR of 250mg/mmol or PCR of 300mg/mmol.
- Hypoalbuminaemia <30g/L - our normal albumin range is 34-34g/L.
- Oedema
We can also include hypercholestrolaemia as a feature of nephrotic syndrome.
The patient must meet these criteria to be considered as having nephrotic syndrome.
The GFR is often normal to mildly reduced.
It may be primary or secondary in aetiology:
Primary nephrotic syndromes | Secondary nephrotic syndromes |
Minimal change disease | Diabetic nephropathy |
Membranous nephropathy | Lupus nephritis |
Focal segmental glomerulosclerosis | Myeloma |
Membranoproliferative glomerulonephritis | Amyloid |
Pre-eclampsia |
Pathophysiology
In a normal glomerulus, the fenestrated endothelium, glomerular basement membrane (GBM) and podocytes all prevent the passage of large molecules. When there is damage to the podocytes, large proteins (such as albumin) are able to pass through from the blood into urine → proteinuria, hypoalbuminaemia and oedema (due to an imbalance of hydrostatic and osmotic pressures).
The belief is that the liver aims to compensate for the loss in osmotic pressure by increasing lipoprotein synthesis → hyperlipidaemia.
😷 Presentation
- Peripheral and peri-orbital oedema
- Systemic presentations
- Malignancy features
- Features of chronic infection
- Features of heart failure
🧰 Management
We can treat complications:
- Oedema - diuretics (furosemide) & fluid + salt restriction.
- Proteinuria - ACEI/ARB
- Treat underlying cause
🚨 Complications
- Hypercoagulability and thrombosis - a life-threatening complication of nephrotic syndrome. It occurs due to a loss of anti-thrombin III, protein C and S and increased hepatic synthesis of pro-coagulant factors + platelet activation.
- Hyperlipidaemia
- CKD
- Infection - due to immunoglobulin loss.
- Hypocalcaemia - as vitamin D and calcium-binding protein in urine.
Let’s discuss some forms of nephrotic syndrome:
Pathophysiology
It makes up 1/4th of adult nephrotic syndromes and 3/4ths of child nephrotic syndrome (in children it is associated with viral URTI preceding it).
It is mostly idiopathic but can be associated with nephrotoxic drugs (such as lithium, NSAIDs, rifampicin), malignancies, infections.
It is the only form of glomerulonephritis that does NOT lead to kidney failure.
The pathophysiology for MCD involves T-cell and cytokine mediated destruction of the basement membrane leading to a loss of anions (as it usually is negatively charged and repels these anions). This loss of anions causes a reduction in the electrostatic charge which causes increased permeability to albumin → increased albumin excretion (hypoalbuminaemia).
😷 Presentation
The triad of nephrotic syndrome is:
- Oedema (peri-orbital and peripheral oedema)
- Hypoalbuminaemia
- Proteinuria (only intermediate-sized proteins such as albumin and transferrin are able to pass through) - this is seen as frothy urine.
- + Normal blood pressure
🔍 Investigations
🏆 The gold-standard is renal biopsy. We can then look for histological changes with microscopy:
- Light microscopy will seem normal (as there are minimal changes histologically).
- Electron microscopy will show podocyte fusion and pedicel effacement.
🧰 Management
Children presenting with nephrotic syndrome are presumed to have MCD and are treated empirically:
- Oral corticosteroids - is effective in 80% of cases.
- Cyclophosphamide is used 2nd line if refractory to oral corticosteroids.
The prognosis for MCD is good, but it is not uncommon for patients to relapse:
- 1/3rd will have one episode.
- 1/3rd will have infrequent relapses.
- 1/3rd will have frequent relapses (that stop before adulthood).
Pathophysiology
The most common cause of glomerulonephritis (25%) and the 3rd most common cause of end-stage renal failure. It’s pathophysiology is not well understood, but it is believed to be involving circulating antibodies against antigens that are found the surface of podocytes, leading to their destruction.
It occurs due to:
- Idiopathic
- Infections - syphilis, hepatitis B, malaria.
- Malignancy - prostate, lung, lymphoma and leukaemia.
- Drugs - penicillamine, gold, NSAIDs.
- Autoimmune disorders - such as SLE, thyroiditis, rheumatoid arthritis, Sjogren’s.
😷 Presentation
The triad of nephrotic syndrome is:
- Oedema (peri-orbital and peripheral oedema)
- Hypoalbuminaemia
- Proteinuria - frothy urine.
- + Hypertension
🔍 Investigations
🏆 The gold-standard is renal biopsy.
With microscopy, we can see a diffisuely thickened glomerular basement membrane due to subepithelial antibody deposits.
Serology identifies anti-phospholipase A2 anitbody in 70-80% of cases
🧰 Management
- ACEI/ARB and hypertension management is first-line to decrease proteinuria. It is also shown to improve prognosis.
- If there is high risk of progression of the disease, immunosuppression is required:
- Corticosteroid + another agent such as cyclophosphamide or chlorambucil.
- High-risk patients also require anticoagulation
Once again, we can divide the prognosis into thirds:
1/3 will have spontaneous remission
1/3 will remain with proteinuria
1/3 will develop end-stage renal failure
It is a chronic progress of focal injuries and scarring of the podocytes. It is becoming more and more prevalent and often leads to nephrotic syndrome & CKD and ultimately end-stage renal failure.
It is more common in young adults, Afro-Caribbean ethnicity, and has a high recurrence rate after transplantation.
It may occur as a result of:
- Idiopathic
- Secondary to IgA nephropathy, Sickle cell disease, Bergen’s disease.
- HIV
- Heroin
- Alpert syndrome
🔍 Investigations
🏆 The gold-standard is renal biopsy.
- Light microscopy will show focal scarring and hyalinosis (characteristic of glomerulosclerosis) as well as IgM deposition.
- Electron microscopy may show fusion of podocytes and pedicel effacement.
🧰 Management
- Steroids ± immunosuppressants is first-line (as per above)
A rare cause of nephrotic syndrome, accounting for 10% of adult nephrotic syndrome (higher in low-middle income countries as a result of infection).
Pathophysiology
We can divide into 2 types:
- Immune complex-associated - immune complexes are deposited in the kidneys as a result of infections, monoclonal gammopathy or autoimmunity.
- C3 glomerulopathy - a genetic or acquired defect in the complement pathway which results in a prominent presence of C3 in the kidneys.
🔍 Investigations
🏆 The gold-standard is renal biopsy.
🧰 Management
- ACEI/ARB and hypertension management
The most common cause of death with patients suffering from SLE. It is a severe manifestation that leads to end-stage renal failure.
It may stay asymptomatic for a while before presenting as nephritic or nephrotic syndrome.
🔢 Classification
The International Society of Nephrology and the Renal Pathology Society have created a classification for lupus nephritis based on the histopathologic features:
- Class I: Minimal mesangial lupus nephritis
- Class II: Mesangial proliferative lupus nephritis
- Class III: Focal lupus nephritis
- Class IV: Diffuse lupus nephritis - this is the most common form and most severe form.
- Class V: Lupus membranous nephropathy
- Class VI: Advanced sclerosing lupus nephritis
😷 Presentation
These are the features of SLE. Renal involvement may present as either nephritic or nephrotic syndrome as mentioned previously.
- Rash
- Photosensitivity
- Arthritis
- Serositis
🔍 Investigations
It is a clinical diagnosis.
Renal biopsy may show different features depending on the class that is present. Class IV, which is most common, may show up as a “wire-loop appearance” with thickening of glomerular capillaries and immune complex deposition.
🧰 Management
- SLE patients need to undergo regular monitoring for renal disease. This is done through BP monitoring, and assessing for proteinuria and haematuria on urinalysis.
- ACEI/ARB + BP management is the mainstay of management.
- Class III and IV - BP management + immunosuppression (glucocorticoids + mycophenolate or cyclophosphamide)
- This is followed up with mycophenolate therapy.
Pathophysiology
Amyloidosis involves misfolded protein accumulation extracellularly which leads to organ dysfunction. It makes up 10% of nephrotic syndrome cases.
It is classified according to the protein present extracellularly:
- AL amyloid - immunoglobulin light chain protein (as seen in multiple myeloma)
- AA amyloid - serum amyloid A protein that is an acute phase protein present in inflammation.
🔍 Investigations
Renal biopsy with Congo red staining.
SAP scan - serum amyloid P scan used in nuclear medicine using iodine.
Management
Treat underlying condition
Nephritic syndrome is essentially inflammation of the kidneys with haematuria present. The proteinuria present is due to scarring of the glomeruli due to the chronic inflammation. It simply implies a patient has a group of symptoms, but once again it does not specify the diagnosis. There are also no set criteria (unlike nephrotic syndrome), but has a set of symptoms that are associated with it, such as:
- Peripheral oedema
- Proteinuria <3.5g/day
- Oliguria
- Haematuria
Hypertension is also a more common feature in nephritic syndrome than in nephrotic syndrome. The GFR is moderately-severely reduced in nephritic syndrome.
Nephritic syndrome includes:
- IgA nephropathy
- Vasculitis (Henoch Schonlein Purpura)
- Post-streptococcal glomerulonephritis
- Anti-glomerular basement membrane disease (Goodpasture’s syndrome)
- Rapidly progressive glomerulonephritis
This is the most common form of glomerulonephritis worldwide (in both nephrotic and nephritic syndromes). 20-50% develop end-stage renal failure over a 30 year period.
Pathophysiology
Certain individuals are genetically predisposed to have increased production of a certain type of IgA after a respiratory or gastrointestinal infection. These forms of IgA form immune complexes that easily get dislodged in the mesangium and activate the complement system → glomerular injury.
😷 Presentation
- Predominantly male with recent history of infection
- Microscopic or gross haematuria that is synpharyngitic (at the time of pharyngitis)
- Elevated BP
- Mild proteinuria <1g/day
- On rare occasions can lead to rapidly progressive glomerulonephritis.
🔍 Investigations
🏆 Renal biopsy - shows IgA deposition within the mesangium.
🧰 Management
Management is dependant on the severity of the disease:
- Isolated haematuria with no/minimal proteinuria (0.5-1g/day) and normal eGFR → no treatment required.
- 🥇 Persistent proteinuria (>1g/day) + normal/slightly reduced GFR → ACEI/ARB
- 🥈 Active disease (reduced GFR) or failure to responde to ACEIs → immunosuppression (corticosteroids)
Prognosis
1/4th of patients develop end-stage renal failure
Gross haematuria is a marker of good prognosis
Male gender, proteinuria (>2g/day), hypertension, smoking, hyperlipidaemia are all poor prognostic factors.
HSP is an IgA-mediated small vessel vasculitis that is the most common form of vasculitis in childhood with IgA deposition in the kidneys, joints and gut. We will discuss it again in the CCC on vasculitis.
😷 Presentation
It has a clinical triad of:
- Palpable purpuric rash on the extensor surfaces (legs and buttocks)
- Abdominal pain
- Arthritis
Other symptoms include: haematuria and renal failure.
🔍 Investigations
It is a clinical diagnosis that can be confirmed by the presence of IgA and C3 in the skin with immunofluorescence. Renal biopsy will show similar findings to IgA nephropathy (IgA deposits in the mesangium).
🧰 Management
- Arthralgia → analgesia
- Nephropathy/enteropathy → corticosteroids
Prognosis is usually very good as it is usually self-limiting, especially in children who do not have renal involvement. Only about 1/3rd of patients will relapse.
This is a rare form of small vessel vasculitis where there are auto-antibodies to type IV collagen found in glomerular and alveolar membranes → renal and lung manifestations of Goodpasture’s syndrome.
⚠️ Risk factors
It is more common in men at a 2:1 ratio. It also has a bimodal age distribution (20-30 and then again at 60-70). Another association is HLA-DR2.
😷 Presentation
- Pulmonary haemorrhage → dyspnoea and haemoptysis
- Renal disease → oliguria/anuria, haematuria, AKI, renal failure, proteinuria
🔍 Investigations
- Presence of anti-GBM antibodies which can be detected in serum or on renal biopsy
- Raised transfer factor which is secondary to pulmonary haemorrhage.
🧰 Management
- Plasma exchange + immunosuppression
- Cyclophosphamide + steroids
Typically occurs 1-2 weeks after group A ß-haemolytic streptococcus (GAS) infection of the pharynx (usually strep. pyogenes).
It can also occur 2-6 weeks after GAS skin infection. Young children are the most commonly affected.
It ultimately is due to immune complex deposition in the glomeruli.
😷 Presentation
Features of nephritic syndrome:
- Haematuria
- Proteinuria (<3g/day)
- Hypertension
- Oliguria
Other symptoms include general malaise and headache
🔍 Investigations
- Bloods
- Raised anti-streptolysin O (ASOT) is used for confirmation of the diagnosis of a recent streptococcal infection.
- Low levels of C3
🧰 Management
- Supportive therapy
- Antibiotics
RPGN is an aggressive manifestation of glomerulonephritis that rapidly progresses to end-stage renal failure within days-weeks.
It is associated with the presence of epithelial crescents within the glomerulus.
It occurs due to:
- Small vessel/ANCA vasculitis
- Goodpasture’s syndrome
- Werner’s granulomatosis
- SLE
It may also occur due to other forms of glomerulonephritis that then transform into RPGN, such as IgA and membranous glomerulonephritis.
😷 Presentation
- Nephritic syndrome features (haematuria, proteinuria, hypertension, oliguria)
- Features of the underlying disease, for example haemoptysis with Goodpasture’s syndrome.
🔍 Investigations
🏆 Renal biopsy - will show epithelial crescents in the glomeruli.
🧰 Management
- Corticosteroids + cyclophosphamide
Differentiating IgA nephropathy and post-streptococcal glomerulonephritis
- IgA nephropathy usually occurs 1-2 days after infection while PSGN occurs 1-2 weeks after infection.
- IgA nephropathy renal biopsies show immune complexes of IgA while PSGN renal biopsies show immune complexes of IgG.
- PSGN is associated with low complement levels.
