Nephrotic syndrome

Dr VelmuruganAssistant Professor

Department of Medicine

What is Nephrotic syndrome?

The term "nephrotic syndrome" refers to a distinct constellation of clinical and laboratory features of renal disease.

COMPONENTS

Heavy proteinuria (protein excretion greater than 3.5 g/24hours/1.73m2

Hypoalbuminemia (less than 3 g/dL) Peripheral edema Hyperlipidemia ThrombosisMinimal hematuria and sometimes

Hypertension

Pathophysiology

General Clinical Aspects

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MINIMAL CHANGE DISEASE

• Also called as lipoid nephrosis or foot process disease.

• It comprises 20% nephrotic cases in adults.

• While 80% of nephrotic cases in children.

Idiopathic (majority) In association with systemic disease or drugs.

- Drug induced interstitial nephritis induced by NSAIDs, rifampin, interferon alpha.

- Hodgkin’s disease and other lymphoproliferative malignancy.

- HIV infection.

MAJOR CAUSES OF MCD

LAB PARAMETERS

• Microscopic hematuria present in 20-30%• Hypertension and renal failure are very rare.• In children urine contains albumin principally• In adults proteinuria is typically non

selective.

PATHOLOGY

• Light microscopy - no changes.• Immuno-fluorescence - typically negative for

immunoglobulin and C3.• Electron microscopy – diffuse effacement of

the foot processes of visceral epithelial cell.

Identify

Histopathology of MCD

IMMUNOFLUORESCNCE

ELECTRON MICROSCOPY

TREATMENT

• MCD is highly steroid responsive and carries an excellent prognosis.

• Approximately 90% children and 50% of adults enter remission following 8 week of high dose oral glucocorticoid.

• Adults – 1-1.5 mg/kg body weight (prednisone) per day for 4 weeks, followed by 1 mg/kg/day on alternate day for 4 weeks.

• Up to 90% of adults enter remission if therapy extended for 20-24 weeks.

• Steroid dependent – relapse occur whenever dose is reduced or within two weeks of discontinuation of steroid.

• Steroid responder – absence of protein in urine for three consecutive days.

• In frequent relapse - <3 relapse in a year.• Frequent relapse - > 3 relapse in a year.• Steroid resistance – no response to treatment after

6 month of therapy

Treatment of relapse and steroid dependent MCD

• Cyclophosphamide – induction of remission with Predinisone followed by institution of cylcophosphamide (2 mg/kg) for 8-12 weeks.

• Chlorembucil - 0.1 to 2.0 mg/kg/day Side effect – higher incidence of malignancy

Treatment of storied resistant MCD • Pulse methylprednisolone

- May induce remission in some corticosteroid resistant children

• Cyclosporine- 5mg/kg/day• Levamisole – 2.5mg/kg/day on alternate day.

- It is an antihelmenthic drug (Immunomodulating role)

- Transient cytopenia may occurs in 2/3rd patients.

MEMBRANOUS GLOMERULOPATHY

• Leading cause of idiopathic nephrotic syndrome in adults (30 to 40%) with male to female ratio of 2 :1

• Proteinuria is usually non selective• Microscopic hematuria is present in up to 50% of cases• Hypertension in only 10-30% of patients

• Idiopathic (majority)• In association with systemic diseases or drugs

CONDITIONS ASSODATED WITH MEMBRANOUS GLOMERALOPATHY

INFECTIONS

Syphilis Malaria Leprosy Hydatid disease Filariasis Enterococcal endocarditis

Systemic auto immune diseases

SLE Rheumatoid arthritis Sjogren's syndrome Hashimoto's disease Grave’s disease Primary biliary cirrhosis Ankylosing spondylitis Myasthenia gravis

NEOPLASIA

• Ca breast,lung, colon, stomach, and esophagus

• Melanoma• Renal cell carcinoma• Neuroblastoma • Carotid body tumor

Drugs

• Gold • Penicillamine • Captopril • NSAIDs • Probenecid • Trimethadione• Mercury

Miscellaneous

Sarcoidosis Diabetes mellitus Sickle cell disease Crohn's disease Guillain-Barre syndrome, Fanconi's syndrome Alpha-1 antitrypsin deficiency

Pathology

• Light microscopy – diffuse thickening of GBM without evidence of inflammation or cellular proliferation.

• Immunofluorescence – granular deposition of IgG, C3 and compliments (C5b-9)

The deposits are directly visualized byfluorescent anti-IgG, revealing diffuse granular capillary loop staining

Stage I—sub-epithelial deposits A few small, flat, electron-dense deposits are seen on the epithelial surface of the GBM.

Stage II—'spike' formation 'Spikes' protruding from epithelial surface of GBM become clearly visible. The spikes extend between the electron-dense deposits, and are present in virtually every capillary loop.

Stage III—incorporation of deposits Electron-dense deposits become surrounded by and incorporated into the GBM. This results in an irregular thickening of the GBM.

Stage IV—disappearing deposits The deposits incorporated within the GBM lose their electron density. Areas of the GBM will have a vacuolated or lucent appearance.

Stage V—reparation stage During this 'healing' phase, the deposits have become completely rarified, and the GBM appearance is returning to normal.

Poor prognosis

• Male gender• Older age • Hypertension • Severe proteinuria • Hyperlipidemia • Impaired renal function

TREATMENT

• Nephrotic syndrome remits spontaneously and completely in up to 40% of patients

• Glucocorticoids have failed to show consistent improvement

• Cyclophosphamide, chlorambucil, and cyclosporine, Mycopthenolate mofetil and rituximab

• Transplantation

• The pathognomonic morphologic lesion in FSGS is sclerosis with hyalinosis involving portions (segmental) of fewer than 50% (focal) of glomeruli on a tissue section.

FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS

• Nephrotic proteinuria• Hypertension • Mild renal insufficiency • Abnormal urine sediment that contains red

blood cells and leukocytes• Proteinuria is nonselective in most cases.

• Idiopathic (majority) • In association with systemic diseases or drugs

HIV infectionDiabetes mellitus Fabry's disease Sialidosis Charcot-Marie-Tooth disease

• As consequence of sustained glomerular capillary hypertension Congenital oligonephropathies Unilateral renal agenesis Oligomeganephronia Acquired nephron loss Surgical resection Reflux nephropathy Glomerulonephritis or tubulointerstitial nephritis Other adaptive responses Sickle cell nephropathy Obesity with sleep apnea syndrome Familial dysautonomiaMiscellaneous Heroin use

ETIOLOGY OF FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS

• Light microscopy - Entrapment of amorphous hyaline material.

• Electron microscopy - evidence of damage to visceral epithelial cell.

TREATMENT• First - course of corticosteroid treatment• other drugs (Azathioprine, Cyclosporine, Tacroliumus,

Mycophenolate, Mofetil) when ineffective. • High-dose prednisone is clearly more effective than

dosages less than 1 mg/kg/day. • Third, response of FSGS to corticosteroids is much

slower in adults than in children and that steroid resistance cannot be pronounced before a minimum of 4 months of full-dose corticosteroid treatment

• Is characterized by thickening of the GBM and proliferative changes on light micros copy.

• Two major types : Type I MPGN and type II MPGN.Type I MPGN• The hallmark is presence of subendothelial and mesangial

deposits on electron microscopy that contents C3 and IgG and IgM rarely IgA.

• It is associated with a variety of chronic infection (bacterial endocarditis, HIV, hepatitis B and C), systemic immune complex diseases (SLE, cryoglobulinemia), and malignancies (leukemias, lyphomas).

MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

Type II MPGN• Type II MPGN is an autoimmune disease in which

patients have an IgG autoantibody, termed C3 nephritic factor, that binds to C3 convertase, the enzyme that metabolizes C3, and renders it resistant to inactivation and deposits on GBM.

• Type II MPGN is associated with partial lipodystrophy.

• Poor prognosis than type I MPGN.

Treatment approach

1. Patients with rapidly progressive renal failure- crescents on histopathology -- pulse methylprednisolone therapy followed by oral prednisone and cyclophosphamide.

2. Patients with microscopic haematuria, proteinuria (<3 g), and normal renal function should be followed up every 3 months. They can be treated with ACE inhibitors.

3. Patients with chronic renal failure should be managed conservatively.

4. Patients with HCV-associated MPGN should be treated with IFN-α and immunosuppressive agents should be avoided.

• Nephropathy complicates 30% of cases of type I DM and approximately 20% of cases type IIDM.

DIABETIC NEPHROPATHY

RISK FACTORS hyperglycemia,systemic hypertensionglomerular hypertensionHyperfilteration proteinuria cigarette smoking hyperlipidemia gene polymorphisms affecting the activity of renin

angiotensin aldosteron axis.

• Diabetic nephropathy is usually diagnosed on clinical grounds without a renal biopsy.

• Supportive clues are the presence of normal sized or enlarged kidney

• Evidence, proliferative diabetic retinopathy, and a bland urinary sediments

• Retinopathy is found in 90% and 60% of patients with type I and type II diabetes mellitus respectively, who develop nephropathy.

• The earliest morphologic abnormalities nephropathy are thickening of the GBM and expansion mesangium due to accumulation of extracellular matrix.

• Prominent nodular matrix expansion (classical Kimmel steil-Wilson lesion) are often found.

Nodular mesangial expansion, so-called Kimmelstiel-Wilson nodules, with increased mesangial matrix and cellularity, microaneurysm formation in the glomerulus

TREATMENT• Aim is to control blood sugar, systemic blood pressure and glomerular

capillary blood pressure.• ACE in inhibitor and ARBs are drugs of choice for both systemic blood

pressure & intraglomerular hypertension.

RENAL AMYLOIDOSIS

• Glomeruli are involved in 75 to 90% of patients.• Hypertension is present in 20-25%.• Renal size is usually normal or slightly enlarged. • A minority of patients present with renal failure.• Rectal biopsy and abdominal fat pad biopsy reveal

amyloid deposits in about 75% of patients and may obviate the need for renal biopsy.

Amyloidosis shows amorphous, acellular expansion of the mesangium, with material often also infiltrating glomerular basement membranes, vessels, and the interstitium, with apple-green birefringence by polarized Congo red stain

• Renal biopsy earliest pathologic changes are mesangial expansion by amorphous hyaline material and thickening of GBM. Further deposition results in large nodular esinophilic masses.

• When stained with congo red these deposit show apple – green birefringence under polarized light.

• Electron microscopy reveals non branching extracellular amyloid fibrils..

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