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Nephrotic Syndrome
A clinical syndrome with heavy proteinuria, hypoprotenemia, edema and hyperlipidemia. Idiopathic NS due to primary glomerular disease. Secondary to identifiable diseases. Common glomerular diseases presenting as NS in adults: - Minimal Change Nephropathy (MCN) - Focal Segmental Glomerulosclerosis (FSGS) - Membranous Nephropathy (MN) - Membrane Proliferative GN (MPGN) II - Cryoglobulinemic MPGN - Amyloidosis - Diabetic nephropathy.

Pathogenesis
Noninflammatory damage to the glomerular capillary wall. Proteinuria results from alterations in the charge or size selectivity of the glomerular capillary wall, this increases glomerular permeability to plasma proteins. Albumin is the principal urinary protein lost, other plasma proteins (hormone-carrying proteins) also lost in the urine.

Signs and Symptoms


Asymptomatic proteinuria Edema Edema starts initially in areas of high intravascular hydrostatic pressure (feet & ankles) and in areas in which hydrostatic pressure is lowest as the periorbital and scrotal areas.

Lab Findings
Heavy proteinuria >3.5 g/1.73 m2 /24 hours. Lipiduria Minimal hematuria Hypoalbuminemia Hypercholestrolemia

Spot urine protein to creatinine ratio, which is numerically similar to the 24 hours urinary protein

Complications
1. Hyperlipidemia
- Is a consequence of increased synthesis and decreased catabolism of lipoproteins. - Clearance of chylomicrons and VLDLs is reduced in patients with NS. - Hyperlipidemia of NS may be severe and characterized by high LDL/HDL cholesterol ratio.

2. Thrombosis - Antithrombin III, proteins C and S and factors IX, XI and XII (due to increased urinary loss). - Plasma fibrinogen, tissue plasminogen activator and platelet aggregability are all increased. - These abnormalities lead to an increased incidence of venous and arterial thrombosis. - Renal vein thrombosis is common in membranous nephropathy.

3. Vitamin D deficiency and hypocalcemia


- Due to loss of binding protein in the urine - 25-hydroxyvitamin D, which is bound to vitamin D-binding protein, is also lost in the urine.

4. Infection
- Patients with NS have urinary loss of immunoglobulins and defects in complement cascade, this results in a higher susceptibility to infection, especially with encapsulated organisms such as streptococcus pneumoniae. - Immunosuppressive therapy used for treatment of glomerular disease contributes to the increased risk of infection.

5. Hypoalbuminemia
- Secondary to losses in the urine and increased albumin catabolism. 6. Malnutrition - Massive proteinuria causes negative nitrogen balance with loss of lean body mass.

7. Anemia
- Urinary loss of EPO and transferrin lead to iron-resistant microcytic hypochromic anemia.

Treatment
Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers; These agents work by lowering intraglomerular capillary hydrostatic pressure and prevent the development of hemodynamically mediated focal segmental glomerulosclerosis. ARBs also decrease the formation of tumor growth factor (TGF)-1, which has been shown to play a role in the progressive renal fibrosis. NSAIDs probably work by altering glomerular hemodynamics or glomerular BM permeability but these drugs may cause acute renal failure, salt and water retention and hyperkalemia. Low protein diet; 0.7g protein/kg/day decreases urinary protein excretion, low protein diet in general may lead to malnutrition.

Minimal Change Nephropathy (MCN, Nil Lesion)


Common cause of NS in children. Peak incidence between 6 to 8 years of age. Causes 70-90% of nephrotic syndrome in childhood but only 10-15% of NS in adults. Usually presents as primary renal disease Can be associated with: - Hodgkins disease - Allergies - Use of NSAID (there is significant interstitial nephritis) Presentation: Edema with benign urinary sediment, microscopic Hematuria is present in 20 -30%. Hypertension and renal failure are rare.

Pathology
LM normal glomeruli, there may be mild mesangial hypercellularity. IF negative for immunoglobulin. EM diffuse effacement of the foot processes of visceral epithelial cells with weakening of slit pore membranes.
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- In children the proteinuria is selective, urine contains albumin with minimal amounts of higher molecular weight proteins such as IgG and alpha 2 macroglobulin. - Selective proteinuria and foot process effacement suggests injury to podocytes and loss of fixed negative charge of the glomerular BM, in adults proteinuria is non-selective.

Treatment
Spontaneous remission occurs in 30-40/ of children. Steroid therapy is given to children with heavy proteinuria, 60 mg /square meter of body surface area daily for 4 weeks, 40 mg /m2 on alternate days for 4 weeks, then reduce the dose gradually. Adults 1-1.5 mg /kg /day for 4 weeks followed by 1 mg / kg on alternate days for 4 weeks. Steroid dependent, relapse of prturia when steroid dose is reduced. Frequently relapsing, who relapse more than three times per year. In these patients cyclophosphamide, 2-3 mg /kg/ day or chlorambucil 0.10.2 mg /kg/day started after steroid induced remission and continue for 8-12 weeks. Mycofenolate mofetil & cyclosporine also effective in decreasing proteinuria in patients with MCN.

Membranous Nephropathy
Common cause of NS in adults , peak incidence 30-50 years of age, : is 2:1 Rare in childhood Is the most common cause of NS in elderly. Primary /idiopathic MN Secondary MN - Infection: hepatitis B &C syphilis, malaria, schistosomiasis, leprosy, filariasis. - Cancer: breast, lung, kidney, stomach, esophagus, colon, neuroblastoma . - Drugs: gold ,mercury ,penicillamine ,NSAID - Myasthenia gravis, primary biliary cirrhosis - Autoimmune diseases: SLE, rheumatoid arthritis, Sjgrens syndrome, Hashimoto's thyroiditis, myasthenia. - Other systemic diseases: Fanconi's syndrome, sickle cell anemia, Crohns disaese, sarcoidosis, Guillain-Barr syndrome.

L.M. thickened capillary wall

EM electron dense deposit subepithelial side of BM

IF diffuse granular capillary loop deposits

Pathology
LM diffuse thickening of GBM. IF diffuse granular subepithelial deposition of IgG and C3, along the glomerular capillary wall. EM reveals electron-dense subepithelial deposits.

Pathogenesis
Antibodies to a podocyte surface antigen, with complement dependent podocyte injury.

Features
Presents as NS and nonselective proteinuria. Microscopic hematuria is seen in up to 50% of patients Spontaneous remission in about one third of the cases and often occur late in the course after years of NS. One-third develops repeated relapses but maintain normal renal function. 10-20/ show progressive decline in GFR and develop ESRD in 10-15 years or die from complications of NS. Poor prognostic features are : Male gender Old age Hypertension at the time of presentation Persistence of proteinuria Incidence of renal vein thrombosis, pulmonary embolism and DVT is higher among patients with MN

Treatment
Edema Dyslipidemia Hypertension Renin-angiotensin system inhibitor is recommended Immunosuppressive recommended in patients with primary MN and persistent proteinuria (>3.0 g/24h)

Focal Segmental Glomerulosclerosis


Renal injury characterized by segmental glomerular scars that involve some but not all glomeruli Presents as proteinuria Incidence is increasing, it represents up to one-third of cases of NS in adults.

Pathology
Pathologic changes are most prominent in glomeruli located at the corticomedullary junction Main pathological changes include a well-defined segmental increase in matrix and obliteration of capillary loops In addition to focal and segmental scarring ,other variants have been described: - Cellular lesions with endocapillary hypercellularity and heavy proteinuria - Collapsing glomerulopathy with segmental or global glomerular collapse and a rapid decline in renal function - Glomerular tip lesion with a better prognosis

Types
Primary Secondary Viruses: HIV/Hepatitis B/Parvovirus Hypertensive nephropathy Reflux nephropathy Cholestrol emboli Drugs Heroin/analgesics Oligomeganephronia Renal dysgenesis Alport's sickle cell disease Lymphoma Radiation nephritis Familial podocytopathies

Features
FSCS can present with Varying level of proteinuria Hematuria Hypertension
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Renal insufficiency May remit spontaneously, but treatment induced remission of proteinuria significantly improves prognosis

Treatment
Of primary type Renin angiotensin inhibitors Steroids for proteinuria ,cyclosporine in steroid responsive patients helps to ensure remissions Primary FSGS recurs in 25-40%of renal transplanted patients Of secondary type depend on treating the underlying cause and controlling proteinuria

Membranoproliferative GN
Is an immune mediated GN characterized by thickening of the GBM with mesangioproliferative changes 70% of patients have hypocomplementemia Ideopathic type usually presents in childhood or young adults Type I disease (most common) Idiopathic SBE SLE Hepatitis C with or without cryoglobulinemia Mixed cryoglobulinemia Hepatitis B Cancer lung, breast and ovary Type II disaese (Dense Deposit Disease) Ideopathic C3 nephritic factor-associated Partial lipodystrophy Type III disease Ideopathic Copmlement receptor deficiency

Type I MPGN Most proliferative of the three types, is due to glomerular deposition of circulating immune complexes or their in situ formation, and shows mesangial proliferation with lobular segmentation and mesangial interposition between the capillary BM and endothelial cells, producing a double contour on renal biopsy Subendothelial deposits and low C3 are typical Type II MPGN (dense deposit disease) Low serum C3 ,dense thickening of the GBM (intramembranous dense deposits and C3) Glomerular tuft has a lobular appearance Type III MPGN is less common than the other types Subepithelial deposits along widened segments of the GBM that appear laminated and disrupted It is focal in distribution

Presentation
Presents with proteinuria, hematuria and pyuria (30%) Fatigue and malaise ,common in children with type I disease Acute nephritic picture with RPGN in (25%) of patients Low serum C3 is common finding 50% of patients develop end stage disease 10 years after diagnosis Nephrotic syndrome, hypertension and renal failure carry poor prognosis

Treatment
With proteinuria ,renin-angiotensin blockers Steroids may be used in patients with primary MPGN Secondary type ,treat the underlying cause 9infection ,autoimmune disease ,neoplasm) Can recur in the transplanted kidney

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Mesangioproliferative GN
Presents with varying degree of proteinuria and hematuria May be seen in IgA nephropathy ,malaria ,resolving post-infectious GN ,class II lupus nephritis Primary mesanioproliferative GN is seen in 15% of renal biopsies Characterized by expansion of the mesangium ,may be associated with mesangial hypercellularity ,thin single contoured capillary walls ,with mesangial deposits Variable clinical course With isolated hematuria have a benign course Heavy proteinuria ,occasionally progress to renal failure Treatment ,ACEI ,steroids ,cytotoxic agents

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Done by:

ARMA 2012

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