NEPHROTIC SYNDROME

 NEPHROTIC SYNDROME

• It is glomerular basement membrane disease characterised by

  • Massive proteinuria

  • Hypoalbuminemia

  • Hyperlipidemia and lipiduria

  • Generalized edema

Causes of nephrotic syndrome are 

Primary causes 

• Membranous nephropathy

• Minimal change disease

• Focal segmental glomerulonephritis

• Membranoproliferative glomerulonephritis

• Other proliferative glomerulonephritis (Ig A nephropathy)

Secondary causes

• Diabetes Mellitus

• Amyloidosis

• SLE

• Drugs (NSAID, Pencillamine, heroine)

• Infections (malaria, syphilis, hepatitis B and C, HIV)

• Malignant disease (carcinoma, lymphoma)

• Miscellaneous (Bee-sting allergy, hereditary nephritis)

PATHOPHYSIOLOGY

• Massive proteinuria –

  • daily loss of 3.5g or more of protein/24hrs

  • Normal a small amount of protein i.e. 20 to 150 mg/day passes through the glomerular filtration barriers and is reabsorbed by the tubules.

  • If excess of protein is filtered exceeding the capacity of tubules for reabsorption, these proteins appear in urine.

  • Highly selective proteinuria consists of low molecular weight proteins (albumin, 70KD, transferrin, 76KD molecular weight)

  • Poorly selective proteinuria – high molecular weight globulins in addition to albumin

  • In nephrotic syndrome there is loss of albumin (molecular weight 66,000)

• Hypoalbuminemia –

  • with plasma albumin levels less than 3g/dl

  • These may be due to

    • Increased loss of albumin

    • Increased renal catabolism

    • Inadequate hepatic synthesis of protein

• Hyperlipidemia –

  • exact mechanism is not known but may be due to stress on liver for synthesis of proteins to compensate proteinuria

  • This causes increased synthesis of lipoproteins and there is increased blood levels of total lipids, cholesterol, triglycerides, VLDL and LDL but decrease in HDL

  • Increased lipoproteins may also be due to abnormal transport of circulating lipid particles and increased lipid catabolism

  • Lipidemia is followed by lipiduria

• Generalised edema –

  • due to fall in colloid osmotic pressure consequent upon hypoalbuminemia

  • Na and H2O retention further contribute to Oedema

  • Na and water retention may due to compensatory secretion of aldosterone mediated by the hypovolemia enhanced renin secretion, stimulation of sympathetic system and a reduction in the secretion of natriuretic factors such as atrial peptides

Patients develop arterial and venous thrombosis due to

• Increases urinary loss of antithrombin –III

• Hyperfibrinogenemia from increased synthesis in liver

• Decrease in fibrinolysis

• Increases platelet aggregation

• Altered levels of proteins C

COMPLICATIONS 

Nephrotic syndrome patients are vulnerable for

• Infection – especially staphylococcal and pneumococcal probably due to loss of immunoglobulin in urine

• Thrombotic and thromboembolic complication due to loss of endogenous anticoagulants (Antithrombin III) in urine

• Renal vein thrombosis seen in membranous nephropathy as a consequence of hypercoagulable state.

MEMBRANOUS GLOMERULONEPHRITIS

• Characterised by diffuse thickening of glomerular capillary wall due to the subepithelial accumulation of electron dense immunoglobulin deposits

• They can be

  • Primary (idiopathic) – 75% of cases

  • Secondary-associated with

    • Drugs –penicillamine, Captropril, gold NSAIDS

    • Malignant tumors – carcinomas of the lung and colon and melanoma

    • SLE

    • Infections- chronic hepatitis B and hepatitis C, syphilis, schistosomiasis

    • Autoimmune disorders – such as thyroiditis

Morphology

• Light microscopy – Glomeruli either appear normal or exhibit uniform diffuse thickening of the glomerular capillary wall.

• Electron microscopy – thickening is caused by irregular electron dense deposits containing immune complexes between basement membrane and overlying epithelial cells with effacement of podocyte foot.

• BM material is laid down between these deposits appearing as irregular spikes protruding from the spikes.

• These spikes are best seen by silver stains which color the BM but not deposits.

• These spikes thickens to produce dome like protrusions and eventually close over the immune deposits, burying them within a markedly thickened irregular membrane

• Immunofluorescent microscopy

  • Demonstrates both immunoglobulin and complement in the deposits

  • As the disease progresses – segmental sclerosis occurs with later total sclerosis

  • Epithelial cells contain protein reabsorption droplets and there may be considerable interstitial mononuclear cell inflammation

Clinical features

• Nephrotic syndrome – most common cause in adults

• Proteinuria (15%)-non selective

• Hematuria

• Mild hypertension (15% to 35%)

Prognosis

• Prognosis is good in women with remission and in those without nephrotic syndrome.

• 40% of patients may have remission

• 10% of patients die or develop renal failure in 10 years

• 40% develop severe chronic disease or end stage renal  disease

MINIMAL CHANGE DISEASE

• Synonym – Lipoid nephrosis, Foot process disease, Nil deposit disease.

• It is a benign disorder characterised by diffuse effacement of foot processes of visceral epithelial cells (podocytes) detectable only by EM in the glomeruli that appear virtually normal by light microscope

• Most frequent cause of nephrotic syndrome in children but less common in adults.

• Age peak incidence is between 2 & 6 years

• Immune deposits are absent in glomeruli but immunological basis for disease is suggested due to

  • Clinical association with respiratory infections and prophylactic immunizations

  • Response to corticosteroids and other immunosuppressive therapy

  • Association with other atopic disorders (eczema or rhinitis)

  • Increased incidence in patients with hodgkins lymphoma in whom there is the defect in T-cell mediated immunity)

Pathogenesis

• Involves immune dysfunction that results in elaboration of factors that damage visceral epithelial cells and cause proteinuria

• Exact nature of the injury is probably mutation of a renal protein called Nephrin

• Nephrin resembles an immunoglobulin like cell adhesion receptors that participate in cell-cell and cell matrix interaction. Thus this probably causes adhesion defect to visceral epithelial cells of glomerular basement membrane. This leads to detachment of epithelial cells causing proteinuria

• Defects in charge barrier may cause proteinuria (not proved)

MORPHOLOGY

• Light microscopy – Normal glomeruli

• Electron microscopy –

  • GBM appears normal and no electron dense material is deposited

  • Principal lesion-visceral epithelial cells show uniform diffuse effacement of foot processes and cytoplasm with loss of recognisable intervening slit diaphragms

  • Such change can be seen in the diseases also like membranous glomerulopathy or DM

  • Such change is associated with normal glomeruli on LM than the diagnosis of minimal change diseases is made

• Cells of proximal tubules are laden with lipids and protein reflecting tubular reabsorption of lipoproteins passing through diseased glomeruli-thus the historical name is lipoid nephrosis

• Immunofluorescence studies –No immunoglobulin or complement deposits

• Disease is completely reversible after administration of corticosteroids

Clinical features

• • Massive proteinuria but renal function remaining normal

  • NO HTN or hematuria

  • Proteinuria is highly selective most of the protein being albumin

  • Characteristic feature complete remission by corticosteroids and prognosis is excellent.

MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

• Considered a pattern of immune mediated injury rather than a specific disease

• MPGN is classified into groups

  • Type-I – characterised by deposition of immune complexes containing Ig G and complement

  • Type –II (Dense deposit disease)-In this activation of complement is an important factor.This belongs the group of disorders called C3 glomerulopathies

Pathogenesis

• Pathogenesis – Type I MPGN

  • Immune complex of IgG and complement gets deposited in the glomeruli and there is activation of both classical and alternate pathways of complement activation

  • Antigens involved are unknown but believed to be proteins derived from infectious agents such as hepatitis C and B viruses which behave either as planted antigen often first binding to or being trapped with in glomerular structures or are contained in performed immune complexes deposited from the circulation.

• Pathogenesis – Type II MPGN

  • In this there is activation of alternate complement pathway

  • C3 is converted to C3bBb by bacterial polysacharides, endotoxins and IgA aggregates in the presence of factors B, D and magnesium

  • C3bBb also called C3 convertase whose degradation is prevented by circulating autoantibody, C3 nephritic fator (C3NeF) thus causing activation of the alternative pathway

  • There is continuous degradation of C3 to C3b by C3 convertase producing hypocomplementemia

  • However how C3NeF is related to the nature of glomerular injury and dense deposits is still unknown

Morphology

• Glomeruli are large and hypercellular

• Hypercellularity is produced both by proliferation of both cells in mesangium and so called endothelial proliferation involving capillary endothelium and infiltrating leukocytes.

• Glomeruli have an “lobular“ appearance due to the proliferative mesangial cells and increased mesangial matrix.

• GBM is thickened and often shows a “double contour” or “form track” appearance especially evident in silver or PAS stains .This is caused by “duplication” of the basement membrane (also referred to as splitting) usually as a result of BM synthesis in response to subendothelial deposits of immune complexes.

• Type I MPGN:

  • Electron microscopy: Characterised by the presence of discrete subendothelial electron dense deposits

  • Mesangial and occasional subepithelial deposits may also be present

  • Immunoflouresence shows IgG, IgM and C3 deposited in a glanular pattern and every complement components (C1Q and C4) are often also present indicating are immune complexes pathogenesis

• Type II MPGN

  • Is characterised by deposition of dark, ribbon like electron dense material in the central layer of (Lamina Densa) of glomerular basement membrane

  • Immunofluorescence – C3 deposition on both sides of the basement membrane in irregular granular or linear pattern

  • C3 can also be identified in mesangium in the ring shaped aggregates

Clinical features:

• Most patients with primary MPGN present as in adolescence or as young adults with nephrotic syndrome and a nephritic component manifested by hematuria

• Disease may undergo remission or may follow slowly progressive but unremitting course

• 50% develop Chronic renal failure within 10 years

FOCAL SEGMENTAL GLOMERULOSCLEROSIS

• Common cause of nephrotic syndrome in adults

• As the name implies lesion is characterised by sclerosis of some but not all glomeruli (focal) and in the effected glomeruli only a portion of capillary tuft is involved (segmental)

• Clinically manifests as acute or subacute onset of nephrotic syndrome or non nephrotic proteinuria

• HTN, microscopic haematuria and some degree of azotaemia are commonly present.

• FSGS occurs in following settings

  • Primary disease (idiopathic FSGS)

  • Association with other conditions like

    • HIV infection (HIV associated nephropathy)

    • Heroin addiction (Heroin nephropathy)

    • Sickle cell disease

    • Massive obesity

  • As secondary event in previously active necrotising lesions in case of focal glomerulonephritis (ex:IgA nephropathy)

  • Component of adaptive response to loss of renal tissues eg:

    • Renal ablation, renal agenesis or dysplasia

    • Reflux nephropathy

    • In advanced stages of other renal disorders such as hypertensive nephropathy

  • Uncommon inherited forms of nephrotic syndrome – caused by mutations in genes that encode proteins localised to the slit diaghragm like podocin,α-actinin 4 and TRPC6 (transient receptor potential calcium channel-6)

• Pathogenesis

  • • Characterised by degeneration and focal disruption of visceral epithelial cells with effacement of foot processes resembling diffuse epithelial cell change

    • Epithelial damage is the hall mark of FSGS

    • Different mechanisms causing epithelial damage are

      • Circulating factors

      • Genetically determined defects affecting components of the slit diaphragm complex like nephrin, podocin, actinin α and TRPC6

    • Hyalinosis and sclerosis stem from entrapment of plasma proteins in extremely hyper permeable foci and increased ECM deposition

Morphology

• Light microscopy

  • Focal and segmental lesions may involve only a minority of the glomeruli

  • In sclerotic segments there is collapse of capillary loops, increase in matrix and segmental deposition of plasma proteins along the capillary wall, hyalinosis which may become so pronounced to occlude capillary lumens.

  • Lipid droplets and foam cells are often present

  • Glomeruli which appear normal on LM show increased mesangial matrix

• On Electron microscopy –

  • both sclerotic and non sclerotic areas show diffuse effacement of foot process and there may be focal detachment of epithelial cells and denudation of underlying GBM

• By immunofluorescence microscopy 

  • IgM &C3 may be present in sclerotic areas and in the mesangium

  • With progression of the disease increased numbers of glomeruli become involved and sclerosis spreads leading to fibrosis

Clinical course

• Little tendency for spontaneous remission

• Response to corticosteroid therapy are variable

• Children have better prognosis than adults

• 20% of patients have unusual rapid course with intractable massive proteinuria ending in renal failure with in 2 years

Reference 

1. Vinay kumar, Abul K.Abbas, Nelson Fausto, Jon C. Aster. Robbins and Cotran Pathologic basis of disease. 8th edition.

2. Harsh mohan. Text book of Pathology.8th edition.2019

3. A.K.Mandal, Dr. Sharmana Choudhary. Textbook of Pathology for MBBS. Vol II. Second edition 2017.