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Minimal change disease


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Minimal change disease

  1. 1. Minimal Change Disease/ Minimal Change Nephropathy • Minimal change disease (MCD), also known as • Minimal Change Nephropathy • lipoid nephrosis • nil lesions or • nil disease.
  2. 2. Minimal Change Disease/ Minimal Change Nephropathy • Minimal change disease (MCD), also known as • Minimal Change Nephropathy • lipoid nephrosis • nil lesions or • nil disease.
  3. 3. MCD It refers to a histopathologic lesion in the glomerulus that almost always is associated with nephrotic syndrome.
  4. 4. Lipoid Nephrosis • The term lipoid nephrosis was used to describe the finding of lipids in the renal tubular cells • as well as lipid-laden proximal tubular cells or macrophages known as oval fat bodies in the urine.
  5. 5. Epidemiology • Age: 1-7y (90%) & >80y • Adults (10-15%) • Teenager: 50% NS due to MCD • Sex: Boys> Girls • Association with Autoimmune disorders • Association with Hematologic malignancies
  6. 6. Epidemiology • Minimal Change Disease is most common in very young children but can occur in older children and adults (10-15%). It is by far the most common cause of nephrotic syndrome (NS) in children between the ages of 1 and 7, accounting for the majority (about 90%) of these diagnoses.
  7. 7. Lipoid Nephrosis-Epidemiology • Among teenagers who develop NS, it is caused by minimal change disease about halfthe time.
  8. 8. Epidemiology of MCD Among children less than 10 years of age, boys seem to be more likely to develop minimal change disease than girls. Minimal change disease is being seen with increasing frequency in adults over the age of 80.
  9. 9. Epidemiology • People with one or more autoimmune disorders are at increased risk of developing minimal change disease. • Having minimal change disease also increases the chances of developing other autoimmune disorders.
  10. 10. Epidemiology of Lipoid Nephrosis • MCD is associated with malignancies, particularly hematologic malignancies, such as Hodgkin’s disease, non-Hodgkin lymphomas, or leukemias. • Colorectal cancer-associated MCD is uncommon and has been reported in only a few cases to date.
  11. 11. Causes- Idiopathic The cause is unknown, but the disease may occur after or be related to: • Allergic reaction (autoimmune etiology) • Medication such as NSAID • Tumors (Hematologic tumors) • Vaccinations • Viral infections (Such as EBV)
  12. 12. Pathology -Idiopathic The pathology of minimal change disease is unclear and is currently considered idiopathic . The pathology does not appear to involve complement, immunoglobulins, or immune complex deposition.
  13. 13. Factors which may involve in the Pathogenesis of MCD • 1. Disorder of T-cell- secretion of cytokines. • 2. Circulating T cell factor- Hemopexin • 3. Endothelin 1 • 4. Nephrin • 5. Dysferlin • 6. CD 80 • 7.CTLA-4 • 8.PTPRO/ GLEPP1 • 9.HLA-DR 7 • 10. Synaptopodin
  14. 14. Mechanism of Nephrotic syndrome • Rather, an altered cell-mediated immunologic response the abnormal secretion of lymphokines (cytokines13,12,4,18) by T cells (T lymphocytes)is thought to reduce the production of anions in the glomerular basement membrane, thereby increasing the glomerular permeability to serum albumin through a reduction of electrostatic repulsion.
  15. 15. Mechanism of foot processes effacement It is postulated that MCD is a disorder of T cells, which release a cytokine (IL-12,4,13,18) that injures the glomerular epithelial foot processes podocytes swell up & foot processes effaced. This, in turn, leads to a decreased synthesis of polyanions. Polyanion: a molecule or chemical complex having negative charges at several sites
  16. 16. Pathology (Pathophysiology) A circulating T-cell factor/permeability factor (Hemopexin) causes podocyte cytoskeleton disorganization leading to increased glomerular capillary permeability and/or changes (neutralize negative charges of heparan sulfate) in glomerular basement membrane heparan sulfate glycosaminoglycans resulting in proteinuria.
  17. 17. Pathology •The loss of anionic charges is also thought to favor foot process fusion (effacement).
  18. 18. Pathology •IL-13 overexpression can cause podocyte foot process fusion (effacement) and proteinuria.
  19. 19. Hemopexin- beta-1B- glycoprotein • Hemopexin also known as beta-1B- glycoprotein is a protein that in humans is encoded by the HPX gene and belongs to hemopexin family of proteins
  20. 20. ARF- Endothelin-1 • In patients who develop acute renal failure, endothelin 1 (This peptide is a potent vasoconstrictor and is produced by vascular endothelial cells). expression is greater in the glomeruli, vessels, and tubules than in the nonacute renal failure group.
  21. 21. Congenital Nephrotic Syndrome & Nephrin • The glomerular epithelial cells (podocytes) and the slit diaphragm connecting the podocyte foot processes play a primary role in the development of proteinuria. • Nephrin is a major component of the slit diaphragm.
  22. 22. Congenital Nephrotic syndrome & Nephrin • The slit diaphragm is often missing in MC nephrotic syndrome (MCD) kidneys. The role of nephrin and the slit diaphragm in MCD is not known. However, genetic variants of a glomerular filter protein may play a role in some patients with MCD.
  23. 23. Congenital Nephrotic syndrome & Nephrin • Nephrin is a protein necessary for the proper functioning of the renal filtration barrier. Nephrin is a protein that is a structural component of the slit diaphragm. • A defect in the gene for nephrin, NPHS1, is associated with congenital nephrotic syndrome and causes massive amounts of protein to be leaked into the urine, or proteinuria.
  24. 24. Dysferlin • A lack of glomerular dysferlin expression is associated with minimal- change nephropathy. • Dysferlin also known as dystrophy-associated fer-1-like protein is a protein that in humans is encoded by the DYSF gene. • Dysferlin is linked with skeletal muscle repair.
  25. 25. Dysferlin • A defect in the DYSF gene, located on chromosome 2p12-14, results in either of two types of muscular dystrophy; Miyoshi myopathy (MM) and Limb-girdle muscular dystrophy type 2B (LGMD2B).
  26. 26. CD 80 (B7-1) • CD 80, a protein found in B cells and responsible for T-cell activation, is found to be increased in patients with MCD.
  27. 27. Minimal change disease: a CD80 podocytopathy • Recently, increased expression of CD80 (also termed B7-1) on podocytes was identified as a mechanism for proteinuria. • CD80 is inhibited by binding to CTLA-4, which is expressed on regulatory T cells.
  28. 28. CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), also known as CD152 (Cluster of differentiation 152), is a protein receptor that downregulates the immune system. • Interleukin-13 or microbial products via Toll-like receptors could be factors that induceCD80 expression on podocytes. • CTLA-4 appears to regulate CD80 expression in podocytes, and to be alteredin minimal change disease patients.
  29. 29. CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) • Proteinuria in minimal change disease is caused by persistent CD80 expression in podocytes,possibly initiated by stimulation of these cells by antigens or cytokines.
  30. 30. Genetics • Protein tyrosine phosphatase receptor type O (PTPRO)- also known as glomerular epithelial protein 1 (GLEPP1) has been shown to be mutated in a number of cases.
  31. 31. •Increased risk of MCD in those with possession of HLA-DR7 allele
  32. 32. Synaptopodin & Response to Steroids • Synaptopodin is a proline-rich protein intimately associated with actin microfilaments present in the foot processes of podocytes. Greater synaptopodin expression in podocytes is associated with a significantly better response to steroid therapy. Thus, this marker could be used in the future to help determine appropriate therapy.
  33. 33. Pathology- Morphology Light Microscopy: • For years pathologists found no changes when viewing specimens under light microscopy; hence the name minimal change disease/Nil lesions/Nil disease.
  34. 34. Morphology • Lipoid Nephrosis: • Cells of the Proximal Tubule are often filled with lipids but this is probably secondary to resorption of lipoproteins which are normally not filtered by a healthy glomerulus (This is why this disease was originally called "Lipoid Nephrosis")
  35. 35. Morphology • Immunofluorescence –No deposition of immune complexes
  36. 36. Pathology- Morphology • Electron microscopy: HALLMARKS 1.Diffuse loss of (diffuse & uniform effacement of) visceral epithelial cells (podocyte) foot processes, 2.Vacuolation, and 3. Growth of microvilli on the visceral epithelial cells. Occasional focal detachments.
  37. 37. MORPHOLOGY Diffuse & Uniform Effacement Of Foot process
  38. 38. Effacement of foot processes Diffuse Loss of Foot processes UNIFORM & DIFFUSE
  39. 39. Clinical features • Nephrotic syndrome: • Hyperproteinuria, • Hypoalbuminemia, • Edema, • Hyperlipidemia, • Lipidemia & • Coagulopathy.
  40. 40. Prognosis • Good. • >90% respond to corticosteroids • Proteinuria recurs in > 2/3 of cases • Some of whom become steroid dependent • < 5% develop CRF after 25 years.