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Nephrotic Syndrome
Nephrotic Syndrome
! RENAL
Nephrotic syndrome
NOTES
Overview
Nephrotic syndrome is broadly defined as a triad of heavy proteinuria > 3.5 g/day,
hypoalbuminaemia, and oedema.
The nephritic syndrome describes a very classic presentation of glomerular disease that is
characterised by a triad of:
Nephrotic syndrome is one of the hallmarks of glomerular disease. For more general information
see our notes on Glomerular disease.
Aetiology
The cause of nephrotic syndrome may be broadly divided into primary or secondary.
Nephrotic syndrome may be due to a disease that causes primary glomerular injury (primary) or
glomerular injury as part of a wider systemic process (secondary). Confusingly, some causes of
primary nephrotic syndrome may also occur as a secondary adaptive response to a systemic illness.
For example, focal segmental glomerulosclerosis can be both primary and an adaptive response to
severe obesity, certain drugs (e.g. heroin) or reflux nephropathy.
Primary
Due to a primary renal glomeruli injury
Secondary
Glomerular injury due to a wider systemic illness
Diabetes mellitus
Amyloidosis
Human immunodeficiency virus
Clinical presentation
Patients with nephrotic syndrome typically present with features of fluid overload.
Due to loss of protein (principally albumin) across the glomeruli there is loss of oncotic pressure
and increased movement of fluid into the interstitial space that leads to oedema. Other complex
factors are implicated in the development of oedema.
Symptoms
Fatigue
Poor appetite
Peripheral oedema
Periorbital oedema
Shortness of breath: typically from pleural effusions and/or pulmonary oedema
Foamy urine: due to excess protein loss
Signs
The salient feature is the presence of fluid overload.
Identification of nephrotic syndrome requires investigation into the potential complications and
looking for an underlying cause. Its is important to check a lipid profile, coagulation, renal function
in all cases. Often, a renal biopsy is required to determine the diagnosis.
Management
The management of nephrotic syndrome depends on the underlying cause.
Complications
Patients with nephrotic syndrome are at risk of both arterial and venous thrombotic
complications.
Thrombotic complications
Bloods clots are observed in 10-40% of patients with nephrotic syndrome. This can occur in both
the arterial and venous system, but Deep venous thrombosis and Pulmonary embolism (PE) are
particularly common. Patients should be assessed for leg swelling and features of PE (chest pain,
shortness of breath).
The exact cause is not well understood but thought to be due to a loss of natural anticoagulants
(e.g. antithrombin III, protein C/S) and increased levels of fibrin and platelet activation.
Hyperlipidaemia
A variety of lipid abnormalities may occur in nephrotic syndrome, which can include
hypercholesterolaemia and hypertriglyceridaemia. A fall in oncotic pressure increases the rate of
lipoprotein synthesis in the liver that results in a high level of cholesterol. In addition, impaired
metabolism of triglycerides is thought to occur due to reduced activity of lipoprotein lipase (this
enyzme breaks down very-low-density lipoproteins and intermediate-density lipoproteins) due to
loss of circulating activating factors.
Recurrent infections
Patients are at increased risk of infections, particularly encapsulated bacteria, due to loss of
immunoglobulins through the glomeruli.
Minimal change disease is considered the most common cause nephrotic syndrome in children. In
children under the age of 10 years old, it accounts for ~90% of cases. In adults, it accounts for a
much smaller proportion (~10%) of nephrotic syndrome.
The condition is characterised by fusion of podocyte foot processes under electron microscopy.
Consequently, it may also be termed a ‘podocytopathy’ to reflect the site of pathology in the
glomeruli. The actual cause of this foot process fusion is incompletely understood. There is
suspected to be immune dysfunction that leads to production of a permeability factor that disrupts
the filtration barrier.
Diagnosis
In children, minimal change disease is usually a presumptive diagnosis in the presence of nephrotic
syndrome because of how common the condition is in this age group. Treatment can be initiated
and response assessed.
In adults, the diagnosis is harder to make and usually involves renal biopsy to investigate the cause
of nephrotic syndrome.
Management
The principal treatment of minimal change disease is systemic glucocorticoids (e.g. prednisolone).
This will often lead to complete remission. In patients who do not respond, further courses of
prednisolone or more intensive immunosuppressive can be used.
FSGS
Focal segmental glomerulosclerosis describes a histological lesion seen in some cases of
nephrotic syndrome.
Focal segmental glomerulosclerosis (FSGS) is a histological term that refers to sclerosis in parts of
at least one glomerulus. It is broadly classified as primary, secondary, or genetic. It is a common
cause of nephrotic syndrome, especially adults.
Secondary FSGS represents an adaptive response to renal injury that is usually associated with less
significant proteinuria and renal impairment. This response is a combination of glomerular
hypertrophy (increase in cell proliferation) and hyperfiltration (abnormally high glomerular
filtration rate). The exact mechanism initiating this abnormal response is often not identified, but
classic causes include severe obesity, reflux nephropathy and reduction in kidney mass (due to
compensatory hyperfiltration of the remaining kidney mass).
Diagnosis
FSGS is a histological diagnosis made on renal biopsy. There are a number of histological variants
that may be present. The presentation of FSGS in childhood suggests an underlying genetic cause.
Management
It is crucial to differentiate between primary and secondary causes of FSGS because the treatment
differs between groups. Primary FSGS is more akin to minimal change disease and is treated with
immunosuppressive medications. Treatment of secondary FSGS should be targeted towards the
suspected underlying cause (e.g. weight loss of obesity).
Membranous nephropathy
Membranous nephropathy is one of the most common causes of nephrotic syndrome in
adults.
Secondary MN occurs in the context of an underlying infection, drug use, or a systemic disorder.
Typical causes include systemic lupous erythematosus, viral hepatitis, prostate cancer, or even
NSAID use.
Diagnosis
Traditionally, the diagnosis of MN requires histological analysis following renal biopsy. However, the
presence of typical abnormal antibodies (e.g. anti-PLA2R) that are seen in primary MN enables a
serological diagnosis in patients presenting with nephrotic syndrome.
Management
The treatment of MN depends on the natural history of the condition as some patients may have
spontaneous remission. In patients at high risk of disease progression, who haven’t already
developed irreversible renal damage, immunosuppressive agents may be used in primary MN.
Treatment of secondary MN generally targets the underlying cause (e.g. removal of culprit drug).
Renal amyloidosis
Amyloidosis refers to the extracellular deposition of fibrils that contain a variety of
proteins.
There are at least 38 human precursors to amyloid fibrils. Forms of hereditary amyloidosis are due
to genetic mutations in genes that encode the precursor proteins. In acquired forms, there is
usually excess formation of precursor proteins such as light chain fragments seen in AL
amyloidosis from plasma cell malignancies or excess serum amyloid A precursor protein seen in AA
amyloidosis from chronic inflammatory disorders.
Diagnosis
The diagnosis of renal amyloid can be made on biopsy with identification of amyloid fibrils using
Congo red staining (causes apple-green birefringence under polarised light). A diagnosis may be
made by sampling tissue from another site due to the systemic nature of the condition (e.g.
performing a ‘fat-pad’ biopsy from near the umbilicus).
Management
The treatment of amyloidosis depends on the underlying cause (e.g. AA amyloidosis, hereditary
amyloidosis). In patients with renal involvement, supportive therapy is needed for managing
nephrotic syndrome. In those with severe end-stage renal disease, dialysis may be considered if
appropriate.
References
Kelepouris, E. et al. Overview of heavy proteinuria and the nephrotic syndrome. Uptodate. 2021.
KDIGO. Clinical Practice Guideline for Glomerulonephritis. 2021. Available online.
Carton, J. et al. Clinical Pathology. Oxford core texts. 2006.
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