Nephrotic Syndrome: Definition, Causes & Diagnosis

Nephrotic Syndrome

• It is defined by a triad of heavy proteinuria, hypoalbuminemia, and edema
• Hyperlipidaemia and thrombotic disease are frequently observed but are not required for diagnosis

Heavy Proteinuria

• Protein excretion of >3.5g/24 hours is observed
• PCR (protein creatinine ratio) >300mg/mmol
• ACR (albumin creatinine ratio) >250mg/mmol

Hypoalbuminaemia

• Serum albumin < 35g/L is usually observed
• In most cases, the value is actually less than 30g/L

Causes of Nephrotic Syndrome

• Nephrotic syndrome can either be a primary or secondary disease
• Primary indicates pathological process causing podocyte dysfunction begins directly at the level of the glomerulus
• Secondary indicates an ongoing systemic process involves the glomerulus and causes podocyte dysfunction indirectly or secondarily

Primary Causes

• Minimal-change nephropathy occurs in 70-90% of children and 10-15% of adults
• Membranous nephropathy occurs in 30% of adults
• Focal glomerulosclerosis occurs in 15% of adults
• Membranoproliferative glomerulonephritis also occurs

Secondary Causes

• Diabetes mellitus
• Systemic Lupus erythematosus
• Amyloidosis and paraproteinemia
• Viral infections like hepatitis B, hepatitis C, and HIV

Associations of Minimal Change Disease

• Often idiopathic
• Rarely, it is secondary to immune stimulus (e.g., infection, immunization), tumours (e.g., Hodgkin lymphoma), or certain drugs (e.g., NSAIDs)

Associations of Membranous Nephropathy

• Primary membranous nephropathy is associated with anti-PLA2R antibodies
• Secondary causes include infections (HBV, HCV, malaria, syphilis), autoimmune diseases (e.g., SLE), tumors (e.g., lung cancer, prostate cancer), and medications (e.g., NSAIDs, penicillamine, gold)

Associations of Focal Segmental Glomerular Sclerosis (FSGS)

• Idiopathic
• Infection: HIV-associated nephropathy (HIVAN), parvovirus B19
• Drugs: Pamidronate, lithium, A interferon, and heroin
• Congenital or acquired nephron mass reduction: Renal dysplasia, partial or unilateral nephrectomy
• Hyperfiltration as part of a disease process: Morbid obesity
• Any cause of glomerular disease with progressive scarring: IgAN, Alport syndrome, thrombotic microangiopathy, vasculitis
• NPHS1 and NHPS2 mutations

Associations of Membranoproliferative Glomerulonephritis (MPGN)

• Haematological and solid organ malignancies, HBV/HCV, SLE, cryoglobulinemia, sickle cell disease

Pathophysiology

• Glomerular filtration apparatus dysfunction occurs mostly at podocytes level and can become dysfunctional via different mechanisms
• These mechanisms correspond to the underlying causative disease processes such as podocyte foot-process effacement or direct podocyte damage and/or podocyte cell death

Minimal Change Disease Process

• Release of cytokines leads to damage of podocytes effacement and/or fusion of podocyte foot processes
• This then alters the permeability of the glomerular filtration apparatus

Membranous Nephropathy Disease Process

• Anti-phospholipase A2 receptor antibodies (anti-PLA2R antibodies) bind to PLA2R (an autoantigen in glomerular podocytes)
• This forms immune complexes that activate the complement system and leading to podocyte injury
• IgG and Complement C3 deposition leads to immune-mediated inflammation and injury of glomerular podocytes and filtration structures

Membranoproliferative Glomerulonephritis (MPGN) Disease Process

• Continuous complement C2 and C3 activation and depletion occurs
• This leads to inflammation in the glomerular filtration apparatus

Focal Segmental Glomerular Sclerosis (FSGS) Disease Process

• IgM deposits lead to immune-mediated inflammation, sclerosis of glomeruli
• Followed by damage and loss of podocytes

Diabetes Mellitus Disease Process

• Chronic hyperglycaemia occurs
• Glycation (also called non-enzymatic glycosylation or NEG) of the basement membrane (protein glycation) happens
• Arteriole hyperfiltration occurs, increasing in GFR (increase in intraglomerular pressure)
• Leads to increased permeability and thickening of the basement membrane and stiffening of the efferent
• Followed by progressive glomerular hypertrophy, increase in renal size, and glomerular scarring (glomerulosclerosis)
• All leads to worsening of filtration capacity

Amyloid Nephropathy Disease Process

• Deposition of amyloid (e.g., AL amyloidosis, AA amyloidosis) in various organs (the kidney is the most commonly involved organ) occurs
• Followed by amyloid deposition in glomeruli
• And then mesangial expansion nodular sclerosis

Lupus Nephritis Disease Process

• Mesangial and/or subendothelial deposition of immune complexes (e.g., anti-dsDNA antibodies, anti-Sm antibodies) occurs
• Followed by expansion and thickening of mesangium, capillary walls, and/or glomerular basement membrane

Cardinal Symptoms of Nephrotic Syndrome

• Oedema, which can have a rapid and severe onset; typically starts with periorbital oedema; peripheral oedema (pitting); pleural effusion; pericardial effusion; ascites; in severe cases, anasarca
• Frothy urine
• Malaise and fatigue

Other Symptoms of Underlying Disease

• Petechial rash (SLE, Vasculitis, Haematological Malignancy)
• Weight loss/night sweats is indication of malignancy
• Joint pain/swelling (SLE, RA, CTD)
• RUQ pain, jaundice and lymphadenopathy (HBV/HCV/HIV)
• Dyspnoea, haemoptysis is lung cancer sarcoidosis symptom

Symptoms of Nephrotic Syndrome Complications

• Leg pain and erythema (DVT) presents
• Dyspnoea (pulmonary oedema)
• Recurrent infection (excretion of immunoglobulin)
• Nausea and vomiting (GIT oedema)
• Postural syncope (hypovolaemia)
• Symptoms of hypocalcaemia (e.g., tetany, paraesthesia, muscle spasms)

Signs of Nephrotic Syndrome

• Tachycardia (hypovolaemia)
• Periorbital oedema
• Calf redness/tenderness (DVT)
• Limb oedema
• Hepatitis/HIV
• Lung Crackles (Pulmonary oedema)
• Sacral oedema (pulmonary)
• Jaundice (sickle cell disease)
• Elevated JVP and wide pulse pressure is sign of (pericardial effusion and tamponade)
• Tachypnoea (pulmonary oedema)
• Muscle wasting (SLE/RA)
• Skin erythema (cellulitis)
• Pyrexia (underlying infectious cause)
• Needle marks (IV drug use)
• Abdo tenderness (pancreatitis)
• Frothy urine (lipiduria)

Differential Diagnosis

• Nephritic Syndrome
• Congestive Cardiac Failure (increased venous pressure)
• Liver failure Cirrhosis (albumin deficiency and increased portal venous pressure)
• Nutritional deficiency and Protein-losing enteropathy (albumin deficiency)
• Profound hypothyroidism
• Lymphoedema

Differential Diagnosis for Pitting Oedema

• Reduced oncotic pressure - Nephrotic syndrome and/or cirrohosis/hepatic failure, severe malnutrition, protein losing enteropahty
• Raised venous pressure - Right heart failure or biventricular failure, volume overload, or immobility
• Drug related - Due to calcium channel blockers or long-term corticosteroids

Investigations

• Investigations fall under 2 categories - diagnosing nephrotic syndrome or confirming an underlying cause

Investigations for Diagnosing Nephrotic Syndrome

• 24-hour urine collection is done for measurement of protein excretion ->3.5g/24 hours (normal is approximately 0.15g/24 hours)
• Urine protein : creatinine ratio (PCR) is an alternative to 24-hour urine collection -> 300mg/mmol (normal is 2.5 in men and 3.5mg/mmol in women)
• Urine albumin : creatinine ratio (ACR) can be used as alternative to 24-hour urine collection ->250mg/mmol (normal is 15mg/mmol)
• PLA2Receptor antibodies - Positive in Membranous nephropathy in 70% of cases
• Renal biopsy - Biopsy is useful for: confirming the diagnosis histologically, prognostication, and to inform management decisions

Minimal Change Disease Biopsy

• Minimal change disease biopsy specimen under electron microscopy shows podocytes foot processes effaced or fused

Membranous Nephropathy Biopsy

• Membranous nephropathy biopsy specimen shows thickening of glomerular capillary loops and the GBM IgG and C3, immune complex deposition forms "spikes" on silver stain

Membranoproliferative disease Biopsy

• Membranoproliferative disease biopsy specimen under electron microscopy shows immune complexes form dense deposits in the mesangium and split the basement membrane

FSGS Biopsy

• FSGS biopsy shows black coloured segments representing scarring of glomerular segments so scarred segments become useless for filtering

Investigations for Secondary Causes

• A Full Blood Count (FBC) can indicate leukemia if WBCs are elevated, SLE if there is neutropenia, or any chronic disease if anemia is present
• Viral serology may identify a possible cause of secondary glomerular pathology
• Autoantibody panel: ANA, ANCA, anti-double stranded DNA indicates SLE and/or rheumatoid arthritis
• Urinalysis for Bence Jones Proteins: Indicates amyloidosis or myeloma
• SPEP/Immunofixation/serum free light chains test helps to screens for myeloma
• Complement levels: Low C3 and C4 indicative of SLE
• Cryoglobulins: indicate vasculitis, HIV, HCV, lymphoproliferative disorders, and mixed connective tissue diseases

Management

• Management includes, management of fluid overload of oedema, reducing ongoing proteinurea, management of underlying cause, and management of disease complication

Management of Fluid Overload and Oedema

• Fluid is restricted to 1L/day, and dietary Sodium is restricted to < 3 g/day
• Patients require diuresis with loop diuretics such as frusemide. Also thiazide diuretics like Metolazone can be added to loop diuretics in refractory oedema cases
• Aim is for between 0.5 – 1kg weight loss per day must be kept to avoid excessive intravascular volume depletion
• Note: higher doses of diuretics are usually required compared to standard doses

Management of Proteinuria

• Elimination or reduction of proteinuria is a major treatment goal
• This can lead to increased serum albumin, decreased oedema, metabolic effects of heavy proteinuria (e.g., hyperlipidaemia), reduction in risk of thromboembolism and infection, slowed progression of chronic kidney disease
• Anti RAAS inhibitor drugs such as ACEI/ARB are commonly indicated
• A low sodium diet is required, as is a thiazide and mineralocorticoid. Dietary protein must be tailored properly

Management of the Underlying Cause for Minimal Change Disease

• Corticosteroids (highly responsive) must be used - Prednisolone 1mg/kg for 4 – 16 weeks
• immunosuppression w/ cyclophosphamide must be had if relapse is frequent

Management of the Underlying Cause for Membranous nephropathy

• Initial management should include a conservative therapy including an RAAS inhibitor such as ACEI or ARB
• Consider immunosuppressive therapy w/ Prednisone AND cyclophosphamide if severe or refractory
• Alternativley , cyclosporine, tacrolimus, OR rituximab

Management of the Underlying Cause for Membranoproliferative disease (MPGN)

• immunosuppression is indicated in declining renal function

Management of the Underlying Cause for Focal segmental glomerular sclerosis (FSGS)

• immunosuppression is indicated in primary disease only and in conjunction with ACE/ARB.
• calcineurin inhibitors like tacrolimus are indicated as 2nd line agents if the response to corticosteroids is poor

Management of the Underlying Cause for Diabetic nephropathy

• Must have Strict glycaemic control
• RAAS inhibition (e.g., ACEI or ARB) must be considered as must Optimization of blood pressure control
• Close surveillance and timely referral to renal replacement therapy if ESRD is anticipated

Management of the Underlying Cause for Amyloid

• Treat plasma cell dyscrasia with AL amyloidosis treatment, AA amyloidosis will require a separate treatment

Management of the Underlying Cause for lupus nephritis

• requires Consult with a nephrologist. and may need induction and maintenance therapy. Drugs can include IV glucocorticoids as maintenance

Common Complications of Nephrotic Syndrome

• Hypercoagulability and Thrombotic may lead to arterial thromboembolism, and serum albumin drops below 30 g/L. Hypercoagulable state is thought to be due to the renal loss of antithrombin III protein
• Atherosclerotic complications is combination high risk of stroke and infarction
• increased risk of infection, from encapsulated bacteria
• Protein Malnutrition and Vitamin D deficiency
• Chronic kidney disease can occur in FSGS and membranous nephropathy and lead to ESRD

Management of Potential Complications for Thrombosis

• Prophylaxis with serium albumin and anti cholinergics may be needed, this is required if albumin is < g/dL or if there is a high clotting risk. Thrombophilia may increase that clotting risk
• low molecular weight heparing may be used

Renal Vein Thrombosis Causes and Symptoms

• Thrombus formation in the renal veins or their branches is key
• hypercoagulable states (e.g., malignancies, antiphospholipid syndrome, nephrotic syndrome), leads to flank pain and LDH
• Diagnose w/ angiography and dopplers, treat with anti cholinergics

Management of Potential Complications for Dyslipidaemia

• Lipid-lowering therapy (Statin can be used)

Management of Potential Complications for infection

• Screen for hepatitis B, HIV, latent TB is required
• vaccination must be updated frequently
• Consider pneumocystis pneumonia prophylaxis w/ steriods

Prognosis for Nephrotic Syndrome in Children

• The prognosis for minimal change disease and steroid dependent cases is usually excellent
• 40% of membranous patients have spontaneous remission
• 30-50% of FSGC patients progress to ESKD

Case Study Diagnosis

• A 50-year-old patient presents with edema, "frothy" urine, and is diagnosed with Type 1 Diabetes Mellitus
• Likely diagnosis? Nephrotic Syndrome secondary to Diabetes Mellitus

Final Summary Notes

• The cardinal clinical feature of nephrotic syndrome is generalised oedema.
• Nephrotic syndrome can be a primary or secondary phenomenon, with secondary causes being of infectious, autoimmune and malignant aetiology.
• Whether or not the cause is primary or secondary, the cause must be properly managed