Nephrotic Syndrome

Overview

Overview Nephrotic syndrome is a relatively rare but important manifestation of kidney disease.Nephrotic syndrome classically presents with heavy proteinuria, minimal hematuria, hypoalbuminemia, hypercholesterolemia, edema, and hypertension. In general, all patients with hypercholesterolemia secondary to nephrotic syndrome should be treated with lipid-lowering agents because they are at increased risk for cardiovascular disease. Nephrotic syndrome has serious complications and must be part of the differential diagnosis for any patient presenting with new onset edema. All patients should be referred to a nephrologist for further investigation, which often include a renal biopsy.

Remember Classic tetrad of Nephrotic syndrome is proteinuria (>3g/24hr), hypoalbuminemia, hypercholesterolemia an oedema.

Remember Glomerulonephritis is divided into two broad groups:
Nephritic glomerulonephritis (Basement membrane/endothelium injury causing Haematuria)
Nephrotic glomerulonephritis (Podocyte injury causing proteinuria)

Nephrotic Syndrome

Watch Video Nephrotic Syndrome - Overview

Classification

The page will focus on four common nephrotic syndromes towards the end:

Minimal Change Disease
Focal Segmental Disease
Membranous Glomerulonephritis
Diabetic Nephropathy

Side note Most common cause of chronic kidney disease and nephrotic syndrome is Diabetic nephropathy.

Watch Video Nephrotic Syndrome Types

Kidney and Glomerular Anatomy

The kidneys are retroperitoneal organs (at the back of abdomen) and lies between T11 and L3, the left kidney lying slightly higher than the right kidney.

The kidney is surrounding by an outer membrane called the renal capsule. The outer layer of the kidney is the renal cortex where most of the nephrons are situated. The inner layer is the renal medulla which contain renal pyramids. The renal pyramids drain urine into the minor - major calyces before draining to the renal pelvis then the ureter.

Arterial blood supply

Abdominal Aorta → Renal arteries
The renal artery branches into smaller and smaller arteries until finally becoming afferent arterioles which supply individual glomeruli

The Nephrons are the functional units of the kidney. There are millions. The nephron is made up of:

Bowman's capsule - afferent arteriole enters the bowmans capsule and forms t and efferent exits
Proximal convoluted tubule
Loop of Henle (descending and ascending)
Distal convoluted tubule
Collecting ducts

The glomerulus is a network of blood vessels that are located within the bowman's capsule. To understand the cause, pathophyiology and effect of glomerulonephritis it is important to learn the layers of the glomerulus + bowman's capsule

From inside out the layers are:

Endothelial cells of the blood vessels
Glomerular basement membrane
Podocytes
Bowman's space
Parietal cells.
In the center of the glomerulus are the mesangial cells which help in regulating blood flow the glomeruli.

Signs and Symptoms

Examination

Oedema

Periorbital oedema
Peripheral edema
Ascites

Hypoalbuminemia

Tiredness
Leuconychia

Dyslipidemia

Eruptive xanthomata
Xanthelasmata

Breathlessness with chest pain (Pulmonary Oedema and pleural effusion)

Frothy Urine

Differential Diagnosis

This section will mainly focus on the Primary Aetiology + Diabetic Nephropathy

Primary Aetiology of Nephrotic Syndrome

Minimal Change Disease
Membranous Glomerulonephritis
Focal Segmental Glomerulosclerosis

Secondary Aetiology Nephrotic Syndrome

Diabetic Nephropathy
Amyloidosis
Systemic lupus erythematosus
Infections - HIV, Hep B, Hep C
Drugs - Gold, Antimicrobial agents
Cancer - Multiple Myeloma, lymphoma

Other causes of bilateral swollen legs (because one of the classic presentations of nephrotic syndrome is oedema)

Heart failure
Lymphoedemea
Hypoalbuminaemia
Hepatic failure

Investigations

General

Urine Dipstick
Mid-Stream Urine - microscopy
Full blood count
EUC
LFT
Plasma Ca2+

Check for other systemic diseases and causes of nephrotic syndrome

CRP
Glucose
Serum Immunoglobulins
Urine Immunoglobulins
Autoimmune screen (ANA, dsDNA, C3, C4)
Hepatititis B & C
HIV

Chest Xray - if breathless (effusion)

Abdominal or renal ultrasound

Renal biopsy to perform microscopy, immunofluorescence and Electromicrography

Pathophysiology

Nephrotic Glomerulonephritis is a renal condition affecting the podocytes. This causes a leaky glomeruli leading to proteinuria and subsequent hyperlipidemia, hypoalbuminemia and oedema.

Minimal Change Disease

Overview Minimal change disease (MCD), sometimes known as nil lesion, causes 70–90% of nephrotic syndrome in childhood but only 10–15% of nephrotic syndrome in adults. Minimal change disease usually presents as a primary renal disease but can be associated with several other conditions, including Hodgkin’s disease, allergies, or use of nonsteroidal anti-inflammatory agents.

Clinical Presentation

Children
Anorexia
GI disturbance
Infections
Irritability
Oedema (peritorbital, genital)
Ascites
Oliguria

Minimal Change Disease The most common presentation of MCNS is oedema. MCNS is characterised by oedema, selective proteinuria, hypoalbuminaeia, hypercholesterolaemia, and a normal glomerular filtration rate. Renal Biopsy: The only abnormality is diffuse effacement and fusion of epithelial cell fot processes.

Renal Biopsy

Light Microscopy: nil
Immunoflourescence: occasional IgG in the mesangium
Electron microscopy: consistently demonstrates an effacement of 177 the foot process supporting the epithelial podocytes with weakening of slit-pore membranes.

Management

Prednisone - First line
Cyclophosphamide - If steroid toxicity and relapsing nephrotic syndrome

Side note After initial treatment, proteinuria <0.3 g/day is defined as complete remission; a reduction of baseline proteinuria by >50% with a final value <3 g/day is defined as partial remission.

Remember 90% 0f patients experience a frequently relapsing or steroid-dependent course with steroid toxicity. These patients are candidates for treatment with second line drugs - cyclophosphamide or tacrolimus.

Complications

Infections (including spontaneous peritonitis)
Thrombosis - due to haemoconcenration and loss of proteins such as antithrombin III, leading to a procoagulant state.
Hypovolaemia - due to loss of plasma water into the tissues with consequent fall in circulating blood volume.
Relapse of Minimal Change Disease in Adulthood

Side note Relapses occur in 70–75% of children after the first remission, and early relapse predicts multiple subsequent relapses.

Focal Segmental Glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) refers to a pattern of renal injury characterised by segmental glomerular scars that involve some but not all glomeruli; the clinical findings of FSGS largely manifest as proteinuria. When the secondary causes of FSGS are eliminated, the remaining patients are considered to have primary FSGS.

Side note The incidence of this disease is increasing, and it now represents up to one-third of cases of nephrotic syndrome in adults.

Renal Biopsy

Light Microsopy: focal and segmental glomerular sclerosis or consolidation
Immunoflorecence: usually show no staining for immunoglobulins or complement
Electron Microscopy:

Management

ACE inhibitors
Angiotensin II receptor blockers

Membranous Glomerulonephritis

Membranous glomerulonephritis (MGN), or membranous nephropathy, accounts for approximately 30% of cases of nephrotic syndrome in adults, with a peak incidence between the ages of 30 and 50 years and a male to female ratio of 2:1.

Remember Membranous glomerulonephritisis is rare in childhood and the most common cause of nephrotic syndrome in the elderly.

Renal Biopsy

Light Microscopy: Diffuse global capillary wall thickening in the absence of significant glomerular hypercellularity
Electron Microscopy: Uniform thickening of the basement membrane along the peripheral capillary loops is seen by light microscopy on renal biopsy
Immunofluorescence demonstrates diffuse granular deposits of IgG and C3, and electron microscopy typically reveals electron-dense subepithelial deposits.

Diabetic Nephropathy

Overview Type II Diabetes Mellitus is the leading cause of Chronic Kidney Disease. It is classified as a secondary nephrotic syndrome. ~10% have nephropathy at diagnosis and up to half will go on to develop it over the next 20yrs. 20% of people with Type II diabetes will develop end stage kidney disease. Everyone with Diabetes should be screened yearly for microalbuminuria.

Clinical features - Nephrotic Syndrome with signs and symptoms of diabetes (hyperglycemia)

Pathological features Diabetic nephropathy is defined by characteristic structural and functional changes. The predominant structural changes include

Mesangial expansion
Glomerular basement membrane thickening
Glomerular sclerosis
Podocytopathy

Staging
Class I	Isolated glomerular basement membrane thickening. There is no evidence of mesangial expansion, increased mesangial matrix, or global glomerulosclerosis involving >50 percent of glomeruli.
Class II	Mild (class IIa) or severe (class IIb) mesangial expansion.
Class III	At least one Kimmelstiel-Wilson lesion (nodular intercapillary glomerulosclerosis) is observed on biopsy and there is <50 percent global glomerulosclerosis.
Class IV	Advanced diabetic sclerosis. There is >50 percent global glomerulosclerosis.

Management and Prognosis Microalbuminuria is reversible if caught early and managed vigorously.