Glomerulopathies refer to a set of diseases characterised by injury to renal glomeruli.
Glomerulopathies are an important cause of acute kidney injury (AKI) and they account for approximately 15% of end-stage renal disease (ESRD).
Learning and teaching about the glomerulopathies is complicated by a combination of misleading, complex and redundant nomenclature. In this note we will attempt to categorise the glomerulopathies in a manner that aids learning and understanding. It should, however, be remembered that these categorisations are limited and overlap often exists.
These are conditions where glomerular disease is the result of primary renal pathology.
These are systemic disorders where part of the disease process involves injury to the renal glomeruli.
The glomerulus is the site of ultrafiltration within the kidneys.
Each glomerulus contains a tuft of capillaries surrounded by a capsule (Bowman’s capsule). These capillaries are supported by a series of cells and connective tissue known as the mesangium.
Fluid and other substances may pass from the capillaries into the urinary space of the glomerulus and then pass into the proximal convoluted tubule of the nephron. This passage of fluid is guarded by three layers that make up the ‘filtration barrier’.
The filtration barrier is composed of three structures:
Damage to the normal glomerular structure and filtration barrier can lead to structural alteration and disruption of glomerular filtration. This can lead to leakage of blood (haematuria) and protein (proteinuria), which forms the hallmark of glomerular disease.
Damage to glomeruli may occur secondary to deposition of immune or non-immune material, or direct immune attack of components of the glomerular structure.
Deposition of circulating immune complexes can lead to fixing of complement and activation of a pro-inflammatory response. Deposition of non-immune material can occur in diabetes mellitus and amyloid.
Direct immune attack is seen in conditions such as anti-glomerular basement membrane (GBM) disease. Circulating antibodies are directed to proteins on the basement membrane, which initiates a pro-inflammatory response. This type of disease process may also be seen in small vessel vasculitis, where immunoglobulins are directed to antigens on the endothelial cells of the capillary tuft.
Injury to the glomeruli can lead to typical histological patterns of disease. These patterns are microscopic descriptions of what is seen within the glomeruli under the microscope and include proliferative, non-proliferative and necrotising changes. The type of pattern is usually associated with a specific clinical presentation.
Collectively, these histological responses, in association with the clinical presentation and serological markers, aids the diagnosis.
The characteristic clinical features of glomerular pathology include both nephrotic and nephritic patterns of presentation.
The nephrotic pattern can range from mild asymptomatic proteinuria to nephrotic syndrome and rarely acute kidney injury.
The nephritic pattern can range from mild asymptomatic haematuria to nephritic syndrome and rapidly progressive glomerulonephritis associated with acute kidney injury and marked renal impairment
Nephrotic and nephritic syndromes are associated with a constellation of clinical features that point towards a diagnosis of glomerulopathy.
Nephrotic syndrome is a clinical presentation that is characterised by a triad of heavy proteinuria (> 3.5 g/day), oedema and hypoalbuminaemia.
Nephrotic syndrome is a consequence of structural changes in the glomeruli in response to glomerular injury. It causes excessive leakage of key plasma molecules including albumin.
This leads to the typical features of heavy proteinuria and hypoalbuminaemia. The reduction in serum albumin causes a lowering of oncotic pressure which can lead to oedema. Patients with nephrotic syndrome are more at risk of infections due to the loss of immunoglobins from the glomerulus.
Hyperlipidaemia is another common feature of nephrotic syndrome. This occurs due to a loss of oncotic pressure, which leads to elevated levels of cholesterol, low-density lipoprotein and triglycerides within the serum.
Another key feature of nephrotic syndrome is development of a hypercoagulable state. The reason for this is not completely understood, but thought to be due to the loss of key anti-clotting factors such as anti-thrombin III, plasminogen, and protein C and S.
The typical histological changes that occur in nephrotic syndrome are non-proliferative structural alterations that can lead to thickening of the basement membrane and glomerular sclerosis.
A number of conditions are associated with nephrotic syndrome, which includes minimal change disease, membranous glomerulopathy, and focal segmental glomerulosclerosis (FSGS).
Minimal change disease is the most common cause of nephrotic syndrome in children, but can also occur in adults. The cause of the condition is largely unknown, but it is characterised by normal glomerular appearance under light microscopy. Under electron microscopy, fusion of epithelial foot processes is seen.
Glucocorticoids are generally considered the treatment of choice in minimal change disease. However, more immunosuppressive agents may be required in patients that do not respond or have multiple relapses.
Nephritic syndrome is a clinical presentation that is characterised by haematruia, proteinuria, oliguria and hypertension.
Nephritic syndrome is usually a consequence of proliferative changes that occur in the glomerulus leading to the presence of blood in the urine. The development oliguria and acute kidney injury are often sudden and hypertension can develop because of impaired glomerular filtration with enhanced tubular reabsorption.
Under the microscope there could be the presence of urinary red cell casts, leucocytes, sub-nephrotic range proteinuria (< 3.5 g/day) and dysmorphic red cells that are typical of glomerular haematuria. This constellation of urinary findings is often referred to as ‘nephritic urinary sediment’.
Importantly, nephritic syndrome and rapidly progressive glomerulonephritis (RPGN) form part of a spectrum of immunological mediated proliferative damage to the renal glomeruli.
RPGN may lead to a rapid decline in glomerular filtration and potentially end-stage renal disease within weeks to months. Typical causes include anti-GBM disease and ANCA-associated vasculitides.
Nephritic syndrome is associated with a proliferative response within the glomeruli leading to a marked increase in cellularity, which is observed as mesangial and endothelial proliferation and inflammatory cell infiltration.
Proliferative changes may be focal of diffuse. Diffuse proliferation is more likely to be associated with acute nephritic syndrome compared to focal changes that may show less severe haematuria and kidney injury.
The development of RPGN is associated with the formation of crescents as part of the necrotising histological response. Crescents result from thrombosis and rupture of glomerular capillaries leading the classical crescent moon shape on histology, which compresses surrounding glomerular structures.
RPGN is characterised by extensive crescent formation (> 50%) and rapidly progressive renal dysfunction. Due to these histological finding, RPGN may also be termed crescentic glomerulonephritis.
Common causes of nephritic syndrome seen in clinical practice include IgA nephropathy, small-vessel vasculitis, lupus nephritis and post-streptococcal glomerulonephritis (PSGN).
Throughout most of the world, IgA nephropathy is the most common cause of primary glomerulonephritis. It typically presents with a nephritic pattern, with a range of different severities, and is characterised by linear IgA deposition within the mesangium of the glomeruli.
Classically, the disease leads to recurrent episodes of visible haematuria in young men and generally follows an upper respiratory tract infection (URTI). The clinical progression is variable, but it is estimated that up to 50% of patients will have persistent disease resulting in end-stage renal disease and the need for renal replacement therapy.
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