Nephrotic syndrome

Nephrotic syndrome is broadly defined as a triad of heavy proteinuria > 3.5 g/day, hypoalbuminaemia, and oedema.

The nephrotic syndrome describes a very classic presentation of glomerular disease that is characterised by a triad of:

• ‘Nephrotic-range’ proteinuria (> 3.5 g/day)
• Hypoalbuminaemia (< 35 g/L)
• Oedema (e.g. peripheral, periorbital)

In addition, hyperlipidaemia, increased risk of venous/arterial thrombosis and higher risk of infection is typical of the syndrome. This is because of loss of important proteins (e.g. immunoglobulins, albumin) through the glomeruli.

Nephrotic syndrome is one of the hallmarks of glomerular disease. For more general information see our notes on Glomerular disease.

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.

We discuss some of these conditions further below.

Primary

Due to a primary renal glomeruli injury

• Minimal change disease
• Focal segmental glomerulosclerosis
• Membranous nephropathy

Secondary

Glomerular injury due to a wider systemic illness

• Diabetes mellitus
• Amyloidosis
• Human immunodeficiency virus

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.

• Oedema: peripheral, periorbital
• Ascites: fluid in the peritoneal cavity
• Effusions: dull percussion note and reduced air entry

The diagnosis of nephrotic syndrome is based on the identification of the typical triad.

A diagnosis of nephrotic syndrome is based on the triad of:

• ‘Nephrotic-range’ proteinuria (> 3.5 g/day)
• Hypoalbuminaemia (< 35 g/L)
• Oedema (e.g. peripheral, periorbital)

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.

The management of nephrotic syndrome depends on the underlying cause.

An accurate diagnosis of the underlying cause of nephrotic syndrome is essential to offer treatment. General supportive measures are required in all patients such as monitoring renal function, lowering blood pressure, treating oedema and high cholesterol and managing thrombotic complications.

For more broad management strategies see notes on Glomerular disease.

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.

Acute kidney injury

Renal impairment may be seen in nephrotic syndrome due to a variety of complex mechanisms but it is less common compared to glomerulonephritis (i.e. causes of nephritic syndrome).

Minimal change disease accounts for the majority of cases of nephrotic syndrome in young children.

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.

Aetiology & pathophysiology

The majority of cases of minimal change disease are idiopathic (primary). However, some cases are associated with a distinct underlying cause (secondary). These include:

• Drugs (e.g. NSAIDs)
• Malignancy (e.g. lymphoproliferative disorders)
• Infections (e.g. syphilis – rarely)

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.

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.

Aetiology & pathophysiology

Primary FSGS is thought to occur due to a circulating factor that damages podocytes in the glomeruli leading to foot process effacement. This refers to a loss of podocyte foot process structure, causing them to spread out and this reduces the effectiveness of the filtration barrier.

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 is one of the most common causes of nephrotic syndrome in adults.

Membranous nephropathy (MN) is characterised by glomerular basement membrane thickening in the absence of significant cellular proliferation on histology. It is a common cause of nephrotic syndrome in adults and may be primary or secondary.

Aetiology & pathophysiology

Primary MN is thought to occur due to an autoimmune reaction against important antigens in the filtration barrier. This leads to the development of autoantibodies, formation of immune deposits and subsequent thickening of the glomerular basement membrane. Antibodies directed against the phospholipase A2 receptor (PLA2R) that are highly expressed on podocytes are a major cause of primary MN seen in up to 80% of cases. Rarer antigen targets have been identified.

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).

Amyloidosis refers to the extracellular deposition of fibrils that contain a variety of proteins.

Renal amyloidosis is an important cause of nephrotic syndrome. There is excess deposition of amyloid fibrils in the glomerulus leading to nephrotic syndrome. It is commonly seen in two systemic forms of amyloidosis known as AL amyloidosis (excess light chains due to plasma cell disorders) and AA amyloidosis (excess precursor protein due to chronic inflammation).

Aetiology & pathophysiology

Amyloid fibrils can contain a variety of insoluble proteins. They are derived for soluble proteins (e.g. immunoglobulin light chains, amyloid precursors) that undergo conformational/structural changes for a variety of reasons. They subsequently form a beta-pleated sheet configuration that is resistant to degradation. Deposition in organs leads to disruption of normal tissue function and development of organ failure.

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.