Medicine – Causes of Nephrotic Syndrome

Nephrotic syndrome is a clinical syndrome caused by marked glomerular protein loss. It is characterised by:

Heavy proteinuria.

Hypoalbuminaemia.

Generalised oedema.

Hyperlipidaemia.

Lipiduria.

The causes can be divided broadly into primary glomerular diseases and secondary systemic causes.

1. Diabetes Mellitus

Diabetes mellitus is one of the most important secondary causes of nephrotic-range proteinuria.

Diabetic kidney disease causes progressive damage to the glomerular filtration barrier through:

Glomerular basement membrane thickening.

Mesangial expansion.

Intraglomerular hypertension.

Glomerulosclerosis.

2. Diabetic Nephropathy

As diabetic kidney disease progresses, patients may develop:

Increasing albuminuria.

Heavy proteinuria.

Nephrotic syndrome.

Progressive CKD.

A classic histological finding is:

Kimmelstiel–Wilson nodular glomerulosclerosis.

3. Glomerular Diseases

A major group of causes is:

Primary glomerular disease.

Important nephrotic glomerular disorders include:

Minimal change disease.

Focal segmental glomerulosclerosis.

Membranous nephropathy.

Membranoproliferative glomerulonephritis in some cases.

4. Minimal Change Disease

Minimal change disease is the:

Most common cause of nephrotic syndrome in children.

It is characterised by:

Podocyte foot-process effacement on electron microscopy.

Light microscopy is usually:

Normal or nearly normal.

5. Focal Segmental Glomerulosclerosis

FSGS causes:

Focal and segmental glomerular scarring.

It commonly presents with:

Proteinuria.

Nephrotic syndrome.

Hypertension.

It has a greater risk of progression to CKD than typical minimal change disease.

6. Membranous Nephropathy

Membranous nephropathy is an important cause of:

Adult nephrotic syndrome.

It is characterised by:

Diffuse thickening of the glomerular capillary wall

with:

Subepithelial immune deposits.

Primary cases are often associated with:

PLA2R antibodies.

7. Myeloma

Multiple myeloma can cause renal disease and proteinuria.

However, the mechanism needs clarification.

Myeloma classically produces excess:

Monoclonal immunoglobulin light chains.

These can cause:

Cast nephropathy.

AL amyloidosis.

Monoclonal immunoglobulin deposition disease.

8. Myeloma and Nephrotic Syndrome

Myeloma itself does not always cause a classic albumin-predominant nephrotic syndrome.

Nephrotic syndrome is particularly likely when myeloma is associated with:

AL amyloidosis

or

Monoclonal immunoglobulin deposition disease.

Therefore:

MYELOMA + NEPHROTIC SYNDROME → THINK AL AMYLOIDOSIS OR MONOCLONAL DEPOSITION DISEASE.

9. Amyloidosis

Amyloidosis is an important cause of heavy proteinuria and nephrotic syndrome.

Amyloid deposits accumulate within the kidney, especially in the:

Glomeruli.

This disrupts the filtration barrier and causes:

Marked protein loss.

10. AL Amyloidosis

AL amyloidosis results from:

Monoclonal immunoglobulin light chains.

It is associated with:

Plasma-cell disorders

including:

Multiple myeloma.

Renal presentation commonly includes:

Nephrotic syndrome.

11. AA Amyloidosis

AA amyloidosis results from chronic elevation of:

Serum amyloid A protein.

It is associated with chronic inflammatory or infectious diseases such as:

Rheumatoid arthritis.

Chronic inflammatory disorders.

Tuberculosis.

Chronic osteomyelitis.

It can also cause:

Nephrotic syndrome and progressive CKD.

12. Systemic Lupus Erythematosus

SLE can cause several patterns of lupus nephritis.

Nephrotic syndrome is particularly associated with:

Class V membranous lupus nephritis.

However, severe proliferative lupus nephritis can also cause heavy proteinuria.

13. Lupus Nephritis

Lupus nephritis may present with:

Proteinuria.

Haematuria.

Nephritic syndrome.

Nephrotic syndrome.

Hypertension.

Reduced renal function.

Therefore, the urinary pattern depends on the histological class.

14. Infections

Several infections can cause nephrotic syndrome through:

Immune-complex glomerular injury

or

Secondary amyloidosis.

The original list includes:

Malaria.

Leprosy.

Hepatitis B.

These are recognised associations, although their importance varies by geography and disease prevalence.

15. Hepatitis B

Hepatitis B virus is a classic infectious cause of nephrotic syndrome.

It is particularly associated with:

Membranous nephropathy.

It can also be associated with:

Membranoproliferative glomerulonephritis.

16. Hepatitis C

An important modern addition is:

Hepatitis C virus.

Hepatitis C is particularly associated with:

Mixed cryoglobulinaemia

and

Membranoproliferative glomerulonephritis.

This often produces a mixed nephritic-nephrotic picture.

17. HIV

Another important infectious association is:

HIV.

HIV is classically associated with:

Focal segmental glomerulosclerosis,

especially the collapsing variant.

This can cause:

Heavy proteinuria and nephrotic syndrome.

18. Malaria

Malaria can be associated with glomerular disease and proteinuria.

Certain forms have historically been linked to:

Immune-complex nephropathy

and nephrotic syndrome.

The clinical importance depends heavily on the regional epidemiology.

19. Leprosy

Leprosy can occasionally cause renal disease through:

Immune-complex glomerulonephritis

or

Secondary amyloidosis.

Therefore it can be associated with:

Proteinuria and nephrotic syndrome.

20. Pre-eclampsia

Pre-eclampsia is a pregnancy-specific hypertensive disorder associated with:

New-onset hypertension after 20 weeks’ gestation

plus maternal organ dysfunction, often including:

Proteinuria.

21. Proteinuria in Pre-eclampsia

Proteinuria may become:

Heavy or even nephrotic-range.

This results from glomerular endothelial injury.

The characteristic renal lesion is:

Glomerular endotheliosis.

22. Pre-eclampsia Is Not Usually a Primary Nephrotic Disease

Pre-eclampsia can produce substantial proteinuria and oedema, but the patient should be considered in the context of:

Pregnancy + hypertension + maternal systemic disease.

Therefore it is a secondary cause of nephrotic-range proteinuria rather than a primary nephrotic glomerulopathy.

23. Accelerated or Severe Hypertension

The original notes include:

Accelerated hypertension.

Severe hypertension can injure the glomeruli and renal microvasculature.

This may produce:

Proteinuria.

Haematuria.

AKI.

24. Hypertension and Nephrotic-Range Proteinuria

Typical chronic hypertensive nephrosclerosis usually causes:

Low-to-moderate proteinuria,

not classic heavy nephrotic-range proteinuria.

Therefore, severe nephrotic syndrome in a hypertensive patient should prompt consideration of:

An additional glomerular disease.

However, severe or malignant hypertension can occasionally produce marked proteinuria.

25. Drugs

Several drugs can produce nephrotic syndrome by causing glomerular injury.

The original list includes:

Gold.

Penicillamine.

Captopril.

NSAIDs.

These are recognised associations.

26. Gold

Gold salts were historically used in:

Rheumatoid arthritis.

They can cause:

Membranous nephropathy

and therefore:

Proteinuria or nephrotic syndrome.

Because gold therapy is now rarely used, this is mainly an historical or examination association.

27. Penicillamine

Penicillamine may cause:

Membranous nephropathy.

This can present with:

Heavy proteinuria

or

Nephrotic syndrome.

28. Captopril

Captopril has historically been associated with:

Membranous nephropathy

and significant proteinuria.

This complication is uncommon with modern ACE inhibitor use.

ACE inhibitors overall are more commonly used to:

Reduce proteinuria

rather than cause it.

29. NSAIDs

NSAIDs are particularly important because they can cause more than one form of renal disease.

They are associated with:

Minimal change disease.

Acute interstitial nephritis.

Sometimes the two occur together.

30. NSAIDs and Nephrotic Syndrome

NSAID-associated minimal change disease can produce:

Nephrotic syndrome.

Interestingly, the usual hypersensitivity features of AIN, such as:

Fever.

Rash.

Eosinophilia

may be absent.

31. Malignancy

An important secondary cause not included in the original list is:

Malignancy.

Certain cancers are associated with specific glomerular disorders.

32. Hodgkin Lymphoma

Hodgkin lymphoma is classically associated with:

Minimal change disease.

The renal disease may improve when the underlying lymphoma is treated.

33. Solid Tumours

Some solid malignancies are associated with:

Membranous nephropathy.

The relationship is particularly important in older adults with otherwise unexplained membranous nephropathy.

34. Obesity

Severe obesity can cause adaptive glomerular hyperfiltration leading to:

Secondary FSGS.

This may produce:

Significant proteinuria

and occasionally nephrotic-range proteinuria.

35. Sickle Cell Disease

Sickle cell disease can also cause:

Secondary FSGS

and progressive glomerular damage.

Patients may develop:

Proteinuria.

Albuminuria.

Progressive CKD.

36. Congenital and Genetic Causes

Some nephrotic syndromes arise from inherited abnormalities affecting:

Podocytes

or

Slit diaphragm proteins.

Examples include mutations involving proteins such as:

Nephrin.

Podocin.

These are especially important in:

Congenital or childhood nephrotic syndrome.

37. Primary versus Secondary Causes – Note Form

Primary glomerular causes:

Minimal change disease.

FSGS.

Membranous nephropathy.

Some forms of MPGN.

Secondary causes:

Diabetes mellitus.

Amyloidosis.

SLE.

Infections.

Malignancy.

Drugs.

Pregnancy-related disease such as pre-eclampsia.

Systemic disorders causing secondary glomerular injury.

38. Infection Causes – Note Form

Hepatitis B:

Classically membranous nephropathy.

Can also cause MPGN.

Hepatitis C:

Cryoglobulinaemic MPGN.

HIV:

Classically FSGS, especially collapsing FSGS.

Malaria:

Immune-mediated glomerular disease in selected forms.

Leprosy:

Immune-complex disease or secondary amyloidosis.

39. Drug Causes – Note Form

NSAIDs:

Minimal change disease.

AIN ± nephrotic syndrome.

Gold:

Membranous nephropathy.

Penicillamine:

Membranous nephropathy.

Captopril:

Rarely associated with membranous nephropathy/proteinuria.

40. Malignancy Associations – Note Form

Hodgkin lymphoma:

Minimal change disease.

Solid tumours:

Can be associated with membranous nephropathy.

Plasma-cell disorders / myeloma:

AL amyloidosis.

Monoclonal immunoglobulin deposition disease.

These may cause nephrotic syndrome.

41. Important Corrections to the Original Notes

The term:

“GN”

is very broad.

For nephrotic syndrome, the important glomerular diseases to remember specifically are:

MINIMAL CHANGE DISEASE.

FSGS.

MEMBRANOUS NEPHROPATHY.

SOME MPGN PATTERNS.

Myeloma should be understood more precisely.

Nephrotic syndrome in myeloma is particularly associated with:

AL AMYLOIDOSIS

or

MONOCLONAL IMMUNOGLOBULIN DEPOSITION DISEASE.

Accelerated hypertension can cause marked renal injury and proteinuria, but classic nephrotic-range proteinuria should also prompt a search for:

Underlying glomerular disease.

Important modern infectious causes to add include:

HEPATITIS C

and

HIV.

The drug association with:

Gold

and

Penicillamine

remains classically examinable, although these drugs are now used far less often.

42. High-Yield Cause–Disease Associations

Diabetes mellitus → diabetic glomerulosclerosis.

Amyloidosis → heavy proteinuria/nephrotic syndrome.

SLE → especially membranous lupus nephritis for nephrotic presentation.

HBV → membranous nephropathy.

HCV → MPGN / cryoglobulinaemic GN.

HIV → FSGS.

Hodgkin lymphoma → minimal change disease.

Solid tumour → membranous nephropathy.

NSAIDs → minimal change disease ± AIN.

Gold / penicillamine → membranous nephropathy.

Myeloma → AL amyloidosis / monoclonal deposition disease.

Key Clinical Pattern

The main causes of nephrotic syndrome can be remembered as:

PRIMARY GLOMERULAR DISEASE + SYSTEMIC DISEASE + INFECTION + MALIGNANCY + DRUGS.

The highest-yield associations are:

CHILD → MINIMAL CHANGE DISEASE.

ADULT → MEMBRANOUS NEPHROPATHY OR FSGS.

DIABETES → DIABETIC KIDNEY DISEASE.

SLE → MEMBRANOUS LUPUS NEPHRITIS.

AMYLOIDOSIS → HEAVY PROTEINURIA.

HBV → MEMBRANOUS.

HCV → MPGN.

HIV → FSGS.

HODGKIN LYMPHOMA → MINIMAL CHANGE.

NSAIDs → MINIMAL CHANGE ± AIN.

MYELOMA → AL AMYLOIDOSIS / MONOCLONAL DEPOSITION DISEASE.