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Nephrotic Syndrome

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Nephrotic syndrome\: characterised by proteinuria, hypoalbuminemia, and oedema due to damage to the glomerular

Aetiology\: can be primary (e.g. minimal change disease, FSGS) or secondary (e.g. diabetes, lupus, infections, drugs).
Risk factors\: genetic mutations (NPHS1, NPHS2), medical comorbidities (e.g. diabetes, amyloidosis), infections (HIV,
hepatitis B/C), and drugs (NSAIDs, heroin).
Clinical features\: facial swelling in children, dependent oedema in adults, frothy urine, lethargy, and weight gain.
Complications\: hyperlipidaemia, thrombosis (due to loss of antithrombotic factors), immunode
immunoglobulins), and renal impairment.
Investigations\: urinalysis (proteinuria), UPCR, U&Es (creatinine, urea), liver function tests (low albumin), and renal biopsy to
determine aetiology.
Management\: supportive care (diuretics, ACE inhibitors, anticoagulation, statins), immunosuppression (steroids, rituximab),
and renal transplant for severe cases.
Prognosis\: variable depending on the cause; minimal change disease responds well to steroids, while others may require
long-term immunosuppression or renal replacement therapy.
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A comprehensive topic overview

Introduction

The nephron is the functional unit of the kidney and is responsible for the formation of urine and the removal of waste from
the blood. 1
The glomerulus is the

2
Diseases of the glomerulus are referred to as glomerulonephropathies. This can be broadly divided into nephrotic
syndrome and nephritic syndrome.
In nephrotic syndrome, there is damage to the
to the leakage of proteins into the urine, clinically referred to as proteinuria. 3
The loss of protein from the body results in
hypoalbuminemia, hyperlipidemia, oedema, and other complications.
In the UK, nephrotic syndrome is de
3
Proteinuria (>3.5 g protein/24hrs)
Hypoalbuminemia (\<35 g/L)
Oedema
The onset of nephrotic syndrome may occur at any age and depends on the disease’s aetiology. It is most commonly
diagnosed in children aged between one and six years old. 4
The incidence in children under 18 is two to seven cases per
100,000.
3
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Aetiology

Nephrotic syndrome may have a number of aetiologies. Diseases of the glomerulus are classi
secondary. 5
Primary diseases a
secondary causes are when the kidney disease is driven by another disease or process (e.g. cancers, drugs, infections).
Below are some of the most common causes of nephrotic syndrome\:

Congenital nephrotic syndrome

Congenital nephrotic syndrome is de6
patients are prone to complications, including thrombosis and infection.
These
Untreated, patients would experience end-stage renal disease by two-to-three years of age. A kidney transplant is the
only viable form of treatment for congenital nephrotic syndrome; most patients will undergo a transplant by two years of
age.

Minimal change nephropathy

Minimal change nephropathy is the most common cause of nephrotic syndrome in children. 5
This disease causes damage
to the glomerulus, resulting in massive protein excretion. 5
Presentation typically occurs with abrupt onset facial swelling at
around two years of age.
Minimal change nephropathy may have an idiopathic origin or be caused by secondary diseases, including lymphoma,
non-steroidal anti-in
Histological examination requires a more precise electron microscope.
7

Focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) occurs when scar tissue forms over the glomerulus, damaging the
barrier. The condition may be idiopathic or secondary to\:
8
Drugs, including heroin, bisphosphonates, or anabolic steroids
Sickle cell disease
Infection
Re

Membranous glomerulonephropathy

Membranous glomerulonephropathy is the most common cause of nephrotic syndrome in adults. Approximately 80% of
cases are primary, idiopathic glomerulonephropathies. 70% of these primary cases are associated with anti-PLA2R
antibodies.
9
Secondary causes of membranous glomerulonephropathies include infections, cancers, certain medications, heavy metal
poisoning, and autoimmune diseases.
9

Amyloidosis

Amyloidosis is a rare condition where extracellular protein deposits build up in multiple organs, including the kidneys.
10
Amyloidosis associated with nephrotic syndrome is broadly divided into AL amyloidosis and AA amyloidosis.
10
AL amyloidosis is the most common form of amyloidosis in developed countries. It is caused by the accumulation of an
immunoglobulin light chain protein.
AA amyloidosis is typically triggered by an inrheumatoid arthritis.
10
Amyloidosis is typically diagnosed between ages 60 and 70 and more commonly occurs in men. Renal amyloidosis
generally has a poor prognosis; AL amyloidosis is associated with poorer outcomes than AA amyloidosis.
10

Diabetic nephropathy

Diabetic nephropathy, also known as diabetic kidney disease, is a complication of both type 1 diabetes and type 2
diabetes. 12 12
High blood glucose levels damage the renal blood vessels. Over time, this damages the glomerulus, resulting
in nephrotic syndrome.
Approximately 30-40% of diabetic patients will develop diabetic nephropathy.
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Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disorder. 12
It results in several symptoms, including joint pain,
muscle pain, and a butter
lungs, heart, and kidneys.
Lupus nephritis is the renal disease caused by SLE.
12

Risk factors

Nephrotic syndrome may be caused by a number of renal and non-renal conditions. Certain risk factors may increase the
likelihood of developing nephrotic syndrome. These include\:
Genetic mutations in NPHS1 or NPHS2 (which encode proteins integral to podocyte cells)
11
Medical co-morbidities (e.g. diabetes, lupus, amyloidosis, and re
12
Long-term NSAID use
12
Anticancer drugs (may damage the
13
Illicit drugs (e.g. heroin and cocaine)
14
Infections (e.g. HIV, hepatitis B, hepatitis C, and malaria)
12

Clinical features

History and examination

Obtaining a detailed history and examination is the most important step in determining a diagnosis, and a thorough
abdominal exam should be performed.
Symptoms of nephrotic syndrome vary between adult and paediatric populations and the underlying aetiology. The most
consistent clinical features are\:
Facial swelling (typically the initial symptom in children)
3
Dependent oedema (more common in adults; typically restricted to the legs, feet, and arms)
3
Weight gain (result of
Frothy urine (due to proteinuria)
Lethargy
Anorexia
Other clinical features
Other clinical features of nephrotic syndrome may include\:
Hyperlipidaemia\: caused by increased hepatic production of triglycerides. This is poorly understood but thought to be
due to hypoalbuminemia and changes to albumin-bound lipids. 5
Hyperlipidaemia leads to an increased cardiovascular
risk pro
5
Thrombosis\: caused by loss of antithrombotic factors in the urine and increased production of prothrombotic factors
in the liver. 5
Patients are at increased risk of venous thromboembolism and often require anticoagulation.
Immunode
5
Renal impairment and hypertension\: due to intrinsic damage to the kidney from the underlying disease process.

Di

When nephrotic syndrome is suspected, it is important to consider alternative di
present with similar clinical signs or symptoms\:
3
Systemic diseases\: chronic hypertension, multiple myeloma, anaphylaxis
Hepatic disease\: hepatic insu
Cardiac conditions\: hereditary angioneurotic oedema, congestive cardiac failure
Gastrointestinal conditions\: exudative enteropathy, lymphangiectasia, malnutrition
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Investigations

Bedside investigations

Relevant bedside investigations include\:
15
Urinalysis\: to determine the level of protein in the urine. This will be raised in nephrotic syndrome
Urine protein\:creatinine ratio (UPCR)\: quanti

Laboratory investigations

Relevant laboratory investigations include\:
3,15
Urea and electrolytes\: creatinine and urea levels in the blood will indicate kidney function
Liver function tests\: protein and albumin will be decreased
Lipid pro\: may show increased cholesterol and triglycerides
HbA1c\: raised in diabetic nephropathy
Serological testing\: for secondary causes if indicated by clinical context. These may include antinuclear antibodies
(systemic lupus erythematosus), and hepatitis B and C serological tests

Imaging

A renal ultrasound is indicated to exclude other diagnoses. Non-speci
oedema and hypoalbuminemia.
16

Biopsy

A renal biopsy is usually required for histological examination to determine the underlying cause and guide
management.
15

Diagnosis

Clinically, nephrotic syndrome is de
1. Proteinuria (>3.5 g protein/24hrs)
2. Hypoalbuminemia (\<35 g/L)
3. Oedema

Proteinuria

albumin).
5
Proteinuria is caused by increased basement membrane permeability, causing increased urinary protein loss (including
Patients may describe passing frothy urine, or excess protein may be detected on urine sampling. Urine protein\:creatinine
ratio (UPCR) is typically >300 mg/mmol.

Hypoalbuminemia

In nephrotic syndrome, hypoalbuminemia is caused by loss of albumin in the urine. Albumin is a protein made by the liver
and is lost through the damaged glomerulus.
Albumin is the most prevalent plasma protein and is largely responsible for maintaining plasma oncotic pressure.

Oedema

Low albumin is associated with peripheral oedema. Hypoalbuminemia causes reduced plasma oncotic pressure and,
therefore, leads to
5
Usually, the liver would be able to compensate by increasing albumin production. However, for unknown reasons, the liver
cannot compensate in those with nephrotic syndrome.
5
Oedema is also believed to be related to excess salt and
Classi
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Various terms are used to classify nephrotic syndrome depending on the histology. These terms describe the histological
pattern of disease on renal biopsy and are generally not speci
The exception to this is FSGS; a disease entity causing nephrotic syndrome de
segmental glomerulosclerosis on histology.
Terms used to describe glomerular disease
Focal\: a
Di
Segmental\: a
Global\: a
Proliferative\: increase in the number of cells in the glomerulus
Crescent\: a proliferation of cells within the Bowman’s capsule that squashes the glomerular capillaries, giving a
crescent appearance

Management

The treatment of nephrotic syndrome may vary depending on the aetiology. Broadly, treatment can be divided into
supportive management, immunosuppression, and renal transplant.

Supportive management

Supportive measures are designed to manage the symptoms of nephrotic syndrome through mediation of the renal
system or alternative physiological systems. In low-risk patients, supportive measures may result in remission without the
5
need for immunosuppression. They include\:
Salt and
ACE inhibitors/ARBs\: to reduce proteinuria
Venous thromboembolism prophylaxis\: due to hypercoagulability
Pneumococcal vaccine\: due to immunosuppression
Statin therapy\: to manage dyslipidaemia and reduce cardiovascular disease risk
Diabetic control\: to reduce HbA1c in diabetic nephropathy

Immunosuppression

The immune system has been linked to primary nephrotic syndrome through the damage of epithelial cells of the
glomerulus by autoreactive B cells and autoantibodies. 17
Immunosuppression regimens vary depending on the aetiology
and the degree of steroid-resistance, and include\:
3
Corticosteroids (e.g. prednisolone)
Rituximab
Cyclophosphamide
Calcineurin inhibitors (e.g. tacrolimus)
Minimal change disease is typically steroid responsive, whilst the other causes of nephrotic syndrome may require a
combination of immunosuppressants.

Renal transplant

The prognosis of nephrotic syndrome varies drastically depending on the aetiology. Certain cases have excellent
treatment outcomes, while other patients will require dialysis and then a kidney transplant to achieve recovery.
18
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References

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Regenerative Nephrology (Second Edition). 2022.
Tapia C, Bashir K. N e p h r o t i c S y n d r o m e . StatPearls Publishing. 2023. Available from\: [LINK].
National Health Service. N e p h r o t i c s y n d r o m e i n c h i l d r e n . 2022. Available from\: [LINK].
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Latif W. F o c a l S e g m e n t a l G l o m e r u l o s c l e r o s i s ( F S G S ) . PennMedicine. 2023. Available from\: [LINK].
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Physiology & Pharmacology\: O
2013 Aug 1;17(4)\:347–57. Available from\: [LINK].
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Nagai K. I m m u n o s u p p r e s s i v e A g e n t O p t i o n s f o r P r i m a r y N e p h r o t i c S y n d r o m e \: A R e v i e w o f N e t w o r k M e t a-A n a l y s e s a n d
C o s t-E
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[LINK].

Reviewer

Dr Mohammed Abdulla
Senior Lecturer and Researcher

Related notes

Acute Kidney Injury (AKI)
Chronic Kidney Disease (CKD)
Glomerular Disease (Glomerulonephropathies)
Haemodialysis
Henoch-Schönlein Purpura (IgA Vasculitis)

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Contents

Introduction
Aetiology
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Risk factors
Clinical features
Di
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